Pharmacology Flashcards

Question

What is the Schild equation used for?

Answer 1

It has some relevance to quantifying the affect of the competitive antagonist on the agonist's potency. If you plot in as the Schild plot on a graph it can help determine whether one drug is acting as a competitive antagonist against another one

Answer 2

**C'/C - 1 = [B]/Kb** C' is concentration of the agonist in the prescence of competitive antagonist C is concentration of the agonist in the absence of competitive antagonist [B] is the concentration of the competitive antagonist Kb is the equilibrium dissociation constant describing the combination of the competitive antagonist with the receptor

Answer 3

An intermediate molcule for an intracellular signal transduction cascade, which is used to transmit and amplify the signal between an extracellular stimulus and an intracellular effector

Answer 4

* The drug receptor or receptor-ligand interaction often does not result in the direct action of the intracellular effector * The intermediate molecule created is synthesised or released in response to the receptor-ligand interaction, and then degraded afterwards * The rate of synthesis or degradation of this molecule is tightly regulated to control the magnitude of response to receptor activation, and this regulation can be used to amplify or dampen the response

Answer 5

It can act locally or it can diffuse distally to convey the signal to a multitude of targets; and multiple secondary messenger systems can interact to produce complex responses to receptor-ligand binding

Answer 6

* **Hydrophobic molecules** such as DAG and phosphatidylinosotols which do most of their work from the intermembrane space * **Hydrophilic molecules** such as cAMP, cGMP and IP3 which diffuse freely into the cytosol * **Ions** such as ionised potassium, calcium, and sodium * **Gases** such as nitric oxide and carbon monoxide which diffuse easily through lipid and water * **Soluble proteins** such as JAK/STAT, NF-kB

Answer 7

Cyclic adenosine monophosphate is a cyclic nucleotide secondary messenger

Answer 8

It is produced when G-protein activates adenylyl cyclase. It is degraded by phosphodiesterases

Answer 9

Its main downstream targets include protein kinase A (PKA), EPAC and cyclic nucleotide-gated ion channels

Answer 10

It plays an important role in mediating the response to catecholamines, glycogenelysis, insulin secretion, vision and olfactory sense

Answer 11

* a phosphate group (or two or three) * sugar (classically a pentose sugar such as ribose) * a nitrogenous nucleobase

Answer 12

* mobilisation of stored energy eg. glycogenolysis * vasopressin-mediated water retention * parathyroid hormone mediated calcium homeostasis * response to catecholamines (beta-adrenergic)

Answer 13

Cyclic guanosine monophospate is a cyclic nucleotide secondary messenger

Answer 14

* cGMP is produced when guanylyl cyclase is activated by nitric oxide or by a naturetic peptide and this make cGMP from GTP * cGMP is degraded by phosphodiesterases

Answer 15

**Protein kinase G (PKG) activation** * smooth muscle relaxation by decreased intracellular calcium availability * negative inotropic effect by reduction of myofilament calcium responsiveness * increased angiogenesis **cGNP-gated ion channels** * mainly unselective cation channels in retinal and olfactory neuroepithelium and in nephrons **cGMP-modulated phosphodiesterase** * cGMP can bind to phosphodiesterases which increase their activity against both cGMP and cAMP, resulting in the inhibition of both secondary messengers

Answer 16

* PKG decreases IP3 activity, densisitises myofibrils to calcium, and decreases intracellular calcium availability by several other mechanisms * The net effect of cGMP is smooth muscle relaxation

Answer 17

Mainly related to its activation by nitric oxide, leading to increased calcium ion uptake into sarcoplasmic reticulum and a decrease in intracellular calcium, and therefore smooth muscle relaxation

Answer 18

The y-axis is response (% of maximal) The x-axis is drug concentration (log) The red line is a full agonist The blue line is a partial agonist The outer dotted line is Emax

Answer 19

The blue one is a full agonist The green one is a full agonist with a non-competitive antagonist The red one is a full agonist with a competitive antagonist

Answer 20

The apparent volume into which a drug disperses in order to produce the observed plasma concentration It is the parameter relating the concentration of a drug in the plasma to the total amount of drug in the body

Answer 21

To calculate loading doses, much as clearance is used to calculate maintenance dose

Answer 22

Dose / Plasma concentration

Answer 23

It can be expressed as Litres (L), or indexed to body mass L/kg

Answer 24

**V-initial** - Vd of the central compartment (from the rapid distribution phase) Is often affecting by the degree of protein binding - highly protein-bound drugs with have a high V-initial

Answer 25

**V-extrap** - Vd of the tissue compartment (from the elimination phase) Not used for much!

Answer 26

**V-area** - Vd extrapolated from the area under the curve of the concentration curve

Answer 27

**V-ss** - Vd in a steady state model, often the most useful in calculating the loading dose Vss = amount of drug in the body in equilibrium conditions/steady state plasma concentrations

Answer 28

Major determinants are drug properties which affect protein binding and tissue binding: * molecule size * charge * pKa * the lipid/water partition coefficient

Answer 29

* age * gender * body muscle/fat proportion * level of hydration * water distribution (oedema, ascites, APO, pregnancy) * extracorpeal sites of distribution (circuit, filters, oxygenation)

Answer 30

* **Molecule size** - large the molecule, harder it is to move, lower Vd * **Molecule charge** - highly ionised molecules, higher water solubility, less likely to move, lower Vd * **pKa** - determines ionisation and lipid solubility * **Lipid-solubility** - highly lipid soluble molecules have a high Vd due to low fat content of the blood stream * **Water-solubility** - difficult to penetrate lipid bilayer, smaller Vd

Answer 31

(t 1/2) is the time required to reduced the concentration of a drug by a half

Answer 32

t 1/2 = 0.693 x Vd/CL 0.693 is the logarithm of 2, it represents the exponential rate of elimination

Answer 33

An increase in Vd causes an increase in half life A decrease in the clearance causes an increase in half life

Answer 34

**5!** (50% -> 75% -> 87.5% -> 93.75% -> 96.875)

Answer 35

It will usually increase its duration of action by one half-life (because it's clearance is a logarithm function)

Answer 36

First order kinetics drugs have a constant half-life regardless of concentration With zero order kinetics drugs, the term becomes meaningless, one instead refers to a dose or concentration removed over time

Answer 37

**First order elimination kinetics** - a constant **proportion** (e.g. percentage) of a drug is eliminated per unit time **Zero order elimination kinetics** - a constant **amount** (e.g. milligrams) of a drug is eliminated per unit time

Answer 38

First order kinetics is a concentration dependent process (the higher the concentration, the faster the clearance) Zero order elimination rate is independent from concentration

Answer 39

It describes enzymatic reactions where a maximum rate of reaction is reached when drug concentration achieves 100% enzyme saturation

Answer 40

It describes drug clearance by Michaelis-Menten processes, where a drug an low concentration is cleared via first-order kinetics and at high concentratons via zero-order kinetics (phenytoin or ethanol)

Answer 41

This is a logarithmic function. All enzymes and clearance mechanisms are working at well below their maximum capacity, and the rate of drug elimination is directly proportional to drug concentration

Answer 42

There is a limit on how much enzyme activity there can be before the system becomes saturated. At low concentrations, the more substrate you give, the faster the reaction. At higher concentrations, the rate of the reaction stays the same because all the enzyme molecules are busy

Answer 43

When receiving relatively high doses of drugs, a small change in dose will create a disproportionately large change in concentration

Answer 44

The drugs at higher doses will have a narrow therapeutic index. If the drug concentration required to have a useful effect is above 50% of Vmax, the drug will have a narrow therapeutic index

Answer 45

Dose rate (mg/hr) = dose (mg) / dosing interval (hrs)

Answer 46

Maintenance dose rate (mg/hr) = desired peak concentration (mg/L) / clearance (L/hr)

Answer 47

Loading dose (mg) = desired peak concentration (mg/L) x volume of distribution (L)

Answer 48

The drug accumulates gradually. Steady state is achieved when the dose rate and clearance rate are equal. This takes 3-5 half lives.

Answer 49

Steady state is achieved in steps, but eventually the dose rate and clearance are equal. It takes about 5 half-lives

Answer 50

A loading dose rapidly achieves the peak concentration nessecary to equal the clearance, so the desired effect is achieved and maintained sooner.

Answer 51

By multiplying the desired peak concentration by the volume distribution. If the dosing interval is the same as the half-life, the loading dose should be twice the maintenance dose.

Answer 52

* All the loading and maintenace doses have to be adjusted to bioavailability (higher if low bioavailability) * The slower instestinal absorption of the drug has a 'smoothing' effect on the peaks of concentration, which decreases the concentration-dependent adverse effects

Answer 53

* **Elimination half life** - you often don't wait til this point as you want a certain level of drug in the blood * **Therapeutic index** * **Convenience** - you wouldn't expect a patient to take a drug every 10 minutes forever

Answer 54

The fraction of the dose which reaches systemic circulation intact

Answer 55

**Absolute bioavailability** compares one non-IV route with IV administration **Relative bioavailability** compares one non-IV route with another non-IV route

Answer 56

Bioavailability is measured using the area under the concentration-time curve (**Dost's Law**). The ratio of AUCs is the bioavailability value. Bioavailability (F) = AUC (oral) / AUC (IV)

Answer 57

Drugs are considered bioequivalent if the extents and absorption of drugs are so similar that there is likely no clinical difference between their effects

Answer 58

**Generic influences on drug bioavailability** * Drug concentration at side of administration * Surface area of the absorptive site * Drug pKa * Drug molecule size * pH of the surrounding fluid **Factors affecting GI absorption** * Gastric and intestinal motility * Tablet disintegration * Intestinal, bile and bile salt content * Metabolism by gut wall and by bacteria * First pass metabolism **Factors affecting first pass metabolism** * Drug absorption and metabolism from the gut * Metabolism in the gut wall and the bloodstream * Hepatic blood flow and enzyme activity **Bioavailability from transdermal and mucosal routes** * Mucosal blood flow * Drug lipophilicity * Factors affecting membrane penetration * pH of the mucosal fluid

Answer 59

Morphine is a drug that has poor bioavailability

Answer 60

Phenytoin is highly protein-bound, so is highly affected by the low plasma albumin in critically unwell patients

Answer 61

Gentamicin is rapidly cleared from the kidneys, so is cleared slowly with poor renal function. It is an example of how the doses aren't changed but the dosing intervals can be extended

Answer 62

It has increased renal clearance in the context of hyperdynamic circulatory states, for example in early sepsis so it's doses need to be closely monitored

Answer 63

Those that have small molecular volumes, or possess polar characteristics. These can be readily re-absorbed by the glomerular filtrate. If they can not be renally excreted, they are often metabolised into molecules that can be

Answer 64

**Phase I** reactions convert the drug to a more polar environment via oxidation, reduction or hydrolyses If it is not polar enough, **phase II** reactions take place, in which an endogenous substrate such as glucuronic acid, sulphuric acid or an amino acid combine with the drug to form a higher polar conjugate

Answer 65

The principal organ is the liver. Other organs include GI tract, the lungs, the kidneys, the brain and the skin.

Answer 66

After oral administration, many drugs are absorbed intact from the small intestine and trasported first via the portal system to the liver, where they undergo extensive metabolism This is called the **first pass effect**

Answer 67

Many drug-metabolising enzymes are housed in the lipophilic endoplasmic reticulum membranes of the liver and other tissues

Answer 68

When the lamellar membranes containing drug enzymes are isolated by homogenisation and fractionation of the cell, they re-form into vesicles called **microsomes** Microsomes retain most of the characteristics of intact membranes including a smooth and rough endoplasmic reticulum

Answer 69

NADPH-cytochrome P450 oxidoreductase and Cytochrome P450 Microsomal oxidations require P450, P450 reductase, a reducing agent (NADPH) and an oxygen molecule

Answer 70

1. Oxidised (Fe3+) P450 combines with a drug substrate to form a complex 2. NADPH donates an electron to the flavoprotein P450 reductase, which reduces the oxidised P450-drug complex 3. A second electron is donated from NADPH via the same P450 reductase, which reduces oxygen, forming an 'activated oxygen'-P450-drug complex 4. This complex transfers activated oxygen to the drug substrate to form the oxidised product

Answer 71

CYP3A4 metabolises over 50% of prescribed drugs

Answer 72

Some of the chemically dissimilar P450 substrate drugs, *induce* P450 expression by enhacing the rate of its synthesis or reducing its rate of degradation Induction results in accelerated substrate metabolism and usually a decrease in the pharmacological action of the inducer and also of co-administered drugs

Answer 73

Beta blockers Warfarin Oral contraceptives Statins Theophylline Amiodarone SSRIs Opioids

Answer 74

**INHIBITORS** **S**ulphonamides **I**soniazid **C**emetidine **K** etoconazole **F**luconazole **A**lcohol **C**iprofloxacin **E**rythromycin **S**odium valproate . **C**hloramphenicol **O**meprazole **M**etronidazole

Answer 75

**Inducers** **S**ulphonylureas **C**arbamazepine **R**ifampicin **A**lcohol - chronic **P**henytoin

Answer 76

* **Phase 1** - test a new intervention for the first time on a small number of people (20-80) to determine a safe dosage range and identify any side effects * **Phase 2** - use a small group of volunteers with the disease (several hundred) to determine efficacy and further evaluate safety * **Phase 3** - use large groups of people (hundreds - thousands) to compare the intervention to other standard interventions * **Phase 4** - after approval, continue to monitor effectiveness or widely spread adverse effects

Answer 77

Arrythmias represent electrical activity that deviates from the normal synchronous and haemodynamically effective electrical function of the heart as a result of an abnormality in impulse initiation and/or propagation

Answer 78

* ischemia or hypoxia * acidosis or alkalosis * electrolyte abnormalities * excessive catecholamine exposure * autonomic influences * drug toxicity * overstretching of cardiac fibres

Answer 79

**Vaughn Williams Classification** 1. **Sodium channel blockers** - a) quinine - b) IV lidocaine - c) flecainide 2. **Beta blockers** - metoprolol, esmolol, bisoprolol 3. **K+ channel blockers** - amiodarone, sotalol 4. **Ca+ channel blockers** - verapamil, diltiazem

Answer 80

It is a drug action that describes when the channels being used more frequently, or are in an inactivated state, are more susceptible to being blocked

Answer 81

* Class 1 action is a **sodium channel blocker** * Subclasses of this action reflect effects on the action potential duration (APD). * **Class 1a drugs** prolong the APD and dissociate from the channel with intermediate kinetics - quinine * **Class 1b drugs** shorten the APD in some tissues of the heart and dissociate from the channel with rapid kinetics - IV lidocaine * **Class 1c drugs** have minimal effects on the APD and dissociate from the channel with slow kinetics - flecainide

Answer 82

**Class 2** action is sympatholytic. Drugs with this action reduce beta-adrenergic activity in the heart - beta blockers - metoprolol, esmolol, bisoprolol

Answer 83

**Potassium channel blockers** manifest as prolongation of the APD. Most drugs with this action block the rapid component of the delayed rectified potassium current. An example is amiodarone

Answer 84

**Calcium channel blockers** slow conduction in regions where the action potential upstroke is calcium dependent, e.g. the SA and AV nodes. Examples include verapamil and diltiazem

Answer 85

* It markedly prolongs the action potential duration (and the QT interval on ECG) by **blocking the potassium channels**. * The APD is prolonged uniformly over a wide range of heart rates, amiodarone does **not** have a reverse use-dependent action * It also significantly **blocks inactivated sodium channels**. Its action potential prolonging action reinforces this effect. * Amiodarone also has **weak adrenergic and calcium-channel blocking** actions. * Consequences of these actions include **slowing the heart rate and AV node conduction**

Answer 86

Amiodarone causes peripheral vasodilation. This action is prominent after IV administration and may be related to the action of the vehicle

Answer 87

* Symptomatic bradycardia * Heart block in patients with known sinus or AV disease * Pulmonary fibrosis * Abnormal LFTs due to hypersensitivity hepatitis * Skin deposits result in photodermatitis and a gray-blue skin discolouration * Asymptomatic corneal microdeposits occur in almost all patients after a few weeks * Rarely optic neuritis, leading to blindness * Hypo or hyperthyroidism

Answer 88

* It is variably absorbed with a bioavailability of 35-60% * It undergoes hepatic metabolism, and the major metabolite desethylamiodarone, is bioactive. * The elimination half-life is complex with a rapid component of 3-10 days (50% of the drug) and a slower component of several weeks * After discontinuation of the drugs, effects are maintained by 1-3 months * It is a substrate for liver cytochrome CYP3A4 and inhibits several cytochrome P450 enzymes and may result in high levels of many drugs, including statins, digoxin and warfarin

Answer 89

* Verapamil blocks both activated and inactivated L-type calcium channels. Thus, it's effect is more marked in tissues that fire frequently, those that are less completely polarised at rest, and those in which activation depends exclusively on calcium current, such as the SA and AV node * It slows the SA node by direct action, but it's hypotensive action may cause a brief reflex tachycardia

Answer 90

It causes peripheral vasodilation, which may be helpful in hypertension and peripheral vasospastic disorders

Answer 91

* Verapamil's cardiotoxic effects are usually dose-related and easily avoided. * It can induce AV block when used in large doses or in patients with AV disease * When used in VT, hypotension and VF can occur * Extracardiac effects include constipation, anxiety and peripheral oedema

Answer 92

* The half-life of verapamil is approx 4-7 hours * It is extensively metabolised by the liver, after oral administration, it's bioavailability is only about 20% * Verapamil dosage is an initial bolus of 5mg over 2-5 minutes, followed by a second bolus if required or a continuous infusion

Answer 93

* Adenosine * Digoxin * Magnesium * Potassium

Answer 94

* **Activation of an inward rectified K+ current** and **inhibition of calcium current**. * The results of these actions are **marked hyperpolarisation** and **suppression of calcium-dependent action potentials**. * When given as a bolus, it directly inhibits AV nodal conduction and increases the AV nodal refractory period but has lesser effects on the SA node.

Answer 95

It's half-life in the blood is <10 seconds It is usually given as a bolus of 6mg, followed by 12mg twice if required

Answer 96

* SOB or chest burning * Feeling like a sense of 'impending doom' * Induction of high-grade AV block * AF * Headache, hypotension, nausea and paraesthesia

Answer 97

* 65-80% of digoxin is absorbed after oral administration * It is not extensively metabolised, almost two thirds is excreted unchanged by the kidney. It's renal clearance is proportional to creatinine clearance. * The half-life is 36-40 hours in patients with normal renal function.

Answer 98

* It **inhibits the Na/K+ATPase pump** in the cell membranes (that transports sodium) * **Mechanical effects** - increases cardiac contraction (**positively inotropic**) by increasing the free calcium concentration. It does this by: 1) increasing intracellular sodium concentration by inhibiting the Na/K+ATPase pump and 2) relatively reducing calcium expulsion from the cell by the sodium calcium exchanger caused by the increased intracellular sodium. * **Electrical effects** - causes an early, brief prolongation of the action potential, followed by a shortening. This is probably from the increased potassium conductance caused by high intracellular calcium. At low doses, it has cardioselective parasympathetic effects by sensitising the baroreceptors, causing central vagus stimulation, and facilitation of muscarinic transmission at the nerve ending-myocyte synapse

Answer 99

* Resting membrane potential is reduced as a result of inhibition of the sodium pump and reduced intracellular potassium. As toxicity progresses, oscillatory depolarising afterpotentials appear following normally evoked action potentials. * When afterpotentials reach threshold, they elicit action potentials (premature depolarisations 'ectopic beats') that are coupled to the preceding normal action potentials. * If afterpotentials happen regularly in the Purkinje system, bigeminy will be seen * With further toxification, after each of these action potentials there will be a suprathreshold afterpotential, and a self-sustaining tachycardia, which may go onto develop AF or VF.

Answer 100

* **GI effects** - anorexia, nausea, vomiting and diarrhoea * **CNS effects** - vagal and chemoreceptor trigger zone stimulation - disorientation and hallucinations

Answer 101

They inhibit each others binding to the NA+/K+ATPase pump. * Hyperkalaemia reduces the effect of digoxin * Hypokalaemia increases the effect of digoxin * Increase cardiac automaticity is inhibited by hyperkalaemia, moderately increased potassium therefore reduces the effects of digoxin

Answer 102

* Hypercalcaemia increases the risk of digoxin toxicity * Hypermagnesaemia reduces the effects of digoxin

Answer 103

* It is an agonist for both **alpha and beta** receptors. It is therefore a very potent vasoconstrictor and cardiac stimulant. * It is **positively inotropic and chronotropic** (predominantly beta 1 receptors) and causes vasoconstriction in many vascular beds (alpha receptors). * It also activates beta 2 receptors in some vessels, leading to their vasodilation and therefore **decreasing peripheral vascular resistance**, explaining the transient hypotension that can follow administration

Answer 104

* **Noradrenaline** is an agonist for both **alpha 1 and 2 receptors** and also activates **beta 1** with a similar potency to adrenaline but has relatively little effect on beta 2 receptors. * Consequently, noradrenaline **increases peripheral resistance** and both **systolic and diastolic blood pressures**. * Compensatory baroreceptor activation tends to overcome the direct positive chronotropic effects of noradrenaline but the positive inotropic effects on the heart are maintained

Answer 105

* It is the immediate precursor in the synthesis of noradrenaline. * It's use promotes vasodilation in the renal, splanchnic, coronary, cerebral via activation of **D1 receptors** * Dopamine activates **beta 1 receptors** in the heart. * High doses of dopamine may mimic the effects of noradrenaline

Answer 106

* Most innervated vascular smooth muscle - contraction * Pupillary dilator muscles - contraction * Pilomotor smooth muscle - contraction (erects hair) * Prostate - contraction * Heart - increases contraction

Answer 107

* **Post-synaptic neurons** - probably multiple actions * **Platelet** - aggregation * **Adrenergic and cholinergic nerve terminals** - inhibits transmitter release * **Some vascular smooth muscle** - contraction * **Fat cells** - increase lipolysis

Answer 108

* **Heart** - inotropic and chronotropic * **Juxtuglomerular cells** - increases renin release

Answer 109

* **Respiratory** - promotes smooth muscle relaxation * **Uterine** - promotes smooth muscle relaxation * **Vascular smooth muscle** - promotes smooth muscle relaxation

Answer 110

**Bladder** - relaxes detrusor muscle

Answer 111

* **Delta 1** - smooth muscle - dilates renal blood vessels * **Delta 2** - nerve endings - modulates transmitter release

Answer 112

Organic nitrates Calcium channel blockers Beta blockers

Answer 113

* The liver contains a high-capacity nitrate reductase that ultimately inactivates the drug, therefore oral bioavailability is low (<10-20%) * The sublingual route is preferred as it avoids the first-pass effect. Both nitroglycerin and isosorbide dinitrate reach therapeutic blood levels within a few minutes via this route * The duration of effect is 15-30 minutes. * Other routes include oral, transdermal and buccal absorption. * Once absorbed, the half-life is only 2-8 minutes * The bioavailability of isosorbide mononitrate is 100% and it is metabolised to isosorbide dinitrate * Excretion is largely by the kidney

Answer 114

* The drug must be bioactivated with the release of nitric oxide * Nitroglycerin can be denitrated by glutathione S-transferase in smooth muscle and other cells * A mitochondrial enzyme, aldehyde dehydrogenase isoform 2 (ALDH2) and ALDH3 appears to be key in the activation and release of nitric oxide from nitroglycerin and pentarythritol tetranitrate. * Free nitrate ion is released, which is then converted to NO. NO combines with the heme group of soluble guanylyl cyclase, activating it and causing an increase in cGMP.

Answer 115

All segments of the vascular system from large arteries through to large veins relax in response to nitroglycerin. With veins responsing at the lowest concentrations and arteries at slightly higher ones. The epicardial coronary arteries are sensitive, but concentric atheromas can present significant dilation. On the other hand, eccentric lesions permit an increase in flow when nitrates relax the smooth muscle on the side away from the lesion.

Answer 116

There is marked relaxation of veins, with increased venous capitance and decreased ventricular preload. Pulmonary vascular pressures and heart size are significantly reduced. In the absense of heart failure, cardiac output is reduced. In heart failure, preload is often abnormally high; by reducing preload, it may have a beneficial effect on cardiac output in this condition Because venous capitance is increased, orthostatic hypotension may be marked and syncope can result

Answer 117

The indirect effects of nitroglycerin consist of those compensatory responses evoked by baroreceptors and hormonal mechanisms responsing to decreased arterial pressure, this often results in tachycardia and increased cardiac contractility. Retention of salt and water may also be significant, especially with intermediate and long acting nitrates.

Answer 118

Dilation of large epicardial coronary arteries may improve oxygen delivery in the presence of eccentric atheromas or collateral vessels. Temporal artery pulsations and a throbbing headache associated with meningeal artery pulsations are common effects of GTN.

Answer 119

Relaxation of smooth muscle of the bronchi, GI tract and GU tract have been demonstrated experimentally but have limited clinical effect due to the short half-life. But, recently nitrates have been used to enhance erections. The resulting increase in cGMP causes relaxation in the erectile tissue.

Answer 120

NO released from the nitroglycerin stimulates guanylyl cyclase in platelets as in smooth muscle. The increase in cGMP that results is responsible for a decrease in platelet aggregation.

Answer 121

Orthostatic hypotension Tachycardia Throbbing headache

Answer 122

Elevated intracranial pressure Rarely, transdermal GTN patches have ignited during DCR so they should be removed during shocks

Answer 123

With continuous exposure to nitrates, isolated smooth muscle may develop complete tolerance progressively with long-acting preparations or continuous infusions. Diminished release of NO resulting from reduced bioactivation may be partly responsible. Systemic compensation also may play a role

Answer 124

* **Decreased venous return to the heart** and resulting **reduction of intracardiac volume** are important beneficial haemodynamic effects of nitrates * Arterial pressure also decreases. * **Decreased intraventricular pressure** and left ventricular volume are associated with **decreased wall tension and decreased myocardial oxygen requirement.** * IV or sublingual nitrate administration consistently increases the caliber of the large epicardial coronary arteries except where blocked by concentric atheromas. * Coronary arteriolar resistance tends to decrease, though to a lesser extent * The reduction in oxygen demand is the major mechanism for the relief of effort angina

Answer 125

Relaxing the smooth muscle of the epicardial coronary arteries and relieving coronary artery spasm

Answer 126

Both by dilating the epicardiac coronary arteries and simultaneously reducing myocardial oxygen demand. Also by decreasing platelet aggregation

Answer 127

Short acting Sublingual Long acting oral Long acting transdermal Slow release buccal Slow release sublingual

Answer 128

They are orally active agents and are characterised by high first-pass effect, high plasma protein binding and extensive metabolism Verapamil and Diltiazem are also used by the IV route

Answer 129

* The voltage-gated L type calcium channel blocked in cardiac and smooth muscle consists of α1, α2, β, γ, and δ subunits. * Nifedipine and other dihydropyridines, verapamil and diltiazem all bind to the α1 unit. * The drugs act on the inner side of the membrane and **bind more effectively to open channels and inactivated channels**. * Binding of the drug **reduces the frequency** of opening in response to depolarisation. * The result is a marked **decrease in transmembrane calcium current**, which in **smooth muscle results in long-lasting relaxation** and in cardiac muscle results in **reduction in contractility** thoughout the heart and **decreases in sinus node pacemaker rate and AV node conduction velocity**.

Answer 130

The cells are relaxed by the calcium channel blockers. Vascular smooth muscle appears to be the most sensitive, but similar relaxation can be shown to bronchiolar, GI and uterine smooth muscle. Blood pressure is reduced. The reduction in peripheral vascular resistance is one mechanism by which these agents may benefit the patient with angina

Answer 131

**Dihydropyridines** * Amlodipine * Nifedipine **Miscellanous** * Diltiazem * Verapamil

Answer 132

In general, the dihydropyridines have a greater ratio of vascular smooth muscle effects relative to cardiac effects than diltiazem and verapamil.

Answer 133

Excitation-contraction coupling in all cardiac cells requires calcium influx, so these drugs reduce cardiac contractility in a dose-dependent fashion. In some cases, cardiac output may also decrease. This reduction in cardiac mechanical function is a way in which the calcium channel blockers can reduce the oxygen requirement in patients with angina. Impulse generation in the SA node and conduction in the AV node may be reduced or blocked by calcium channel blockers

Answer 134

Verapamil and diltiazem block tachycardias in calcium-dependent cells (the AV node) more selectively than the dihydropyridines. On the other hand, the dihydropyridines appear to block smooth muscle calcium channels more than diltiazem and verepamil so are therefore less depressant on the heart

Answer 135

Because it uses intracellular pools of calcium to support excitation-contraction coupling and does not require as much transmembrane calcium influx.

Answer 136

**Serious but rare**: cardiac depression including bradycardia, AV block, cardiac arrest and heart failure. **Troublesome but not harmful** - flushing, dizziness, nausea, constipation and peripheral oedema

Answer 137

**Amlodipine** - 30-50 hours **Nifedipine** - 4 hours **Diltiazem** - 3-4 hours **Verapamil** - 6 hours

Answer 138

* CCBs decrease myocardial contracile force, which reduces myocardial oxygen requirements * Calcium channel block in arterial smooth muscle decreases arterial and intraventricular pressure * Peripheral vasodilation causes a decline in left ventricular wall stress, which reduces myocardial oxygen requirements * Decreased heart rate decreases oxygen requirements * Verapamil and diltiazem decrease AV node conduction, often being effective in the management of SVT and in decreasing the ventricular rate in AF or A flutter

Answer 139

They can cause worsening of failure as a result of their negative inotropic effects

Answer 140

They decrease heart rate, blood pressure and contractility which decreases myocardial oxygen requirements at rest and during exercise. Lower heart rate is also associated with an increase in diastolic perfusion time that may increase coronary perfusion.

Answer 141

Asthma and other bronchospastic conditions, severe bradycardia, AV block, bradycardia-tachycardia syndrome and unstable left ventricular failure

Answer 142

Fatigue Impaired exercise toleracne Insomnia Unpleasant dreams Worsening of claudication Erectile dysfunction

Answer 143

* It is a non-selective β blocker. * Decreases BP primarily as a result of a decrease in cardiac output. * Inhibits the stimulation of renin production by catecholamines (mediated by β1 receptors) * May also act on peripheral presynaptic β adrenoreceptors to reduce sympathetic vasoconstrictor nerve activity

Answer 144

* **Bioavailibility** - 25% * **Half-life** - 3-5 hours

Answer 145

Metoprolol is approximately equipotent to propranolol in inhibiting stimulation of β1 adrenoreceptors in the heart but 50-100-fold less potent than propranolol in blocking β2 receptors because it in a β1 selective beta blocker, therefore is better for patients with asthma or peripheral vascular disease

Answer 146

* It is extensively metabolised by CYP2D6 with high first-pass metabolism. * Has a relatively short half-life (4-6 hours) but the extended release preparation can be dosed once daily * Dose is not affected by renal function

Answer 147

* It is β1 selective * It is not extensively metabolised and is excreted primarily in the urine with a half-life of 6 hours * It is usually dosed once daily - it is reported to be less effective than metoprolol * Patients with reduced renal function should recieve lower doses

Answer 148

* Non-selective β-receptors antagonists * Not appreciably metabolised and are excreted to a considerable extent in the urine * Patients with reduced renal function should receive lower doses

Answer 149

* β1-selective blockers * Primarily metabolised in the liver * Have long half-lives * Can be administered once daiy

Answer 150

These drugs have both β-blocking and vasodilating effects. * **Labetalol** is a β and α blocker. It has a 3:1 ratio of β:α antagonism after oral dosing. BP is lowered by reduction of systemic vascular resistance (α blockade) without significant alteration in HR or cardiac output. It is usually given OD or IV as required * **Carvedilol** is a non-selective β-adrenoceptor blocker and α blocker. The average half life is 7-10 hours and is usually given BD. It is useful in heart failure and HTN together * **Nebivolol** is a highly β1-selective blocker with vasodilating properties that are *not* mediated by α blockage. It causes a decrease in peripheral vascular resistance, causing vasodilation. It is extensively metabolised and has active metabolites. The half-life is 10-12 hours but it can be given OD. It is thought to have less adverse effects that other antihypertensives

Answer 151

* It is a β1-selective blocker that is rapidly metabolised * It has a short half-life of 9-10 minutes and is given IV, often as a loading dose then continuous infusion * It is often used intra-operatively

Answer 152

A **diuretic** is an agrent that increases urine volume. A **natiuretic** causes an increase in renal sodium excretion A **aquaretic** increases excretion of solute-free water

Answer 153

* It is present in many nephron sites, but the predominant location is the epithelial cells of the proximal convoluted tububle. * It catalyses the dehydration of H₂CO₃ to CO₂ at the luminal membrane and rehydration of CO₂ to H₂CO₃ in the cytoplasm.

Answer 154

* The prototypical carbonic anhydrase inhibitor is **acetazolamide**. * By blocking carbonic anhydrase, inhibitors blunt NaHCO₃ reabsorption and cause diuresis.

Answer 155

* They are well absorbed after oral administration. * An increase in urine pH from the HCO₃ diuresis is apparent within 30 minutes, maximal at 2 hours and persists for 12 hours after a single dose. * Excretion of the drug is by secretion in the proximal tubule S2 segment, therefore dosing must be reduced in renal insufficiency

Answer 156

* Inhibition of carbonic anhydrase activity profoundly depresses HCO₃ reabsorption in the PCT. At maximal safe inhibitor dosage, 85% of the HCO₃ reabsorptive capacity of the superficial PCT is inhibited. * Therefore, it causes significant HCO₃ losses and hyperchloremic metabolic acidosis. * Because of reduced HCO₃ in the glomerular filtrate and the fact that HCO₃ depletion leads to enhanced NaCl reabsorption by the remainder of the nephron, the diuretic efficacy decreases significantly with use over several days.

Answer 157

* **Glaucoma** - the reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure * **Urinary alkalisation** - uric acid and cystine may form stones in acidic urine, it can be used in the first few days * **Metabolic acidosis** - when the alkalosis is due to excessive use of diuretics with HF patients, IV replacement is contraindicated and acetazolamide can be used to rapidly correct the metabolis alkalosis and correction of volume overload * **Acute mountain sickness** - in serious cases with cerebral oedema, carbonic anhydrase inhibitors can decrease CSF formation and by decreasing the pH of the CSF and brain, it can increase ventilation and diminish symptoms.

Answer 158

* **Hyperchloremic metabolic acidosis** - predictably from the chronic reduction of body HCO₃ stores * **Renal stones** - calcium phosphate salts are relatively insoluble in alkalike pH, which means the potential for renal stone formation is higher * **Renal potassium wasting** occurs because the increased Na+ presented to the collecting tubule (with HCO₃) is partially reabsorbed, increasing the lumen-negative electrical potential in that segment and enhacing K⁺ secretion. * **Drowsiness and paresthesias**

Answer 159

In the normal individual, the PCT reabsorbs almost all of the glucose filtered by the glomeruli. 90% of the glucose reabsorption occurs through SGLT2, but inhibiting this transporter using the currently available drugs will result in glucose excretion of only 30-50% of the amount filtered

Answer 160

Angiotensin II has been shown to induce SGLT2 production via the AT1 receptor. Thus, blockade of the RAA axis may result in lower SGLT2 availability

Answer 161

* They are rapidly absorbed by the GI tract. * The elimination half-life of dapagliflozin is 10-12 hours * Up to 70% of the given dose is excreted in the urine in the form of 3-O-glucuronide * The drugs are not recommended in patients with more severe renal failure or advanced liver disease

Answer 162

Dapagliflozin Canagliflozin Empagliflozin Ipragliflozin

Answer 163

Loop diuretics selectively inhibit NaCl reabsorption in the thick ascending loop.

Answer 164

* The are rapidly absorped. * They are eliminated by the kidney by glomerular filtration and tubular secretion. * Absorption of oral torsemide is more rapid (1 hour) that than of furosemide (2-3 hours) and is nearly as complete with IV administration. * The duration of effect for furosemide is usually 2-3 hours. The effects of torsemide lasts 4-6 hours.

Answer 165

* Loop diuretics **inhibit NKCC2, the luminal Na/K/2Cl transporter** in the thick ascending loop of Henle. * Thus, the loop diuretics **reduce the absorption of NaCL** and also diminish the lumen-positive potential that comes from K+ recycling. * This positive potential normally drives divalent cation reabsorption in the TAL, and by reducing this potention, loop diuretics cause an **increase in Mg and Ca excretion.** * Loop diuretics have also been shown to induce the expression of COX-2, **increasing PGE2**, which inhibits salt transport in the TAL. * They **increase renal blood flow** via prostaglandin actions on kidney vasculature

Answer 166

Loop diuretics can cause an increase in Mg and Ca excretion. In disorders that cause hypercalcaemia, Ca excretion can be enhanced by treatment with loop diurectics combined with saline infusion.

Answer 167

Loop diuretics induce the expression of COX-2. NSAIDs blunt COX activity, which can interfere with the actions of loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal is healthy patients but may be significant in patients with nephrotic syndrome of hepatic cirrhosis

Answer 168

* Loop agents have direct effects on blood flow through several vascular beds via prostaglandin actions. * They **reduce pulmonary congestion and left ventricular filling pressures** in heart failure before a measurable increase in urinary output occurs. * Their effects on peripheral vascular tone are also due to **release of renal prostaglandins** that are induced by the diuretics

Answer 169

* **Hyperkalaemia** - loop diuretics can significantly enhance urinary excretion of K+. * **AKI** - loop agents can increase the rate of urine flow and enhance K+ excretion in acute renal failure. * **Anion overdose** - they are useful in treating toxic ingestions of bromide, fluoride and iodide, which are reabsorbed in the TAL. Saline solution must be administered to replace urinary losses of Na and to provide CL, so as to avoid extracellular fluid volume depletion

Answer 170

* **Hypokalaemic metabolic alkalosis** - by inhibiting salt reabsorption in the TAL, loop diuretics increase Na delivery to the collecting duct. Increase Na delivery leads to increased secretion of K+ and H+ by the duct, causing hypokalaemic metabolic alkalosis. * **Ototoxicity** - occasionally cause dose-related hearing loss that is usually reversible * **Hyperuricaemia** and precipitated attacks of gout, cause by hypovolaemia-associated enhancement of uric acid reabsorption in the proximal tubule. * **Hypomagnesaemia** is a predictable consequence of the chronic use of loop agents

Answer 171

All thiazides can be administered orally, but there are differences in their metabolism: * **Chlorothiazide**, the parent of the group, is not very lipid-soluble and must be given in relatively large doses. It is the only thiazide available for parenteral administration. * **Hydrochlorothiazide** is considerably more potent and should be used in much lower doses All thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system. As a result, thiazide may blunt uric acid secretion and elevate serum uric acid level.

Answer 172

* Thiazides **inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking Na/Cl transporter (NCC).** * Thiazides **enhance Ca reabsorption**, likely due 1) in the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption; 2) in the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na/Ca exchange in the basolateral membrane and increases overall reabsorption of Ca2+. * The action of thiazides depends in part of renal prostaglandin production, like loop diurectics

Answer 173

HTN HF Nephrolithiasis due to idiopathic hypercalciuria Nephrogenic diabetes insipidus

Answer 174

* **Hypokalaemic metabolic alkalosis** - similar to loop diuretics * **Impaired carbohydrate tolerance** - due to both impaired pancreatic release of insulin and diminished tissue utilisation of glucose. * **Hyperlipidaemia** * **Hyponatraemia** due to a combo of hypovolaemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and incresed thirst * **Impaired uric acid metabolism & gout** * Serious but rare: haemolytic anaemia, thrombocytopaenia, acute necrotising pancreatitis

Answer 175

Bendroflumethiazide Hydrochlorothizaide Indapamide Chlorothiazide

Answer 176

Spironolactone Amiloride Eplerenone

Answer 177

The prevent K+ secretion by antagonising the effects of aldosterone in collecting tubules. * Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone) *OR* * By inhibition of Na+ influx through ion channels in the luminal membrane (amiloride, triamterene).

Answer 178

Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone. * Onset and duration of its action are determined substantially by the active metabolites canrenone and 7-α-spironolactone, which are produced in the liver and have long half-lives (12-20 hours and approx 14 hours, respectively). * Spironolactone binds with high affinity and potently inhibits the androgen receptor, which is an important side effect in males (gynaecomastia and decreased libido)

Answer 179

It is a spironolactone analog with much greater selectivity for the mineralocorticoid receptor. It is several hundredfold less active on androgen and progesterone receptors that spironolactone and therefore, eplerenone has considerably fewer adverse effects.

Answer 180

They reduce sodium absorption in the collecting tubules and ducts. Potassium absorption (and K+ secretion) at this site is regulated by aldosterone. * Spironolactone and eplerenone bind to mineralocorticoid receptors and blunt aldosterone activity. * Amiloride and triamterene do not block aldosterone but instead directly interfere with Na+ entry through the epithelial Na+ channels in the apical membrane of the collecting tubule.

Answer 181

* Potassium-sparing diuretics are most useful in states of **mineralocorticoid excess** or **hyperaldosteronism due to primary hypersecretion** (Conn's syndrome, ectopic ACTH production) or **secondary hyperaldosteronism** (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome) * Eplerenone may interfere with some of the fibrotic and inflammatory effects of aldosterone. Thus, it can slow the progression of albuminuria in diabetic patients. * Eplerenone has been found to reduce myocardial perfusion defects after MI

Answer 182

* **Hyperkalaemia** - they reduce urinary excretion of K+, the risk of this is greatly increased by renal disease or by use of other drugs that reduce or inhibit renin (beta blockers, NSAIDs) or angiotensin II activity (ACE inhibitors, angiotensin receptor inhibitors * **Hyperchloraemic metabolic acidosis** - by inhibiting H+ secretion in parallel with K+ secretion * **Gynaecomastia** - synthetic steroids may cause endocrine abnormalities by actions on other steroid receptors.

Answer 183

Chronic renal insufficiency due to risk of K+ Patient with liver disease may have impaired metabolism of triamterene and spironolactone

Answer 184

The proximal tubule and descending limb of Henle's loop are freely permeable to water. Any osmotically active agent that is filtered by the glomerulus but not reabsorbed causes water to be retained in these segments and promotes a water diuresis. Such agents can be used to reduce intracranial pressure and to promote prompt removal of renal toxins

Answer 185

* Mannitol is poorly absorbed by the GI tract, and when administered orally, it causes osmotic diarrhoea rather than diuresis. It must be given IV * Mannitol is not metabolised and is excreted by glomerular filtration within 30-60 minutes, without any important tubular reabsorption or secretion * It must be used cautiously in patients with even mild renal insufficiency

Answer 186

* Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle's loop. * Through osmotic effects, they also oppose the action of ADH in the collecting tubule. * The presence of a non-reabsorbable solute such as mannitol prevents the normal absorption of water by interposing a countervailing osmotic force. As a result, urine volume increases. * The increase in urine flow decreases the contact time between fluid and the tubular epithelium, thus reducing Na+ as well as water reabsorption. * The resulting natuiresis is of lesser magnitude than the water diuresis, leading eventually to excessive water loss and hypernatraemia.

Answer 187

Osmotics diuretics alter Starling forces so that water leaves cells and reduces intracellular volume. This effect is used to reduce intracranial pressure in neurologic conditions and to reduced intraocular pressure before ophthalmologic procedures.

Answer 188

A dose of 1-2g/kg mannitol is administered IV. ICP should fall in 60-90 minutes.

Answer 189

At times, the rapid lowering of serum osmolality at initiation of dialysis results in symptoms. Many nephrologists also use mannitol to prevent adverse reactions when first stating patients on haemodialysis

Answer 190

* **Extracellular volume expansion** - mannitol is rapidly distributed in the extracellular compartment and extracts water from cells. Prior to the diuresis, this leads to expansion of the extracellular volume and hyponatraemia. This may complicate heart failure and may produce florid pulmonary oedema. Headache, nausea and vomiting are commonly observed * **Dehydration, hyperkalaemia and hypernatreamia** - excessive use of mannitol without adequate water replacement can ultimately lead to severe dehydration, free water losses, and hypernatraemia. As water is exctracted from cells, intracellular K+ concentration rises, leading to cellular losses and hyperkalaemia. * **Hyponatraemia** - when used in patients with severe renal impairment, parenterally administered mannitol cannot be excreted and is retained in the blood. This causes osmotic extraction of water from cells, leading to hyponatraemia without a decrease in serum osmolality * **Acute renal failure**

Answer 191

The indirect thrombin inhibitors are called this because their antithrombotic effect is exerted by their interaction with a separate protein, antithrombin. Examples include: * Unfractionated heparin (also known as high molecular weight heparin) * LMWH * Fondaparinux They bind to antithrombin and enhance its inactivation of factor Xa.

Answer 192

It is a heterogenous mixture of sulfated mucopolysaccharides. It binds to endothelial cell surfaces and a variety of plasma proteins. Its biological acitivity is dependent upon the endogenous anticoagulant **antithrombin**.

Answer 193

* Antithrombin inhibits clotting factor proteases, especially thrombin (IIa), IXa, Xa, by forming equimolar stable complexes with them. * In the absence of heparin, these reactions are slow; in the presence of heparin, they are accelerated 1000-fold. * The active heparin molecules bind tightly to antithrombin and cause a conformational change in this inhibitor * The conformational change of antithrombin exposes its active site for more rapid interaction with the proteases (activated clotting factors) * Heparin functions as a cofactor for the reaction without being consumed. Once the complex is formed, heparin is released intact for renewed binding to more antithrombin.

Answer 194

* HMWH with high affinity for antithrombin markedly inhibit blood coagulation by inhibiting all three factors, especially thrombin and factor Xa * LMWH inhibits activated factor X but has less effect on thrombin than the HMWH. * LMWH have equal efficacy, increased bioavailability from the subcut site of injection, and less frequent dosing requirements

Answer 195

* Close monitoring of PTT or anti-Xa units is necessary in patients received unfractionated heparin. * Weight-based dosing of LMWH results in predictable pharmacokinetics so the levels are not generally measured except in renal insufficiency, obesity and pregnancy, where it can be determined by anti-Xa levels.

Answer 196

* **Bleeding** risk, osteoporosis, alopecia, mineralocorticoid deficiency * **HIT** - a systemic hypercoagulable state that occurs in 1-4% of individuals treated with UFH.

Answer 197

* HIT * hypersensitivity to the drug * active bleeding * haemophilia * thrombocytopaenia * HTN * ICH * infective endocarditis * TB * abortion * advanced hepatic or renal disease

Answer 198

After an inital bolus of 80-100 units/kg, a continuous infusion of about 15-22 units/kg per hour is required to maintain the anti-Xa activitiy in the range of 0.3-0.7units/ml

Answer 199

**Prophylatic dose** - 30mg BD or 40mg OD subcut **Treatment dose** - 1mg/kg subcut every 12 hours for an anti-Xa level of 0.5-1 unit/ml.

Answer 200

* **Prophylactic dose** 5000 units subcut OD * **Treatment dose** 200 units/kg OD for venous disease or 120 units/kg BD for ACS

Answer 201

* It actively bind antithrombin with high specific activity, resulting in efficient inactivation of factor Xa. * It has a long half-life of 15 hours, allowing for OD dosing subcut

Answer 202

* It is generally administered orally and has 100% oral bioavailability * Over 99% of racemic warfarin is bound to plasma albumin, which may contribute to its small volume of distribution, its long half-life in plasma (36 hours) and lack of urinary excretion of unchanged drugs

Answer 203

* It blocks the γ-carboxylation of several glutamate residues in prothrombin and factors VII, IX, and X as well as the endogenous anticoagulant proteins C and S. * The blockade result in incomplete coagulation factor molecules that are biologically inactive. * The protein carboxylation reaction is coupled to the oxidation of vitamin K. The vitamin must then be reduced to reactivate it. * Warfarin prevents reductive metabolism of the inactive vitamin K epoxide back to its active hydroquinone form.

Answer 204

* There is an 8 to 12 hour delay in the action of warfarin. * Its anticoagulant effect results from a balance between partially inhibited synthesis and unaltered degradation of the four vitamin K-dependent clotting factors. * The resulting inhibition of coagulation is dependent on their degradation half-lives in the circulation. These half-lives are 6, 24, 40 and 60 hours for factors VII, IX, X and II, respectively.

Answer 205

Protein C and factor VII have a relatively short half life (6 hours). Thus, the immediate effect of warfarin is to deplete the procoagulant factor VII and anticoagulant protein C, which can paradoxically create a transient hypercoagulable state due to residual activity of the longer half-life procoagulants in the face of protein C depletion.. For this reason, warfarin cannot be used in active hypercoagulability

Answer 206

Warfarin crosses the placenta readily and can cause a haemorrhagic disorder in the fetus. Cutaneous necrosis with reduced activity of protein C sometimes occurs during the first weeks of therapy in patients who have inherited deficiency of protein C.

Answer 207

It shoukd be initiated with standard doses of 5-10mg. The initial adjustment of PT takes about 1 week, which usually results in a maintenance dose of 5-7mg/d.

Answer 208

It is the prothrombin time ratio (patient prothrombin time/mean of normal prothrombin time for lab)

Answer 209

* For **prophylaxis and treatment of thrombotic disease** - 2-3 * **Artificial valves** - 2.5-3.5

Answer 210

Patients with advanced cancers, typically of GI origin

Answer 211

They mainly involve cytochrome P450 CYP2C9 enzyme induction, enzyme inhibition and reduced plasma protein binding.

Answer 212

Pharmacodynamic mechanisms for interactions with warfarin are synergism (impaired haemotasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and an altered physiological control loop for vitamin K (hereditary resistance to oral anticoagulants)

Answer 213

Warfarin used clinically is a racemic mixture composed of equal amounts of two molecules. *S*-warfarin is four times more potent that *R*-warfarin.

Answer 214

They stereoselectively inhibit the metabolic transformation of *S*-warfarin

Answer 215

They inbibit metabolism of both *R*-warfarin and *S*-warfarin

Answer 216

Aspirin by its effect on platelet function. Hepatic disease and hyperthyroidism by increasing the turnover rate of clotting factors

Answer 217

They eliminate the bacteria in the intestinal tract that produce vitamin K and, like warfarin, also directly inhibit vitamin K epoxide reductase

Answer 218

They cause a marked **decrease** of the anticoagulant effect by induction of the hepatic enzymes that transform racemic warfarin.

Answer 219

It binds warfarin in the intestine and reduced its absorption and bioavailability

Answer 220

* **Increased vitamin K** - increased synthesis of clotting factors * **Diuretics chlorthalidone and spironolactone** - affecting clotting factor concentration * **Hereditary resistance** - mutation of vitamin K reactivation cycle molecules * **Hypothyroidism** - decreased turnover rate of clotting factors

Answer 221

* Ethanol * Phenothiazines * Benzodiazepines * Acetaminophen * Opioids * Indemethacin * Most antibiotics

Answer 222

By: * stopping the drug * administering oral or parenteral vitamin K1 (phytonadione) * FFP * Prothrombin complex concentrates * Recombinant factor VIIa It is important to note that due to the long half-life of warfarin, a single dose of vitamin K or rFVIIa may not be sufficient

Answer 223

Rivaroxaban, apixaban, edoxaban.

Answer 224

They inhibit factor Xa, in the final common pathway of clotting.

Answer 225

* High oral bioavailability when taken with food * Following an oral dose, the peak plasma level is achieved within 2-4 hours * The drug is extensively protein-bound * It is a substrate for the cytochrome P450 system and the P-glycoprotein transporter. Drugs inhibiting these result in increased rivaroxaban effect. * 1/3 of the drug is secreted in the urine and feces. * The drug half-life is 5-9 hours in patients aged 20-45 and is increased in the elderly and in those with impaired renal or hepatic function

Answer 226

* Oral bioavailability of 50% and prolonged absorption, resulting in a half-life of 12 hours with repeat dosing * The drug is a substrate of the cytochrome P450 and P-glycoprotein, therefore drugs that inhibit both of these, result in increased drug effect * It is excreted in the urine and feces * Drug effect is increased in both renal or hepatic function

Answer 227

* It is a once-daily Xa inhibitor with a 62% oral bioavailability * Peak drug concentrations occur 1-2 hours after dosage and are not affected by food. * The drug half-life is 10-14 hours. * Edoxaban does not induce CYP450 enzymes * No dose reduction is required with concurrent use of P-glycoprotein inhibitors. * It is primarily excreted unchanged in the urine

Answer 228

* Prevention of embolic stroke in patients with AF without valvular heart disease * VTE prophylaxis following hip or knee surgery * Treatment of VTE

Answer 229

* **Prophylactic dose** is 10mg PO OD for 35 days for for hip replacement or 12 days for knee replacement * **Treatment dose** of DVT/PE is 15mg BD for three weeks then 20mg OD for 3-6 months depending on risk factors and clinical presentation

Answer 230

* **AF** - 5mg BD * **VTE** - 10mg BD for the first week then 5mg BD from then on * **Prophylactic dose** following hip or knee surgery is 2.5mg BD

Answer 231

**Andexanet alfa** is a factor Xa 'decoy' molecule without procoagulant activities that competes for binding to anti-Xa drugs.

Answer 232

* Dabigatran and its metabolites are direct thrombin inhibitors. * Following oral administration, dabigatran etexilate mesylate is converted to dabigatran * The oral bioavailability is 3-7% in normal volunteers * The drug is a substrate for the P-glycoprotein efflux pump; therefore P-glycoprotein inhibitors should be avoided in patients with impaired renal function * The half-life of the drug is 12-17 hours * Renal impairment results in prolonged drug clearance

Answer 233

**Prevention** of stroke and systemic embolism in non-valvular atrial fibrillation - 150mg BD, halved if CrCl <30.

Answer 234

**idarucizumab** is a humanised monoclonal antibody Fab fragment that binds to dabigatran and reverses the anticoagulant effect. - 5MG IV

Answer 235

* They rapidly lyse thrombi by catalysing the formation of the serine protease plasmin from its precursor zymogen, plasminogen. * These drugs create a generalised lytic state when administered IV * Thus, both protective haemostatic thombi and target thromboemboli are broken down

Answer 236

* It is a protein synthesised by streptococci that combines with the proactivator plasminogen. * This enzymatic complex catalyses the conversion of inactive plasminogen to active plasmin

Answer 237

It is a human enzyme synthesised by the kidney that directly converts plasminogen to active plasmin.

Answer 238

* These activators preferentially activate plasminogen that is bound to fibrin, which confines fibrinolysis to the formed thrombus and avoids systemic activation * Recombinant human t-PA is manufactured as **alteplase**. * **Reteplase** is another recombinant human t-PA from which several amino acid sequences have been deleted * **Tenecteplase** is a mutant form of t-PA that has a longer half-life, it can be given as an IV bolus

Answer 239

* PE with haemodynamic instability * Severe DVT such as superior vena caval syndrome * Ascending thrombophlebitis of the iliofemoral vein * Sometimes AMI

Answer 240

* IV loading dose of 250,000 units * Maintenance dose of 100,000units/hour for 24-72 hours

Answer 241

* Loading dose of 300,000 units given over 10 minutes * Maintenance dose of 300,000 units/hour for 12 hours

Answer 242

* Loading bolus 15mg * 0.75mg/kg over 30 minutes * 0.5mg/kg over 60 minutes

Answer 243

It is given as a single IV bolus from 30-50mg depending on body weight.

Answer 244

1) **Agents generated outside the platelet** that interact with platelet membrane receptors e.g. catecholamines, collagen, thrombin, prostacyclin 2) **Agents generated within the platelet** that interact with membrane receptors e.g. ADP, prostaglandin D2, prostaglandin E2, and serotonin 3) **Agents generated within the platelet that act within the platelet** e.g. prostaglandin endoperoxides and thromboxane A2, the cyclic nucleotides cAMP and cGMP and calcium ion.

Answer 245

* **Aspirin** - inhibition of prostaglandin synthesis * **Clopidogrel, prasugrel, ticlopidine** inhibition of ADP-induced platelet aggregation * **Abciximab, tirofiban, eptifibatide** block glycoprotein IIb/IIIa receptors on platelets

Answer 246

* The prostaglandin **thromboxane A2** causes platelets to change shape, release their granules and aggregate. * Aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of the COX enzyme.

Answer 247

* Nausea, dyspepsia and diarrhoea in up to 20% of patients * Haemorrhage in 5% * Leukopaenia in 1%

Answer 248

**NSTEMI** - 300mg loading dose followed by 75mg daily **STEMI** - 75mg daily **Recent MI, stroke or PVD** - 75mg daily

Answer 249

* The antithrombotic effects are dose dependent, within 5 hours after the loading dose, 80% of platelet activity will be inhibited * The duration of the antiplatelet effect is 7-10 days

Answer 250

It confers biologic activity upon prothrombin and factors VII, IX, and X by participating in their postribosomal modification

Answer 251

It is a fat-soluble substance found primarily in leafy green vegetables. The dietary requirement is low because the vitamin is additionally synthesised by bacteria that colonise the human intestine.

Answer 252

Vitamins K1 and K2. K1 (phytonadione) is found in food. K2 is found in human tissues and is synthesisted by intestinal bacteria

Answer 253

* It is available clinically in oral and parenteral forms * Onset of effect is delayed for 6 hours but the effect is complete by 24 hours when treating depression of prothrombin activity caused by excess warfarin.

Answer 254

It can produce dyspnoea, chest and back pain and even death

Answer 255

Muscarinic and nicotinic subgroups

Answer 256

Ganglion blockers and neuromuscular junction blockers make up the antinicotinic drugs

Answer 257

* Five types of muscarinic receptors have been identified. * M1 - M5. * M1 receptor is on CNS neurons, autonomic postganglionic cell bodies, and many presynaptic sites * M2 is in the myocardium, smooth muscle organs, and some neuronal sites * M3 receptors are most common on effector cell membranes, especially glandular and smooth muscle cells * M4 and M5 are less prominent and play a greater role in the CNS than in the periphery

Answer 258

Atropine Glycopyrrolate Hyoscine

Answer 259

* Atropine is a tertiary amine alkaloid ester of tropic acid. * It is found in the plant *Atropa belladonna* * The commercial atropine is racemic *d,l*-hyoscyamine. The *l*(-) isomers of both alkaloids are at least 100 times more potent than the *d*(+) isomers

Answer 260

* Natural alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut and subconjunctival membranes. (benztropine, atropine) * In contrast, only 10-30% of a dose of quaternary antimuscarinic drug is absorbed after oral administration, reflecting the decreased lipid solubility of the charged molecule (ipratropium, tiotropium, glycopyrrolate)

Answer 261

* Atropine and other tertiary agents are widely distributed in the body. Significant levels are achieved in the CNS within 30 minutes to 1 hour, and this can limit the dose tolerated when the drug is taken for its peripheral effects. * In contrast, quaternary derivatives are poorly taken up by the brain and therefore are relatively free - at low doses- of CNS effects

Answer 262

* After administration, the elimination of atropine from the blood occurs in two phases: the half-life (t1/2) of the rapid phase is 2 hours and that of the slow phase is approximately 13 hours. * About 50% of the dose is excreted unchanged in the urine. Most of the rest appears in the urine as hydrolysis and conjugation products. * The drug's effects on parasymathetic function declines rapidly in all organs except the eye. Effects on the iris and ciliary muscle persists for >72 hours.

Answer 263

* It causes reversible blockade of cholinomimetic actions at muscarinic receptors. * When atropine binds to the muscarinic receptor, it prevents actions such as the release of inositol triphosphate (IP3) and the inibition of adenylyl cyclase that are caused by by muscarinic agonists. * It blocks the actions of acetylcholine as an inverse agonist.

Answer 264

* The salivary, bronchial, and sweat glands. * Secretion of acid by the gastric parietal cells is the least sensitive. * In most tissues, antimuscarinic agents block exogenously administered cholinoceptor agonists more effectively than endogenously released acetylcholine

Answer 265

Atropine is highly selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, and action at non-muscarinic receptors are generally undetectable clinically

Answer 266

* **M1** - increase IP3 and DAG - *Pirenzepine, dicyclomine* * **M2** - decrease cAMP, increase potassium channel current - *Gallamine* * **M3** - increase IP3 and DAG - *oxybutynin, tolterodine, solifenacin*

Answer 267

* **CNS** - **reduce the tremor** of Parkinson's disease; reduce vestibular disturbances, especially motion sickness; slow long-lasting sedative effects on the brain - can cause **excitement, agitation, hallucinations** and coma * **Eye** - **mydriases** due to blockage of pupillary muscle contraction; **cycloplegia**, inability to focus and accomodate due to weakened contraction of ciliary muscle; **dry eyes** due to reduced lacrimal secretion * **CVS** - **tachycardia** by blocking vagal slowing * **Respiratory** - **bronchodilation** and reduce secretion, can reduce larygospasm * **GI tract** - **dry mouth** due to reduced salivary secretion, gastric secretion is blocked, **prolonged gastric emptying time** * **GU tract** - relaxes smooth muscle of the uerters and bladder wall and slows voiding * **Sweat glands** - supresses thermoregulatory sweating, blocks innervation of eccrine sweat glands and can cause fever

Answer 268

* The **SA node is very sensitive to muscarinic receptor blockage**. Moderate to high therapeutic doses of atropine cause tachycardia in the innervated and spontaneously beating heart by **blockage of vagal slowing** * However, lower doses often result in **initial bradycardia** before the effects of peripheral vagal block become manifest. This slowing may be due to block of prejunctional M1 receptors on vagal postganglionic fibres that normally limit acetylcholine release in the sinus node. * The same mechanisms operate in the AV node, in the presence of high vagal tone, atropine can significantly **reduce the PR interval on the ECG by blocking muscarinic receptors in the AV node**. * Muscarinic effects on atrial muscle are similarly blocked, but these effects are of no clinical significance except in atrial flutter and fibrillation. The ventricles are less affected by antimuscarinic drugs at therapeutic levels of a lesser degree of vagal control.

Answer 269

Most blood vessels, except those in thoracic and abdominal viscera, receive no direct innervation from the parasymapthetic system. However, parasympathetic nerve stimulation dilates coronary arteries, and sympathetic cholinergic nerves cause vasodilation in the skeletal muscle vascular bed. Atropine can block this vasodilation. Furthermore, almost all vessels contain endothelial muscarinic receptors that mediate vasodilation.

Answer 270

* **Parkinsons disease** - in conjunction with levodopa * **Motion sickness** - certain vestibular disorders respond to antimuscaricin drugs, often scopolamine * **Ophthalmologic disorders** - mydriasis greatly faclititates ophthalmoscopic examination of the retina * **Respiratory disorders** - can be used preanaesthetic to reduce laryngospasm; patient with COPD benefit from bronchodilators, especially antimuscarinic agents - *ipratropium, tiotropium, aclidinium* and *umeclidinium*. They are used an inhalation drugs along or in combination with a long acting β-adrenoceptor agonist. * **Cardiovascular disorders** - bradycardia due to marked reflex vagal discharge. * **GI disorders** - can provide relief from traveller's diarrhoea * **Urinary disorders** - provide symptomatic relief from urinary urgency caused by minor inflammatory bladder disorders

Answer 271

* **Atropine** - duration 5-6 days - 0.5-1% concentration * **Scopolamine** - duration 3-7 days - 0.25% concentration * **Homatropine** - duration 12-24 hours - 2-5% concentration * **Cyclopentolate** - duration 3-6 hours - 0.5-2% concentration * **Tropicamide** - duration 15-60 minutes - 0.1-1% concentration

Answer 272

* Tiotropium (t1/2 - 25 hours) and umeclidiniium (t1/2 - 11 hours) have a longer bronchodilator action than ipratropium (t1/2 - 2 hours) and can be given once daily because they dissociate slowly from M3 receptors * Aclidinium (t1/2 - 6 hours) is administered twice daily

Answer 273

* Receptors for acetylcholine on the urothelium and on afferent nerves as well as the detrusor muscle provide a broad basis for the action of antimucsarinic drugs in the treatment of overactive bladder. * **Oxybutynin**, is somewhat selective for M3 receptors, is used to relieve bladder spasm ater urologic surgery * **Darifenacin** and **solifenacin** are antagonists that have greater selectivity for M3 receptors than oxybutynin or trospium, so have OD dosing * **Tolterodine** and **fesoterodine**, M3 selective antimuscarinics, are available for use in adults with urinary incontinence.

Answer 274

Oral oxybutynin or instillation of the drug by catheter into the bladder in such patients appears to improve bladder capacity and continence to reduced infection and renal damage. Transdermally applied oxybutynin or its oral extended-release formation reduced the need for multiple daily doses.

Answer 275

* They have an adjunct role in therapy of BPH when bladder symptoms (increased urinary frequency) occur. * Treatment with α-adrenoceptor antagonist combined with a muscarinic antagonist reduces urinary frequency

Answer 276

* The **rapid-onset type** is usually apparent within 30 minutes to 2 hours after ingestion of the mushrooms and be caused by a variety of toxins, some produce upset stomach, some hallucinations, some produce signs of muscarinic excess. Atropine can help * **Delayed-onset mushrooms** poisoning mainfests its first symptoms 6-12 hours after ingestion. Although the initial symptoms usually include nausea and vomiting, the major toxicity involved hepatic and renal cellular injury by amatoxins that inhibit RNA polymerase. Atropine is of no value here.

Answer 277

* **Dry mouth** - dry as a bone * **Mydriasis** - blind as a bat * **Tachycardia, hot and flushed skin** - red as a beet * **Agitation and delirium** - mad as a hatter

Answer 278

* Generally treated symptomatically.You can use physostigmine, but small doses are giving very slowly via IV. * Symptomatic treatment may require temperature control with cooling blankets and seizure control with diazepam

Answer 279

* It is associated with all of the peripheral signs of parasympathetic blockade but few or none of the CNS effects of atropine. * These more polar drugs may cause significant ganglionic blockade, however, with marked orthostatic hypertension. * Treatment, if required, can be carried out with a quarternary cholinesterase inhibitor such as neostigmine.

Answer 280

* They are relative not absolute * Angle-closure glaucoma * In elderly men, antimuscarinic should always be used with caution and should be avoided in those with a history of prostatic hyperplasia * Because the antimuscarinic drugs slow gastric emptying, they may *increase* symptoms in patients with gastric ulcer

Answer 281

* Ganglion-blocking agents competitively block the action of acetylcholine and similar agonists at neuronal nicotinic receptors of both parasympathetic and sympathetic autonomic ganglion * Their lack of selectivity conders sucha broad range of undesirable effects that they have limited clinical use

Answer 282

* Unconsciousness * Amnesia * Analgesia * Inhibition of autonomic reflexes * Skeletal muscle relaxation

Answer 283

* Anaesthetics affect neurons at various cellular locations, but the primary focus has been on the **synapse**. * A presynaptic action may alter the release of neurotransmitters, where a postsynaptic effect may change the frequency or amplitude of impulses exiting the synapse. * The cumulative effect of these actions may produce strengthened inhibition or diminished excitation within key areas of the CNS.

Answer 284

* **Volatile anaesthetics** (halothane, isoflurane, desflurane, sevoflurane) have low vapor pressures and thus high boiling points so that they are liquid at room temperature (20°C) and sea-level ambient pressure * **Gaseous anaesthetics** (nitrous oxide, xenon) have high vapor pressures and low boiling points they they are in gas form at room temperature. The characteristics of volatile anaesthetics make it necessary that they be administered using precision vaporisers.

Answer 285

The main targets studied are neuronal ion channel that mediate impulse conduction in the CNS: * Chloride channels and potassium channels remain the primary **inhibitory** ion channels considered legitimate candidates of anaesthetic action * **Excitatory** ion channel targets include those activated by acetylcholine, by glutamate, or by serotonin.

Answer 286

1. Inspired concentration and ventilation 2. Solubility 3. Cardiac output 4. Alveolar-venous partial pressure difference

Answer 287

* The ratio between inspired concentration (partial pressure) and alveolar concentration is the driving force. We can only change the partial pressure * The partial pressure of anaesthetic in the inspired gas mixture determines the maximum partial pressure that can be achieved in the alveoli as well as the rate of rise of the partial pressure in the alevoli

Answer 288

* To accelerate induction, the anaesthetist increases the inspired anaesthetic partial pressure to create a steeper gradient between inspired and alveolar partial pressure * This fractional rise in anaesthetic partial pressure during induction is usually expressed as a ratio of alveolar concentration (F_A) over inspired concentration (F_I); the faster F_A/F_I approaches 1 (representing inspired-to-alveolar equilibrium), the faster anaesthesia onset will be during an inhaled induction

Answer 289

* The alveolar ventilation, which can be changed increased by increasing the tidal volume and resp rate to deliver larger amounts of anaesthetic agent faster. * The magnitude of the effect is much greater for inhaled anaesthetics with high blood solubility than for those with low blood solubility.

Answer 290

The tendency for a given inhaled anaesthetic to pass from the gas phase of the alveolus into the pulmonary capillary blood is determined by the blood:gas partition coefficient.

Answer 291

* An increased ventilation supplies more anaesthetic molecules to the alveolus, a more soluble anaesthetic (blood:gas partition coefficient >1) will traverse the alveolar capillary membrane more readily, preventing a rise in its alveolar partial pressure. * Thus, increased ventilation will replenish the alveolar anaesthetic concentration for a highly soluble anaesthetic but it is not necessary for an anaesthetic with low solubility. * Therefore, an increase in ventilation produces only a small change in alveolar partial pressure of an anaesthetic with low blood solubility, but can significantly increase the partial pressure of agents with moderate to high blood solubility such as halothane

Answer 292

* As you already know, the blood:gas coefficient is a useful index of solubility and defines the relative affinity of an anesthetic for the blood compared to the affinity for inspired gas. * When an anesthetic with low blood solubility partitions between gas in the lung and pulmonary capillary blood, equilibrium is quickly established and the blood concentration rises rapidly. * Conversely, for anaesthetics with greater solubility, more molecules dissolve in the blood before partial pressure change significantly, and arterial concentration of the gas increases less rapidly.

Answer 293

* The blood:gas coefficient of 0.47 means that at equilibrium, the concentration in blood is less than half the concentration in the alveolar space (gas). * A larger blood:gas partition coefficient causes a greater uptake of anaesthetic into the pulmonary blood flow and therefore increases the time required for F_A/F_I to approach equilibruim

Answer 294

* Changes in the flow rate of blood through the lungs also affect the uptake of anaesthetic gases from the alveolar space. * An increase in pulmonary blood flow (ie, increased cardiac output) will increase the uptake of anaesthetic, thereby slowing the rate by which F_A/F_I rises and decreasing the rate of induction of anaesthesia.

Answer 295

The increased uptake of anaesthetic into the blood caused by increased cardiac output will be distributed to all tissues. Since cerebral blood flow is well regulated, the increased anaesthesia uptake caused by increased cardiac output will predominantly be distributed to tissues that are not involved in the site of action of the anaesthetic

Answer 296

* The anaesthetic partial pressure difference between alveolar and mixed venous blood is dependent mainly on uptake of the anaesthetic by the tissues, including non-neuronal tissues. * Depending on the rate and extent of tissue uptake, venous blood returning to the lungs may contain significantly less anaesthetic than arterial blood. * Anaesthetic uptake into tissues is influenced by factors similar to those that determine transfer of the anaesthetic from the lung to the intravascular space, including tissue:blood partition coefficients, rates of blood flow to the tissues, and concentration gradients. * The greater this difference in anaesthetic gas concentrations, the more time it will take to achieve equilibrium with brain tissue

Answer 297

Those that are highly perfused (e.g. brain, heart, liver, kidneys, and splanchnic bed). Combined these tissues receive over 75% of the resting cardiac output. In the case of volatile anaesthetics with relatively high solubility in highly perfused tissues, venous blood concentration initially is very low, and equilibrium with the alveolar space is achieved slowly

Answer 298

* During maintenance, the drug continues to be transferred between various tissues at rates dependent on the solubility of the agent, the concentration gradient between the blood and the respective issue, and the tissue blood flow. * Although muscle and skin constitute 50% of the total body mass, anaesthetics accumulate more slowly in these tissues than in highly perfused tissues (e.g. brain) because they receive less blood. * Although most anaesthetic agents are highly soluble in adipose tissues, the relatively low blood perfusion to these tissues delays accumulation, and equilibrium is unlikely to occur with most anaesthetics during a typical 1-3 hour operation.

Answer 299

**Minimal alveolar concentration (MAC)** (%) It is the anasthetic concentration that produces immobility in 50% of patients exposed to a noxious stimulus

Answer 300

The combined effect of ventilation, solubility in the different tissues, cardiac output, and blood flow distribution determines the rate of tise of F_A/F_I

Answer 301

When the partial pressure of the anaesthetic in the brain reaches a threshold concentration determined by its **potency**.

Answer 302

* For an insoluble agent like desflurane, the alveolar partial pressure can quickly equilibrate through the blood and brain compartments to reach anaesthetising concentrations. * However, for an agent like halothane, its greater solubility in blood and other tissue compartments (higher partition coefficients) produces a steeper decline in the concentration gradient from lung to brain, causing a delayed onset of anaesthesia. * Therefore administering a larger concentration of halothane and increased alveolar ventilation are the two strategies that can by used by anaesthetists to speed up the rate of induction with halothane.

Answer 303

* **MAC** - >100% * **Blood:Gas partition coefficient** - 0.47 * **Brain:Blood partition coefficient** - 1.1

Answer 304

* No metabolism * Incomplete anaesthetic * Rapid onset and recovery

Answer 305

* **MAC** - 6-7% * **Blood:gas coefficient** - 0.42 * **Brain:blood coefficient** - 1.3

Answer 306

* Metabolism <0.05% * Low volatility * Poor induction agent (pungent) * Rapid recovery

Answer 307

* **MAC** 2.0% * **Blood:gas partition coefficient** 0.69 * **Brain:blood coeffecient** 1.7

Answer 308

* Metabolism - 2-5% (flouride) * Rapid onset and resovery * Unstable in soda-lime

Answer 309

* **MAC** - 1.40% * **Blood:gas partition coefficient** - 1.40 * **Brain:blood partition coefficient** - 2.6

Answer 310

* Metabolism <2% * Medium rate of onset and recovery

Answer 311

* **MAC** - 1.7% * **Blood:gas partition coefficient** - 1.80 * **Brain:blood coefficient** - 1.4

Answer 312

* Metabolism - 8% * Medium rate of onset and recovery

Answer 313

* **MAC** 0.75% * **Blood:gas partition coefficient** - 2.30 * **Brain:blood partition coefficient** - 2.9

Answer 314

* Metabolism >40% * Medium rate of onset and recovery

Answer 315

The rate of elimination of the anaesthetic from the brain, which is determined by similar things to induction: blood:gas partition coefficient, pulmonary blood flow and tissue solubility of the anaesthetic

Answer 316

When the anaesthetists discontinues the administration of the anaesthetic agent to the lung, the alveolar concentration falls rapidly. Insoluble anaesthetics that prefer the gas phase over blood will then rapidly diffuse into the alveolus and be removed from the body by the process of lung ventilation.

Answer 317

* First, transfer of an anaesthetic from the lungs to blood during induction can be enhanced by increasing its concentration in inspired air, but the reverse transfer process cannot be enhanced because the concentration in the lungs cannot be reduced below zero. * Second, at the beginning of the recovery phase, the anaesthetic gas tension in different tissues throughout the body may be quite variable, depending on the specific agent and the duration of anaesthesia. In contrast, at the start of induction of anaesthesia, the initial anaesthetic tension is zero in all tissues.

Answer 318

Inhaled anaesthetics that are relatively insoluble in blood (i.e. possess low blood:gas partition coefficients) and brain are eliminated faster than the more soluble anaesthetics

Answer 319

* The washout of nitrous oxide, desflurane, and sevoflurane occurs at a rapid rate, leading to a more rapid recovery from their anaesthetic effects compared with halothane and isoflurane. * Halothane is approximately twice as soluble in brain tissue and five times more soluble in blood than nitrous oxide and desflurane; its elimination therefore takes place more slowly, and recovery from halothane- and isoflurane-based anaesthesia is predictably less rapid.

Answer 320

* The **duration of exposure** to the anaesthetic can have a significant effect on the speed of emergence from anaesthesia, especially in the case of the more soluble anaesthetics. * Accumulation of anaesthetics in muscle, skin, and fat increases with prolonged exposure (especially in **obese patients**), and blood concentration may decline slowly after discontinuation as the anaesthetic is slowly eliminated from these tissues. * Although recover after a short exposure to anaesthesia may be rapid even with the more soluble agents, recovery is slow after prolonged administration of halothane or isoflurane

Answer 321

Since the concentration of anaesthetic in the inspired gas cannot be reduced below zero, hyperventilation is the only way to speed recovery

Answer 322

* Modern inhaled anaesthetics are eliminated mainly by ventilation and are only metabolised to a very small extent, thus, metabolism of these drugs does not play a significant role in their elimination * Hepatic metabolism may also contribute to the elimination of and recovery from some older volatile anaesthetics. For example, halothane is eliminated more rapidly that enflurane because over 40% of inspired halothane is metabolised during an average anaesthetic procedure, whereas less than 10% of enflurane is metabolised over the same period.

Answer 323

Halothane > enflurane > sevoflurane > isoflurane > desflurane > nitrous oxide Nitrous oxide is not metabolised by human tissues

Answer 324

* Inhaled and IV anaesthetics decrease the metabolic activity of the brain. * A decreased cerebral metabolic rate (CMR) generally causes a reduction in blood flow within the brain. * However, volatile anaesthetics may also produce cerebral vasodilation, which can increase cerebral blood flow. * The net effect on cerebral flow (increase, decrease, or not change) depends on the concentration of anaesthetic delivered.

Answer 325

* At 0.5 MAC, the reduction in cerebral metabolic rate (CMR) is greater than the vasodilation caused by anaesthetics, so cerebral blood flow is decreased. * Conversely, at 1.5 MAC, vasodilation by the anaesthetic is greater than the reduction in CMR, so cerebral blood flow is increased. * At 1.0 MAC, the effects are balanced and cerebral blood flow is unchanged.

Answer 326

* An increase in cerebral blood flow is clinically undesirable in patients who have increased ICP because of brain tumour, ICH or head injury. * Therefore, administration of high concentrations of volatile anaesthetics is best avoided in patients with increased ICP. * Hyperventilation can be used to attenuate this response; decreasing the PaCO₂ through hyperventilation causes cerebral vasoconstriction. If the patient is hyperventilated before the volatile agent is started, the increase in ICP can be minimised

Answer 327

* Nitrous oxide can increase cerebral blood flow and cause raised ICP. This effect is most likely caused by activation of the sympathetic nervous sytem. * Therefore, nitrous oxide may be combined with other agents (IV anaesthetics) or techniques (hyperventilation) that reduced cerebral blood flow in patients with increased ICP.

Answer 328

* **Stage 1 - anaesthesia**: the patient initially experiences analgesia without amnesia * **Stage 2 - excitement**: the patient appears delirious and may vocalise but is completely amnesic. Respiration is rapid, and heart rate and blood pressure increase. Duration and severity of this light stage of anaesthesia are shortened by rapidly increasing the concentration of the agent. * **Stage 3 - surgical anaesthesia**: begins with slowing of respiration and HR and extends to complete cessation of spontaneous respiration (apnea). Four planes of stage III are described based on changes in ocular movements, eye reflexes, and pupil size, indicating increasing depth of anaesthesia * **Stage 4 - medullary depression** - represents severe depression of the CNS, including the vasomotor center in the medulla and respiratory centre in the brainstem. Without circulatory and respiratory support, death would rapidly ensue in stage IV

Answer 329

* They depress normal cardiac contractility. As a result, all volatile agents tend to decrease mean arterial pressure in direct proportion to their alveolar concentration. * With halothane and enflurane, the reduced arterial pressure is caused primarily by myocardial depression (reduced cardiac output) and there is little change in systemic vascular resistance. * In contrast, isoflurane, desflurane and sevoflurane produce greater vasodilation with minimal effect on cardiac output. * These differences may have important implications for patients with heart failure. Because isoflurane, desflurane, and sevoflurane better preserve cardiac output as well as reduce preload (filling), and afterload (resistance), these agents may be better choices for patients with impaired myocardial function.

Answer 330

* Nitrous oxide also depresses myocardial function in a concentration-dependent manner. * This depression may be significantly offset by a concomitant activation of the sympathetic nervous system resulting in preservation of cardiac output. * Therefore, administration of nitrous oxide in combination with the more potent volatile anaesthetics can minimise circulatory depressant effects by both anaesthetic-sparing and sympathetic-activating actions

Answer 331

* Because all inhaled anaesthetics produce a dose-dependent decrease in arterial blood pressure, activation of autonomic nevous system reflexes may trigger an increase in heart rate * However, halothane, enflurane, and sevoflurane have little effect on heart rate, probably because they attenuate baroreceptor input into the autonomic nervous system * Desflurane and isoflurane significantly increase heart rate because they cause less depression of the baroreceptor reflex. * In addition, desflurane can trigger transient sympathetic activation - with elevated catecholamine levels - to cause marked increases in heart rate and blood pressure during administration of high desflurane concentrations or when desflurane concentrations are changed rapidly.

Answer 332

* Inhaled anaesthetics tend to reduce myocardial oxygen consumption, which reflects depression of normal cardiac contractility and decreased arterial blood pressure. * In addition, inhaled anaesthetics produce coronary vasodilation. The net effect of decreased oxygen demand and increased coronary flow (oxygen supply) is improved myocardial oxygenation. * However, other factors such as surgical stimulation, intravascular volume status, blood oxygen levels, and withdrawal of perioperative β blockers, may tilt the oxygen supply-demand balance toward myocardial ischaemia.

Answer 333

* Halothane and, to a lesser extent, other volatile anaesthetics sensitise the myocardium to epinephrine and circulating catecholaemines. * Ventricular arrhythmias may occur when patients under anaesthetia with halothane are given sympathomimetic drugs or have high circulating levels of endogenous catecholamines (e.g anxious patients, administration of epinephrine-containing local anaesthetics, inadequate intraoperative anaesthesia or analgesia, patients with pheuchromocytomas). * This effect is less marked for isoflurane, sevoflurane, and desflurane.

Answer 334

* All volatile anaesthetics possess varying degrees of bronchodilating properties, an effect of value in patients with active wheezing and in status asthmaticus. * However, airway irritation, which may provoke coughing or breath-holding, is induced by the pungency of some volatile anaesthetics. * The pungency of isoflurane and desflurane makes these agents less suitable for induction of anaesthesia in patients with active bronchospasm. These reactions rarely occur with halothane and sevoflurane, which are considered nonpungent. * Therefore, the bronchodilating action of halothane and sevoflurane makes them the agents of choice in patients with underlying airway problems. * Nitrous oxide is also nonpungent and can facilitate inhalation induction of anaesthesia in a patient with bronchospasm.

Answer 335

* The control of breathing is significantly affected by inhaled anaesthetics. * With the exception of nitrous oxide, all inhaled anaesthetics cause a dose-dependent decrease in tidal volume and an increase in resp rate, resulting in a rapid, shallow breathing pattern. * However, an increase in respiratory rate varies among agents and does not fully compensate for the decrease in tidal volume, resulting in a decrease in alveolar ventilation. * In addition, all volatile anaesthetics are respiratory depressants, as defined by a reduced ventilatory response to increased levels of CO₂ in the blood. * By this hypoventilation mechanism, all volatile anaesthetics increase the resting level of PaCO₂ in spontaneously breathing patients.

Answer 336

* Volatile anaesthetics raise the apneic threshold (PaCO₂ level below which apnea occurs through lack of CO₂-driven respiratory stimulation) and decrease the ventilatory response to hypoxia. * Clinically, the respiratory depressant effects of anaesthetics are overcome by assisting (controlling) ventilation mechanically. * The ventilatory depression produced by inhaled anaesthetics may be counteracted by surgical stimulation; however, low, subanaesthetic concentrations of volatile anaesthetic present after surgery in the early recovery period can continue to depress the compensatory increase in ventilation normally caused by hypoxia.

Answer 337

Inhaled anaesthetics also depress mucocilliary function in the airway. During prolonged exposure to inhaled anaesthetics, mucus pooling and plugging may result in atelectasis and the development of postoperative respiratory complications, including hypoxameia and respiratory infections.

Answer 338

* Inhaled anaesthetics tend to decrease GFR and urine flow. * Renal blood flow may also be decreased by some agents, but filtration fraction is increased, implying that autoregulatory control of efferent arteriole tone helps compensate and limits the reduction in GFR. * In general these anaesthetic effects are minor compared with the stress of surgery itself and usually reversible after discontinuation of the anaesthetic

Answer 339

* Volatile anaesthetics cause a concentration-dependent decrease in portal vein blood flow that parallels the decline in cardiac output produced by these agents. * However, total hepatic blood flow may be relatively preserved as hepatic artery blood flow to the liver may increase or stay the same. * Although transient changes in liver function tests may occur following exposure to volatile anaesthetics, persistent elevation in liver enzymes is rare except following repeated exposures to halothane

Answer 340

* Nitrous oxide appears to have little effect of uterine musculature * However, the halogenated anaesthetics are potent uterine muscle relaxants and produce this effect in a concentration dependent fashion. * This pharmacological effect can be helpful when profound uterine relaxation is required for intrauterine fetal manipulation or manual extraction of a retained placenta during delivery. * However, it can also lead to increased uterine bleeding after delivery when uterine contraction is desired

Answer 341

* Metabolism of enflurane and sevoflurane may generate compounds that are potentially nephrotoxic. although their metabolism can liberate nephrotoxic fluoride ions, significant renal injury has been reported only for enflurane with prolonged exposure. * The insolubility and rapid elimination of sevoflurane may prevent toxicity. This drug may be degraded by CO₂ absorbents in anaesthesia machines to form a nephrotoxic vinyl ether compound termed "compound A" which, in high concentrations, has caused proximal tubular necrosis in rats, but no reports of renal injury in humans has been reported

Answer 342

* Prolonged exposure to nitrous oxide decreases methionine synthase activity, which theoretically could cause megaloblastic anaemia. * Megaloblastic bone marrow changes have been observed in patients after 12-hour exposure to 50% nitrous oxide. * Chronic exposure of dental personnel to nitrous oxide in inadequately ventilated dental operating suites is a potential occupational hazard.

Answer 343

* **All inhaled anaesthetics can produce some carbon monoxide (CO)** from their interaction with strong bases in dry carbon dioxide absorbers. * CO binds to haemoglobin with high affinity, reduced oxygen delivery to tissues. Desflurane produces the most CO, and intraoperative formation of CO has been reported. * **CO production can be avoided simply by using fresh carbon dioxide absorbent** and by preventing its complete desiccation.

Answer 344

Malignant hyperthermia is an inheritable genetic disorder of skeletal muscle that occurs in susceptible individuals exposed to volatile anaesthetics while undergoing general anaesthesia. The depolarising muscle relaxant succinylcholine may also trigger malignant hyperthermia.

Answer 345

The malignant hyperthermia syndrome consists of muscle rigidity, hyperthermia, rapid onset of tachycardia and hypercapnia, hyperkalaemia, and metabolic acidosis following exposure to one or more triggering agents.

Answer 346

A specific biochemical abnormality - an increase in free cytosolic calcium concentration in skeletal muscle cells - may be the underlying cellular basis of malignant hyperthermia.

Answer 347

* Malignant hyperthermia susceptibility is characterised by genetic heterogeneity, and several predisposing clinical myopathies have been identified * It has been associated with mutations in the gene coding for the skeletal muscle ryanodine receptor (RyR1, the calcium release channel on the sarcoplasmic reticulum), and mutant alleles of the gene encoding the α₁ of the skeletal muscle L-type voltage-dependent calcium channel

Answer 348

* Genetic testing cannot definitely determine malignant hyperthermia susceptibility. * Currently, the most reliable test to establish susceptibility is the in vitro caffeine-halothane contracture test using skeletal muscle biopsy samples. * Genetic counselling is recommended for family members of a person who has experienced a well-documented malignant hyperthermia reaction in the operating room

Answer 349

Hepatic dysfunction following surgery and general anaesthesia is most likely caused by hypovolaemic shock, infection conferred by blood transfusion, or other surgical stresses rather than by volatile anaesthetic toxicity. However, a small subset of individuals previously exposed to halothane developed fulminant hepatic failure. Cases of hepatitis following exposure to other volatile anaesthetics, including enflurane, isoflurane, and desflurane, have rarely been reported

Answer 350

1 in 20,000-35,0000

Answer 351

* A lipophilic group (eg. an aromatic ring) connected by an intermediate chain via an ester or amine to an ionisable group (eg. a tertiary amine) * In addition to the general physical properties of the molecules, specific stereochemical configurations are associated with differences in the potency of stereoisomers (eg. levobupivacaine, ropivacaine). * Because ester links are more prone to hydrolysis than amide links, esters usually have a shorter duration of action.

Answer 352

Local anaesthetics are weak bases and are usually made available clinically as salts to increase solubility and stability

Answer 353

* In the body, they exist either as the uncharged base or as a cation. * The relative proportions of these two forms are governed by their pK_a and the pH of the body fluids according to the Henderson-Hasselbach equation, which can be expressed as:

Answer 354

If the concentration of base and conjugate acid are equal, the second portion of the Henderson-Hasslebach equation drops out as log 1 = 0, leaving: **pK_a = pH** (when base concentration = conjugate acid concentration So the lower the pK_a, the greater the proportion of uncharged weak bases at a given pH.

Answer 355

* Because the pK_a of most local anaesthetics is in the range of 7.5-9.0, the charged, cationic form will consitute the larger percentage at physiological pH. * A glaring exception is **benzocaine**, which has a pK_a around 3.5, and thus exists solely as the nonionized base under normal physiological conditions

Answer 356

* The issue of ionisation is important because the cationic form is the most active at the receptor site. * It is complex because the receptor site for local anaesthetics is at the inner vestibule of the sodium channel, and the charged form of the anaesthetic penetrated biologic membranes poorly. * Thus, the uncharged form is important for cell penetration. After penetration into the cytoplasm, equilibration leads to formation and binding of the charged cation at the sodium channel, and hence the production of a clinical effect * Drugs may also reach the receptor laterally through what has been termed the hydrophobic pathway.

Answer 357

* Local anaesthetics are less effective when they are injected into infected tissues because the low extracellular pH favors the charged form, with less of the neutral base available for diffusion across the membrane * Conversely, adding bicarbonate to a local anaesthetic, will raise the effective concentration of the nonionised form and thus shorten the onset time of a regional block.

Answer 358

Dosage Site of injection Drug-tissue binding Local tissue blood flow Use of vasoconstrictor (adrenaline) Physicochemical properties of the drug itself * anaesthetics that are more lipid soluble are generally more potent, have a longer duration of action and take longer to achieve their clinical effect * extensive protein binding also serves to increase the duration of action

Answer 359

Application of local anaesthetic to a highly vascularised area such as the tracheal mucose or the tissue surrounding intercostal nerrves results in more rapid absorption and thus higher blood levels than if the local anaesthetic in injected into a poorly perfused tissue such as subcutaneous fat.

Answer 360

The intercostal blocks are among the highest, and sciatic and femoral among the lowest

Answer 361

When vasoconstrictors are used with local anaesthetics, the resultant reduction in blood flow serves to reduce the rate of systemic absorption and thus diminishes peak serum levels. This effect is generally most evident with short-acting, less potent, and less lipid-soluble anaesthetics.

Answer 362

* Anaesthetics delivered into the subarachnoid space will be diluted with CSF and the pattern of distribution will be dependent upon a host of factors, among the most critical being the specific gravity relative to that of CSF and the patients position. * Solutions are termed hyperbaric, isobaric, and hypobaric, and respectively descend, remain relatively static, or ascend, within the subarachnoid space due to gravity when the patient sits upright.

Answer 363

* The inital alpha phase reflects rapid distribution in blood and highly perfused organs (e.g. brain, liver, heart, kidney), characterised by a steep exponential decline in concentration. * This is followed by a slowed declining beta phase reflecting distribution into less well perfused tissue (e.g. muscle, gut), and may assume a nearly linear rate of decline.

Answer 364

The potential toxicity of the local anaesthetics is affected by the protective effort afforded by uptake by the lungs, which serve to attenuate the arterial concentration, though the time course and magnitude of this effect have not been adequately characterised.

Answer 365

They are converted to more water-soluble metabolites in the liver (amide type) or in plasma (ester type), which are excreted in the urine.

Answer 366

* Since local anaesthetics in the uncharged form diffuse readily through lipid membranes, little or no urinary excretion of the neutral form occurs * Acidification of urine promotes ionisation of the tertiary amine base to the more water-soluble charged form, leading to more rapid elimination.

Answer 367

* Ester-type local anaesthetics are hydrolysed very rapidly in the blood by circulating butyrylcholinesterase to inactive metabolites. * For example, the half-lives of procaine and chloroprocaine in plasma are less than a minute. * However, excessive concentrations may accumulate in patients with reduced or absent plasma hydrolysis secondary to atypical plasma cholinesterase

Answer 368

The amide local anaesthetics undergo complex biotransformation in the liver, which includes hydroxylation and *N*-dealkylation by liver microsomal cytochrome P450 isozymes.

Answer 369

Prilocaine > lidocaine > mepivacaine > ropivacaine, bupivacaine, levobupivacaine (slowest) Toxicity from amide-type local anaesthetics is more likely to occur in patients with hepatic disease.

Answer 370

The hepatic elimination of local anaesthetics in patients anaesthetised with volatile anaesthetics (which reduce liver blood flow) is slower than in patients anaesthetised with IV anaesthetic.

Answer 371

2 - 3 nodes of Ranvier

Answer 372

* The primary mechanism of action of local anaesthetics is blockade of voltage-gated sodium channels. * When progressively increasing concentrations of a local anaesthetic are applied to a nerve fiber, the threshold for excitation increases, impulse conduction slows, the rate of rise of the action potential declines, action potential amplitude decreases, and, finally, the ability to generate an action potential is completely abolished. * These progressive effects result from binding of the local anaesthetic to more and more sodium channels. * If the sodium current is blocked over a critical length of the nerve, propagation across the blacked area is no longer possible.

Answer 373

It is both **voltage and time dependent**: * Channels in the rested state, which predominate at more **negative membrane potentials**, have a much **lower affinity** for local anaesthetics than activated (open state) and inactivated channels, which predominate at more positive membrane potentials. Therefore, the effect of a given drug concentration is more marked in rapidly firing axons than in resting fibers. * Between successive action potentials, a portion of the sodium channels will recover from the local anaesthetic block. The recovery from drug induced block is 10-1000 times slower than recovery of channels from normal inactivation. As a result, the refractory period is lengthened and the nerve conducts fewer action potentials

Answer 374

* Elevated extracellular calcium partially antagonises the action of local anaesthetics owing to the calcium-induced increase in the surface potential on the membrane (which favours the low-affinity rested state) * Conversely, increases in extracellular potassium depolarise the membrane potential and favor the inactivated state, enhancing the effect of local anaesthetics.

Answer 375

* At clinically relevant concentrations, local anaesthetics are potentially active at countless other channels (e.g. potassium and calcium), enzymes (eg. adenylyl cyclase) and receptors (NMDA, G protein-coupled, 5-HT₃, neurokinin-1 [substance P receptor]) * Circulating anaesthetics also demostrate antithrombotic effects, having an impact on coagulation, platelet aggregation, and the microcirculation, as well as modulation of inflammation

Answer 376

Bupivacaine - 28 mins Lidocaine - 10 mins Mepivacaine - 7 mins Prilocaine - 5 mins Ropivacaine - 23 mins

Answer 377

Bupivacaine - 3.5 hours Lidocaine - 1.6 hours Mepivacaine - 1.9 hours Prilocaine - 1.5 hours Ropivacaine - 4.2 hours

Answer 378

Bupivacaine - 72L Lidocaine - 91L Mepivacaine - 84L Prilocaine - 261 L Ropivacaine - 47L

Answer 379

Bupivacaine - 0.47L/min Lidocaine - 0.95L/min Mepivacaine - 0.78L/min Prilocaine - 2.84L/min Ropivacaine - 0.44L/min

Answer 380

* It has been traditionally taught that local anaesthetics preferentially block smaller diameter fibers first because the distance over which such fibers can passively propagate an electrical impulse is shorter. However, a variable proportion of large fibers are blocked prior to the disappearance of the small fiber component of the compound action potential. * Most notably, myelinated nerves tend to be blocked before unmyelinated nerves of the same diameter. * Blockade by local anaesthetics is more marked at higher frequencies of depolarisation due to their state-dependent mechanism.

Answer 381

* Sensory fibers have a high firing rate and relatively long action potential duration. * Motor fibers fire at a slower rate and have a shorter action potential duration. * As type A delta and C fibers participate in high-frequency pain transmission, this characteristic may favour blockade of these fibers earlier and with lower concentrations of local anaesthetics

Answer 382

Anesthetic placed outside the nerve bundle will reach and anesthetise the proximal fibers located at the outer portion of the bundle first, and sensory block will occur in sequence from proximal and distal.

Answer 383

* Topical application (nasal mucosa, wound margins) * Injection in the vicinity of peripheral nerve endings (perineural infiltration) * Major nerve trunks (blocks), and injection into the epidural and subarachnoid spaces surrounding the spinal cord.

Answer 384

* It begins with sympathetic transmission and progressing to temperature, pain, light touch, and finally motor block. * This is most readily appreciated during onset of spinal anaesthesia, where a spatial discrepancy can be detected, the most vulnerable components achieving greater dermatomal spread. Thus, loss of sensation of cold will be roughly two segments above the analgesic level for pinprick, which is turn will be roughly two segments rostral to loss of light touch recognition.

Answer 385

1) Localised neuronal uptake is enhanced because of higher sustained local tissue concentrations that can translate clinically into a longer duration block. This may enable more prolonged procedures, extended duration of post op pain control, and lower total anaesthetic requirement 2) Peak blood levels will be lowered as absorption is more closely matched to metabolism and elimination, and the risk of systemic toxic effects is reduced.

Answer 386

It exerts a direct analgesic effect mediated by postsynaptic α₂ adrenoreceptors within the spinal cord.

Answer 387

* It can potentiate the neurotoxicity of local anaesthetics used for peripheral nerve blocks or spinal anaesthesia. * Further, the use of a vasoconstricting agent in an area that lacks adequate collateral flow (e.g. digital block) is generally avoided.

Answer 388

Esclating doses of anaesthetic appear to exert the following systemic actions: 1) low concentrations may preferentially suppress ectopic impulse generation in chronically injured peripheral nerves 2) moderate concentrations may suppress central sensitisation, which would explain therapeutic benefit that may extend beyond the anaesthetic exposure 3) higher concentrations will produce general anaesthetic effects and may culminate in serious toxicity

Answer 389

1) systemic effects following inadvertent intravascular injection or absorption of the local anaesthetic from the site of administration 2) neurotoxicity resulting from local effects produced by direct contact with neural elements

Answer 390

* CNS toxicity * Cardiotoxicity

Answer 391

* All local anaesthetics have the ability to produce sedation, light-headedness, visual and auditory disturbances, and restlessness when high plasma concentrations result from rapid absorption or inadvertent intravascular administration. * An early symptom is circumoral and tongue numbness and metallic taste * At higher concentrations, nystagmus and muscular twitching occur, following by tonic-clonic convulsions.

Answer 392

* Local anaesthetics apparently cause depression of cortical inhibitory pathways, thereby allowing unopposed activity of excitatory neuronal pathways. * This transitional stage of unbalanced excitation (ie. seizure activity) is then followed by generalised CNS depression

Answer 393

Premedication with a parenteral benzodiazpeine (eg. diazepam or midazolam) will provide prophylaxis against local anaesthetic-induced CNS toxicity but little, if any, effect on cardiovascular toxicity, potentially delaying recognition of a life-threatening overdose

Answer 394

* It is critical to prevent hypoxaemia and acidosis, which potentiate anaesthetic toxicity. * Rapid tracheal intubation can facilitate adequate ventilation and oxygenation, and is essential to prevent pulmonary aspiration of gastric contents in patients at risk.

Answer 395

Benzodiazepine are advocated as first line drugs - 0.03-0.06mg/kg Midazolam - because of their haemodynamic stability, but small doses of propofol (0.25-0.5mg/kg) were considered acceptable alternatives, as they are often more immediately available in the setting of local anasethetic administration.

Answer 396

Bupivacaine

Answer 397

A relatively simple, practical, and apparently effective therapy for resistant bupivacaine cardiotoxicity is the use of IV lipid emulsion. Some of its effect is related to its ability to extract a lipophilic drug from aqueous plasma, thus reducing its effective concentration at tissue targets, a mechanism termed "lipid sink"

Answer 398

The studies have demonstrated myriad deleterious effects including conduction failure, membrane damage, enzyme leakage, cytoskeletal disruption, accumulation of intracellular calcium, disruption of axonal transport, growth cone collapse and apoptosis. It is not to do with voltage-gated sodium channel blockade so the clinical effect and toxicity are not tightly linked.

Answer 399

A syndrome of transient pain or dysesthesia, or both, have been linked to lidocaine for spinal anaesthetics.

Answer 400

* Based on concerns for cardiotoxicity, bupivacaine is often avoided for techniques that demand high volumes of concentrated anaesthetic. * In contrast, relatively low concentrations (< 0.25%) are frequently used to achieve prolonged peripheral anasethetic and analgesia for post-op pain control. It if often the agent of choice for epidural infusions used for post-op pain control and for labor analgesia.

Answer 401

Prilocaine has the highest clearance of the amino-amide anasethetics, imparting reduced risk of systemic toxicity.

Answer 402

**E**utectic **M**ixture of **L**ocal **A**naesthetics. This formulation, containing 2.5% lidocaine and 2.5% prilocaine, permits anaesthetic penetration of the keratinised layer of skin, producing localised numbness

Answer 403

Lidocaine, bupivacaine, prilocaine, articaine, ropivacaine

Answer 404

Chloroprocaine Cocaine Procaine Tetracaine Benzocaine

Answer 405

**Phase 1 block (depolarising)** - its neuromuscular effects are like those of acetylcholine except that it produces a longer effect at the myoneural junction. * It reacts with the **nicotinic receptor** to open the channel and cause **depolarisation of the motor end plate**, and this in turn spreads to the adjacent membranes, causing transient contractions of muscle motor units. * Because it is **not metabolised** effectively at the synapse, the depolarised **membranes remain depolarised** and unresponsive to subsequent impulses (ie. a state of depolarising blockade). * Furthermore, because excitation-contraction coupling requires end-plate repolarisation ("repriming") and repetitive firing to maintain muscle tension, a **flaccid paralysis** occurs.

Answer 406

They interfere with transmission at the neuromuscular end plate and lack CNS activity. They are used primary as adjuncts during general anaesthesia to optimise surgical conditions and to facilitate endotracheal intubation in order to ensure adequate ventilation.

Answer 407

* The arrival of an **action potential** at the motor nerve terminal causes an **influx of calcium** and release of the neurotransmitter **acetylcholine** * Acetylcholine then diffuses across the synaptic cleft to activate **nicotinic receptors** located at the motor end plate, cause the channel to open. * The subsequent movement of sodium and potassium through the channel is associated with graded depolarisation of the end plate membrane. * The change in voltage is termed the **motor end plate potential**

Answer 408

* The magnitude of the end plate potential is directly related to the amount of acetylcholine released. * If the potential is small, the permeability and the end plate potential return to normal without an impulse being propagated from the end plate region to the rest of the muscle membrane. * However, if the end plate potential is large, the adjacent muscle membrane is depolarised, and an action potential will be propagated along the entire muscle fiber. Muscle contraction is then initiated by excitation-contraction coupling

Answer 409

* One type is located on the presynaptic motor axon terminal, and activation of these receptors mobilises additional transmittors for subsequent release by moving more acetylcholine vesicles towards the synaptic membrane * The second type of receptor is found on extrajunctional cells and is not normally involved in neuromusclar transmission. However, under certain conditions (eg, prolonged immobilisation, thermal burns), these receptors may proliferate sufficiently to affect subsequent neuromusclar transmittion.

Answer 410

* First, pharmacological blockade of the physiologic agonist acetylcholine is characteristic of the antagonist neuromuscular blocking drugs (ie, non-depolarising neuromuscular blocking drugs). These drugs prevent access of the transmitted to its receptor and thereby prevent depolarisation. The prototype of this nondepolarising subgroup is ***d*- tubocurarine**. * The second mechanism can be produced by an excess of depolarising agonist, such as acetylcholine. This seemingly paradoxical effect of acetylcholine also occurs at the ganglionic nicotinic acetylcholine receptor. The prototypical depolarising blocking drug is **succinylcholine**

Answer 411

* All of the available neuromuscular blocking drugs bear a **structural resemblance to acetylcholine**. For example, succinylcholine is two acetylcholine molecules linked end-to-end * In contrast to the linear structure of succinylcholine and other depolarising drugs, the non-depolarising agents (e.g. pancuronium) concert the "double-acetylcholine" structure in one of two types of bulky, semi-rigid ring systems. * Another feature common to all currently used neuromuscular blockers is the presence of one of two quarternary nitrogens, which makes them poorly lipid soluble and limits entry into the CNS

Answer 412

They are highly polar compounds and inactive orally; they must be administered parenterally

Answer 413

* The rate of disappearacne of a nondepolarising neuromuscular blocking drug from the blood is characterised by a rapid initial distribution phase following by a slower elimination phase. * Neuromuscular blocking drugs are highly ionised, do not readily cross cell membranes, and are not strongly bound in peripheral tissues. Therefore, their volume of distribution (80-140 mL/kg) is only slightly larger than the blood volume

Answer 414

* The duration of neuromuscular blockade produced by non-depolarised relaxants is strongly correlated with the elimination half-life * Drugs that are excreted by the kidney typically have longer half-lives, leading to longer durations of action (>35 minutes) * Drugs eliminated by the liver tend to have shorter half-lives and durations of action.

Answer 415

* Pancuronium, rocuronium, vecuronium * All steroidal muscle relaxants are metabolised to their 3-hydroxy, 17-hydroxy, or 3-17-dihydroxy products in the liver * The 3-hydroxy metabolites are usually 40-80% as potent as the parent drug

Answer 416

**Vecuronium** and **Rocuronium** tend to be more dependent on biliary excretion or hepatic metabolism for their elimination. The duration of action of these relaxants may be prolonged significantly by patients with impaired liver function

Answer 417

* Atracurium is an intermediate-acting isoquinoline nondepolarising muscle relaxant. * In addition to hepatic metabolism, atracurium is inactivated by a form of spontaneous breakdown known as Hofmann elimination. * The main breakdown products are laudanosine and a related quaternary acid, neither of which possess any neurmuscular blocking properties. * Laudanosine readily crosses the blood-brain barrier, and high blood concentrations may cause seizures and an increase in the volatile anaesthetic requirement.

Answer 418

Atracurium has several steroisomers, and the potent isomer **cisatracurium** is very common. Although it resembles atracurium, it has less dependence on hepatic inactivation, produced less laudanosine, and is much less likely to release histamine. Therefore, it has all the advantages of atracurium with fewer adverse effects.

Answer 419

The extremely short duration of action of suxamethonium (5-10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase in the liver and plasma, respectively.

Answer 420

* Rapid hydrolysis by butyrylcholinesterase and psuedocholinesterase in the liver and plasma, respectively. * Plasma cholinesterase metabolism is the predominant pathway for suxamethonium elimination * The primary metabolite of succinylcholines, succinylmonocholine, is rapidly broken down to succinic acid and choline. * Because plasma cholinesterase has an enormous capacity to hydrolyse succinylcholine, only a small percentage of the original IV dose ever reaches the neuro-muscular junction

Answer 421

* Because there is little, if any, plasma cholinesterase at the motor end plate, a succinylcholine-induced blockade is terminated by its diffusion away from the end plate into extracellular fluid * Therefore, the circulating levels of plasma cholinesterase influence the duration of action of succinylcholine by determining the amount of the drug that reaches the motor end plate.

Answer 422

* Neuromuscular blockade produced by suxamethonium can be prolonged in patient with an abnormal genetic variant of plasma cholinesterase. The **dibucaine number** is a measure of the ability of a patient to metabolise suxamethonium and can be used to identify at-risk patients. * Under standardised test condition, dibucaine inhibits the normal enzyme by 80% and the abnormal enzyme by only 20%

Answer 423

* **Elimination** - spontaneous * **Clearance** - 6.6mL/kg/min * **Duration** - 20-35 minutes

Answer 424

* **Elimination** - mostly spontaneous * **Clearance** - 5-6mL/kg/min * **Duration** - 25-44 minutes

Answer 425

* **Elimination** - kidney (80%) * **Clearance** - 1.7-1.8mL/kg/min * **Duration** - >35 minutes

Answer 426

* **Elimination** - liver (75-90%) and kidney * **Clearance** - 2.9mL/kg/min * **Duration** - 20-35 mins

Answer 427

* **Elimination** - Plasma ChE² (100%) * **Clearance** - >100mL/kg/min * **Duration** - <8 minutes

Answer 428

* When small doses are administered, they act predominantly at the nicotinic receptor site by competing with acetylcholine. * In larger doses, they can enter the pore of the ion channel to produce a more intense motor blockade. This action further weakens neuromuscular transmission and diminishes the ability of the acetylcholine inhibitors (eg. neostigmine, pydridostigmine) to antagonise the effect of nondepolarising muscle relaxants * They can also block prejunctional sodium channels. As a result of this action, muscle relaxants interfere with the mobilisation of acetylcholine at the nerve ending and cause fade of evoked nerve twitch contractions.

Answer 429

The least potent non-depolarising relaxants (e.g. rocuronium) have the fastest onset and the shortest duration of action.

Answer 430

One consequence of the surmountable nature of the post-synaptic blockade produced by nondepolarising muscle relaxants is the fact that tetanic stimulation (rapid delivery of electrical stimuli to a peripheral nerve) releases a large quality of acetylcholine and is followed by transient posttetanic facilitation of the twitch strength (ie. relief of blockade)

Answer 431

* **Rocuronium** - antagonistic * **Suxamethonium** - phase 1 - augmented - phase 2 - antagonistic

Answer 432

* **Rocuronium** - none * **Suxamethonium** - Phase 1 - fasciculations - Phase 2 - none

Answer 433

* **Rocuronium** - unsustained (fade) * **Suxamethonium** - Phase 1 - sustained² (no fade) - Phase 2 - unsustained (fade)

Answer 434

* **Rocuronium** - yes * **Suxamethonium** - Phase 1 - no - Phase 2 - yes

Answer 435

* **Rocuronium** - 30-60 minutes ³ * **Suxamethonium** - Phase 1 - 4-8 minutes - Phase 2 - >20 minutes ³

Answer 436

**Phase 1 block (depolarising)** - its neuromuscular effects are like those of acetylcholine except that it produced a longer effect at the myoneural junction. * It reacts with the nicotinic receptor to open the channel and cause depolarisation of the motor end plate, and this in turn spreads to the adjacent membranes, causing transient contractions of muscle motor units. * Because it is not metabolised effectively at the synapse, the depolarised membranes remain depolarised and unresponsive to subsequent impulses (ie. a state of depolarising blockade). * Furthermore, because excitation-contraction coupling requires end-plate repolarisation ("repriming") and repetitive firing to maintain muscle tension, a flaccid paralysis occurs.

Answer 437

* With prolonged exposure to suxamethonium, the initial end plate depolarisation decreases and the membrane becomes repolarised. * Despite this repolarisation, the membrane cannot easily be depolarised again because it is **desensitised**. * The mechanism for this desensitising phase is unclear but some evidence indicates that channel block may become more important than agonist action at the receptor in phase 2. * Regardless of the mechanism, the channels behave as if they are in a prolonged closed state. * Later in phase 2, the characteristics of the blockade are nearly identical to those of a non-depolarising block (a nonsustained twitch response to a tetanic stimulus), with possible reversal by acetylcholinesterase inhibitors.

Answer 438

1) single-twitch stimulation 2) train-of-four (TOF) stimulation 3) tetanic stimulation

Answer 439

* A single supramaximal electrical stimulus is applied to a peripheral nerve at frequencies from 0.1Hz to 1.0Hz. * The higher frequency is often used during induction and reversal to more accurately determine the peak (maximal) drug effect.

Answer 440

* TOF stimulation involved four successive supramaximal stimuli given at intervals of 0.5 seconds (2Hz). * Each stimulus in the TOF causes the muscle to contract, and the relative magnitude of the response of the fourth twitch compared with the first twitch is the TOF ratio.

Answer 441

* With a depolarising block, all four twitches are reduced in a dose-related fashion. * With a nondepolarising block, the TOF ratio decreases (fades) and is inversely proportional to the degree of blockage. * During recovery from nondepolarising block, the amount of fade decreases and the TOF ratio approaches 1.0.

Answer 442

A TOF ratio greater than 0.7. However, complete clinical recovery from a nondepolarising block is considered to require a TOF greater than 0.9.

Answer 443

Tetanic stimulation consists of a very rapid (30-100Hz) delivery of electrical stimuli for several seconds.

Answer 444

* During a non-depolarising neuromuscular block (and a phase 2 sux block), the response is not sustained and fade of twitch reponses is observed. * Fade in response to tetanic stimulation is normally considered a presynaptic event. However, the degree of fade depends primarily on the degree of neuromuscular blockade. * During a partial non-depolarising blockade, tetanic nerve stimulation is followed by an increase in the posttetanic twitch reponse, so-called **posttetanic facilitation** of neuromuscular transmission. * During intense neuromuscular blockade, there is no response to either tetanic or posttetanic stimulation. * As the intensity of the block diminishes, the response to posttetanic twicth stimulation reappears

Answer 445

* 5 seconds of 50Hz tetany is applied, followed by 3 seconds of rest, followed by 1Hz pulses for about 10 seconds (10 pulses). * The counted number of muscle twitches provides an estimation of the depth of blockade. * For instance, a post-tetanic count of 2 suggests no twitch response (by TOF) for about 20-30 minutes, and a post-tetanic count of 5 correlates to a no-twitch response (by TOF) of about 10-15 minutes

Answer 446

* It is used when it is not possible to record the responses to single-twitch, TOF, or tetanic stimulation. * In this pattern, three nerve stimuli are delivered at 50Hz followed by a 700ms rest period and then by two or three additional stimuli at 50Hz. * It is easier to detect fade in responses to double-burst stimulation than to TOF stimulation. * The absense of fade in response to double-burst stimulation implies that clinically significant residual neuromsucular blockade does not exist.

Answer 447

* Administration of tubocurarine, 0.1-0.4mg/kg IV, initially causes motor weakness, followed by the skeletal muscles becoming flaccid and inexcitable to electrical stimulation. * In general, larger muscles (eg, abdominal, trunk, paraspinous, diaphragm) are more rapidly resistant to neuromusclar blockade and recover more rapidly than smaller muscles (eg, facial, foot, hand). * The diaphragm is usually the last muscle to be paralysed and the first one to recover

Answer 448

Rocuronium has the most rapid onset time (60-120 seconds)

Answer 449

* Following the administration of suxamethonium (0.75-1.5mg/kg IV), transient muscle fasciculations occur over the chest and abdomen within 30 seconds, although general anaesthesia and the prior administration of a small dose of a nondepolarising muscle relaxant tend to attenuate them. * As paralysis develops rapidly (<90 seconds), the arm, neck and leg muscles are initially relaxed followed by the respiratory muscles. * As a result of succinycholine's rapid hydrolysis by cholinesterase in the plasma (and liver), the duration of the neuromuscular block typically lasts less than 10 minutes.

Answer 450

* Vecuronium, cisatracurium, and rocuronium have minimal, if any, cardiovascular effects. * Pancuronium and atracurium produce cardiovascular effects that are mediated by autonomic of histamine receptors. * Tubocurarine and, to a lesser extent, atracurium can produce hypotension as a result of systemic histamine release, and with larger doses, ganglionic blockade may occur with tubocurarine. * Pancuronium causes a moderate increase in HR and a smaller increase in CO. * Bronchospasm may be produced by neuromuscular blockers that release histamine (eg, atracurium), but after induction of general anaesthesia, insertion of an endotracheal tube is the most common cause of bronchospasm.

Answer 451

* It can cause cardiac arrhythmias, especially when administered during halothane anaesthesia. * The drug stimulates autonomic cholinoreceptors, including the nicotinic receptors at both sympathetic and parasympathetic ganglia and muscarinic receptors in the heart (eg, sinus node). * The negative inotropic and chronotropic responses to succinylcholine can be attenuated by administration of an anticholinergic drug (atropine). * At large doses of sux, positive inotropic and chronotropic effects may be observed. * On the other hand, bradycardia has been repeatedly oberved when a second dose of sux is given less than 5 minutes after the first dose.

Answer 452

* **Hyperkalaemia** - during administration of sux, potassium is released from muscles, likely due to fasciculations. Patients with burns , nerve damage or neuromusclar disease, closed head injury and other trauma may develop proliferation of extrajunctional acetylcholine receptors. If this is great enough, sufficient potassium may be released to result in cardiac arrest * It may be associated with the rapid onset of **increased intraocular pressure** (< 60 seconds), peaking at 2-4 minutes, and declining after 5 minutes. * In heavily muscled patient, the fasciculations associated may cause an **increase in intragastric pressure**, increasing the risk of regurgitation and aspiration. * **Myalgias** are a common post-op complaint of heavily muscled patients and those who receive large doses of sux.

Answer 453

* Anaesthetics * Antibiotics * Local anaesthetics * Anti-arrhythmics

Answer 454

* Inhaled (volatile) anaesthetics potentiate the neuromuscular blockade produced by nondepolarising muscle relaxants in a dose-dependent fashion. * Inhaled anaesthetics augment the effects of muscle relaxants in the following order: isoflurane (most); sevoflurane, desflurane, halothane, and nitrous oxide (least)

Answer 455

1) Nervous system depression at sites proximal to the neuromuscular junction (CNS) 2) Increased muscle blood flow (due to peripheral vasodilation produced by volatile anaesthetics), which allows a larger fraction of the injected muscle relaxant to reach the neuromuscular junction 3) Decreased senstitivity of the post-junctional membrane to depolarisation

Answer 456

* There is enhancement of neuromusular blockade by antibiotics (aminoglycosides). * Many of the antibiotics have been shown to cause a depression of evoked release of acetylcholine similar to that caused by administering magnesium. * The mechanism of this prejunction effect appears to be blockade of specific P-type calcium channels in the motor nerve terminal.

Answer 457

* In small doses, local anaesthetics can depress post-tetanic potentiation via a prejunctional neural effect. * In large doses, local anaesthetics can block neuromuscular transmission. With these higher doses, local anaesthetics block acetylcholine-induced muscle contractions as a result of blockade of the nicotinic receptor ion channels.

Answer 458

* **Myasthenia gravis** enhances the neuromuscular blockade produced by these drugs. * **Advanced age** is associated with a prolonged duration of action from non-depolarising relaxants as a result of decreased clearance of the drugs by the liver and kidneys. As a result, the dose of these drugs should be reduced in older patients. * Conversely, patients with **severe burns** and those with **upper motor neuron disease** are resistant to non-depolarising muscle relaxants. Probably due to proliferation of extrajunctional receptors, which results in an increased dose requirement for the non-depolarising relaxant to block a sufficient number of receptors.

Answer 459

* The cholinesterase inhibitors (**neostigmine** and **pyridostigmine**) antagonise them by increasing the availability of acetylcholine at the motor end plate, mainly by inhibition of acetylcholinesterase. To a lesser extent, these cholinesterase inhibitors also increase the release of this transmitted from the motor nerve terminal. * In contrast, **edrophonium** antagonises neuromuscular blockade purely by inhibiting acetylcholinesterase activity. It has a more rapid onset of action but may be less effective than neostigmine in the presence of profound neuromuscular blockade.

Answer 460

* It is a rapid reversel agent of the steroid neuromuscular blocking agents rocuronium and vecuronium * It binds tightly to rocuronium in a 1:1 ratio. By binding to plasma rocuronium, sugammadex decreases the free plasma concentration and establishes a concentration gradient for rocuronium to diffuse away from the neuromuscular junction back into the circulation, where it is quickly bound by free sugammadex.

Answer 461

* 2mg/kg to reverse shallow neuromuscular blackade (spontaneous recovery has reached the second twitch in TOF stimulation) * 4mg/kg to reverse deeper blockade (1-2 posttetanic count and no reponse to TOF stimulation) * 16mg/kg for immediate reversal following administration of a single dose of 1.2mg/kg of rocuronium.

Answer 462

* In patients with normal renal function, the sugammadex-rocuronium complex is typically excreted unchanged in the urine within 24 hours * In patients with renal insufficiency, complete urinary elimination may take much longer.

Answer 463

* Anaphylaxis * Hypersensitivity reactions such as nausea, pruritis, and urticaria * Marked bradycardia that may progress to cardiac arrest * It can decrease the efficacy of the progesterone oral contraceptive and a non-hormonal contractive is recommended for 7 days post-sugammadex use.

Answer 464

IV anaesthetics used for induction of general anaesthesia are lipophilic and preferentially partition into highly perfused lipophilic tissues (brain, spinal cord), which accounts for their rapid onset of action

Answer 465

Regardless of the extent and speed of their metabolism, termination of the effect of a single bolus is determined by redistribution of the drug into less perfused and inactive tissues such as skeletal muscle and fat. Thus, all drugs used for induction of anaesthesia have a similar duration of action when administered as a single bolus dose despite significant differences in their metabolism.

Answer 466

Thiopental, midazolam, propofol, ketamine

Answer 467

Because its pharmacokinetic profile allows for continuous infusions, propofol is a good alternative to inhaled anaesthetics for maintenance of anaesthesia and is a common choice for sedation.

Answer 468

When used during maintenance of anaesthesia, propofol infusion can be supplemented with IV opioids and neuromuscular blockers as needed to completely avoid the use of inhaled anaesthetics.

Answer 469

**Diazepam** - 0.3-0.6mg/kg **Ketamine** - 1-2mg/kg **Midazolam** - 0.1-0.3mg/kg **Propofol** - 1-2.5mg/kg **Thiopental** - 3-5mg/kg

Answer 470

**Diazepam** - 15-30 minutes **Ketamine** - 5-10 minutes **Midazolam** - 15-20 minutes **Propofol** - 3-8 minutes **Thiopental** - 5-10 minutes

Answer 471

* Propofol is an alkyl phenol with hypnotic properties that is chemically distinct from other groups of IV anaesthetics. * Because of its poor solubility in water, it is formulated as an emulsion containing 10% soybean oil, 2.25% glycerol, and 1.2% lecithin, the major component of the egg yolk phosphatide fraction. * It has a pH of approx 7, and has a propofol concentration of 1%.

Answer 472

The presumed mechanism of action of propofol is through potentiation of the chloride current mediated through the GABA_A receptor complex

Answer 473

* It is rapidly metabolised in the liver; the resulting water-soluble compounds are presumed to be inactive and are excreted through the kidneys. * Plasma clearance is high and exceeds hepatic blood flow, indicating the important of extrahepatic metabolism, which presumably occurs in the lungs and may account for the elimination of up to 30% of a bolus dose of the drug.

Answer 474

The recovery from propofol is more complete, with less "hangover" than that observed with thiopental, likely due to the high plasma clearance.

Answer 475

The transfer of propofol from the plasma (central) compartment and the associated termination of drug effect after a single bolus dose are mainly the result of redistribution from highly perfused (brain) to less-well-perfused (skeletal muscle) compartments. Awakening after an induction dose of propofol usually occurs within 8-10 minutes.

Answer 476

The **context-sensitive half-time** of a drug describes the elimination half-time after discontinuation of a continuous infusion as a function of the duration of the infusion. It is an important parameter in assessing the suitability of a drug for use as maintenance anaesthetic.

Answer 477

The context-sensitive half-time of propofol is brief, even after a prolonged infusion, and therefore, recovery occurs relatively promptly.

Answer 478

* Propofol acts as hypnotic but does not have analgesia properties. * Although the drug leads to general suppression of CNS activity, excitatory effects such as twitching or spontanous movement are occasionally observed during induction anaesthesia.

Answer 479

* Propofol **decreases cerebral blood flow and the cerebral metabolic rate for oxygen** (CMRO₂), which **decreases ICP and intraocular pressure**; the magnitude of these changes is comparable to thiopental. * Although propofol can produce a desired decrease in ICP, the combination of reduced cerebral blood flow and reduced MAP due to preipheral vasodilation can critically decrease cerebral perfusion pressure.

Answer 480

* Compared with other induction drugs, propofol produces the **most pronounced decrease in systemic blood pressure**; this is a result of profound **vasodilation in both arterial and venous circulations** leading to reductions in preload and afterload. * Because the hypotensive effects are further augmented by the inhibition of the normal baroreflex response, the vasodilation only leads to a **small increase in heart rate**.

Answer 481

The drop is systemic BP caused by propofol is more pronounced with increased age, in patients with reduced intravascular fluid volume, and with rapid injection.

Answer 482

* Propofol is a potent respiratory depressant and generally produces apnoea after an induction dose. * A maintenance infusion reduces minute ventilation through reductions in tidal volume and resp rate, with the effect on tidal volume being more pronounced. * In addition, the ventilatory response to hypoxia and hypercapnia is reduced.

Answer 483

Propofol causes a greater reduction in upper airway reflexes than thiopental does, which makes it well suited for instrumentation of the airway, such as placement of LMA

Answer 484

Yes, pain on injection is a common complaint and can be reduced by premedication with an opioid or co-administration with lidocaine. Dilution of propofol and the use of larger veins for injection can also reduce the incidence and severity of injection pain

Answer 485

* The most common use of propofol is to facilitate induction of general anaesthesia by bolus injection of 1-2.5mg/kg IV. * Increasing age, reduced cardiovascular reserve, or premedication with benzodiazepines or opioids reduces the required induction dose * Children require high doses (2.5-3.5mg/kg)

Answer 486

The required plasma concentration is 1-2mcg/ml, which can be achieved with a continuous infusion at 25-75 mcg/kg/min.

Answer 487

Thiopental

Answer 488

* The anaesthetic effect of barbiturates presumably involves a combination of **enhancement of inhibitory transmission** and **inhibition of excitatory neurotransmission**. * Although the effects on inhibitory transmission probably result from activation of the GABA_A receptor complex, the effects on excitatory transmission are less well understood

Answer 489

Yes, it undergoes hepatic metabolism, mostly by oxidation but also by *N*-dealkylation, desulfuration, and destruction of the bartbituric acid ring structure.

Answer 490

* Although thiopental is metabolised slowly and has a long elimination half-life (11 hours), recovery after a single bolus injection is comparable to that of propofol (5-10 minutes) because it depends on redistribution to inactive tissue sites rather than on metabolism. * However, if administered through repeated bolus infection or continuous infusion, recovery will be markedly prolonged because elimination will depend on metabolism under these circumstances.

Answer 491

They produce dose-dependent CNS depression ranging from sedation to general anaesthesia when adminitered as bolus injections. They do not produce analgesia.

Answer 492

They are potent cerebral vasoconstrictors and produce predictable decreases in cerebral blood flow, cerebral blood volume, and ICP. As a result they decrease the cerebral metabolic rate of O₂ consumption in a dose-dependent manner up to a dose at which they suppress all EEG activity.

Answer 493

Patients with space-occupying intracranial lesions. They may provide neuroprotection from focal cerebral ischaemia (stroke, surgical retraction, temporary clips during aneurysm surgery), but probably not from global cerebral ischaemia (eg, from cardiac arrest).

Answer 494

* The **decrease in systemic blood pressure** associated with administration of barbiturates for induction of anaesthesia is primarily due to peripheral vasodilation and is usually smaller than the blood pressure decrease associated with propofol * There are also transient **direct negative inotropic** effects on the heart

Answer 495

Patients with hypovolaemia, cardiac tamponade, cardiomyopathy, coronary artery disease, or cardiac valvular disease because such patients are less able to compensate for the effects of peripheral vasodilation.

Answer 496

* Barbiturates are respiratory depressants, and a usual induction dose of thiopental or methohexital typically produces transient apnea. * Barbiturates lead to decreased minute ventilation through reduced tidal volumes and respiratory rate and also decrease the ventilatory responses to hypercapnia and hypoxia.

Answer 497

Suppression of laryngeal and cough reflexes in thiopental is not as profound as after an equianaesthetic propofol administration, which makes barbiturates an inferior choice for airway intrumentation in the absence of neuromusclar blocking drugs.

Answer 498

The principal clinical use of thiopental (3-5mg/kg IV) is for induction of anaesthesia, which usually occurs in less than 30 seconds.

Answer 499

Midazolam, lorazepam, and less frequently, diazepam.

Answer 500

The highly lipid-soluble benzodiazepines rapidly enter the CNS, which accounts for their rapid onset of action, followed by redistribution to inactive tissues sites and subsequent termination of the drug effect.

Answer 501

* Despite its prompt passage into the brain, midazolam is considered to have a **slower effect-site equilibration time** than propofol and thiopental. * IV doses of midazolam should be sufficiently spaced to permit the peak clinical effect to be recognised before a repeat dose is considered.

Answer 502

Midazolam has the shortest context-sensitive half-time, which makes it the only one of the three benzodiazepine drugs suitable for continuous infusion.

Answer 503

* Benzodiazepines decrease CMRO₂ and cerebral blood flow but to a smaller extent than propofol or the baribiturates. * Patients with decreased intracranial compliance demonstrate little or no change in ICP after the administration of midazolam.

Answer 504

The CNS effects of benzodiazepines can be promptly terminated by administration of the selective benzodiazepine antagonist flumenazil, which improves their safety profile.

Answer 505

* If used for the induction of anaesthesia, midazolam produces a greater decrease in systemic blood pressure than comparable doses of diazepam. * These changes are most likely due to peripheral vasodilation as cardiac output is not changed.

Answer 506

* Benzodiazepines produce minimal depression of ventilation, although transient apnea may follow rapid IV administration of midazolam for induction of anaesthesia. * Another problem affecting ventilation is airway obstruction induced by the hypnotic effects of benzodiazepines.

Answer 507

* Midazolam (1-2mg IV) is effective for premedication, sedation during regional anaesthesia, and brief therapeutic procedures. * Midazolam is also the most commonly used oral premedication for children; 0.5mg/kg administered orally 30 minutes before induction of anaesthesia provides reliable sedation and anxiolysis in children without producing delayed awakening. * General anesthesia can be induced by the administration of midazolam (0.1-0.3mg/kg IV)

Answer 508

Midazolam has a more rapid onset, with greater amnesia and less post-op sedation, than diazepam.

Answer 509

* The onset of unconsciousness is slower after the administration of midazolam than it is after thiopental, propofol, or etomidate. * Delayed awakening is a potential disadvantage, limiting the usefulness for induction of general anaesthesia

Answer 510

* Ketamine is a partially water-soluble and highly lipid-soluble phencyclidine derivative differing form most other IV anaesthetics in that it produces significant analgesia * Of the two stereoisomers, the *S*(+) form is more potent than the *R*(-) isomer, but only the racemic mixture of ketamine is usually used.

Answer 511

It is known as "dissociative anaesthesia", wherein the patient's eyes remain open with a slow nystagmic gaze (cataleptic state).

Answer 512

Ketamine's mechanism of action is complex, but the major effect is probably produced through inhibition of the NMDA receptor complex

Answer 513

* The high lipid solubility of ketamine ensures a rapid onset of its effect * The effect of a single bolus injection is terminated by redistribution to inactive tissue sites. * Metabolism occurs primarily in the liver and involves *N*-demethylation by the cytochrome P450 system. * Norketamine, the primary active metabolite, is less potent and is subsequently hydroxylated and conjugated into water-soluble inactive metabolites that are excreted in urine

Answer 514

* If ketamine is administered at the sole anaesthetic, amnesia is not as complete as with the benzodiazepines. * Reflexes are often preserved, but it cannot be assumed that patients are able to protect the upper airway * Their eyes remain open and the pupils are moderately dilated with a nystagmic gaze. * Frequently lacrimation and salivation are increased, and premedication with an anticholinergic drug may be indicated to limit this effect

Answer 515

* In contrast to other IV anaesthetics, ketamine is considered to be a cerebral vasodilator that **increases** cerebral blood flow, as well as CMRO₂. * Thus, ketamine has traditionally not been recommended for use in patients with increased ICP.

Answer 516

* Such reactions may include vivid colourful dreams, hallucinations, out-of-body experiences, and increased and distorted visual, tactile, and auditory sensitivity. * These reactions can be associated with fear and confusion, but a euphoric state may also be induced, which explains the potential for abuse of the drug.

Answer 517

* Ketamine can produce transient but significant **increases in systemic blood pressure, heart rate, and cardiac output**, presumable by centrally mediated sympathetic stimulation. * Ketamine is also considered to be a direct myocardial depressant. This is usually masked by its stimulation of the sympathetic nervous system but may become apparent in critically ill patients with limited ability to increase their sympathetic nervous system activity.

Answer 518

* Ketamine is not thought to produce significant respiratory depression. * Transient hypoventilation and, in rare cases, a short period of apnea can follow rapid administration of a large IV dose for induction of anaesthesia. * Especially in children, the risk of laryngospasm because of increased salivation must be considered; this risk can be reduced by premedication with an anticholinergic drug.

Answer 519

* Induction of anaesthesia can be achieved with ketamine, 1-2 mg/kg IV or 4-6 mg/kg IM. * General anaesthesia can be achieved with the infusion of ketamine, 15-45mcg/kg/min, plus 50-70% nitrous oxide or by ketamine alone, 30-90 mcg/kg/min

Answer 520

* Hepatic metabolism accounts for the clearance of all benzodiazepines. The patterns and rates of metabolism depend on the individual drug. * Most benzodiazepines undergo microsomal oxidation (phase 1 reactions)catalysed by cytochrome P450 isozymes. * the metabolites are subsequently conjugated (phase 2 reactions) to form glucuronides that are excreted in the urine.

Answer 521

* The metabolites are conjugated (phase 2 reactions) to form glucuronides that are excreted in the urine. * However, many phase 1 metabolites of benzodiazepines are pharmacologially active, some with long half-lives. * For example, desmethyldiazepam, which has an elimination half-life of more than 40 hours, is an active metabolite of chlordiazepoxide, diazepam, prazepam, and clorazepate.

Answer 522

* Time to peak blood levels - 1-2 hours * Half life - 12-15 hours * Rapid oral absorption

Answer 523

* Time to peak blood levels - 1-2 hours * Half-lives of diazepam - 20-80 hours * It has active metabolites and erratic bioavailability from IM injection

Answer 524

* Time to peak levels - 1-6 hours * Half-lives of major metabolites - 10-20 hours * No active metabolites

Answer 525

* Time to peak blood levels - 2-3 hours * Half-life of major metabolites - 10-40 hours * Slow oral absorption

Answer 526

They bind to molecular components of the GABA_A receptor in neuronal membranes in the CNS. This receptor, which functions as a chloride ion channel, is activated by the inhibitory neurotransmitter GABA.

Answer 527

* A major form of the GABA_A receptor that is found in many regions of the brain consists of two α1 subunits, two β2 subunits, and one γ2 subunit. * In this isoform, the two binding sites for GABA are located between adjacent α1 and β2 subunits, and the binding pocket for benzodiazepines (the BZ site of the GABA_A receptor) is between an α1 and the γ2 subunit.

Answer 528

* Benzodiazepines potentiate GABAergic inhibition at all levels of the neuraxis, including the spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex and cerebral cortex. * They appear to increase the efficiency of GABAergic synaptic inhibition. They do not substitute for GABA but appear to enhance GABA's effects allosterically without directly activating GABA_A receptors or opening the associated chloride channels. * The enhancement in chloride ion conductance induced by the interaction on benzodiazepines with GABA takes the form of an increase in the *frequency* of channel-opening events.

Answer 529

* Barbiturates also facilitate the actions of GABA at multiple sites in the CNS, but - in contrast to benzos - they appear to increase the *duration* of the GABA-gated chloride channel openings. * At high concentrations, the barbiutrates may also be GABA-mimetic, directly activating chloride channels. * They are less selective than benzodiazepines, because they also depress the actions of the excitatory neurotransmitted glutamic acid via binding the AMPA receptor.

Answer 530

1) **Agonists** facilitate GABA actions, and this occurs at multiple BZ binding sites 2) **Antagonists** are typified by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines 3) **Inverse agonists** act as negative allosteric modulators of GABA-receptor function.

Answer 531

1) The latency of sleep onset is decreased (time to fall asleep) 2) The duration of stage 2 NREM (non-rapid eye movement) is increased 3) The duration of REM (rapid eye movement) sleep is decreased 4) The duration of stage 4 NREM slow-wave sleep is decreased

Answer 532

Decreased responsiveness to a drug following repeated exposure.

Answer 533

An altered physiological state that requires continuous drug administration to prevent an abstinance or withdrawal syndrome.

Answer 534

* Flumenazil is a competitive antagonist of benzodiazepines. * When given IV, it acts rapidly but has a short half-life (0.7-1.3 hours) due to rapid hepatic clearance

Answer 535

* Ethanol is a small water-soluble molecule that is absorbed rapidly from the GI tract. * After ingestion of alcohol in the fasting state, peak blood alcohol concentrations are reached within 30 minutes. * Distribution is rapid, with tissue levels approximating the concentration in blood. * Over 90% of alcohol consumed is oxidised in the liver; much of the remainder is excreted through the lungs and in the urine.

Answer 536

It approximates total body water (0.5-0.7L/kg).

Answer 537

After an equivalent oral dose of alcohol, women have a higher peak concentration than men, in part because women have a lower total body water content and in part because if differences in first-pass metabolism.

Answer 538

At levels of ethanol usually achieved in blood, the rate of exidation follows zero-order kinetics; that is, it is independent of time and concentration of the drug.

Answer 539

The typical adult can metabolise 7-10g (150-220 mmol) of alcohol per hour, the equivalent of approx one drink.

Answer 540

* The primary pathway for alcohol metabolism involves alcohol dehydrogenase (ADH), a family of cytosolic enzymes that catalyse the conversion of alcohol to acetaldehyde. * During conversion of ethanol by ADH to acetaldehyde, hydrogen ion is transferred from ethanol to the cofactor nicotinamide adenine dinucleotide (NAD⁺) to form NADH. * As a result, alcohol oxidation generates an excess of reducing equivalents in the liver, chiefly as NADH.

Answer 541

* It is located mainly in the liver, but small amounts are found in other organs such as the brain and stomach. * Some metabolism of ethanol by ADH occurs in the stomach in men, but a smaller amount occurs in women, who appear to have lower levels of the gastric enzyme.

Answer 542

* During chronic alcohol consumption, the microsomal ethanol-oxidising system (MEOS) activity is induced. * The enzyme system uses NADPH as a cofactor in the metabolism of ethanol and consists primarily of cytochrome P450 * As a result, chronic alcohol consumption results in significant increases not only in ethanol metabolism but also in the clearance of other drugs eliminated by the cytochrome P450s that constitute the MEOS system, and in the generation of the toxic byproducts of cytochrome P450 reactions (toxins, free radicals, H₂O₂)

Answer 543

* Much of the acetaldehyde formed from alcohol is oxidised in the liver in a reaction catalysed by mitochondrial NAD-dependent aldehyde dehydrogenase (ALDH). * The product of this reaction is acetate, which can be further metabolised to CO₂ and water, or used to form acetyl-CoA.

Answer 544

* Oxidation of acetaldehyde is inhibited by **disulfiram**, a drug that has been used to deter drinking by patients with alcohol dependence. * When ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache.

Answer 545

50-100mg/dL - sedation, subjective "high", slower reaction times 100-200mg/dL - impaired motor function, slurred speech, ataxia 200-300mg/dL - emesis, stupor 300-400mg/dL - coma >400 mg/dL - respiratory depression, death

Answer 546

Alcohol causes sedation, relief of anxiety and, at higher concentrations, slurred speech, ataxia, impaired judgement, and disinhibited behaviour.

Answer 547

* Ethanol affects a large number of membrane proteins that participate in signalling pathways, including neurotransmitter receptors for amines, amino acids, opioid and neuropeptides; enzymes such as Na₊/K₂-ATPase, adenylyl cyclase, and ion channels. * Acute ethanol exposure enhances the action of GABA at GABA_A receptors. * Ethanol inhibits the ability of glutamate to open the cation channel associated with the *N*-methyl-D-aspartate (NMDA) subtype of glutamate receptors. The NMDA receptor is implicated in many aspects of cognitive function, including learning and memory, which is why blackouts happen

Answer 548

Significant depression of myocardial contractility has been observed in individuals who acutely consume moderate amounts of alcohol

Answer 549

Ethanol is a vasodilater, probably as a result of both CNS effects (depression of teh vasomotor center) and direct smooth muscle relaxation caused by its metabolite, acetaldehyde.

Answer 550

The tissue damage caused by chronic alcohol ingestion results from a combination of the direct effects of ethanol and acetaldehyde, and the metabolic consequences of processing a heavy load of metabolically active substances.

Answer 551

Specific mechanisms implicated in tissue damage include: * increased oxidative stress coupled with depletion of glutathione * damage to mitochondria * growth factor dysregulation * potentiation of cytokine-induced injury

Answer 552

* liver disease * cancer * accidents * suicide

Answer 553

Liver disease 15-30% of chronic heavy drinkers eventually develop severe liver disease.

Answer 554

A multifactorial process involving: * metabolic repercussions of ethanol oxidation in the liver * dysregulation of fatty acid oxidation and synthesis * activation of the innate immune system by a combination of direct effects of ethanol and its metabolites and by bacterial endotoxins that access the liver as a result of ethanol-induced changes in the intestinal tract. * Tumour necrosis factor-α appears to play a pivotal role in the progression of alcoholic liver disease and may be a fruitful therapeutic target.

Answer 555

* Chronic alcohol ingestion is the most common cause of chronic pancreatitis in the Western world. * In addition to its direct toxic effect on pancreatic acinar cells, alcohol alters pancreatic epithelial permeability and promotes the formation of protein plugs and calcium carbonate-containing stones.

Answer 556

* Alcohol withdrawal symptoms usually consist of hyperexcitability in mild cases and seizures, toxic psychosis, and **delirium tremens** in severe cases. * The dose, rate, and duration of alcohol consumption determine the intensity of the withdrawal syndrome.

Answer 557

* Psychological dependence on alcohol is characterised by a compulsive desire to experience the rewarding effects of alcohol and, for current drinks, a desire to avoid the negative consequences of withdrawal. * People who have recovered from alcoholism and become abstinent still experience periods of intense craving for alcohol that can be triggered by environmental cues.

Answer 558

Up-regulation of the NMDA subtype of glutamate receptors and voltage-sensitive Ca²⁺ channels may underlie the seizures that accompany the alcohol withdrawal syndrome

Answer 559

GABA neurotransmission because 1) sedative-hypnotic drugs that enhance GABAergic neurotransmission are able to substitute for alcohol during alcohol withdrawal 2) there is evidence of downregulation of GABA_A-mediated responses with chronic alcohol exposure

Answer 560

* Ethanol modulates neural activity in the brain's mesolimbic dopamine reward circuit and increases dopamine release in the nucleus accumbens * Alcohol affects local concentrations of serotonin, opioids, and dopamine - neurotransmitters involved in the brain reward system.

Answer 561

Generalised symmetric peripheral nerve injury, which begins with distal paraesthesias of the hands and feet. Degenerative changes can also result in gait disturbances and ataxia.

Answer 562

**Wernicke-Korsakoff syndrome** * It is characterised by paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death. * It is associated with thiamine deficiency but rarely is seen in the absence of alcoholism. * Often, the ocular signs, ataxia, and confusion improve promptly upon administration of thiamine.

Answer 563

1) Cardiomyopathy and heart failure 2) Arrhythmias 3) HTN 4) Coronary heart disease

Answer 564

* Heavy alcohol consumption of long duration is associated with a dilated cardiomyopathy with ventricular hypertrophy and fibrosis. * It causes cardiac membrane disruption, depressed function of mitochondria and sarcoplasmic reticulum, intracellular accumulation of phospholipids and fatty acids, and up-regulation of voltage-gated calcium channels.

Answer 565

* Patients with alcohol-induced dilated cardiomyopathy do significantly worse than patients with idiopathic dilated cardiomyopathy, even though cessation of drinking is associated with a reduction on cardiac size and improved function. * The poorer prognosis for patients who continue to drink appears to be in part to interference by ethanol with the beneficial effects of β blockers and ACE inhibitors

Answer 566

* Heavy drinking - and especially "binge" drinking - are associated with both atrial and ventricular arrhythmias. * Patients undergoing alcohol withdrawal syndrome can develop severe arrhythmias that may reflect abnormalities of potassium and magnesium metabolism as well as enhanced release of catcholamines. * Seizures, syncope and sudden death during alcohol withdrawal may be due to these arryhthmias

Answer 567

A link between heavier alcohol consumption and HTN has been firmly established.

Answer 568

Although the deleterious effects of excessive alcohol use on the cardiovascular system are well established, there is strong epidemiological evidence that *moderate* alcohol consumption actually *prevents* coronary heart disease, ischaemic stroke and peripheral arterial disease.

Answer 569

* Serotonin receptors, such as 5-HT_2A receptor and potentially 5-HT_2C. * These receptors modulate the release of dopamine, noradrenaline, glutamate, GABA, and acetylcholine. * Stimulation of 5-HT_2A receptors leads to depolarisation of glutamate neutrons, but also stabilisation of NMDA receptors on postsynaptic neurone.

Answer 570

5-HT_2A- receptor blockade is a key factor in the mechanism of action of clozapine, risperidone, olanzapine, quetiapine, aripiprazole. They are **inverse agonists** of the 5-HT_2A receptor.

Answer 571

* **Penothiazine derivatives** - chlorpromazine * **Thiothixene** * **Butytophenone derivatives** - haloperidol * **Second-generation antipsychotic drugs** - clozapine, olanzapine, quetiapine, risperidone, aripiprazole

Answer 572

* Many are readily but incompletely absorbed * Furthermore, many undergo significant first-pass metabolism * Oral doses of chlorpromazine have systemic availability of 25-35%, whereas haloperidol, which has less first-pass metabolism, has an average of systemic availability of about 65%

Answer 573

* Many antipsychotic drugs are highly lipid soluble and protein bound (92-99%) * They tend to have large volumes of distribution. * They generally have a much longer clinical duration of action than would have been estimated from their plasma half-lives. This is paralleled by prolonged occupancy of D₂ dopamine receptors in the brain by typical antipsychotic drugs.

Answer 574

* Metabolites of chlorpromazine may be excreted in the urine weeks after the last dose of chronically administered drug. * Long-acting injective formulations may cause some blockade of D₂ receptors 3-6 months after the last injection.

Answer 575

Around 6 months! The exception is clozapine, with which the relapse after discontinuation is usually rapid and severe.

Answer 576

Most antipsychotic drugs are almost completely metabolised by oxidation or demethylation, catalysed by liver microsomal cytochrome P450 enzymes.

Answer 577

1. The **mesolimbic-mesocortical** pathway, which projects from cell bodies in the ventral tegmentum in separate bundles of axons to the limbic system and neocortex 2. The **nigrostriatal** pathway, which consists of neurone that project from the substantia nigra to the dorsal striatum, it is involved in the coordination of voluntary movement 3. The **tuberoinfundibular** system - arising in the arcuate nuclei and periventricular neurons and releasing dopamine into the pituitary portal circulation. Dopamine released by these neurons physiologically inhibits prolactin secretion from the anterior pituitary. 4. The **medullary-periventricular** pathway consists of neurons in the motor nucleus of the vagus, which is involved in eating behaviour. 5. The **incertohypothalamic** pathway forms connections from the medial zone incerta to the hypothalamus and amygdala, which appears to regular the anticipatory motivational phase of copulatory behaviour

Answer 578

* The **D₁-like receptor group** (D₁, D₅), which increases cAMP and is not correlated with the therapeutic potency of antipsychotics * The **D₂-like** receptor group (D₂, D₃, D₄), which decreases cAMP

Answer 579

They block D₂ receptors stereoselectively for the most part, and their binding affinity is very strongly correlated with clinical antipsychotic and extrapyramidal potency. At least 60% occupancy of striatal D₂ receptors is required for efficacy.

Answer 580

Second generation antipsychotic drugs such as clozapine and olanzapine are effective at lower occupancy levels (30-50%) of D₂ receptors, most likely because of their concurrent high occupancy of 5HT_2A receptors.

Answer 581

**Muscarinic cholinoreceptor blockade** - loss of accommodation, dry mouth, difficulty urinating, constipation **α-Adrenoreceptor blockade** - orthostatic hypotension, impotence, failure to ejaculate

Answer 582

**Dopamine-receptor blockade** - Parkinson's syndrome, akathisia, dystonia **Supersensitivity of dopamine receptors** - tardive dyskinesia **Muscarinic blockade** - toxic-confusional state

Answer 583

**Dopamine-receptor blockade resulting in hyperprolactinaemia** - amenorrhoea, galactorrhea, infertility, impotence

Answer 584

Schizophrenia, bipolar disorder, psychotic depression and treatment-resistant depression, schizoaffective disorder

Answer 585

An aliphatic phenothiazine

Answer 586

* It is a butyrophenone * Advantages - parenteral form also available * Disadvantages - severe extrapyramidal syndrome

Answer 587

* It is a dibenzodiazepine * Advantages - may benefit treatment-resistant patients; little extrapyramidal toxicity * Disadvantages - may cause agranulocytosis in up to 2% of patients; dose-related lowering of seizure threshold

Answer 588

* It is a benzisoxazole * Advantage - broad efficacy; little to no extrapyramidal system dysfunction at low doses * Disadvantage - extrapyramidal system dysfunction and hypotension with higher doses

Answer 589

* It is a thienobenzodiazepine * Advantages - effective against negative as well as positive symptoms; little or no extrapyramidal system dysfunction * Disadvantages - weight gain; dose-related lowering of seizure threshold

Answer 590

**Haloperidol** - 2-60mg daily **Clozapine** - 300-600mg daily **Olanzapine** - 10-30mg daily **Quetiapine** - 150-800mg daily **Risperidone** - 4-16mg daily **Aripiprazole** - 10-30mg daily

Answer 591

It is caused by a relative cholinergic deficiency secondary to super sensitivity of dopamine receptors in the caudate-putamen. Early recognition is important, since advanced cases may be difficult to reverse.

Answer 592

Usually between the 6th and 18th weeks of therapy. Because of the risk, patients receiving clozapine must have weekly blood counts for the first 6 months of treatment and every 3 weeks thereafter.

Answer 593

* This life-threatening disorder occurs in patients who are extremely sensitive to the extrapyramidal effects of antipsychotic agents. * The initial symptom is marked muscle rigidity. If sweating is impaired, as it often is during treatment with anticholinergic drugs, fever may ensue, often reaching dangerous levels. * The stress leukocytosis and high fever associated with the syndrome suggest an infection process. * Autonomic instability, with altered BP and HR is often present. * A severe form of extrapyramidal syndrome follows.

Answer 594

Muscle-type CK levels are usually elevated, reflecting muscle damage.

Answer 595

It is believed to result from an excessively rapid blockade of postsynaptic dopamine receptors.

Answer 596

* Early in the course, vigorous treatment of the extrapyramidal syndrome with antiparkinsonism drugs is worthwhile. * Muscle relaxants, particularly diazepam, are often useful * If fever is present, cooling by physical measures should be tried.

Answer 597

* They are rarely fatal. * In general, drowsiness proceeds to coma, with an intervening period of agitation. * Neuromuscular excitability may be increased and proceed to convulsions. * Pupils are miotic, and deep tendon reflexes are decreased.

Answer 598

**Absorption** - virtually complete within 6-8 hours; peak plasma levels in 30 minutes to 2 hours **Distribution** - in total body water; slow entry into intracellular compartments; some sequestration in bone **Metabolism** - none **Excretion** - virtually entirely in urine; lithium clearance about 20% of creatinine; plasma half-life about 20 hours.

Answer 599

**Target plasma concentration** 0.6-1.4mEq/L **Dosage** - 0.5mEq/kg/day in divided doses

Answer 600

* It both suppresses inositol signalling through **depletion of intracellular inositol** and **inhibits GSK-3**, a multifunctional protein kinase. * **GSK-3** is a component of diverse intracellular signalling pathways. These include signalling via **insulin/insulin-like growth factor, brain-derived neurotrophic factor (BDNF) and the Ant pathway**. * Lithium induced inhibition of GSK-3 results in reduction of phosphorylation of β-catenin, which allows **β-catenin to accumulate and translocate to the nucleus**. There, β-catenin **facilitates transcription of a variety of proteins**. * The pathways that are facilitated by the accumulation of β-catenin via GSK-3 inhibition modulate **energy metabolism, provide neuroprotection, and increase neuroplasticity**.

Answer 601

* Lithium is closely related to sodium in its properties * It can substitute for sodium in generating action potentials and in Na⁺-Na⁺ exchange across the membrane. * At therapeutic concentrations, it does not significantly affect the Na⁺-Ca²⁺ exchanger or the Na⁺/K⁺-ATPase pump

Answer 602

**Inositol monophosphatase** - the rate-limiting enzyme in inositol recycling; it is inhibited by lithium, resulting in depletion of substrate IP₃ **Inositol polyphosphate 1-phosphatase** - another enzyme in isositol recycling; inhibited by lithium, resulting in depletion of substrate for IP₃ production **Biphosphate nucleotidase** - involved in AMP production; inhibited by lithium; may be target that results in lithium-induced nephrogenic diabetes insipidus

Answer 603

Usually 10-12 hours after the last dose

Answer 604

* An initial determination of serum lithium concentration should be obtained about **5 days after the start of treatment**, at which time steady-state conditions should have been attained to determine the desired level and will show whether increases or decreases in the dose are required. * The serum concentration attained with the adjusted dosage can be checked after **another 5 days**. * Once the desired concentration has been achieved, levels can be measured at increasing intervals unless the schedule is influence by intercurrent illness.

Answer 605

* The frequency and severity of previous episodes * A crescendo pattern of appearance * The degree to which the patient is willing to follow a program of indefinite maintenance therapy * Patients with a history or two or more mood cycles or any clearly defined bipolar I diagnoses.

Answer 606

* Renal clearance of lithium is reduced about 25% by **diuretics (eg, thiazides)**, and doses may need to by reduced by a similar amount. * A similar reduction in lithium clearance is found with several of the newer **NSAIDs** that block synthesis of prostaglandins

Answer 607

* **Tremor** can be alleviated with propranolol and atenolol * **Decreased thyroid function** is reversible and non-progressive, TFTs should be monitored every 6-12 months * **Nephrogenic diabetes insipidus** - polydipsia and polyuria are common adverse effects due to a loss of responsiveness for ADH, it is resistant to vasopressin but response to amiloride. * **Oedema** is common due to the effect of lithium on sodium retention. * **Bradycardia-tachycardia** "sick sinus" syndrome because the ion further depresses the sinus node. * **Leukocytosis, transient acneiform eruptions and folliculitis**

Answer 608

The **monoamine hypothesis** - a deficit in function of amount of monoamines is central to the biology of depression The **neurotrophic hypothesis** - eutrophic and endocrine factors play a major role

Answer 609

* Nerve growth factors such as **brain-derived neurotrophic factor (BDNF)** are critical in the regulation of neural plasticity, resilience, and neurogenesis. * Depression is associated with the loss of neurotrophic support and antidepressant therapies increase neurogenesis and synaptic connectivity in cortical areas such as the hippocampus. * BDNF is thought to exert its influence on neuronal survival and growth effects by activating the tyrosine kinase receptors B in both neurone and glia. * Depression appears to be associated with a drop in BDNF levels in the CSF and serum as well as with a decrease in tyrosine kinase receptor B activity and a decrease in the size of the hippocampus.

Answer 610

* It suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin (5-HT), noradrenaline (NE) and dopamine (DA). * The excitatory neurotransmitter glutamate appears to be elevated in the CSF of depressed patients and decreased glutamine/glutamate ratio in their plasma.

Answer 611

* It is associated with **elevated cortisol levels**, non suppression of ACTH release in the dexamethasone suppression test and chronically elevated levels or corticotropin-releasing hormone. * **Thyroid dysregulation** has also been reported in depressed patients. These include a blunting of response to thyrotropin to thyrotropin-releasing hormone and elevations in circulating thyroxine during depressed states. * **Estrogen deficiency states**, which occur in the postpartum and postmenopausal periods, are thought to play a role in the ethology of depression in some women.

Answer 612

* Fluoxetine, sertraline, citalopram, paroxetine, fluvoxamine, escitalopram * They are all highly lipophilic

Answer 613

**Selective serotonin-noradrenaline reuptake inhibitors** and **Tricyclic antidepressants**

Answer 614

Venlafaxine, desvenlafaxine and duloxetine. They have applications in the treatment of pain disorders including neuropathies and fibromyalgia. also GAD, stress urinary incontinence and vasomotor symptoms of menopause.

Answer 615

* All SNRIs bind the serotonin and noradrenaline transporters, as do the TCAs * However, unlike the TCAs, the SNRIs do not have much affinity for other receptors.

Answer 616

* **5-HT₂ Receptor Blockers** - trazodone and nefazodone - used for major depression, sedation and hypnosis * **Tetracyclics** - mirtazapine, bupropion - increased release of noradrenaline and 5-HT - used for major depression, sedation * **Monoamine oxidase inhibitors** - selegiline, phenelzine - irreversible selective MAO-B inhibition - used for Parkinson's and unresponsive depression

Answer 617

Most have fairly rapid oral absorption, achieve peak plasma levels within 2-3 hours, are tightly bound to plasma proteins, undergo hepatic metabolism and are really cleared.

Answer 618

* It is metabolised to an active product, norfluoxetine, which may have plasma concentrations greater than those of fluoxetine. * The elimination half-life of norfluoxetine is about three times longer than fluoxetine and contributes to the longest half-life of all the SSRIs

Answer 619

**Citalopram** - 80% **Escitalopram** - 80% **Fluoxetine** - 70% **Paroxetine** - 50% **Sertraline** - 45%

Answer 620

Duloxetine - 50% Venlafaxine - 45%

Answer 621

**Amitriptyline** - 45% **Trazadone** - 95% **Mirtazapine** - 50%

Answer 622

Both have similar half-lives of about 8-11 hours. They have the lowest protein binding of all antidepressants.

Answer 623

* They tend to be well absorbed and have long half-lives (around 30 hours). * They undergo extensive metabolism via demethylation, aromatic hydroxylation, and glucuronide conjugation. * Only about 5% of TCAs are excreted unchanged in the urine.

Answer 624

* The **serotonin transporter (SERT)** is a glycoprotein embedded in the axon terminal and cell body membranes of serotonergic neurons. * When extracellular **serotonin binds** to receptors on the transport, conformational changes occur in the transport and **serotonin, Na⁺ and Cl^- are moved into the cell**. * Binding of intracellular K⁺ then results in the release of serotonin inside the cell and return of the transporter to its original confirmation. * **SSRIs allosterically inhibit** the transport by binding the SERT receptor at a site other than the serotonin binding site. * At therapeutic doses, about **80% of the activity of the transporter is inhibited**

Answer 625

* SNRIs bind both the serotonin and the noradrenaline transporters. * The noradrenaline transporter (NET) is structurally very similar to the 5-HT transporter, it is a domain complex that allosterically binds noradrenaline. The NET also has a moderate affinity for dopamine. * Venlafaxine is a weak inhibitor of NET, whereas the other SNRIs are more balanced inhibitors of both SERT and NET.

Answer 626

The SNRIs lack the potent antihistamine, α-adrenergic blocking, and anticholinergic effects of the TCAs. Thus, they tend to by favoured over the TCAs due to their better tolerability.

Answer 627

They resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and noradrenaline reuptake.

Answer 628

* Clomipramine has relatively little affinity for NET but potently binds SERT. * Nortriptyline is relatively more selective for NET. * Imipramine has more serotonin effect initially, but its metabolite, desipramine, then balances this effect with more NET inhibition.

Answer 629

* It is an antagonist of the presynaptic α₂ auto receptor and enhances the release of both noradrenaline and 5-HT. * In addition, it is an antagonist of 5-HT₂ and 5-HT₃ receptors. * Finally, mirtazepine is a potent H₁ antagonist, which is associated with the drug's sedative effects.

Answer 630

* Major depression - both acute and chronic * Anxiety disorders including PTSD, OCD, social anxiety disorder, GAD and panic disorder. * Pain disorders - particularly TCAs * Premenstrual dysphoric disorder - 2/52 every month is as effective as every day * Smoking cessation * Bulimia but don't appear to be helpful in anorexia

Answer 631

* Panic disorder is characterised by recurrent episodes of brief overwhelming anxiety, which often occur without a precipitant * GAD is characterised by chronic, free-floating anxiety and undue worry that tends to be chronic in nature

Answer 632

**Citalopram** - 20-60mg/day **Escitalopram** - 10-30mg/day **Fluoxetine** - 20-60mg/day **Paroxetine** - 20-60mg/day **Sertraline** - 50-200mg/day

Answer 633

**Venlafaxine** - 75-375mg/day **Desvenlafaxine** - 50-200mg/day

Answer 634

15-45mg/day

Answer 635

* **Increased serotonergic activity in the gut** - nausea, GI upset, diarrhoea - usually tend to improve after the first week * Diminished sexual function and interest * Increase in headaches and insomnia. * Weight gain

Answer 636

* They have many of the serotonergic adverse effects associated with SSRIs. * In addition, they also have noradrenergic effects including increased BP and HR, and CNS activation such as insomnia, anxiety and agitation.

Answer 637

* The are primarily anticholinergic effects such as dry mouth, constipation, urinary retention, blurred vision and confusion. * The α-blocking property often result in orthostatic hypotension.

Answer 638

* Overdose can induce lethal arrhythmias, including VF and VT. In addition, BP changes and anticholinergic effects including altered mental state and seizures are someones seen * A 1500mg dose (< 7 days supply) is enough to be lethal in many patients * Treatment typically involves cardiac monitoring, airway support, and gastric lavage. Sodium bicarb is often administered to displace the TCA from cardiac sodium channels.

Answer 639

Autonomic instability, hyperadrenergic symptoms, psychotic symptoms, confusion, delirium, fever and seizures.

Answer 640

HTN, hyperreflexia, tremor, clonus, hyperthermia, hyperactive bowel sounds, diarrhoea, mydriasis, agitation, coma - onset within hours

Answer 641

SSRIs SNRIs MAOIs Linezolid Tramadol Ondansetron Sumatriptan MDMA LSD

Answer 642

Sedation (benzodiazepines), paralysis, intubation, and ventilation; consider 5-HT₂ block with chlorpromazine

Answer 643

* All penicillins have the basic structure of a thiazolidine ring (A) is attached to a β-lactam ring (B) that carries a secondary amino group. * Hydrolysis of the β-lactam ring by bacterial β-lactamases yields penicilloic acid, which lacks antibacterial activity

Answer 644

* Cephalosporins, monobactams, carbapenems, and β-lactamase inhibitiors * All are β-lactam compounds, so named because of their four-membered lactic ring

Answer 645

1) **Penicillins** - these have greatest activity against Gram-positive organisms, Gran-negative cocci, and non-β-lactamase-producing anaerobes. However, they have little activity against Gram-negative rods, and they are susceptible to hydrolysis by β-lactamases 2) **Antistaphylococcal penicillins (eg, nafcillin)** - these penicillins are resistant to staphylococcal β-lactamases. They are active against staphylococci and streptococci but not against enterococci anaerobic bacteria and Gram-negative cocci and rods 3) **Extended-spectrum penicillins (aminopenicillins and antipseudomonal penicillins)** - these drugs retain the antibacterial spectrum of penicillin and have improved activity against Gram-negative rods. Like penicillin, however, they are relatively susceptible to hydrolysis by β-lactamases

Answer 646

* Crystalline sodium penicillin G contains approximately 1600 units per mg (1 unit = 0.6mcg; 1 million units of penicillin = 0.6g) * Semisynthetic penicillins are prescribed by weight rather than units

Answer 647

The minimum inhibitory concentration of any penicillin (or other antimicrobial) is usually given in mcg/mL

Answer 648

* Most penicillins are formulated as the sodium or potassium salt of the free acid * Potassium penicillin G contains about 1.7 mEq of K⁺ per million units of penicillin (2.8mEq/g) * Nafcillin contains Na⁺, 2.8 mEq/g.

Answer 649

* In dry crystalline form, penicillin slats are stable for years at 4°C. * Solutions lose their activity rapidly (eg within 24 hours at 20°C) and must be prepared fresh for administration.

Answer 650

* Penicillins, like all β-lactam antibiotics, inhibit bacterial growth by interfering with the **transpeptidation reaction** of bacterial cell wall synthesis. * The cell wall is composed of a complex, cross-linked polymer of polysaccharides and peptides known as peptidoglycan. * The polysaccharide contains alternating amino sugars, *N*-acetylglucosamine and *N*-acetylmuramic acid. A five-amino-acid peptide is linked to the *N*-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine. * **Penicillin-binding-protein** (PBP, an enzyme) removes the terminal alanine in the process of forming a cross-link with a nearby peptide. Cross-links give the call wall its rigidity. * Beta-lactam antibiotics, structural analogs of the natural D-Ala-D-Ala substrate, covalently bind to the active site of PBPs. **This binding inhibits the transpeptidation reaction and halts peptidoglycan synthesis and the cell dies**.

Answer 651

Beta-lactam antibiotics kill bacterial cells only when they are actively growing and synthesising cell walls.

Answer 652

1) inactivation of antibiotic by β-lactamase (most common) 2) modification of target PBPs 3) impaired penetration of drug to target PBPs 4) antibiotic efflux

Answer 653

* Some, such as those produced by *Staph. aureus, H. infleunzae,* and *E.coli*, are **relatively narrow in substrate specificity**, preferring penicillins to cephalosporins * Other β-lactamases eg, AmpC β-lactamase produced by *Pseudomonas aeruginosa* and *Enterobacter* and extended-spectrum β-lactamases (ESBLs) in Enterobacteriacae, **hydrolyse both cephalosporins and penicillins**. * **Carbapenems are highly resistant to hydrolysis by penicillinases and cephalosporinases**, but they are hydrolysed by metalla-β-lactamases and carbapenemases.

Answer 654

* Altered target PBPs are the basis of methicillin resistance in staphylococci and of penicillin resistance in pneumococci and most resistant enterococci. * These resistant organisms produce PBPs that have low affinity for binding β-lacatam antibiotics, and they are not inhibited except in relatively high, often not clinically achievable, drug concentrations.

Answer 655

* Only in **gram-negative species** because of the impermeable outer membrane of their cell wall, which is absent in Gram-positive bacteria * Beta-lactam antibiotics cross the outer membrane and **enter Gram-negative organisms via outer membrane protein channels called porins** * Absence of the proper channel or down-regulation of its production can greatly **impair drug entry into the cell.** * Poor penetration alone is usually not sufficient to confer resistance because enough antibiotic eventually enters the cell to inhibit growth. * However, this barrier can become important in the presence of a β-lactamase, even a relatively inefficient one, as long as it can hydrolyse drug faster than it enters the cell

Answer 656

* Penicillins are **widely distributed** in body fluids and tissues with a few exceptions * They are **polar molecules**, so intracellular concentrations are well below those found in extracellular fluids * Penicillin concentrations in most tissues are equal to those in serum * Penicillin is also **excreted into sputum and breast milk** to levels of 3-15% of those in the serum * **Penetration into the eye, the prostate and the CNS is poor**.

Answer 657

* Penicillin is rapidly excreted by the kidneys; small amounts are excreted by other routes * Tubular secretion accounts for about 90% of renal excretion, and glomerular filtrations accounts for the remainder.

Answer 658

* The normal half-life of penicillin G is approximately 30 minutes but, in renal failure, may be as long as 10 hours * Ampicillin and the extended-spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour

Answer 659

**Amoxicillin (PO)** - adult 0.5-1g TID - paed 20-40mg/kg/d in three doses **Amoxicillin/Potassium clavulanate (PO)** - adult 875/125mg BD - paed - 20-40mg/kg/d in three doses **Tazocin (IV)** - adult 3.375-4.5g 4-6 hourly - paed 300mg/kg/d in 4-6 doses

Answer 660

**Amoxicillin and Co-amoxiclav** - CrCl 50ml/min - 66% of dose - CrCl 10ml/min - 33% of dose **Tazocin** - CrCl 50ml/min - 50-75% of dose - CrCl 10ml/min - 25-33% of dose

Answer 661

* Oral penicillins should be given 1-2 hours before or after a meal * They should no be given with food to minimise binding to food proteins and acid inactivation * This is not the case for amoxicillin.

Answer 662

* Penicillin G is a drug of choice for infections caused by streptococci, meningococci, some enterococci, penicillin-susceptible pneumococci, staphylococci confirmed to be non-β-lactamase-producing, *Treponema pallidum*, some *Clostridium* species, *Actinomyces* and certain other Gram-positive rods. * Depending on the organism, the site, and the severity of the infection, effective doses range between 4 and 24 million units per day administered IV in 4-6 divided doses.

Answer 663

Penicillin V, the oral form of penicillin, is indicated only in minor infections because of its relatively poor bioavailability, the need for dosing four times a day, and its narrow antibacterial spectrum Amoxicillin is often used instead

Answer 664

* Benzathine penicillin and procaine penicillin G for IM injection yield low but prolonged drug levels. * A single IM injection of benzathine penicillin, 1.2 million units, is effective treatment for β-haemolytic streptococcal pharyngitis * Given, IM once every 3-4 weeks, it prevents re-infection * Benzathine penicillin G, 2.4 million units IM once a week for 1-3 weeks, is effective in the treatment of syphilis.

Answer 665

* Ampicillin and amoxicillin * Amoxicillin is better absorbed orally * Amoxicillin, 250-500mg TDS is equivalent to the same amount of ampicillin QDS

Answer 666

* These drugs have greater activity than penicillin against Gram-negative bacteria because of their enhanced ability to penetrate the Gram-negative outer membrane. * Like Penicillin G, they are inactivated by many β-lactamases

Answer 667

It is given orally to treat bacterial sinusitis, otitis, and LRTIs

Answer 668

Ampicillin and amoxicillin are the most active of the oral β-lactam antibiotics against pneumococci with elevated MICs to penicillin and are the preferred β-lactam antibiotics for treating infections suspected to be caused by these strains.

Answer 669

* Ampicillin, but not amoxicillin, is effective for shigellosis * Ampicillin, at dosages of 4-12g/d IV, is useful for treating serious infections caused by susceptible organisms, including anaerobes, enterococci, *L monocytogenes*, and β-lactamase-negative strains of Gram-negative cocci and bacilli such as *E coli*, and *Salmonella*

Answer 670

* The ureidopenicillin piperacillin is also active against many Gram-negative bacilli, such as *Klebseilla pneumonia* and *P aeruginosa* * Piperacillin is available only as a co-formulation with the β-lactamase inhibitor tazobatam. * Due to the propensity of *P aeruginosa* to develop resistance during therapy, an antipseudomonal β-lactam is sometimes used in combination with an aminoglycoside or fluoroquinolone.

Answer 671

* Allergic reactions include anaphylactic shock (<0.05%); serum sickness-type reactions (now rare - urticaria, fever, joint swelling, angiooedemia, pruritis, and respiratory compromise occurring 7-12 days after exposure) and a variety of skin rashes * Oral lesions, hives, interstitial nephritis (an autoimmune reaction to a penicillin-protein complex), eosinophilia, haemolytic anaemic and other haematological disturbances, and vasculitis may occur * In patients with renal failure, penicillin in high doses can cause seizures * Large doses of penicillins given orally may lead to GI upset, particularly nausea, vomiting, and diarrhoea * Ampicillin has been associated with pseudomembranous colitis * Secondary infections such as vaginal candidiasis may occur

Answer 672

The antigenic determinants are degradation products of penicillins, particularly penicilloic acid and products of alkaline hydrolysis bound to host protein.

Answer 673

* Cephalosporins are similar to penicillins but are more stable to many bacterial β-lactamases and, therefore, have a broader spectrum of activity. * However, strains of *E coli* and *Klebsiella* expressing extended-spectrum β-lactamases that can hydrolyse most cephalosporins are a growing clinical concern

Answer 674

* The intrinsic antimicrobial activity of natural cephalosporins is low, but the attachment of various R₁ and R₂ groups has yielded hundreds of potent compounds, many with low toxicity.

Answer 675

* Cefazolin * Cefadroxil * Cephalexin * Cephapirin * Cephradine These drugs are very active against Gram-positive cocci, such as streptococci and staphylococci. *E coli, K pneumoniae* and *Proteus mirabilis* are often sensitive to first-generation cephalosporins

Answer 676

* After oral doses of 500mg, peak serum levels are 15-20mcg/ml * Urine concentration is usually very high, but in most tissues levels are variable and generally lower than in serum * Cephalexin is typically given in oral dosages of 0.25-0.5g QDS (15-30mg/kg/d) * Excretion is mainly by glomerular filtration and tubular secretion into the urine. Drugs that block tubular secretion, eg, probenecid, may increase serum levels substantially * In patients with impaired renal function, dosage must be reduced.

Answer 677

* After an IV infusion of 1g, the peak level of cefazolin is approximately 185mcg/mL * The usual IV dosage for adults is 0.5-2g IV every 8 hours * Cefazolin can also be administered IM * Excretion is via the kidney, and dose adjustments must be made for impaired renal function.

Answer 678

* Oral drugs may be used for the treatment of UTIs and staphylococcal or streptococcal infections, including cellulitis or soft tissue abscess * However, oral cephalosporins should not be relied on in serious systemic infections

Answer 679

* Cefazolin penetrates well into most tissues * It is a drug of choice for surgical prophylaxis and for many streptococcal and staphylococcal infections requiring IV therapy * Cefazolin may be used for infections due to *E coli* or *K pneumoniae* when the the organism has been documented to be susceptible * Cefazolin does not penetrate the CNS and cannot be used to treat meningitis

Answer 680

* Cefaclor * Cefamandole * Cefonicid * Cefuroxime * Cefprozil * Loracarbef * Ceforanide In general, second-generation cephalosporins are relatively active against organisms inhibited by first-generation drugs, but, in addition, they have extended Gram-negative coverage. *Klebsiella* are usually sensitive.

Answer 681

* Second-generation cephalosporins may exhibit in vitro activity against *Enterobacter*, but resistant mutants that constitutively express a chromosomal β-lactamase that hydrolyses these compounds are readily selected * They should not be used to treat *Enterobacter* infections.

Answer 682

* The usual dosage for adults is 250-500mg orally BD * Children should be given 20-40mg/kg/d up to a maximum of 1g/day

Answer 683

* After 1g IV infusion, serum levels are 75-125mcg/mL for most second-generation cephalosporins. * Cefoxitin, cefotetan, cefuroxime are examples * All are renally cleared and require dosage adjustments in renal failure * Cefoxitin - 1-2g TDS-QDS * Cefotetan - 1-2g BD * Cefuroxime - 0.75-1.5g TDS

Answer 684

* The oral-second generation cephalosporins are active against β-lactamase-producing *H influenzae* or *Moraxella catarrhalis* and have been primarily used to treat sinusitis, otitis, and LRTIs * Because of their activity against anaerobes, cefoxitin and cefotetan can be used to treat mixed anaerobic infections such as peritonitis, diverticulitis and PID * **Cefuroxime** is sometimes used to treat CAPs because it is active against β-lactamase producing *H influenzae* and also many pneumococci

Answer 685

* Cefoperazone * Cefotaxime * Ceftazidime * Ceftizoxime * Ceftriaxone * Cefixime Compared with second-generation agents, these drugs have expended Gram-negative coverage, and some are able to cross the blood-brain barrier.

Answer 686

* IV infusion of 1g of parenteral cephalosporin produces serum levels of 60-140mcg/mL * Third generation cephalosporins penetrate body fluids and tissues well and IV cephalosporins achieve levels in the CSF sufficient to inhibit most susceptible pathogens

Answer 687

**Cefotaxime** - adult - 1-2g BD-QDS - paed 50-200mg/kg/d in 4-6 doses **Ceftazadime** - adult 1-2g BD-TDS - paed 75-150mg/kd/d TDS **Cefepime** - adult 0.5-2g BD - paed - 75-120mg/kg/day BD-TDS

Answer 688

* Ceftriaxone (half-life 7-8 hours) can be injected OD at a dose of 15-50mg/kd/day. * A single daily 1g dose is sufficient for most serious infections, with 2g every 12 hours recommended for treatment of meningitis and 2g every 24 hours recommended for endocarditis.

Answer 689

IM ceftriazone and azithromycin

Answer 690

* Ceftriaxone excretion is mainly through the biliary tract and no dosage adjustment is required in renal insufficiency. * The other third-generation cephalosporins are excreted by the kidney and therefore require dosage adjustment in renal insufficiency.

Answer 691

* Ceftriaxone and cefotaxime are approved for treatment of **meningitis** caused by all bacterial organisms apart from *L monocytogenes* * Ceftriaxone and cefotaxime are the most active cephalosporins against **penicillin non-susceptible strains of pnuemococci** and are recommended for empirical therapy of serious infections that may be caused by these strains * Other potential indications include empirical therapy of **sepsis in both the immunocompetent and the immunocompromised patient** and treatment of infections for which a cephalosporin is the least toxic drug available.

Answer 692

* **Cefepime** is the only available fourth-generation cephalosporin * It is more resistant to hydrolysis by chromosomal β-lactamases * However, like the third-generation compounds, it is hydrolysed by extended-spectrum β-lactamases. * Cefepine has good activity against ***P aeurginosa*, Enterobacteraicae, methicillin-susceptible *S aureus* and *S pnuemoniae*. It is highly active against *Haemophilus* and *neisseria*** * It is useful in the treatment of ***Enterobacter* infections**

Answer 693

* It penetrates well into the CSF * It is cleared by the kidneys and has a half-life of 2 hours * It's pharmacokinetic properties are very similar to those of ceftazadime.

Answer 694

* The standard dose for cefepime is 1-2g every 12 hours * However, when treating more complicated infections due to *P aeruginosa* or in the setting of immunocompromised, doses are typically increased to 2g TDS. * Because of it's broad-spectrum activity, cefepime is commonly used empirically in patients presenting with febrile neutropaenia

Answer 695

* IV * Active against MRSA * Broad Gram-negative activity not including Pseudomonas Aeruginosa

Answer 696

Overall, the frequency of cross-allergenicity between the two groups of drugs is low (approx 1%)

Answer 697

* Like penicillins, cephalosporins may elicit a variety of **hypersensitivity reactions**, including anaphylaxis, fever, skin rashes, nephritis, granulocytopaenia, and haemolytic anaemia * **Local irritation** can produce pain after IM injection and thrombophlebitis after IV injection * **Renal toxicity**, including interstitial nephritis and tubular necrosis, may occur uncommonly * Cephalosporins that contain a methylthiotetrazole group (cefotetan) may cause **hypoprothrombinaemia and bleeding disorders**

Answer 698

* Monobactams are drugs with a monocyclic β-lactam ring. * Their spectrum of activity is limited to aerobic Gram-negative organisms (including *P aeruginosa*) * Unlike other β-lactam antibiotics, they have no activity against Gram-positive bacteria or anaerobes. * **Aztreonam** is the only monobactam available in the USA

Answer 699

* It has structural similarities to ceftazadime, and it's Gram-negative spectrum is similar to that of the third-generation cephalosporins * It is stable to many β-lactamases with notable exceptions being AmpC β-lactamases and extended-spectrum β-lactamases.

Answer 700

* It penetrates well into the CSF * It is given IV TDS in a dose of 1-2g, providing a peak serum level of 100mcg/mL * The half-life is 1-2 hours and is greatly prolonged in renal failure

Answer 701

In patients with a history of penicillin anaphylaxis, aztreonam may be used to treat serious infections such as pneumonia, meningitis, and sepsis caused by susceptible Gram-negative pathogens

Answer 702

* Occasional skin rashes and elevations of serum aminotransferases occur during administration of aztreonam * Penicillin-allergic patients tolerate aztreonam without reaction * Notably, because of its structural similarity to ceftazadime, there is potential for cross-reactivity, aztreonam should be used with causation in the case of documented severe allergies to ceftazadine

Answer 703

* Traditional β-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) resemble β-lactam molecules, but they have very weak antibacterial action * They are potent inhibitors of many but not all bacterial β-lactamases and can protect hydrolysable penicillins from inactivation by these enzymes.

Answer 704

* The traditional β-lactamase inhibitors are most active against **Ambler class A β-lactamases** (plasma-encoded transposable element [TEM] β-lactamases in particular), such as those produced by staphylococci, *H influenzae, N gonorrhoeae, Salmonella, Shigella, E coli* and *K pneumoniae*. * They are **not good inhibitors of class C β-lactamases**, which typically are chromosomal encoded and inducible, produced by *Enterobacter*, *Citrobacter*, *S marcescens* and *P aeruginosa* * But they **do inhibit chromosomal β-lactamases** of *B fragilis* and *M catarrhalis*.

Answer 705

* An inhibitor extends the spectrum of its companion β-lactam provided that the inactivity against a particular organism is due to destruction by a β-lactamase and that the inhibitor is active against the β-lactamase that is produced.

Answer 706

* The carbapenems are structurally related to other β-lactam antibiotics * **Doripenem, ertapenem, imipenem** and **meropenem** are licensed for use in the US

Answer 707

* Imipenem, the first drug of this class, has a **wide spectrum** with good activity against most **Gram-negative rods, including *P aeruginosa*, Gram-positive organisms and anaerobes**. * It is resistant to most β-lactamases but not carbapenemases or metallo-β-lactamases * *enterococcus faecium*, MRSA, *C diff, Brukholderia cepacia* are resistant

Answer 708

* Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations * Consequently, it is administered together with an inhibitor of renal dehydropeptidase, **cilastatin**, for clinical use

Answer 709

* Doripenem and meropenem are similar to imipenem but have slightly greater activity against Gram-negative aerobes and slightly less activity against Gram-positives. * They are not significantly dragged by renal dehydropeptidase and do not require an inhibitor

Answer 710

* Carbapenems penetrate body tissues and fluids well, including the CSF for all but ertapenem * All are cleared renally, and the dose must be reduced in patients with renal insufficiency

Answer 711

* **Imipenem** is 0.25-0.5g IV TDS-QDS (half-life 1 hour) * **Meropenem** 0.5-1g IV TDS * **Doripenem** 0.5g administered as a 1 or 4 hour infusion TDS * **Ertapenem** has the longest half-life (4 hours) and is administered 1g IV OD or IM.

Answer 712

* A carbapenem is indicated for infections caused by susceptible organisms that are resistant to other available drugs eg, ***P aeruginosa***, and for treatment of **mixed aerobic and anaerobic infections** * Carbapenems are active against many **penicillin-non-susceptible strains of pneumococci** * Carbapenems are highly active in the treatment of ***Enterobacter* infections** because they are resistant to destruction but the β-lactamase produced by these organisms * They may be effective treatment for **febrile neutropaenic patients**

Answer 713

* The most common adverse effects of carbapenems (which tend to be more common with imipenem) are **nausea, vomiting, diarrhoea, skin rashes, and reactions at the infusion sites** * Excessive levels of imipenem in patients with renal failure may lead to **seizures** * Meropenem, doripenem, and ertapenem are much less likely to cause seizures that imipenem.

Answer 714

* It is a glycopeptide antibiotic * It is active primary against Gram-positive bacteria due to its large molecular weight and lack of penetration through Gram-negative cell membranes * The IV product is water soluble and stable for 14 days in the fridge following reconstitution.

Answer 715

* Vancomycin **inhibits cell wall synthesis** by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide * This **inhibits the transglycosylase**, preventing further elongation of the peptidoglycan and cross-linking. * The peptidoglycan is thus weakened, and the **cell becomes susceptible to lysis**. * The cell membrane is also damaged, which contributes to the antibacterial effect

Answer 716

* Resistance to vancomycin in enterococci is due to modification of the D-Ala-D-Ala binding site of the peptidoglycan building back in which the terminal D-Ala is replaced by D-lactate * This results in the loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target and loss of activity * This mechanism is also present in vancomycin-resistant *S aureus* strains, which have acquired the enterococcal resistance determinants.

Answer 717

* These strains have altered cell wall metabolism that results in a thickened cell wall with increased numbers of D-Ala-D-Ala residues, which serve as dead-end binding sites for vancomycin * Vancomycin is sequestered within the cell wall by these false targets and may be unable to reach its site of action

Answer 718

* Vancomycin is bactericidal for Gram-positive bacteria in concentrations of 0.5-10mcg/mL * Most pathogenic staphylococci are killed by 2mcg/mL or less * Vancomycin kills staphylococci **relatively slowly and only if cells are actively dividing**; the rate is less that that of the penicillins both in vitro and in vivo * Vancomycin is **synergistic in vitro with gentamicin and streptomycin** against *Enterococcus faecium* and *Enterococcus faecalis* strains that do not exhibit high levels of aminoglycoside resistance * Vancomycin is **active against many Gram-positive anaerobes including *C. diff***

Answer 719

* Vancomycin is **poorly absorbed** from the GI tract and is administered orally only for the treatment of colitis caused by *C difficile* * Parenteral doses must be administered IV * A 1 hour IV infusion of 1g produces blood levels of 15-30mcg/mL for 1-2 hours * The drug is **widely distributed in the body including adipose tissue** * **CSF levels 7-30%** of simultaneous concentrations are achieved if there is meningeal inflammation * **90% of the drug is excreted by glomerular filtration** * In the presence of renal insufficiency, striking accumulation may occur

Answer 720

* Important indications for parenteral vancomycin are **bloodstream infections and endocarditis caused by MRSA**. * However, vancomycin is not as effective as an anti-staphylococcal penicillin for treatment of serious infections caused by methicillin-susceptible strains. * Vancomycin in combination with gentamicin is an alternative regimen for treatment of **enterococcal endocarditis in a patient with a serious penicillin allergy** * Vancomycin (incombination with cefotaxime, ceftriaxone, or rifampicin) is also recommended for treatment of meningitis suspected or known to be caused by a penicillin-resistant strain of pneumococcus

Answer 721

* The recommended dosage in a patient with normal renal function is 30-60mg/kg/day BD/TDS * The traditional dosing regimen in adults with normal renal function is 1g BD; however, this dose will not typically achieve the trough concentrations (15-20mcg/mL) recommended for serious infections * For serious infections, a starting dose of 45-60mg/kg/day should be given with titration of the dose to achieve trough levels of 15-20 mcg/mL * The dosage in children is 40mg/kg/day in three or four divides doses

Answer 722

* Clearance of vancomycin is directly proportional to creatinine clearance, and the dosage is reduced accordingly in patients with renal insufficiency * For patients receiving haemodialysis, a common dosing regimen is a 1g-loading dose followed by 500mg after each dialysis session

Answer 723

* For *S aureus* infections, recommended trough concentrations are 10-15mcg/mL for mild to moderate infections * 15-20mcg/mL for more serious infections such as endocarditis, meningitis, and necrotising pneumonia

Answer 724

* Most reactions are relatively minor and reversible * Vancomycin is irritated to tissue, resulting in phlebitis at the site of injection * Chills and fever may occur * **Ototoxicity** is rare but **nephrotoxicity** is still encountered regularly with current preparations, especially with high trough levels * Administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities

Answer 725

* This infusion-related flushing is caused by release of histamine * It can be largely prevented by prolonging the infusion period to 1-2 hours or pretreatment with an antihistamine

Answer 726

* Teicoplanin is a glycopeptide antibiotic that is very similar to vancomycin in mechanism of action and antibacterial spectrum * Unlike vancomycin, it can be given IM as well as IV * Teicoplanin has a long half-life (45-70 hours), permitting once daily dosing

Answer 727

* Daptomycin is a novel cyclic lipopeptide fermentation product of *Streptomyces roseoporus*. * Its spectrum of activity is similar to that of vancomycin except that it may be active against vancomycin-resistant strains or enterococci and *S aureus* * In vitro, it has more rapid bactericidal activity that vancomycin

Answer 728

* The precise mechanism of action is not fully understood, but it is known to bind to the cell membrane via calcium-dependent insertion of its lipid tail * This results in depolarisation of the cell membrane with potassium efflux and rapid cell death * It is cleared renally

Answer 729

* 4mg/kg/dose for treatment of skin and soft tissue infections * 6mg/kg/dose for the treatment of bacteraemia and endocarditis OD in patient with normal renal function and every other day in patients with a CrCl <30ml/min * For serious infections, many experts recommend using 8-10mg/kg/dose

Answer 730

* It can cause myopathy, and creatine phosphokinase levels should be monitored weekly * Pulmonary surface antagonises daptomycin, and it should not be used to treat pneumonia * Daptomycin can also cause an allergic pneumonitis in patients receiving prolonged therapy (>2 weeks)

Answer 731

* The aminoglycosides include **streptomycin, neomycin, amikacin, gentamicin, tobramycin** * They are used most widely in combination with other agents to treat drug-resistant organisms

Answer 732

* Aminoglycosides have a hexose ring, to which various amino sugars are attached by glycosidic linkages * They are water-soluble, stable in solution, and more active at alkaline than at acid pH

Answer 733

* Aminoglycosides are irreversible inhibitors of protein synthesis, but the precise mechanism of **bactericidal activity** is unclear * The initial event is **passive diffusion via porin channels across the outer membrane** * Drug is then **actively transported across the cell membrane** into the cytoplasm by an **oxygen-dependent process** * The transmembrane electrochemical gradient supplies the energy for this process, and **transport is coupled to a proton pump** * Inside the cell, aminoglyocisdes bind to **30S-subunit** ribosomal proteins and inhibit protein synthesis (next card)

Answer 734

1) Interference with the initiation complex of peptide formation 2) Misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide and results in a non-functional protein 3) Break-up of polysomes into non-functional monosomes These activities occur more or less simultaneously, and the overall effect is irreversible and leads to cell death

Answer 735

* The **transmembrane electrochemical gradient** supplies the energy for this process, and transport is coupled to a **protein pump** * **Low extracellular pH and anaerobic conditions inhibit transport** by reducing the gradient * Transport may be **enhanced by cell wall-active drugs** such as penicillin or vancomycin; this enhancement may be the basis of the synergism of those antibiotics with aminoglycosides

Answer 736

1) **Production of transferase enzyme that inactivates the aminoglycoside by adenylylation, acetylation, or phosphorylation**; this is the principal type of resistance encountered clinically 2) There is **impaired entry of aminoglycoside into the cell**; this may result from **mutation or deletion of a porin protein** involved in transport and maintenance of the electrochemical gradient or from the conditions under which the oxygen-dependent transport process is not functional 3) The **receptor protein on the 30S ribosomal subunit may be deleted or altered** as a result of a mutation

Answer 737

* Aminoglycosides are **absorbed very poorly from the normal GI tract**, and almost the **entire oral dose is excreted in faeces** after oral administration. However, the drugs may be absorbed if ulcerations are present * Aminoglycosides are usually administered IV as a 30-60 minute infusion * After IM injection, aminoglycosides are well absorbed, giving peak concentration in blood within 30-90 minutes. After a brief distribution phase, peak serum concentrations are identical to those following IV injection * Intrathecal or IV injection is required for high levels in CSF

Answer 738

* The normal half-life of aminoglycosides in serum in **2-3 hours**, increasing to 24-48 hours in patients with significant impairment of renal function * Aminoglycosides are **only partially and irregularly removed by haemodialysis** (40-60% for gentamicin) and even less effectively by peritoneal dialysis

Answer 739

* Aminoglycosides are **highly polar cells that do not enter cells readily** * They are **largely excluded from the CNS and eye** * In the presence of active inflammation, however, CSF levels reach 20% of plasma levels, and, in neonatal meningitis, the levels may be higher * Even after parenteral administration, **concentrations of aminoglycosides are not high in most tissues expect the renal cortex.** * Concentration in most secretions is also modest; in the bile, the level may reach 30% of that in blood * With prolonged therapy, diffusion into pleural or synovial fluid may result in concentrations 50-90% of that of plasma

Answer 740

1) Aminoglycosides exhibit **concentration-dependent killing**; that is, higher concentrations kill a larger proportion of bacteria and kill at a more rapid rate 2) They also have a significant **post-antibiotic effect**, such that the antibacterial activity persists beyond the time during which measurable drug is present. This can last for several hours Because of these properties, a given total amount of aminoglycoside may have better efficacy when administered as a single large dose than when administered as multiple smaller doses

Answer 741

They may exhibit **synergistic killing** against certain bacteria. The effect of the drugs in combination is greater than the anticipated effect of each individual drug; ie, the killing effect of the combination is more additive. The synergy may be important in certain clinical situations, such as endocarditis

Answer 742

* Toxicity is unlikely to occur until a threshold concentration is reached, but, once that concentration is achieved, the time beyond this threshold becomes critical * This threshold is not precisely defined, but a trough concentration above 2mcg/mL is predictive of toxicity. * At clinically relevant doses, the total time above this threshold is greater with multiple smaller doses of drug than with a single large dose.

Answer 743

A single daily dose of 5-7mg/kg of gentamicin or tobramycin is recommended. 15mg/kg for amikacin

Answer 744

The goal is to administer the drug so that the concentrations of <1mcg/mL are present between 18 and 24 hours after dosing.

Answer 745

* Either the dose of drug is kept constant and the interval between doses is increased, or the interval is kept constant and the dose is reduced * Normograms and formulas have been constructed relating serum creating levels to adjutants in traditional treatment regimens. * Because aminoglycoside clearance is directly proportional to the creatinine clearance, a method is directly proportional to the creatinine clearance, a method for determining the aminoglycoside dose is to estimate the creatinine clearance

Answer 746

Doses of gentamicin and tobramycin should be adjusted to maintain peak levels between 5 and 10 mcg/mL (typically between 8 and 10 mcg/mL in more serious infections) and trough levels <2mcg/mL (<1mcg/mL is optimal)

Answer 747

* All aminoglycosides are ototoxic and nephrotoxic. These are more likely to be encountered when therapy is continued for more than 5 days, at higher doses, in the elderly and in the setting of renal insufficiency * Ototoxicity can manifest either as auditory damage, resulting in tinnitus and high-frequency hearing loss initially, or as vestibular damage with vertigo, ataxia and loss of balance. * Nephrotoxicity results in rising serum creatinine levels or reduced creatinine clearance, although the earliest indication often is an increase in trough serum aminoglycoside concentrations * In very high doses, they can produce a curare-like effect with neuromuscular blockade that results in respiratory paralysis. This paralysis is usually reversible by calcium gluconate, when given promptly, or neostigmine.

Answer 748

* They are mostly used against aerobic Gram-negative bacteria, especially when there is concern for drug-resistant pathogens or in critically ill patients * They are almost always used in combination with a β-lactam antibiotic to extend empiric coverage. * Penicillin-aminoglycoside combinations have also been used to achieve bactericidal activity in treatment if enterococcal endocarditis and to shorten duration of therapy for viridans streptococcal endocarditis.

Answer 749

Gentamicin sulfate, 2-10mcg/mL, inhibits in vitro many stains of staphylococci and Gram-negative bacteria, including *P.aeruginosa* and Enterobacteriaecae.

Answer 750

* Streptococci and enterococci are relatively resistant to gentamicin owning to failure of the drug to penetrate into the cell * However, gentamicin in combination with some penicillins or vancomycin produces a potent bactericidal effect, which in part is due to enhanced uptake of drug that occurs with inhibition of cell wall synthesis * Resistance to gentamicin rapidly emerges in staphylococci during monotherapy owing to selection of permeability mutants * Ribosomal resistance is rare * Among Gram-negative bacteria, resistance is most commonly due to plasmid-encoded aminoglycoside-modifying enzymes.

Answer 751

* The enterococcal enzyme that modifies gentamicin is a bifunctional enzyme that also inactivated amikacin, netilmicin and tobramycin but not streptomycin * Gram-negative bacteria that are gentamicin-resistant usually are susceptibly to amikacin, which is much more resistant to modifying enzyme activity

Answer 752

* Gentamicin is mainly used in severe infections caused by Gram-negative bacteria that are likely to be resistant to other drugs, especially *P aeruginosa, Enterobacter, Serratia marcescens, Proteus, and Klebsiella*. * It usually is used in combination with a second agent because an aminoglycoside alone may not be effective for infections outside the urinary tract.

Answer 753

It occurs in 5-25% of patients receiving gentamicin for longer than 3-5 days

Answer 754

* Ototoxicity, which tends to be irreversible, manifests itself mainly as vestibular dysfunction. Loss of hearing can also occur * Ototoxicity is in part genetically determined, having been linked to point mutations in mitochondrial DNA, and occurs in 1-5% for patients receiving gentamicin for more than 5 days

Answer 755

* It is formulated in solution (300mg in 5mL) for inhalation for treatment of *P aeruginosa* LRTI complicating cystic fibrosis * The drug is recommended as a 300mg dose regardless of the patient's age or weight for administration BD in repeated cycles of 28 days on therapy, followed by 28 days off therapy

Answer 756

Doxycycline, minocycline, chlortetracycline

Answer 757

* Free tetracyclines are crystallin amphoteric substances of low solubility * They are available as hydrochlorides, which are more soluble * Such solutions are acidic and fairly stable * Tetracyclines chelate divalent metal ions, which can interfere with their absorption and activity

Answer 758

* Tetracyclines are broad-spectrum bacteriostatic antibiotics that **inhibit protein synthesis** * They enter microorganisms in part by **passive diffusion and in part by an energy-dependent process of active transport**. Susceptible organisms concentrate the drug intracellularly * Once inside the cell, they **bind reversibly to the 30S subunit** of the bacterial ribosome, **blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex**. * This prevents addition of amino acids to the growing peptide.

Answer 759

* Tetracyclines are active against many Gram-positive and Gram-negative bacteria, including certain anaerobes, rickettsiae, chlamydiae, and mycoplasmas * For susceptible organisms, differences in clinical efficacy may be attributable to features of absorption, distribution, and excretion of individual drugs

Answer 760

1) Impaired influx or increased efflux by an active transport protein pump 2) Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome 3) Enzymatic inactivation.

Answer 761

* **Tet(AE) efflux pump-expressing Gram-negative species** are resistant to the older tetracyclines, doxycycline and minocycline * They are susceptible however to tigecycline, which is not a substrate of these pumps * Similarly, a different **pump [Tet(K)] of staphylococci** confers resistance to tetracycline, but not to doxycycline, minocycline or tigecycline, non of which are pump substrates. * The **Tet(M) ribosomal protection protein** expressed by Gram-positives produces resistance to tetracycline, doxycycline, and minocycline, but not to tigecyclime, which because of its bulky *t*-butylglycylamido substituent, has a steric hindrance effect on Tet(M) binding to the ribosome.

Answer 762

* Absorption after oral administration is approximately 60-70% for tetracycline and demeclocycline * It is 95-100% or doxycycline and minocycline * Tigecycline is poorly absorbed orally and must be administered IV

Answer 763

* A portion of an orally administered dose of **tetracycline** remains in the gut lumen, altered intestinal flora, and is excreted in the faeces * Absorption occurs mainly in the **upper small intestine** and is impaired by multivalent cations (Ca²⁺, Mg²⁺, Fe²⁺, Al³⁺); by dairy products and antaids, which contain multivalent cations; and by alkaline pH * **Tetracycline and democycline** should be administered on an **empty stomach**, while **doxycycline and minocycline** absorption is **not impaired by food**

Answer 764

* Tetracyclines are 40-80% bound by serum proteins * Peak levels of 2-4mcg/mL are achieved with a 200mg dose of doxycycline. * Tetracyclines are distributed widely to tissues and body fluids except for CSF, where concentrations are 10-25% of those in serum. * Tetracyclines cross the placenta and are also excreted in breast milk. * As a result of chelation with calcium, they bind to - and damage - growing bones and teeth.

Answer 765

Carbamazepine, phenytoin, barbiturates and chronic alcohol ingestion may shorten the half-life or tetracyclines and doxycycline by 50% due to induction of hepatic enzymes that metabolise the drugs

Answer 766

* Tetracyclines are excreted mainly in bile and urine * Some of the drug excreted in bile is reabsorbed from the intestine and may contribute to maintenance of serum levels * 10-50% of various tetracyclines is excreted into the urine, mainly by glomerular filtration * 10-40% of the drug is excreted in faeces * **Doxycycline and tigecycline, in contrast to other tetracyclines, are eliminated by non-renal mechanisms and do not accumulate significantly in renal failure, requiring no dosage adjustment**

Answer 767

* Short acting - tetracycline, chlortetracycline, and oxytetracycline (half life 6-8 hours) * Intermediate-acting - demeclocycline (half life 12 hours) * Long-acting - doxycycline and minocycline (half-lives of 16-18 hours) The almost complete absorption and slow excretion of doxycycline and minocycline allow for OD dosing, but, by convention, these two drugs are used twice daily

Answer 768

* Rickettsiae and Borrelia incl. Lyme disease and mountain spotted fever * Mycoplasma pneumoniae, chlamydiae and some spirochetes * H.pylori in gastric and duodenal ulcers * Can be used for syphilis * CAP, bronchitis, leptospirosis.

Answer 769

100mg OD or BD

Answer 770

To avoid deposition in growing bones or teeth, it should be avoided in pregnancy women and children younger than 8 years

Answer 771

* Hypersensitivity reactions are uncommon * **GI adverse effects** - nausea, vomiting and diarrhoea due to direct local irritation of the intestinal tract - can cause vaginal or oral candidiasis or C.diff * **Bony structures and teeth** in pregnancy and children * **Other toxicities** - can impair hepatic function, nephrotoxicity, sensitivity to sunlight or UV light, dizziness, vertigo and tinnitus

Answer 772

* The macrolides are a group of closely related compounds characterised by a **macrocyclic lactone ring to which deoxy sugars are attached** * The prototype drug, **erythromycin** consists of two sugar moieties attached to a 14-atom lactone ring. * **Clarithromycin and azithromycin** are semi-synthetic derivates of erythromycin * They are **poorly soluble in water** (0.1%) but dissolves readily in organic solvents. * Solutions are fairly stable at 4°C but lost activity rapidly at 20°C and at acid pH.

Answer 773

* The antibacterial action of erythromycin and other macrolides may be inhibitory or **bactericidal**, particularly at higher concentrations, for susceptible organisms * Inhibition of protein synthesis occurs via binding to the **50S ribosomal RNA**. * The binding site is near the peptidyltransferase centre, and **peptide chain elongation is prevented by blocking of the polypeptide exit tunnel** * As a result, **peptides-tRNA is dissociated from the ribosome**. * Erythromycin also **inhibits the formation of the 50S ribosomal subunit**

Answer 774

* It is active against susceptible strains of **Gram positive organisms**, especially pneumococci, streptococci, staphylococci and corynebacteria. * *Mycoplasma pneumoniae, Chlamydia trachomatis, H pylori, Listeria monocytogenes* are also susceptible * **Gram negative organisms** such as *Neisseria, Bordatella pertussis* as well as some *Rickettsia* species, *Treponema pallidum* and *Campylobacter* are susceptible * H. influenzae is somewhat less susceptible

Answer 775

1) Reduced permeability of the cell membrane or active efflux 2) Production (by Enterobacteriacae) of esterase that hydrolyse macrolides 3) Modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase Efflux and methylase production are the most important resistance mechanisms in Gram-positive organisms.

Answer 776

* Erythromycin base is destroyed by stomach acid and must be administered with enteric coating * Food interferes with absorption * The stearate and ethylsuccinate formulations are fairly acid resistant and somewhat better absorbed

Answer 777

* Large amounts of an administered dose are excreted in the bile, and only 5% is excreted in the urine * Erythromycin is not removed by dialysis * Absorbed drug is distributed widely except to the brain and CSF. * It is taken up by polymorphonuclear leukocytes and macrophages * It traverses the placenta and reaches the fetus

Answer 778

* It is a traditional drug of choice in corynebacteral infections (diphtheria) and in respiratory, neonatal, ocular or genital chlamydia infections * It was used for CAP but resistance is increased * It has been largely replaces by clindamycin for many things

Answer 779

* The oral dosage of erythromycin base or stearate is 0.25-0.5g every 6 hours (for children, 40mg/kg/day) * The dosage of erythromycin ethylsuccinate is 0.4-0.8mg every 6 hours

Answer 780

* Anorexia, nausea, vomiting, and diarrhoea are common * GI intolerance, which is due to a direct stimulant of gut motility, is the most common reason for selecting an alternative to erythromycin * It can produce cholestatic hepatitis (fever, jaundice, impaired liver function) * Fever, eosinophils, and rashes

Answer 781

* Erythromycin metabolites inhibit cytochrome P450 enzymes and thus increase the serum concentrations of numerous drugs, including theophylline, warfarin, cyclosporine and methylprednisolone. * It increases serum concentrations of oral digoxin by increasing its bioavailability

Answer 782

* Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin * Its mechanism of action is the same as erythromycin. * They are similar with respect to antibacterial activity except that clarithromycin is more active against *Mycobacterium avium* complex. It also has activity against *Toxoplasma gondii, and H. influenzae*

Answer 783

* A 500mg dose of clarithromycin produces serum concentrations of 2-3mcg/mL * The longer half-life of clarithromycin (6 hours) compared with erythromycin permits BD dosing * The recommended dosage is 250-500mg BD or 1000mg of the extended release formulation OD * Clarithromycin penetrates most tissues well, with concentrations equal to or exceeding serum concentrations

Answer 784

* It is metabolised in the liver and is partially eliminated in the urine * The major metabolite, 14-hydroxyclarithromycin, also has antibacterial activity and is eliminated in the urine * Dose reduction is recommended for patients with creatinine clearances <30ml/min

Answer 785

The advantages of clarithromycin compared with erythromycin are lower incidence of GI intolerance and less frequent dosing

Answer 786

It is derived from erythromycin by addition of a methylated nitrogen into the lactone ring

Answer 787

Its spectrum of activity, mechanism of action, and clinical uses are similar to those of clarithromycin

Answer 788

* Azithromycin is active against *M avium* complex and *T gondii*. * Azithromycin is slightly less active than erythromycin and clarithromycin against staphylococci and streptococci and slightly more active against *H influenzae* * Azithromycin is highly active against Chlamydia

Answer 789

* A 500mg dose of azithromycin produces relatively low serum concentrations on approx 0.4mcg/mL * However, it penetrates into most tissues (expect CSF) and phagocytic cells extremely well, with tissue concentrations exceeding serum concentrations by 10- to 100-fold * The drug is slowly released from tissues (tissue flat-life of 2-4 days) to produce an elimination half-life approaching 3 days. These unique properties permit OD dosing and shortening of the duration of treatment in many cases

Answer 790

* A single 1g does of azithromycin is as effective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis * As a 500mg loading dose, followed by a 250mg OD dose for 4 days is commonly used alone or in combination with a beta-lactam antibiotic to treat CAP

Answer 791

* It is rapidly absorbed and well tolerated orally * Aliminium and magnesium antacids do not alter bioavailability but delay absorption and reduce peak serum concentrations * Because it has a 15-member not 14-member lactone ring, it does not inactive cytochrome P450 enzymes and, therefore, is free of the drug interactions that occur with erythromycin and clarithromycin

Answer 792

They prolong the QT interval due to an effect on potassium ion channels This can lead to torsades de pointes arrhythmia

Answer 793

Clindamycin is a chlorine-substituted derivative of **lincomycin**

Answer 794

* Like erythromycin, it inhibits protein synthesis by interfering with the formation of initiation complexes and with aminoacyl translocation reactions. * The binding site for clindamycin on the 50S subunit of the bacterial ribosome is identical with that for erythromycin

Answer 795

* Streptococci, staphylococci, and pneumococci are inhibited by clindamycin at a concentration of 0.5-5mcg/ml * Enterococci and Gram-negative aerobic organisms are resistant * *Bacteroides* and other anaerobes are often susceptible, though resistance is increasing, particularly in Gram-negative anaerobes

Answer 796

1) mutation of the ribosomal receptor site 2) modification of the receptor by a constitutively expressed methylase 3) enzymatic inactivation of clindamycin Gram negative aerobic special are intrinsically resistant because of poor permeability of the outer membrane

Answer 797

* Oral doses of clindamycin, 0.15-0.3g every 8 hours (10-20mg/kg/day for children), yield serum levels of 2-3mcg/mL. * When administered IV, 600mg of clindamycin every 8 hours gives levels of 5-15mcg/ml * The drug is about 90% protein bound * It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells

Answer 798

* It is metabolised by the liver, and both active drug and active metabolites are excreted in bile and urine * The half-life is about 2.5 hours in normal individuals increasing to 6 hours in patients with anuria. * No dosage adjustment is required for renal failure

Answer 799

* It is indicated for the treatment of skin and soft-tissue infections caused by streptococci and staphylococci * It is commonly used in conjunction with penicillin G to treat toxic shock syndrome or necrotising fasciitis caused by Group A *Streptococcus*. * It is sometimes used in combination with an aminoglycoside or cephalosporin to treat penetrating wounds of the abdomen and the gut; infections originating the female genital tract (eg, PID, pelvic abscesses) * It is recommended for prophylaxis of endocarditis in patients with specific valvular heart disease who are undergoing certain dental procedures and have significant penicillin allergies.

Answer 800

* Common adverse effects are diarrhoea, nausea, and skin rashes * Impaired liver function (with or without jaundice) and neutropenia sometimes occur * Administration of clindamycin is a risk factor for diarrhoea and colitis due to *C.difficile*

Answer 801

* Crystalline chloramphenicol is a neutral, stable compound. * It is soluble in alcohol but poorly soluble in water * Chloramphenicol succinate, which is used for parenteral administration, is highly water-soluble * It is hydrolysed in vivo with liberation of free chloramphenicol

Answer 802

* Chloramphenicol is an inhibitor of microbial protein synthesis and is bacteriostatic against most susceptible organisms * It binds reversibly to the 50S unit of the bacterial ribosome and inhibits peptide bond formation

Answer 803

* Chloramphenicol is a broad-spectrum antibiotic that is active against both aerobic and anaerobic Gram-positive and Gram-negative organisms. * It is active also against rickettsiae but not chlamydiae * Most gram-positive bacteria are inhibited at concentrations of 1-10mcg/ml, and many gram-negative bacteria are inhibited by concentrations of 0.2-5mcg/mL * *H influenzae, Neisseria meningitidis* and some strains of *Bacteroids* are highly susceptible, for the organisms, chloramphenicol may be bactericidal

Answer 804

* Low-level resistance to chloramphenicol may emerge from large populations of chloramphenicol-susceptible cells by selection of mutants that are less permeable to the drug * Clinically significant resistance is due to production of chloramphenicol acetyl-transferase, a plasmid-encoded enzyme that inactivates the drug

Answer 805

* Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the CNS and CSF, such that concentration of chloramphenicol in brain tissue may be equal to that in serum * The drug penetrates cell membranes readily

Answer 806

* It commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50mg/kg/day after 1-2 weeks * Aplastic anaemia, a rare consequence of chloramphenicol by any route, is an idiosyncratic reaction unrelated to dose. It tends to be irreversible and can be fatal, although it may respond to bone marrow transplantation or immunosuppressive therapy. * Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol. Consequently, this may result in the **gray baby syndrome**, with vomiting, flaccidity, hypothermia, grey colour, shock, and vascular collapse

Answer 807

* Linezolid is a member of the oxazolidinone class of synthetic antimicrobials. * It is active against Gram-positive organisms including staphylococci, streptococci, enterococci, Gram-positive anaerobic cocci, and Gram-positive rods such as corynebacteria, *Nocardia* and *L monocytogenes* * It is also active against *Mycobacterium tuberculosis*

Answer 808

* It is primarily a bacteriostatic agent but is bactericidal against streptococci * It inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis * It's unique binding site, located on 23S ribosomal RNA of the 50S subunit, results in no cross-resistance with other drug classes. * Resistance is caused by mutation of the linezolid binding site on 23S ribosomal RNA

Answer 809

* It is 100% bioavailable after oral administration and has a half-life of 4-6 hours * It is metabolised by oxidative metabolism, yielding two inactive metabolites * It is neither an inducer not an inhibitor of cytochrome P450 enzymes * The recommended dosage for most indications is 600mg BD, either orally or IV

Answer 810

It is approved for vancomycin-resistant *E caecium* infections, health-care associated pneumonia, community acquired pneumonia, and both complicated and uncomplicated skin and soft tissue infections caused by susceptible Gram-positive bacteria.

Answer 811

* Thrombocytopaenia is the most common manifestation (3% of cases) * Anaemia and neutropenia may also occur, most commonly in patients with a predisposition or underlying bone marrow suppression * Cases of optic and peripheral neuropathy and lactic acidosis have been reported with prolonged courses * There are case reports of serotonin syndrome

Answer 812

* Sulphonamides with varying physical, chemical, pharmacologic and antibacterial properties are produced by attaching substituents to the amino group (-SO₂, -NH, -R) or the amino group (-NH₂) of the sulphanilamide nucleus * Sulfonamides tend to be much more soluble at alkaline than at acid pH. * Most can be prepared as sodium salts, which are used for IV administration

Answer 813

* Sulfonamide-susceptible organisms, unlike mammals, cannot use exogenous folate but must synthesis it from PABA. * This pathway is thus essential for the production of purines and nucleic acid synthesis. * As structural analogs of PABA, sulfonamides inhibit both Gram-positive bacteria, such as staph and Gram-negative bacteria such as *E coli, Klebsiella, Salmonella, Shigella* and *Enterobacter* * Activity is poor against anaerobes * *Pseudomonas aeruginosa* is intrinsically resistant to sulphonamide antibiotics

Answer 814

Organisms may have mutations that 1) cause overproduction of PABA 2) cause production of folic acid-synthesising enzyme that has low affinity for sulfonamides 3) impair permeability to the sulfonamide Dihydropteroate synthase with low sulphonamide affinity is often encoded on a plasmid that is transmittable and can disseminate rapidly and widely. Sulfonamide-resistant dihydropteroate synthase mutants also can emerge under selective pressure

Answer 815

1) Oral, absorbable (sulfamethaxazole) 2) Oral, non-absorbable (sulfasalazine) 3) Topical (sodium sulfacetamide) Oral absorbable sulfonamides are absorbed from the stomach and small intestine and distributed widely to tissues and body fluids (including the CNS and CSF), placenta, and fetus.

Answer 816

* Protein binding varies from 20% to over 90% * Therapeutic concentrations are in the range of 40-100mcg/mL of blood * Blood levels generally peak 2-6 hours after oral administration

Answer 817

* A portion of absorbed drug is acetylated or glucuronidated in the liver. * Sulfonamides and inactive metabolites are then excreted in the urine, mainly by glomerular filtration * The dosage of sulfonamides must be reduced in patients with significant renal failure

Answer 818

* Sulfonamides are infrequently used as single agents * Many strains of formerly susceptible species, including meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant * The fixed-drug combination of trimethoprim-sulfamethoxazole is the drug of choice for infections such as *Pneumocystis jiroveci* pneumonia, toxoplasmosis and nocardiosis

Answer 819

**Sulfamethoxazole** is a commonly used absorb agent available as the fixed-dose combination **trimethoprim-sulfamethoxazole**

Answer 820

**Sulfasalazine** is widely used in ulcerative colitis, enteritis and other inflammatory bowel diseases

Answer 821

* Sodium **sulfacetamide** ophthalmic solution or ointment is effective in the treatment of bacterial conjunctivitis and as an adjunctive therapy for trachoma. * **Silver sulfadiazine** is a topical sulfonamide and is preferred to mafenide for prevention of infection of burn wounds

Answer 822

* The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhoea and difficulties referable to the urinary tract. * Stevens-Johnson syndrome, although relatively uncommon (<1% of courses) is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide * Other unwanted effects include stomatitis, conjunctivitis, arthritis, haematopoietic disturbances, hepatitis and rarely, polyarteritis nodosa and psychosis

Answer 823

* It selective inhibits its bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis or purines and ultimately to DNA * The combination of trimethoprim and sulfamethoxazole is often bactericidal, compared with the bacteriostatic activity of a sulfonamide alone

Answer 824

* Resistance to trimethoprim can result from reduced cell permeability, overproduction of dihydrofolate reductase, or production of an altered reductase with reduced drug binding * Resistance can emerge by mutation, although more commonly it is due to plasmid-encoded trimethoprim-resistant dihydrofolate reductases * These resistant enzymes may be coded within transposons on conjugative plasmids that exhibit a broad host range, accounting for rapid and widespread dissemination of trimethoprim resistance amount numerous bacterial species

Answer 825

* Trimethoprim is usually given orally, alone or in combination with sulfamethoxazole, which has a similar half-life * Trimethoprim-sulfamethoxazole can also be given IV * Trimethoprim is well absorbed from the gut and distributed widely in body fluids and tissues, including CSF

Answer 826

* Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug * Therefore, when 1 part trimethoprim is given with 5 parts of sulfamethoxazole, the peak plasma concentrations are in the ratio of 1:20, which is optimal for the combined effects of these drugs in vitro

Answer 827

* About 30-50% of the sulfonamide and 50-60% of the trimethoprim (or their respective metabolites) are excreted in the urine within 24 hours * the dose should be reduced by half for patients with a creatinine clearance of 15-30ml/min

Answer 828

* Trimethoprim (a weak base) concentrates in prostatic fluid and in vaginal fluid, which are more acidic than fluid * Therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs

Answer 829

It can be given alone (100mg BD) in acute UTIs Many community-acquired organisms are susceptible to the high concentrations that are found in the urine (200-600mcg/ml)

Answer 830

* It is effective treatment for a wide variety of infections including *P jiroveci* pneumonia, UTIs, prostatic, and some infections caused by susceptible strains of *Shigella, Salmonella*, and non-TB mycobacteria * It is active against most *Staph aureus* strains, both methicillin resistant and sensitive and against respiratory tract pathogens such as *Haemophilus, Moraxella, Klebsiella* (but not *Mycoplasma pneumoniae*) * However, there is increasing resistance in strains of *E.coli* and *pneumococci*

Answer 831

* One double strength tablet (each tablet contains trimethoprim 160mg plus sulfamethoxazole 800mg) BD is effective treatment for UTIS, prostatitis, uncomplicated skin and soft tissue infections, and infections caused by susceptible strains of *Shigella* and *Salmonella* * Bone and joint infections caused by *S.aureus* can be effectively treated, typically at doses of 8-10mg/kg per day of the trimethoprim component. * One single-strength (80/400) tablet given three times weekly may serve as prophylaxis in recurrent UTIs of some women * The dosage for children treated with shigellosis, UTI or otitis media is 8/40 mg/kg/day divided into two doses

Answer 832

* They can be treated with high doses of either the oral or IV combination (dosed on the basis of the trimethoprim component at 15-20mg/kg/day) * *P jiroveci* can be prevented in immunosuppressed patients by a number of low dose regimens such as one double-strength tablet daily or three times per week

Answer 833

* A solution of the mixture containing 80mg trimethoprim plus 400mg sulfamethoxazole per 5mL diluted in 125mL of 5% dextrose in water can be administered by IV infusion over 60-90 minutes * It is the agent of choice for moderately severe to severe pneumocystis pneumonia * It may be an effective alternative for infections caused by multi drug-resistant species such as *Enterobacter* and *Serratia*; shigellosis; or typhoid

Answer 834

* Trimethoprim produces the predictable adverse effects of an antifolate drugs, especially megaloblastic anaemia, leukopenia, and granulocytopaenia * The combination trimethoprim-sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides. * N&V, diarrhoea, fever, vasculitis, renal damage and CNS disturbances * Patients with AIDS have a particularly high frequency of untoward reactions

Answer 835

* Some examples are norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin * They are synthetic fluorinated analogs of nalidixic acid * They are active against a variety of gram-positive and gram-negative bacteria

Answer 836

* Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. * Inhibition of DNA gyrase prevents the relaxation of positive supercoiled DNA that is required for normal transcription and replication * Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division

Answer 837

* Cipro, enoxacin, lomefloxacin, levofloxacin comprise a second group of similar agents possessing excellent gram-negative activity and moderate to good activity against gram-positive bacteria. They are active against *Enterobacter, P earuginosa, Neisseria meningitidis, Haemophilia* and *Campylobacter*. They can treat methicillin-susceptible staph aureus but not MRSA. * **Moxifloxacin** has improved activity against gram positive organisms, particular *S pneumoniae* * They are active against agents of atypical pneumonia (e.g mycoplasma and chlamydiae)

Answer 838

* Norfloxacin is the least active of the fluoroquinolones * In general, none of the other quinolones are as active as ciprofloxacin against gram-negative organisms

Answer 839

* The first type utilises Qtr proteins, which protect DNA gyrase from the fluoroquinolones * The second is a variant of an aminoglycoside acetyltransferase capable of modifying ciprofloxacin. Both mechanisms confer low-level resistance that may facilitate the point mutations that confer high-level resistance and also may be associated with resistance to other antibacterial drug classes

Answer 840

* After oral administration, the fluoroquinolones are well absorbed (bioavailability of 80-95%) and distributed widely in body fluids * Serum half-lives range from 3-10 hours. The relatively long half-lives of levofloxacin and moxifloxacin permit once-daily dosing * Oral absorption is impaired by divalent and trivalent cations, including those in antacids. Therefore, oral fluoroquinolones should be taken 2 hours before to 4 hours after any products containing these cations

Answer 841

It doesn't! The serum concentrations of IV administered drug are similar to those of orally administered drug

Answer 842

* Most fluoroquinolones, moxifloxacin being an important exception, are eliminated by renal mechanisms, either tubular secretion or glomerular filtration * Dosage adjustment is required for patients with creatinine clearances less than 50mL/min, the exact adjustment depending on the degree of renal impairment and the specific fluoroquinolone being used * Dosage adjustment for renal failure is not necessary for moxifloxacin since it is metabolised in the liver; it should be used in caution in patients with hepatic failure

Answer 843

* Fluoroquinolones (apart from moxifloxacin) are effective in UTIs caused by many organisms, including *P aeruginosa* * They are also effective for bacterial diarrhoea caused by *Shigella, Salmonella*, toxigenic *E coli* and *Campylobacter*. * Apart from norfloxacin, they are used in soft tissues, bones, and joints and in intra-abdominal and respiratory tact infections, including those caused by multi drug-resistant organisms such as *Pseudomonas* and *Enterobacter* * Ciprofloxacin is a drug of choice for prophylaxis and treatment of anthrax * They are suitable for prophylaxis of bacterial infection in neutropenic cancer patients * With their enhanced gram-positive activity and activity against typical pneumonia agents (chlamydia, *Mycoplasma*, and *Legionella*), levofloxacin, gemifloxacin, and moxifloxacin are effective treatment for LRTIs

Answer 844

* They are generally well tolerated * The most common effects are nausea, vomiting, and diarrhoea. * Occasionally, headache, dizziness, insomnia, skin rash, or abnormal LFTs develop * Prolongation of the QTc interval may occur with levofloxacin, gemifloxacin, and moxifloxacin * They may cause growing cartilage damage and cause an arthropathy. Thus, they are not recommended in under 18s as a first-line, although they may be used for pseudomonas infections in CF * Tendonitis, a complication in adults, can be serious because of the risk of tendon rupture. Risk factors for tendonitis include advanced age, renal insufficiency, and concurrent steroid use * They should be avoided in pregnancy * It has also been associated with neuropathy * Although many potential adverse effects are uncommon, they have been take off all first-line treatments

Answer 845

Isoniazid, rifampin, pyrazinamide, and ethambutol * Isoniazid and rifampin are the most active drugs. Administered in combination for 9 months they will cure 95-98% of cases of TB * In practice, therapy is usually initiated with a four drug regimen until susceptibility of the clinical isolate has been determined. * In susceptible isolates, the continuation phase consists of an additional 4 months with isoniazid and rifampin. * If therapy is initiated after the isolate is known to be susceptible to isoniazid and rifampin, ethambutol does not need to be added

Answer 846

* Isoniazid - 300mg/day * Rifampin - 600mg/day * Pyrazinamide - 25 mg/kg/day * Ethambutol - 15-25 mg/kg/day

Answer 847

* It is **bactericidal** for actively growing tubercle bacilli. It penetrates into macrophages and is active against both extracellular and intracellular organisms. * It **inhibits synthesis of mycotic acids**, which are essential components of mycobacterial cell walls. * It is a **prodrug that is activated by KatG**, the mycobacterial catalase-peroxidase. The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycotic acid synthesis.

Answer 848

* Resistance to isoniazid is associated with mutations resulting in **overexpression of *inhA*, which encodes an NADH-dependent acyl carrier protein reductase** * Mutation of **deletion of the *katG* gene** * Promoter mutations resulting in **overexpression of *ahpC***, a gene involved in protection of the cell from oxidative stress * Mutations in *kasA* * Overproducers of *inhA* express low-level isoniazid resistance and cross-resistance to ethionamide * *KatG* mutants express high-level isoniazid resistance and often are not cross-resistant to ethionamide

Answer 849

* It is readily absorbed from the GI tract, optimally on an empty stomach; peak concentrations may be decreased by up to 50% when taken with a fatty meal * A 300mg dose achieves peak plasma concentrations of 3-5 mcg/mL within 1-2 hours. * It diffuses readily into all body fluids and tissues * The concentration in the CNS and CSF ranges between 20-100% of simultaneous serum concentrations

Answer 850

* Metabolism of isoniazid, especially acetylation by liver-*N*-acetyltransferase, is genetically determined * The average plasma concentration of isoniazid in rapid acetylators is about 1/3rd to 1/2 of the that in slow acetylators, and average half-lives are less than 1 hour and 3 hours, respectively. * More rapid clearance of isoniazid by rapid acetylators is usually of no therapeutic consequence when appropriate doses are administered daily but sub-therapeutic concentrations may occur if drug is administered as a once-weekly dose of if there is malabsorption

Answer 851

* Isoniazid metabolites and a small amount of unchanged drug are excreted in the urine * The dosage need not be adjusted in renal failure * Dose adjustment is not well defined in patients with severe pre-existing hepatic insufficiency and should be guided by serum concentrations if a reduction in dose is contemplated. * It inhibits several cytochrome P450 enzymes, leading to increased concentrations of such medications as phenytoin, carbamazepine, and benzodiazepines However, when used in combination with rifampin, a potent CYP enzyme inducer, the concentrations of these medications are usually decreased.

Answer 852

* **Intensive phase** - isoniazid, rifampin, pyrazinamide and ethambutol daily for minimum 8 weeks * **Continuation phase** - isoniazid and rifampin daily for a minimum of 18 weeks

Answer 853

It is usually given orally but can be given parenterally in the same dosage

Answer 854

Isoniazid as a single agent is indicated for treatment of latent TB. The dosage is 300mg/day or 900mg twice weekly and the duration is usually about 9 months

Answer 855

* **Immunologic reactions** - fever and skin rashes are occasionally seen, drug-induced systemic lupus erythematous has been reported * **Isoniazid-induced hepatitis is the most common major toxic effect**. Clinical hepatitis with loss of appetite, vomiting, nausea, jaundice, and RUQ pain occurs in 1% of recipients and can be fatal. The risk increases with age and with alcohol dependence. * **Peripheral neuropathy** is observed in 10-20% of patients give dosages greater than 5mg/kg/day, but is infrequently seen at usual doses. It is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS and uraemia. It is due to relative pyridoxine deficiency, which is readily reversed by administration of pyridoxine

Answer 856

* It is a semisynthetic derivative of rifamycin. * It is active in vitro against Gram-positive organisms, some gram-negative organisms, such as *Nerisseria* and *Haemophilus* species, mycobacteria and chlamydiae

Answer 857

* It binds to the β subunit of **bacterial DNA-dependent RNA polymerase** and thereby **inhibits RNA synthesis**. * Resistance results from any one of several possibly point mutations in *rpoB*, the gene for the β subunit of RNA polymerase. These **mutations result in reduced binding of rifampin** and is not inhibited by it. * Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and penetrates into phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities

Answer 858

* It is well absorbed after oral administration and excreted mainly through the liver into bile * It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in faeces and a small amount excreted in the urine. * Dosage adjustment for renal or hepatic insufficiency is not necessary. * Usual doses result in serum levels of 5-7mcg/mL. It is widely distributed in body fluids and tissues * The drug is relatively highly protein-bound and adequate CSF concentrations are achieved only in the presence of meningeal inflammation

Answer 859

* It strongly induces most cytochrome P450 isoforms, which increases the elimination of numerous other drugs including methadone, anticoagulants, some anticonvulsants, protease inhibitors, contraceptives and a host of others. * Co-administration of rifampin results in significantly lower serum levels of these drugs

Answer 860

* Usually 600 mg/day orally, it must be administered with isoniazid or other anti-TB drugs to patients with active TB to prevent emergence of drug-resistant mycobacteria * In some short-course therapies, 600mg of rifampicin is given twice weekly * Rifampin, 600mg daily for 4 months as a singe drug, is an alternative to isoniazid for patients with latent TB who are unable to take isoniazid. * An oral dose to 600mg BD for 2 days can eliminate meningococcal carriage * Rifampin combination therapy is also used for treatment of serious staph infections such as osteomyelitis, prosthetic joint infections, and prosthetic valve endocarditis

Answer 861

* It imparts a harmless orange colour to urine, sweat and tears. * Occasional adverse effects include rashes, thrombocytopaenia, and nephritis. * It may cause cholestatic jaundice and occasionally hepatitis, and it commonly causes light-chain proteinuria * If administered less often than twice weekly, it may cause a flu-like syndrome characterised by fever, chills, myalgias, anaemia and thrombocytopaenia * It has been associated with acute tubular necrosis

Answer 862

* It **inhibits mycobacterial arabinosyl transferases**, which are encoded by the *embCAB* operon. * Arabinosyl transferases are involved in the polymerisation reaction of arabinoglycan, an **essential component of the mycobacterial cell wall**. * **Resistance** to ethambutol is due to mutations resulting in **overexpression** of *emb* gene products or within the *embB* structural gene.

Answer 863

* Ethambutol is well absorbed from the gut * After ingestion of 25mg/kg, a blood level peak of 2-5mcg/mL, is reached in 2-4 hours. * About 20% of the drug is excreted in faeces and 50% in urine in unchanged form. * Ethambutol accumulates in renal failure, and the dose could be reduced to three times weekly if creatinine clearance is less than 30mL/min * Ethambutol crosses the blood-brain barrier only when the meninges are inflamed. Concentrations in CSF are highly variable, ranging from 4-64% of serum levels in the setting of meningeal inflammation.

Answer 864

* Hypersensitivity to ethambutol is rare * The most common serious adverse event is retrobulbar neuritis, resulting in loss of visual acuity and red-green colour blindness * This dose-related adverse effect is more likely to occur at dodges at 25 mg/kg/day continued for several months * Experts recommend baseline and monthly visual acuity and colour discrimination testing, with particular attention to patients on higher doses or with impaired renal function. It is contra-indicated in children due to this

Answer 865

* It is converted to pyrazinoic acid - the active form of the drug - by mycobacterial pyrazinamidase, which is encoded by *pncA* * **Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions** * Resistance may be due to impaired uptake of pyrazinamide or mutations in *pncA* that impair conversion of PZA to its active form

Answer 866

* It is well absorbed from the GI tract and widely distributed in body tissues, including inflamed meninges * The half-life is 8-11 hours * The parent compound is metabolised by the liver but metabolites are renally cleared, therefore, PZA should be administered at 25-35mg/kg three times weekly (not daily) in haemodialysis patients and those in whom creatinine clearance is less than 30mL/minute

Answer 867

Major adverse effects of PZA include hepatotoxicity (in 1-5% of patients), nausea, vomiting, drug, fever, photosensitivity and hyperuricaemia

Answer 868

* It is selective in its fungicidal effect because it exploits the different in lipid composition of fungal and mammalian cell membranes * **Ergosterol**, a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is **cholesterol** * Amphotericin B binds to ergosterol and alters the permeability of the cell by forming amphotericin B-associated pores in the cell membrane * Amphotericin B combines avidly with lipids (ergosterols) along the double bond-rich side of its structure and associates with water molecules along the hydroxyl-rich side. * This amphipathic characteristic facilities pore formation by multiple amphotericin molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside. * The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell death

Answer 869

It occurs if ergosterol binding is impaired, either by decreasing the membrane concentration of ergosterol, or by modifying the sterol target molecule to reduce its affinity for the drug

Answer 870

* Amphotericin B remains the antifungal agent with the broadest spectrum of action. * It has activity against the clinically significant yeasts, including *Candida albicans* and *Crypotococcus neoformans* and pathogenic moles such as *Aspergillus*.

Answer 871

* Owing to its broad spectrum of activity and fungicidal action, it remains a useful agent for all **life-threatening mycotic infections**, although newer, less toxic agents have largely replaced it for most conditions * Amphotericin B is often used as the initial induction regimen to rapidly reduce fungal burden and then replaced by one of the newer azole drugs for chronic therapy or prevention of relapse. * Such induction therapy is especially important for immunosuppressed patients and those with severe fungal pneumonia, severe cryptococcal meningitis, or disseminated infections with one of the endemic mycoses such as histoplasmosis or coccidioidomycosis.

Answer 872

* For treatment of systemic fungal disease, amphotericin B is given by slow IV infusion at a dosage of 0.5-1 mg/kg/day. * Local or topical administration of amphotericin B has been used with success * Mycotic corneal ulcers and keratitis can be cured with topical drops as well as by direct subconjunctival injection * Fungal arthritis has been treated with adjunctive local injection directly into the joint * Candiduria responds well to bladder irrigation with amphotericin B and this route has been shown to produce no significant toxicity

Answer 873

* **Infusion-related toxicity** - infusion-related reactions are nearly universal and consist of fever, chills, muscle spasm, vomiting, headache and hypotension. They can be ameliorated by slowed the infusion rate or decreasing the daily dose. Many clinicians administer a test dose of 1mg IV to gauge the severity of the reaction * **Cumulative toxicity** - renal damage is the most significant toxic reaction. It occurs in nearly all patients treated with clinically significant doses. A reversible component is associated with decreased renal perfusion and represents a form of pre-renal renal failure. An irreversible component results from renal tubular injury and subsequent dysfunction

Answer 874

* The imidazoles consist of ketoconazole, miconazole, and clotrimazole. The latter two drugs are now used only in topical therapy * The triazoles include itraconazole, fluconazole, voriconazole, isavuconazole

Answer 875

* The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes. * The select toxicity of azole drugs relates to their greater affinity for fungal than for human cytochrome P450 enzymes. * Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for their higher incidence of drug interactions and adverse effects

Answer 876

The spectrum of action of azole medications is broad, including may species of *Candida, C neoformans*, the endemic mycoses, the dermatophytes, and, in the case of itraconazole, posaconazole, isavuconazole and voriconazole, even *Aspergillus* infections.

Answer 877

* As a group, they are relatively non-toxic * The most common adverse reaction is relatively minor GI upset. * All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis * All azole drugs are prone to drug interactions because they affect the mammalian cytochrome P450 enzyme system

Answer 878

* Fluconazole displays a high degree of water solubility and **good CSF penetration**. * Unlike ketoconazole and itraconazole, its **oral bioavailability is high** * Drug interactions are also less common because fluconazole has the **least effect of all the azoles on hepatic microsomal enzymes**. * Because of fewer hepatic enzyme interactions and better GI tolerance, fluconazole has the widest therapeutic index of the azoles, permitting more aggressive dosing in a variety of fungal infections.

Answer 879

The drug is available in oral or IV formulation and is used at a dosage of 100-800 mg/day

Answer 880

* Some examples are caspofungin, micafungin and anidulafungin * These agents are active against *Candida* and *Aspergillus* , but not *C neoformans* or the agents of zygomycosis and mucormycosis

Answer 881

* Echinocandins are available only as IV formulations * **Caspofungin** is administered as a single loading dose of 70mg, followed by a daily dose of 50mg. It is water soluble and highly protein-bound. The half-life is 9-11 hours, and the metabolites are excreted by the kidneys and GI tract. Dose adjustments are required only in the presence of severe hepatic insufficiency * Micafungin displays similar properties with a half-life of 11-15 hours and is used at a dose of 150mg/day for treatment of oesophageal candidiasis, 100mg/day for treatment of candidaemia and 50mg/day for prophylaxis of fungal infections.

Answer 882

They act at the level of the fungal cell wall by inhibiting the synthesis of β(1-3)-glucan. This results in disruption of the fungal cell wall and cell death

Answer 883

* They are extremely well tolerated, with minor GI side effects and flushing reported infrequently * Elevated liver enzymes have been noted in several patients receiving caspofungin in combination with cyclosporine, and this combination should be avoided.

Answer 884

* Nystatin is too toxic for parenteral administration and is only used topically. It is currently available in creams, ointments, suppositories, and other forms for application to skin and mucous membranes. * When used topically, it has little toxicity, although oral use is often limited by the unpleasant taste * It is active against most *Candida* and is most commonly used for suppression of local candidal infections. * Some common indications include oropharyngeal thrush, vaginal candidiasis, and intertriginous candidal infections

Answer 885

* The two most commonly used topically are clotrimazole and miconazole * Both are available over the counter and are often used for vulvovaginal candidiasis * Oral clotrimazole troches are available for treatment of oral thrush and are a pleasant-tasting alternative to nystatin * In cream form, both agents are useful for dermatophytic infections, including tinea corporis, tinea pedis, and tinea cruris.

Answer 886

* Viruses are obligate intracellular parasites; their replication depends primarily on synthetic processes of the host cell. * Therefore, to be effective, antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell. * Non-selective inhibitors of virus replication may interfere with host cell function and result in toxicity

Answer 887

* Three oral nucleoside analogs are licensed for the treatment of HSV and VZV infections: acyclovir, valacyclovir, and famciclovir * They have similar mechanisms of action and comparable indications for clinical use * All are well tolerated

Answer 888

* They shorten the duration of symptoms by approximately 2 days, the time to lesion healing by 4 days and the duration of viral shedding by 7 days in first episodes of genital herpes and shortening of the overall time course by 1-2 days in recurrent genital herpes * Treatment of first-episode genital herpes does not alter the frequency or severity of recurrent outbreaks * Long-term suppression with antiherpes agents in patients with frequent recurrences of genital herpes decreases the frequency of symptomatic recurrences and of asymptomatic viral shedding, thus decreasing the rate of sexual transmission.

Answer 889

* **First episode** - 400mg TDS 7-10 days * **Recurrent episodes** - 800mg TDS 2 days * **Suppression** - 400-800mg BD/TDS

Answer 890

* **First episode** - 250mg TDS for 7-10 days * **Recurrent episodes** - 125mg BD for 5 days * **Suppression** - 250-500mg BD

Answer 891

* **First episode** - 400mg TDS 7-10 days * **Recurrent episodes** 400mg 5 times per day for 5 days * **Suppression** - 400-800mg BD/TDS In recurrent episodes you can also have topical 5% cream 5 times per day for 4 days

Answer 892

10-15 mg/kg IV TDS for 21 days

Answer 893

10-20 mg/kg IV TDS for 14-21 days

Answer 894

**Acyclovir** - 20 mg/kg (maximum 800mg) QDS for 5 days **Valacyclovir** - 20mg/kg (maximum 1g) TDS for 5 days

Answer 895

**Acyclovir** - 800mg five times per day for 7-10 days **Famciclovir** - 500mg TDS for 7 days **Valacyclovir** - 1g TDS for 7 days

Answer 896

The antiherpes agents significantly decrease the total number of lesions, duration of symptoms, and viral shedding in patients with varicella (if begun within 24 hours after the onset of rash) or cutaneous zoster (if begun within 72 hours); the risk of post-herpatic neuralgia is also reduced if treatment is initiated early.

Answer 897

In comparative trials with acyclovir for the treatment of patients with zoster, rates of cutaneous healing with valacyclovir or famciclovir were similar, but the latter agents were associated with shorter duration of zoster-associated pain

Answer 898

Since VZV is less susceptible to the antiherpes agents than HSV, higher doses are required.

Answer 899

* It is an acyclic guanosine derivative with clinical activity against HSV-1, HSV-2 and VZV, but it is approximately 10 times more potent against HSV-1 and HSV-2 than VZV. * In vitro activity against EBV, CMV and HHV-6 is present but weaker

Answer 900

* Acyclovir requires three phosphorylation steps for activation. * It is **converted first to the monophosphate** derivative by the virus-specified thymidine kinase and **then to the di- and triphosphate** compounds by host cell enzymes * Because it requires the viral kinase for initial phosphorylation, acyclovir is **selectively activated** - and the active metabolite accumulates - only in infected cells * Acyclovir triphosphate **inhibits viral DNA synthesis** by two mechanisms: competition with deoxyGTP for the viral DNA polymerase, resulting in **binding to the DNA template as an irreversible complex**; and **chain termination following incorporation into the viral DNA**

Answer 901

* It is low (15-20%) and is unaffected by food * Topical formulations produce high concentrations in herpetic lesions, but systemic concentrations are undetectable by this route

Answer 902

* It is clearly primarily by glomerular filtration and tubular secretion * The half-life is 2.5-3 hours in patients with normal renal function and 20 hours in patients with anuria * It diffuses readily into most tissues and body fluids. CSF concentrations are 20-50% of serum values

Answer 903

* It can develop in HSV or VZV through alteration in either the **viral thymidine kinase or the DNA polymerase**, and clinically resistant infections have been reported in immunocompromised hosts * Most clinical isolates are resistant on the basis of deficient thymidine kinase activity and thus are cross-resistant to valacyclovir and famciclovir

Answer 904

* It is generally well tolerated although nausea, diarrhoea and headache may occur * IV infusion may be associated with reversible renal toxicity (ie crystalline nephropathy or interstitial nephritis) or neurologic effects (eg, tremors, delirium, seizures). However these are uncommon with adequate hydration and avoidance of rapid infusion rates

Answer 905

It is rapidly converted to acyclovir after oral administration via first-pass enzymatic hydrolysis in the liver and intestine, resulting in serum levels that are 3-5 times greater than those achieved with oral acyclovir and approximate those achieved with IV acyclovir

Answer 906

* Oral bioavailability is 54-70% and CSF levels are about 50% of those in serum * Elimination half-life is 2.5-3.3 hours

Answer 907

* After oral administration, famciclovir is rapid deacetylated and oxidised by first-pass metabolism to penciclovir. * It is active in vitro against HSV-1, HSV-2, VZV, EBV, and HBV * As with acyclovir, activation by phosphorylation is catalysed by the virus-specified thymidine kinase in infected cells, followed by competitive inhibition of the viral DNA polymerase to block DNA synthesis * Unlike acyclovir, however, penciclovir does not cause chain termination. * Penciclovir has lower affinity for the viral DNA polymerase that acyclovir, but it achieves higher intracellular concentrations

Answer 908

* The bioavailability of penciclovir from orally administered famciclovir is 70% * The intracellular half-life of penciclovir triphosphate is prolonged, at 7-20 hours. * Penciclovir is excreted primarily in the urine

Answer 909

* Dissemination of infection can include retinitis, colitis, oesophagitis, CNS disease and pneumonitis * The availability for oral valganciclovir has decreased the use of IV ganciclovir for the prophylaxis and treatment of end-organ CMV disease. Oral valganciclovir has replaced oral ganciclovir because of its lower pill burden

Answer 910

**Induction**: 900mg BD for 21 days **Maintenance**: 900mg OD

Answer 911

* It has bioavailability of 60% and should be taken with food * The major route of elimination is renal, through glomerular filtration and active tubular secretion.

Answer 912

* The most common adverse effect is myelosuppression * Other potential adverse effects are nausea, diarrhoea, fever, rash, headache, insomnia and peripheral neuropathy

Answer 913

* Nucleoside-nucleotide reverse transcriptase inhibitors (NRTIs) * Non-nucleoside reverse transcriptase inhibitors (NNRTIs) * Protease inhibitors (PIs) * Fusion inhibitors * CCR5 co-receptor antagonists * Integrase strand transfer inhibitors (INSTIs) These agents inhibit HIV replication at different parts of the cycle

Answer 914

* Administration of combination antiretroviral therapy, typically including at least three antiretroviral agents with different susceptibility patterns, has become the standard of care * Viral susceptibility to specific agents varies among patients and may change with time * Therefore, such combinations much be chosen with care and tailored to the individual * Important factors in the selection of agents for any given patient are tolerability, convenience, and optimisation of adherence. New drugs with high potency, low toxicity and good tolerability increase the feasibility of early, lifelong treatment

Answer 915

* The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase * Incorporation into the growing viral DNA chain causes premature chain termination due to inhibition of binding with the incoming nucleotide * Each agent required intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form

Answer 916

* Typical resistance mutations include M184V, L74V, D67N, and M41L * Lamivudine or emtricitabine therapy tends to select rapidly for the M184V mutation in regimens that are not fully suppressive * While the M184V mutation confers reduced susceptibility to abacivor, didanosine and zalcitabine, it's presence may restore susceptibility to zidovudine

Answer 917

* All NRTIs may be associated with mitochondrial toxicity, which may manifest as peripheral neuropathy, pancreatitis, lipoatrophy, and hepatic steatosis * Less commonly, lactic acidosis may occur, which can be fatal * NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly or metabolic acidosis if unknown cause

Answer 918

* Abacavir * Didanosine * Emtricitabine * Lamivudine * Stavudine * Tenofivir

Answer 919

* The NNRTIs bind directly to HIV-1 reverse transcriptase, resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase activity * The binding site of NNRTIs is near to but distinct from that of NRTIs * Unlikely the NRTI agents, NNRTIs neither complete with nucleoside triphosphates nor require phosphorylation to be active

Answer 920

The second generation NNRTIs (etravirine, rilpivirine) have higher potency, longer half-lives and reduced side-effect profiles compared with older NNRTIs (delavirdine, efavirenz, nevirapine)

Answer 921

* Baseline genotypic testing is recommended prior to iniating NNRTI treatment because primary resistance rates range from approx 2-8%. * It can occur rapidly with mono therapy and can result from a single mutation * The K103N and Y181C mutations confer resistance to the first generation NNRTIs, but not to etravirine or rilpivirine * Other mutations (L100I, Y188C, G190A) may also confer cross-resistance among the NNRTIs class. * There is **NO** cross-resistance between the NNRTIs and the NRTIs; in fact, some nucleoside-resistant viruses display hypersusceptibility to NNRTIs

Answer 922

* As a class, NNRTIs agents tend to be associated with varying levels of GI intolerance and skin rash, the latter of which may be infrequently be serious (eg, Stevens-Johnson syndrome) * A further limitation to use of NNRTI agents as a component of antiretroviral therapy is their metabolism but the CYP450 system, leading to innumerable potential drug-drug interactions * All NNRTI agents are substrate for CYP3A4 and can act as inducers (nevirapine), inhibitors (delavirdine) or mixed inducers and inhibitors (efavirenz, etravirine)

Answer 923

* Delavirdine * Efavirenz * Etravirine * Nevirapine * Rilpivirine

Answer 924

* During the later stages of the HIV growth cycle, the *gag* and *gag-ol* gene products are translated into polyproteins, and these become immature budding particles. * The HIV protease is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature vision core * By preventing post-translational cleavage of the Gag-Pol polyprotein, protease inhibitors (PIs) prevent the processing of viral proteins into functional conformations, resulting in the production of immature, non-infectious viral particles. * Unlike the NRTIs, PIs do not need intracellular activation

Answer 925

* Specific genotypic alterations that confer phenotypic resistance are fairly common with these agents, thus contraindicating monotherapy * Some of the most common mutations conferring broad resistance to PIs are substitutions at the 10,46,54,82,84 and 90 codons; the number of mutations may predict the level of phenotypic resistance * The I50L substitution emerging during atazanavir therapy has been associated with *increased susceptibility* to other PIs

Answer 926

* As a class, PIs are associated with GI intolerance, which may be dose-limiting, and lipodystrophy, which includes both metabolic (hyperglycaemia, hyperlipidaemia) and morphologic (lipoatrophy, fat deposition) derangements * A syndrome of redistribution and accumulation of body fat that results in central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, and a cushingoid appearance has been observed * PIs may be associated with cardiac conduction abnormalities, including PR and QT interval prolongation. A baseline ECG and avoidance of other agents causing prolonged PR and QT intervals should be considered. * Drug-induced hepatitis and rare severe hepatotoxicity have been reported to varying degrees with all PIs * All PIs are extensively metabolised by CYP3A4, creating the possibility for drug-drug interactions

Answer 927

* Atazanavir * Darunavir * Fosamprenavir * Indinavir * Lopinavir * Nelfinavir * Ritonavir * Saquinavir * Tripanavir

Answer 928

* The process of HIV-1 entry into host cells is complex; each step presents a potential target for inhibition * Viral attachment to the host cell entails binding of the viral envelope glycoprotein complex gp160 (consisting of gp120 and gp41) to its cellular receptor CD4 * This binding induces conformational changes in gp120 that enable access to the chemokine receptors CCR5 or CXCR4. * Chemokine receptor binding induces further conformational changes in gp120, allowing exposure to gp41 and leading to fusion of the viral envelope with the host cell membrane and subsequent entry of the viral core into the cellular cytoplasm * **Enfuvirtide** binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes

Answer 929

* Enfuvirtide, which must be administered by subcutaneous infection, is the only parentally administered antiretroviral agent * Metabolism appears to be by proteolytic hydrolysis **without** involvement of the CYP450 system * Elimination half-life is 3.8 hours

Answer 930

* Resistance can result from mutations in gp41; the frequency and significance of this phenomenon are being investigated * However, enfuvirtide lacks cross-resistance with the other currently approved antiretroviral drug classes

Answer 931

* The most common adverse effects are local injection site reactions, consisting of painful erythematous nodules. although frequent, these are typically mild-to-moderate in severity and rarely lead to discontinuation * Other potential side effects include insomnia, headache, dizziness, and nausea * Hypersensitivity reactions may rarely occur, are of varying severity and may recur on re-challenge

Answer 932

* Maraviroc is approved for use in combination with other antiretroviral agents in adult patients infected only with CCR5-tropic HIV-1 * Maraviroc binds specifically and selectively to the host protein CCR5, one of two chemokine receptor necessary for entrance of HIV into CD4+ cells. * Since maraviroc is active against HIV that uses the CCR5 co-receptor exclusively, and not against HIV strains with CXCR4 dual, or mixed tropism, co-receptor tropism should be determined by specific testing before maraviroc is started.

Answer 933

* The absorption is rapid but variable, with the time to maximum absorption generally 1-4 hours after ingestion of the drug * Most of the drug (>75%) is excreted in the faeces, whereas approximately 20% is excreted in urine * Maraviroc is a substrate for CYP3A4 and therefore requires adjustment in the presence of drugs that interact with these enzymes * It is contraindicated in patients with severe or end-stage renal impairment. * It is also a substrate for P-glycoprotein, which limits intracellular concentrations of the drug

Answer 934

* Potential adverse effects include URTIs, cough, pyrexia, rash, dizziness, muscle and joint pain, diarrhoea, sleep disturbance, and elevations in serum aminotransferases * Hepatotoxicity has been reported, which may be preceded by a systemic allergic reaction (ie, pruritic rash, eosinophilia, or elevated IgE) * MI has been observed in patients receiving maraviroc

Answer 935

* The class of agents binds integrase, a viral enzymes essential to the replication of both HIV-1 and HIV-2. * By doing so, it inhibits strand transfer, the third and final step of provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells

Answer 936

* As a class, these agents tend to be well tolerated, with headache and GI effects the most commonly reported adverse effects * Their use in combination antiretroviral regimens or with cobicistat (elvitegravir) means that additional adverse events and/or drug-drug interactions need to be considered as well * The available data suggests that effects upon lipid metabolism are favourable compared with efavirenz and PIs. * Rare severe events include systemic hypersensitivity reactions and rhabdomyolysis.

Answer 937

* Dolutegravir * Elvitegravir * Raltegravir

Answer 938

* The advantages of **nucleoside/nucleotide analogs (NA) therapy** of hepatitis over **interferons (IFN)** include fewer adverse effects and a one-pill-a-day oral administration * The main **advantages of IFN** over NAs are the are the absence of resistance, and achievement of higher rates of viral agglutinin reduction. * However, the **disadvantages of IFN** are that less that 50% of persons treated will respond, its high cost, administration by injection and common adverse effects, which preclude its use in many persons. * A number of **relative and absolute contraindications to IFN also exist**, which include the presence of decompensated cirrhosis and hypersplenism, thyroid disease, autoimmune diseases, severe coronary artery disease, renal transplant disease, pregnancy, seizures and psychiatric illness, concomitant use of certain drugs, retinopathy, thrombocytopaenia

Answer 939

* Interferons are host cytokines that **exert complex antiviral, immunomodulatory, and anti-proliferative actions**. * Interferon alfa appears to function by **induction of intracellular signals** following binding to specific cell membrane receptors, resulting in **inhibition of viral penetration, translation, transcription, protein processing, maturation and release**, as well as **increased host expression of MHC antigens**, enhanced phagocytic activity of macrophages and augmentation of the proliferation and survival of cytotoxic T cells

Answer 940

* Interferon alfa-2b is licensed for the treatment of **chronic HBV infection** * Interferon alfa-2a, interferon alfa-2b and interferon alfacon-2 are licensed for treatment of **chronic HCV infection** * Interferon alfa-2a and interferon alfa-2b may be administered by either **subcut or IM** * Alfa interferons are **filtered at the glomerulus** and undergo rapid proteolytic degradation during tubular reabsorption, such that detection in the systemic circulation is negligible. * Liver metabolism and subsequent biliary excretion are considered minor pathways

Answer 941

* **Pegylation** (the attachment of polyethylene glycol to a protein) **reduces the rate of absorption** following subcutaneous infection, **reduces renal and cellular clearance** and decreases the immunogenicity of the protein, resulting in a **longer half-life and steadier plasma concentrations** * Renal elimination of pegylated interferon alpha-2a and pegylated interferon alfa-2b accounts for about 30% of clearance; dose must be adjusted in renal insufficiency due to impaired clearance.

Answer 942

* A flu-like syndrome that occurs within 6 hours after dosing in more than 30% of patients; it tends to resolve upon continued administration * Transient hepatic enzyme elevations may occur in the first 8-12 weeks of therapy and appear to be more common in responders * Potential adverse effects during chronic therapy include neurotoxicities (mood disorders, depression, somnolence, confusion, seizures), myelosuppression, profound fatigue, weight loss, rash, cough, myalgia, alopecia, tinnitus, reversible hearing loss, retinopathy, pneumonitis, and possibly cardiotoxicity

Answer 943

* The suppression of HBV DNA to undetectable levels, * Seroconversion of HBeAG (or more rarely HbsAg) from positive to negative * Reduction in elevated serum aminotransferase levels These endpoints are correlated with improvement in necroinflammatory disease, a decreased risk of HCC and cirrhosis, and a decreased need for liver transplantation

Answer 944

The covalently closed circular (ccc) viral DNA exists in state form indefinitely within the cell, serving as a reservoir for HBV throughout the life of the cell and resulting in the capacity to reactivate.

Answer 945

* Five oral nucleoside-nucleotide analogs (lamivudine, adefovir dipivoxil, tenofovir disoproxil, tenofovir alafenamide, entecavir, telbivudine) * Two injectable interferon drugs (interferon alfa-2b, pegylated interferon alfa-2a)

Answer 946

* The use of standard interferon has been supplanted by long-acting pegylated interferon, allowing once-weekly rather than daily or thrice-weekly dosing * The advantages of interferon are its finite duration of treatment, the absence of selection of resistant variants and a more durable response * However, adverse effects from interferon are more frequent, and may be more severe. Furthermore, interferon cannot be used in patients with decompensated disease

Answer 947

In general, nucleoside/nucleotide analog therapies have better tolerability and produce a higher response rate than interferons, and are now considered the first line of therapy

Answer 948

* Influenza A, the only strain that causes pandemic, is classified into 16H (hemagglutinin) and 9N (neuraminidase) known subtypes based on surface proteins * Although influenza B viruses usually infect only people, influenza A viruses can infect a variety of animal hosts, including birds, providing an extensive reservoir * Current influenza A subtypes that are circulating among worldwide populations include H1N1, H1N2, and H3N2 * Viruses of the H5 and H7 subtypes may rapidly mutate within poultry flocks from a low to high pathogenic form and have recently expanded their host range to cause both avian and human disease. However, person-to-person spread of these avian viruses to date have been rare, limited and unsustained.

Answer 949

* 3 are neuraminidase inhibitors (oral oseltamivir, inhaled zanamivir, IV permivir) * Treatment is recommended for individuals with severe infection or at high risk for complications * The neuraminidase inhibitors have activity against other influenza A and influenza B * There is currently a low level of resistance

Answer 950

* The neuraminidase inhibitors are **analogs of sialic acid** and interfere with release of progeny influenza A and B virus from infected hosts cells, thus halting the spread of infection within the respiratory tract * These agents **competitively and reversibly interact with the active enzyme site to inhibit viral neuraminidase activity** at low nanomolar concentrations, resulting in clumping of newly released influenza virions to each other and to the membrane of the infected cell.

Answer 951

* Early administration is crucial because replication of influenza virus peaks at 24-72 hours after the onset of illness. * Initiation of a 5-day course of therapy within 48 hours after the onset of illness (75mg BD) modestly decreases the duration of symptoms, as well as duration of viral shedding and viral titer; some studies have shown a decrease in the incidence of complications. * Once daily prophylaxis (75mg OD) is 75-90% effective in preventing disease after exposure

Answer 952

* It is an **orally administered prodrug** that is **activated by hepatic esterases** and **widely distributed** throughout the body * Oral **bioavailability is approx 80%**, plasma protein binding is low, and concentrations in the middle ear and sinus fluid are similar to those in plasma * The **half-life of oseltamivir is 6-10 hours**, and **excretion is by glomerular filtration and tubular secretion**. * Dosage should be adjusted in patients with renal insufficiency

Answer 953

* Potential adverse effects include nausea, vomiting, and headache * Taking oseltamivir with food does not interfere with absorption and may decrease nausea and vomiting * Fatigue and diarrhoea have also been reported and appear to be more common with prophylactic use * Rash is rare

Answer 954

* Metronidazole is a nitroimidazole antiprotozoa drug that also has potent antibacterial activity against anaerobes, including *Bacteroides* and *Clostridium* species. * Metronidazole is selectively absorbed by anaerobic bacteria and sensitive protozoa. * Once taken up by anaerobes, it is **non-enzymatically reduced by reacting with reduced ferredoxin**. * This reduction **results in products** that accumulate in and are **toxic to anaerobic cells** * The metabolites of metronidazole are taken up into bacterial DNA, forming unstable molecules. This action occurs only when metronidazole is partially reduced, and, because this reduction usually happens only in anaerobic cells, it has relatively little effect on human cells or aerobic bacteria

Answer 955

* Metronidazole is well absorbed after oral administration, is widely distributed in tissues, and reaches serum levels of 4-6mcg/mL after a 250mg oral dose * It can also be given IV * The drug penetrates well into the CSF and brain, reaching levels similar to those in serum * It is metabolised in the liver and may accumulate in hepatic insufficiency

Answer 956

* It is indicated for treatment of anaerobic or mixed intra-abdominal infections (in combination with other agents with activity against aerobic organisms), vaginitis (trichomonas infection, bacterial vaginosis), *Clostridium difficile* infection, and brain abscess. * The typical dosage is 500mg TDS orally or IV. * Vaginitis may response to a single 2g dose.

Answer 957

* Adverse effects include nausea, diarrhoea, stomatitis, and peripheral neuropathy with prolonged use * It has a disulfiram-like effect, and patients should be instructed to avoid alcohol * Although teratogenic in some animal, it has not been associated with this effect in humans

Answer 958

* At therapeutic doses, it is **bactericidal for many gram-positive and gram-negative bacteria**; however, *P aeruginosa* and many strains of *Proteus* are inherently resistant * It has a complex mechanism of action that appears to correlate with **rapid intracellular conversion of nitrofurantoin to highly reactive intermediates by bacterial reductases** * These immediately react non-specifically with many ribosomal proteins, and **disrupt metabolic processes and the synthesis of proteins, RNA and DNA**.

Answer 959

* It is well absorbed after ingestion * It is metabolised and excreted so rapidly that no systemic antibacterial action is achieved * The drug is excrete into the urine by both glomerular filtration and tubular secretion * With average daily doses, concentrations of 200mcg/mL are reached in urine * In renal failure, urine levels are insufficient for antibacterial action, but high blood levels cause toxicity. Nitrofurantoin is contraindicated in patients with significant renal insufficiency

Answer 960

* The dosage for UTI in adults in 100mg QDS. A long-acting formulation (**Macro-bid**) can be taken twice daily * The drug should not be used to treat upper urinary tract infection. * A single daily dose of nitrofurantoin, 100mg, can prevent recurrent UTIs in some women

Answer 961

* Anorexia, nausea and vomiting are the principal adverse effects of nitrofurantoin * Neuropathies and pulmonary toxicity may occur, particularly with prolonged use or in patients with renal impairment * Haemolytic anaemic can occur in patients with glucose-6-phosphate dehydrogenase deficiency

Answer 962

* **Disinfectants** are chemical agents or physical procedures that **inhibit or kill microorganisms** * **Antiseptics** are disinfectant chemical agents with sufficiently low toxicity for host cells that they **can be used directly on skin, mucous membranes or wounds** * **Sterilants** kill both **vegetative cells and spores** when applied to materials for appropriate times and temperatures

Answer 963

* **Ethanol** and isopropyl alcohol (**isopropanol**) * They are **rapidly active, killing vegetative bacteria**, *Mycobacterium tuberculosis* and many **fungi, and inactivating lipophilic viruses**. * They probably act by **denaturation of proteins**. They are not used as sterilants because they are not sporicidal, do not penetrate protein-containing organic material, and may not be active against hydrophilic viruses.

Answer 964

* Chlorhexidine is a **cationic biguanide** with very **low water solubility**. Water-soluble chlorhexidine digluconate is used in water-based formulations as an antiseptic. * It is **active against vegetative bacteria and mycobacteria** and has variable activity against fungi and viruses * It strongly **adsorbs to bacterial membranes**, causing **leakage of small molecules and precipitation of cytoplasm proteins**. * It is most effective against gram-positive cocci and less active against gram-positive and gram-negative rods. Spore germination is inhibited by chlorhexidine * It is resistant to inhibition by blood and organic materials. However, anionic and non-ionic agents in moisturisers, neutral soaps and surfactants may neutralise its action

Answer 965

Chlorhexidine gluconate is slower in its action than alcohols, but, because of its persistence, it has residual activity, producing bactericidal action equivalent to alcohols

Answer 966

* They are all **weak organic acids** * Most of these drugs are **well absorbed**, and food does not substantially change their bioavailability. * Most are **highly metabolised**, some by phase I followed by phase II mechanisms and others by direct glucuronidation (phase II) alone. * NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of **P450 enzymes** in the liver. * While **renal excretion** is the most important route for final elimination, nearly all undergo **varying degrees of biliary excretion and reabsorption (enterohepatic circulation)**. * Most of the NSAIDs are **highly protein bound**, usually to albumins. Most (ibuprofen) are racemic mixtures, while naproxen is a single enantiomer and diclofenac has no chiral center

Answer 967

* All NSAIDs can be found in synovial fluid after repeated dosing * Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives

Answer 968

* **CNS system** - headaches, tinnitus, dizziness and rarely, aseptic meningitis * **Cardiovascular** - fluid retention, HTN, oedema and rarely, MI & congestive heart failure * **GI** - abdo pain, dyspepsia, N&V, and rarely, ulcers or bleeding * **Haematologic** - rare thrombocytopaenia, neutropenia or even aplastic anaemia * **Hepatic** - abnormal LFTs and rare liver failure * **Pulmonary** - asthma * **Skin** - rashes, all types, pruritis * **Renal** - AKI, renal failure, hyperkalaemia and proteinuria

Answer 969

* Salicylic acid is a simple organic acid with a pK_a of 3.0 * Aspirin (acetylsalicylic acid) and has a **pK_a of 3.5** * Aspirin is absorbed as such as is rapidly hydrolysed (**serum half-life 15 minutes**) to acetic acid and salicylate by esterases in tissue and blood. * Salicylate is non-linearly bound to albumin. * Alkalisation of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates

Answer 970

* Aspirin irreversibly inhibits platelet COX so that aspirin's antiplatelet effect lasts 8-10 days (the life of the platelet) * In other issues, synthesis of new COX replaces the inactivated enzyme so that ordinary doses have a duration of action of 6-12 hours

Answer 971

* COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostaglandin synthesis by the **COX-2 isozyme induced at sites of inflammation** without affecting the action of the constitutively **active "housekeeping" COX-1 isozyme found in the GI tract, kidneys and platelets**. * COX-2 inhibitors at usual doses have no impact on platelet aggregation, which is mediated by thromboxane produced by the COX-1 isozyme. In contrast, they do inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium. * As a result COX-2 inhibitors do not offer the cardioprotective effects of traditional NSAIDs

Answer 972

* Celecoxib is a selective COX-2 inhibitor - about 10-20 times more selective for COX-2 than COX-1. * It's dosage is 100-200mg BD

Answer 973

* The half life is 11 hours * The urinary excretion of unchanged drug is 27% * It interacts occasionally with warfarin - as would be expected of a drug metabolised via CYP2C9

Answer 974

* Meloxicam preferentially inhibits COX-2 over COX-1. * It is not as selective as celecoxib and may be considered "preferentially" selective rather than "highly" selective.

Answer 975

It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac and naproxen.

Answer 976

Celecoxib and meloxicam

Answer 977

Diclofenac Etodolac Ibuprofen Indomethacin Naproxen Oxaprozin Piroxicam

Answer 978

* GI ulceration may occur less frequently than with some other NSAIDs * It appears to **impair renal blood flow and glomerular filtration rate** * **Elevation of serum aminotransferases** occurs more commonly with this drug than with other NSAIDs

Answer 979

* Half life 1.1 hours * Urinary excretion of unchanged drug - <1% * Dosage - 50-75mg QDS

Answer 980

* The analgesia dose of etodolac is 200-400mg TDS-QDS * The recommended dose in OA and RA is 300mg BD-TDS up to 500mg BD following by a maintenance of 600mg/day

Answer 981

Oral, IV, topical

Answer 982

* Half-life 6.5 hours * Urinary excretion <1%

Answer 983

* Half life - 2 hours * Urinary excretion of unchanged drug - <1%

Answer 984

Nasal polyps, angiooedema, and bronchospastic reactivity to aspirin

Answer 985

* The concomitant administration of ibuprofen and aspirin antagonises the irreversible platelet inhibition induced by aspirin. * Thus, treatment with ibuprofen in patients with increased CVS risk may limit the cardioprotective effects of aspirin * Furthermore, the use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory effect

Answer 986

* It is a potent non-selective COX inhibitor * it also inhibits phospholipase A and C, reduced neutrophil migration and decreases T-cell and B-cell proliferation

Answer 987

* Half life - 4-5 hours * Urinary excretion of unchanged drug - 16% * Recommended anti-inflammatory dose - 50-70mg TDS

Answer 988

* Naproxen is the only NSAID presently marketed as a single enantiomer * It's free fraction is significantly higher in women than in men, but half-life is similar in both sexes. * The incidence of upper GI bleed in over-the-counter use is low but still double that of ibuprofen

Answer 989

* It is a non-selective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocytes migration, decreases oxygen radical production, and inhibits lymphocyte function * Its long half life permits once-daily dosing

Answer 990

Its GI and renal side effects

Answer 991

The relatively expensive, selective COX-2 inhibitor celecoxib is probably safest for patients at high risk for GI bleeding but may have a higher risk of cardiovascular toxicity.

Answer 992

Some surveys suggest that indomethacin and tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin and ibuprofen are least toxic.

Answer 993

* The term **opioid** describes all compounds that work at opioid receptors * The term **opiate** specifically describes the naturally occurring alkaloids: morphine, codeine, thebaine, and papaverine

Answer 994

Morphine is a full agonist at the μ (mu) - opioid receptor, the major analgesic opioid receptor

Answer 995

Morphine exhibits a greater binding affinity at the μ-opioid receptor than does codeine.

Answer 996

* μ (mu) - opioid receptor - the major analgesia opioid receptor * δ (delta) and κ (kappa) nociception * Opioid-receptor-like subtype 1

Answer 997

Simple subsitution of an allyl group on the nitrogen of the full *agonist* morphine plus addition of a single hydroxyl group results in naloxone, a strong μ-receptor antagonist

Answer 998

Chemically, the opioids derived from opium are phenanthrene derivatives and include four or more fused rings, while most of the synthetic opioids are simpler molecules

Answer 999

* The **endorphins**, the pentapeptide **enkephalins** and the **dynorphins**. * These three families of endogenous opioid peptides have overlapping affinities for opioid receptors.

Answer 1000

* The **three precursor proteins** are prepro-opiomelanocortin (POMC), preproenkephalin (proenkephalin A), and preprodynorphin (proenkephalin B). * POMC contains the met-enkephalin sequence, β-endorphin, and several non-opioid peptides, including ACTH. * Preproenkephalin contains six copies of met-enkephalin and one copy of leu-enkephalin. * Leu- and met-enkephalin have slightly higher affinity for the δ than the μ-opioid receptor. * Preprodynorphin yields several active opioid peptides that contain the leu-enkephalin sequence. These are **dynorphin A, dynorphin B**, and α and β **neoendorphins**

Answer 1001

Painful stimuli can evoke release of endogenous opioid peptides under the stress associated with pain or the anticipation of pain, and they diminish the perception of pain

Answer 1002

* In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A - through its binding to κ-opioid receptors - remains controversial * Dynorphin A is also **found in the dorsal horn of the spinal cord** * Increased levels of dynorphin occur in the dorsal horn after tissue injury and inflammation. * This elevated dynorphin level is proposed to **increase** pain and induce a state of long-lasting **sensitisation** and hyperalgesia. * The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system

Answer 1003

* Most opioid analgesics are well absorbed when given by subcutaneous, IM or oral routes. * However, because of the first pass effect, the oral dose of the opioid (eg, morphine) to elicit a therapeutic effect may need to be much higher than the parenteral dose * As there is considerable inter patient variability in first-pass opioid metabolism, prediction of an effective oral dose is difficult * Certain analgesics such as codeine and oxycodone are effective orally because they have reduced first-pass metabolism. * BY avoiding first-pass metabolism, nasal insufflation of certain opioids can rapidly result in therapeutic blood levels * Other routes of opioid administration include oral mucosa via lozenges, and the transdermal route via patches.

Answer 1004

* Although **all opioids bind to plasma proteins with varying affinity**, the drugs **rapidly leave the blood compartment** and localise in highest concentrations in highly perfused tissues such as the brain, lungs, liver, kidneys and spleen * Drug **concentrations in skeletal muscle may be much lower**, but this tissue serves as the main reservoir because of its greater bulk * Even though blood flow to fatty tissue is much lower than to the highly perfused tissues, accumulation can be very important, particularly after frequent high-dose administration of continuous infusion of highly lipophilic opioids that are slowly metabolised (eg, fentanyl)

Answer 1005

The opioids are converted in large part to polar metabolites (mostly glucuronides), which are then readily excreted by the kidneys.

Answer 1006

* Morphine contains free hydroxyl groups, is **primarily conjugated to morphine-3-glucuronide (M3G)**, a compound with neuroexcitatory properties. * Approximately **10% of morphine is metabolised to morphine-6-glucuronide (M6G)**, an active metabolite with analgesic potency four to six times that of its parent compound. * However, these relatively polar metabolites have **limited ability to cross the blood-brain barrier** and probably do not contribute significantly to the usual CNS effects of a single dose of morphine * Importantly, **accumulation of these metabolites may produce unexpected adverse effects** in patients with renal failure or when exceptionally large doses of morphine are administered or high doses are administered over long periods. * This can result in **M3G-induced CNS excitation (seizures)** or **enhanced and prolonged opioid action produced by M6G.** * CNS uptake of M3G and, to a lesser extent, M6G can be enhanced by co-administration of probenecid or of drugs that inhibit the P-glycoprotein drug transporter

Answer 1007

* **Hepatic oxidative metabolism** is the primary route of degradation of the phenylpiperidine opioids and eventually leaves only small quantities of the parent compound unchanged for excretion. * **No active metabolites of fentanyl** have been reported. * The **P450 isozyme CYP3A4 metabolises fentanyl** by *N*-dealkylation in the liver. * CYP3A4 is also present in the mucosa of the small intestine and contributes to the first pass metabolism of fentanyl when it is taken orally.

Answer 1008

* Codeine, oxycodone, and hydrocodone undergo metabolism in the liver by P450 isozyme CYP2D6, resulting in the **production of metabolites of greater potency** * For example, **codeine is demethylated to morphine**, which is then conjugated. * **Hydrocodone is metabolised to hydromorphone** and, like morphine, hydromorphone is conjugated, yielding hydromorphone-3-glucuronide (H3G), which has CNS excitatory properties * Hydromorphone cannot form a 6-glucuronide metabolite. * Similarly **oxycodone is metabolised to oxymorphone**, which is then conjugated to oxymorphone-3-glucuronide (O3G)

Answer 1009

Genetic polymorphism of CYP2D6 has been documented and linked to the variation in analgesic and adverse responses seen among patients.

Answer 1010

* The synthetic opioid methadone is metabolised through several CYP450 pathways, in part accounting for its highly variable bioavailability. * The most important hepatic pathway for metabolism is CYP2B6.

Answer 1011

* Esters (eg, heroin, remifentanil) are rapidly hydrolysed by common plasma and tissue esterases. * Heroin (diacetylmorphine) is hydrolysed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid.

Answer 1012

* Polar metabolites, including glucuronide conjugates of opioid analgesics, are **excreted mainly in the urine** * Small amounts of unchanged drug may also be found in the urine. * In addition, glucuronide conjugates are found in the bile, but **enterohepatic circulation represents only a small portion of the excretory process** of these polar metabolites * In patients with renal impairment the effects of active polar metabolites should be considered before the administration of potent opioids such as morphine or hydromorphone.

Answer 1013

* Opioid agonists produce analgesia by binding to specific G protein-coupled receptors (GPCRs) that are located in brain and spinal cord regions involved in the transmission and modulation of pain * Some effects may be mediated by opioid receptors on peripheral sensory nerve endings

Answer 1014

**Strong** Morphine Hydromorphine Oxymorphine Methadone Fentanyl Sulfentanil Alfentanil Remifenatnil Oxycodone **Partial** Codeine Hydrocodone Buprenorphine

Answer 1015

**Sufentanil** - all receptors **Buprenorphine** is a partial μ receptor agonist and is an antagonist for delta and kappa receptors.

Answer 1016

**Methadone** - 10³mg **Fentanyl** - 0.1mg **Sufentanil** - 0.02mg **Codeine** - 30-60mg **Oxycodone** - 4.5mg **Buprenorphine** - 0.3mg

Answer 1017

**Morphine** - 4-5 hours **Methadone** - 4-6 hours **Fentanyl** - 1-1.5 hours **Codeine** - 3-4 hours **Oxycodone** - 3-4 hours **Buprenorphine** 4-8 hours

Answer 1018

At the molecular level, opioid receptors form a family of proteins that physically couple to G proteins and through this interaction affect ion channel gating, modulate intracellular Ca²⁺ disposition, and alter protein phosphorylation.

Answer 1019

1) They **close voltage-gated Ca²⁺ channels on presynaptic nerve** terminals and thereby reduce transmitter release 2) They **open K⁺ channels and hyperpolarise and thus inhibit postsynaptic neurons**. The presynaptic action - depressed transmitter release - has been demonstrated for a large number of neurotransmitters, including glutamate, the principal excitatory amino acid released from nociceptive nerve terminals, as well as acetylcholine, norepinephrine, serotonin, and substance P

Answer 1020

Analgesia and the euphoriant, respiratory depressant, and physical dependence properties of morphine result principally from actions at μ receptors.

Answer 1021

* All three major receptors are present in high concentrations in the **dorsal horn of the spinal cord.** * Receptors are present both on spinal cord pain transmission neurons and on the primary afferents that relay the pain message to them. * Although opioid **directly inhibit dorsal horn pain transmission neurons**, they **also inhibit the release of excitatory transmitters from the primary afferents**.

Answer 1022

* These include not only the **ascending pathways of pain** transmission beginning with specialised peripheral sensory terminals that transduce painful stimuli but also **descending (modulatory) pathways**. * At these sites, as at others, opioids directly inhibit neurons; yet this action results in the activation of descending inhibitory neurons that send processes to the spinal cord and inhibit paint transmission neurons. * This activation has been shown to result from the inhibition of inhibitory neurons in several locations. Taken together interactions at these sites increase the overall analgesic effect of opioid agonists.

Answer 1023

* When pain-relieving opioid drugs are given systemically, they presumably act upon neuronal circuits normally regulated by endogenous opioid peptides and **part of the pain-relieving action of exogenous opioids may involve the release of endogenous opioid peptides**. * For example, an exogenous opioid agonist (morphine) may act primary and directly at the μ receptor, but this action may evoke the release of endogenous opioids that additional act at δ and κ receptors. * Thus, even a receptor selective ligand can initiate a complex sequence of events involving multiple synapses, transmitters and receptor types

Answer 1024

* Pain associated inflammation seems especially sensitive to peripheral opioid actions * There are functional **μ receptors on the peripheral terminals of sensory neurons** * Activation of these results in a decrease in sensory neuron activity and transmitter release * The **endogenous release of β-endorphin produced by immune cells** within injured or inflamed tissue represents one source of physiologic peripheral μ-receptor activation

Answer 1025

* With frequently repeated therapeutic doses of morphine or its surrogates, there is a gradual loss in effectiveness; this loss of effectiveness is termed **tolerance**. To reproduce the original response, a larger dose must be administered. * Along with tolerance, physical dependence develops. Physical dependence is defined as a characteristic **withdrawal** or **abstinence syndrome** when a drug is stopped or an antagonist is administered

Answer 1026

* IT is poorly understood, but persistent activation of μ receptors appears to play a primary role in its induction and maintenance. * **Receptor recycling** - normally, activation of μ receptors by endogenous ligands results in receptor endocytosis followed by resensitisation and recycling of the receptor to the plasma membrane. However, the **failure of morphine to induce endocytosis of the μ-opioid receptor** is an important component. * **Receptor uncoupling** - tolerance results from a **dysfunction of structural interactions between the μ receptor and G proteins, second-messenger systems, and their target ion channels**. Uncoupling and recoupling of μ receptor function is likely linked to receptor recycling. The NMDA-receptor ion channel complex has been shown to play a critical role

Answer 1027

* In addition to the development of tolerance, persistent administration of opioid analgesics can **increase** the sensation of pain, resulting in a state of hyperalgesia * This phenomenon can be produced with severe opioid analgesics, including morphine, fentanyl, and remifentanil * Spinal dynorphin and activation of the bradykinin and NMDA receptors have emerged as important candidates for the mediation of opioid-induced hyperalgesia.

Answer 1028

* **Analgesia** - both sensory and affective (emotional) components. * **Euphoria** * **Sedation** - there is little or no amnesia, drowsiness and clouding of mentation are common * **Respiratory depression** - by inhibiting brainstem respiratory mechanisms. * **Cough suppression** - may allow accumulation of secretions and thus lead to airways obstruction and atelectasis * **Miosis** - mediated by parasympathetic pathways * **Truncal rigidity** - reduced thoracic compliance and thus interferes with ventilation, this is prevented with the use or neuromuscular blocking agents * **Nausea and vomiting** - activates the brainstem chemoreceptor trigger zone to produce nausea and vomiting * **Temperature** - homeostatic regulation of body temperature is mediated in part by the action of endogenous opioid peptides in the brain * **Sleep architecture** - opioids interact with circadian rhythm and can decrease the percentage of stage 3 and 4 sleep, which may result in fatigue and other sleep disorders

Answer 1029

* Most opioids have **no significant direct effects on the heart** and, other than bradycardia, no major effects on cardiac rhythm. * Opioid analgesics affect cerebral circulation minimally except when PCO₂ rises as a consequence of respiratory depression. **Increased PCO₂ leads to cerebral vasodilation associated with a decrease in cerebral vascular resistance, an increase in cerebral blood flow, and an increase in intracranial pressure**

Answer 1030

* **Constipation** has long been recognised as an effect of opioids, an effect that does not diminish with continued use. * Opioid receptors exist in high density in the GI tract, and the constipating effects of the opioids are mediated through an action on the enteric nervous system as well as the CNS * In the stomach, **motility (rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase** - particularly in the central portion; **gastric secretion of hydrochloric acid is decreased** * Small intestine **resting tone is increased, with periodic spasms**, but the amplitude of non-propulsive contractions is markedly decreased. * In the large intestine, **propulsive peristaltic waves are diminished and tone is increased**; this delays passage of the faecal mass and allows increased absorption of water, which leads to constipation

Answer 1031

* The opioids contract biliary smooth muscle, which can result in biliary colic * The sphincter of Oddi may constrict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase and lipase levels

Answer 1032

* **Renal function is depressed by opioids**. It is believed that in humans this is chiefly due to **decreased renal plasma flow** * In addition, μ opioids have an **antidiuretic effect in humans** * Mechanisms may involve both the CNS and peripheral sites. * Opioids also **enhance renal tubular sodium reabsorption**. * **Ureteral and bladder tone are increased** by therapeutic doses of opioids * Increased sphincter tone may precipitate **urinary retention**, especially in post-op patients. * Occasionally ureteral colic caused by a renal calculus is made worse by opioid increased increase in ureteral tone

Answer 1033

* The opioid analgesics may prolong labour, but μ- and κ-opioid receptors are expressed in human uterine muscle * Fentanyl and pethidine inhibit uterine contractility but only at supraclinical concentrations.

Answer 1034

* Opioids **stimulate the release of ADH, prolactin, and somatotropin** but **inhibit the release of LH**. * Patients receiving chronic opioid therapy can have **low testosterone resulting in decreased libido, energy, and mood**. * Women can experience **dysmenorrhea or amenorrhea**

Answer 1035

* The opiates, such as morphine and codeine, produce flushing and warming of the skin accompanied sometimes by sweating, urticaria, and itching * Although **peripheral histamine release** is an important contributor, all opioids can cause pruritus via a **central (spinal cord and medullary) action of pruritoceptive neural circuits**. * When opioids are administered to the neuraxis by the spinal or epidural route, their usefulness may be limited by intense pruritus over the lips and torso.

Answer 1036

* The opioids modulate the immune system by **effects on lymphocyte proliferation, antibody production, angioneogenesis, and chemotaxis** * In addition, leukocytes migrate to the site of issue injury and release opioid peptides, which in turn help counter inflammatory pain * However, **natural killer cell cytolytic activity and lymphocyte proliferative** responses to mitogens are usually **inhibited** by opioids, which may play a role in tumour progression * Although the mechanisms involved are complex, activation of central opioid receptors could mediate a significant component of the changes observed in peripheral immune function * These effects are **mediated by the sympathetic nervous system** in the case of acute administration **and by the hypothalamic-pituitary-adrenal system** in the case of prolonged administration of opioids.

Answer 1037

* Severe, **constant** pain, is usually relieved with opioid analgesics having high intrinsic activity, whereas sharp, intermittent pain does not appear to be as effectively controlled * The pain associated with cancer and other terminal illnesses must be treated aggressively and often required a multidisciplinary approach for effective management.

Answer 1038

Fixed-interval administration of opioid medication is more effective in achieving pain relief than dosing on demand.

Answer 1039

* Acute pulmonary oedema - reduces anxiety, reduces cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance) * Cough * Diarrhoea * Applications in anaesthetics - can be used as part of induction, maintenance and preparation for post-op analgesia. Also used for epidurals and spinals * PCAs

Answer 1040

* With PCA, the patients controls a parenteral (usually IV) infusion device by pressing a button to deliver a preprogrammed dose of the desired opioid analgesic, called the **demand dose** * A programmable **lockout interval** prevents administration of another dose for a set period of time * In addition, the pumps can be programmed with a **continuous or basal infusion** and the **1- or 4-hour lockout dose**.

Answer 1041

* **Acute** - respiratory depression, N&V, pruritus, urticaria, constipation, urinary retention, delirium, sedation, myoclonus, seizures * **Chronic** - hypogonadism, immunosuppression, increased feeding, increased growth hormone secretion, withdrawal effects, tolerance, dependence, abuse, addiction, hyperalgesia, impairment while driving

Answer 1042

**High** - analgesia, euphoria, mental clouding, sedation, respiratory depression, ADH, N&V, cough suppression **Moderate** - bradycardia **Minimal or none** - miosis, constipation, convulsions

Answer 1043

NMDA-receptor antagonists (eg, **ketamine**) have shown promise in preventing or reversing opioid-induced tolerance

Answer 1044

* Rhinorrhoea * lacrimation * yawning * chills * gooseflesh (piloerection) * hyperventilation * hyperthermia * mydriasis * muscular aches * vomiting * diarrhoea * anxiety * hostility

Answer 1045

* With morphine or heroin, withdrawal signs usually start within 6-10 hours after the last dose. Peak effects are seen at 36-48 hours, after which most of the signs and symptoms gradually subside. By 5 days, most of the effects have disappeared, but some may persist for months * With methadone, several days are required to reach the peak of the abstinence syndrome, and it may last as long as 2 weeks. The slow subsidence of methadone effects is associated with a less intense immediate syndrome, and this is the basis for its use in the detoxification of heroin addicts. However, despite the loss of the physical depended on the opioid, craving for it may persist.

Answer 1046

* A transient, explosive abstinence syndrome - **antagonist precipitated withdrawal** - can be induced by administering naloxone or another antagonist * Within 3 minutes after injection of the antagonist, signs and symptoms similar to those seen after abrupt discontinuation appear, peaking in 10-20 minutes and largely subsiding after 1 hour

Answer 1047

When a weak partial agonist such as pentazocine is given to a patient also receiving a full agonist (eg. morphine), there is a risk of diminishing analgesia or even inducing a state of withdrawal; thus combining a full agonist with partial agonist opioids should be avoided.

Answer 1048

* Carbon dioxide retention caused by respiratory depression results in cerebral vasodilation. * In patients with elevated intracranial pressure, this may lead to lethal alterations in brain function

Answer 1049

1) **Use of pure agonists with weak partial agonists** 2) **Use in patients with head injuries** 3) **Use during pregnancy** - the feast may become physically dependent in utero 4) **Use in patients with impaired pulmonary function** - the depressant properties of the opioid analgesics may lead to acute respiratory failure 5) **Use in patients with impaired hepatic or renal failure** - metabolised in the liver, half-life is prolonged in patients with impaired renal function 6) **Use in patients with endocrine disease** - patients with adrenal insufficiency and those with hypothyroidism may have prolonged and exaggerated responses to opioids

Answer 1050

* **Sedative-hypnotics** - increased CNS depression, particularly respiratory depression * **Antipsychotic agents** - increased sedation, variable effects on respiratory depression, accentuation of cardiovascular effects (antimuscarinic and α-blocking actions) * **Monoamine oxidase inhibitors** - relative contraindication to all opioid analgesics because of the high incidence of hyperpyrexic coma; HTN has also been reported

Answer 1051

Morphine, hydromorphone and oxymorphone. Also heroin

Answer 1052

* **Methadone** can be administered by the oral, IV, subcut, spinal and rectal routes * It is well absorbed from the GI tract, and its bioavailability far exceeds that of oral morphine

Answer 1053

* Methadone is not only a **potent μ-receptor agonist** but its racemic mixture of D- and L-methadone isomers **can also block both NMDA receptors and monoaminergic reuptake transporters** * These non-opioid receptor properties may help explain its ability to relieve difficult-to-treat pain (neuropathic, cancer pain), especially when a previous trial of morphine has failed.

Answer 1054

* Fentanyl is one of the most widely used agents in the family of synthetic opioids * The fentanyl subgroup now includes sufentanil, alfentanil, remifentanil

Answer 1055

* **Sufentanil** is 5-7 times more potent than fentanyl * **Alfentanil** is considerably less potent than fentanyl, but acts more rapidly and has a markedly shorter duration of action * **Remifenatil** is metabolised very rapidly by blood and non-specific tissue esterases, making its pharmacokinetic and pharmacodynamic half-life extremely short.

Answer 1056

* **Codeine, dihydrocodeine, and hydrocodone** have lower binding affinity to μ-opioid receptors than morphine and often have adverse effects that limit the maximum tolerated dose when one attempts to achieve analgesia comparable to that of morphine * **Oxycodone** is more potent.

Answer 1057

* **Buprenorphine** is a potent and long-acting phenanthrene derivative that is a partial μ-receptor agonist (low intrinsic activity) and an antagonist at the δ and κ receptors and it therefore referred to as a mixed agonist-antagonist. * Although buprenorphine is used as an analgesic, it can antagonist the action of more potent μ agonists such as morphine. * It also binds to ORL1, the orphanin receptor.

Answer 1058

* Buprenorphine's long duration of action is due to its who dissociation from μ receptors. * This property renders its effects resistant to naloxone reversal

Answer 1059

* Tramadol is a centrally acting analgesic whose mechanism of action is complex and dependent on ability of the parent drug and its metabolites to block serotonin and norepinephrine reuptake. * Because its analgesic effect is only partially antagonised by naloxone, it is thought to depend loss on its low-affinity binding to the μ receptor for therapeutic activity.

Answer 1060

* Toxicity is associated with **seizures**; the drug is relatively contraindicated in patients with a history of epilepsy and for use with other drugs that lower the seizure threshold. * Another serious risk is the development of **serotonin syndrome**, especially is SSRIs are also being administered. * Other adverse effects include **nausea and dizziness**, but these symptoms typically abate after several days of therapy.

Answer 1061

* Tapentadol is an analgesic with modest μ-opioid receptor affinity and significant norepinephrine reuptake-inhibiting action. * Its analgesic effects were only moderately reduced by naloxone but strongly reduced by an α₂-adrenoceptor antagonist. * Its binding to the norepinephrine transporter (NET) was stronger than that of tramadol, whereas its binding to the serotonin transporter (SERT) was less than that of tramadol

Answer 1062

It carries a risk of seizures in patients with seizure disorders and for the development of serotonin syndrome.

Answer 1063

* The pure opioid antagonist drugs **naloxone, naltrexone** and **nalmefene** are morphine derivatives with bulkier substituents at the N₁₇ position. * These agents have a relatively high affinity for μ-opioid binding sites. * They have lower affinity for the other receptors but can also reverse agonists at δ and κ sites.

Answer 1064

* Naloxone is usually given by injection and has a short duration of action (1-2 hours) when given by this route. Metabolic disposition is chiefly by glucuronide conjugation like that of the agonist opioids with free hydroxyl groups * Naltrexone is well absorbed after oral administration but may undergo rapid first-pass metabolism. It has a half-life of 10 hours, and a single oral dose of 100mg blocks the effects of injected heroin for up to 48 hours.

Answer 1065

* When given in the absence of an agonist drug, these antagonists are almost inert * When given IV to a morphine-treated subject, the antagonist completely and dramatically reverses the opioid effects within 1-3 minutes * In individuals who are acute depressed by an overdose of an opioid, the antagonist effectively normalises respiration, level of consciousness, pupil size, bowel activity, and awareness of pain * In dependent subjects who appear normal while taking opioids, naloxone or naltrexone almost instantaneously precipitated an abstinence syndrome.

Answer 1066

* The usual initial dose is 0.1-0.4mg IV for life-threatening respiratory and CNS depression * Maintenance is with the same drug, 0.4-0.8mg even IV, and repeated wherever necessary. * In using naloxone in the severely opioid-depressed newborn, it is important to start with doses of 5-10mcg/kg and to consider a second dose of up to a total of 25mcg/kg is no response is noted.

Answer 1067

* **Acetaminophen** is the active metabolite of phenacetin and is responsible for its analgesic effect * It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and possesses no significant anti-inflammatory effects

Answer 1068

* It is administered orally or IV or PR * Peak blood concentrations after oral administration are usually reached in 30-60 minutes. * It it poorly bound to plasma proteins and is partially metabolised by hepatic microsomal enzymes to the inactive sulfate and glucuronide * Less than 5% is excreted unchanged * In large doses, a minor but highly reactive metabolite (N-acetyl-*p*-benzoquinone) is important because it is toxic to both liver and kidney * The half-life is 2-3 hours and is relatively unaffected by renal function.

Answer 1069

* In therapeutic doses, a mild reversible increase in hepatic enzymes may occasionally occur * With larger doses, dizziness, excitement, and disorientation may occur * Ingestion of 15g of acetaminophen may be fatal, death being caused by severe hepatotoxicity with centrilobular necrosis, sometimes associated with acute renal tubular necrosis * Early symptoms of hepatic damage include nausea, vomiting, diarrhoea, and abdominal pain * Haemolytic anaemia and methemoglobinaemia are very rare adverse effects.

Answer 1070

Acute ingestion of more than 150/200mg/kg (children) or 7g total (adults) is considered potentially toxic

Answer 1071

* Initially, the patient is asymptomatic or has mild GI upset (nausea, vomiting) * After 24-36 hours, evidence of liver injury appears, with elevated aminotransferase levels and hypoprothrombinaemia * Fulminant liver failure may ensue, leading to metabolic acidosis, hypoglycaemia, encephalopathy, and death * Renal failure may also occur * With acute massive ingestion and very high serum levels, metabolic acidosis can occur in the absence of liver failure * Rarely, it can cause 5-oxoprolinuria due to glutathione depletion.

Answer 1072

* The severity of poisoning is estimated from a serum acetaminophen concentration measurement. * If the level is greater than 150mg/L approximately 4 hours after infection, the patient is at risk for liver injury (chronic alcoholics or patients taking drugs that enhance P450 production of toxic metabolites may be at risk with lower levels) * The antidote acetylcysteine acts as a glutathione substitute, binding the toxic metabolite as it is produced. It is most effective when given early and should be started within 8-10 hours if possible * Liver transplantation may be required for patients with fulminant hepatic failure

Answer 1073

* It is a selective β₂ agonist * Its effects are prompt, efficacious bronchodilation * It is used for acute COPD exacerbations and asthma attacks

Answer 1074

* It is given via aerosol inhalation * Bronchodilation is maximal within 15 minutes and persists for 3-4 hours * Toxicity is tremor and tachycardia * Overdose gives arrhythmias

Answer 1075

* It is a selective β₂ agonist * It has a slow onset, primarily preventative action * It potentiates corticosteroid effects * It is used for bronchodilation and prevention of asthma exacerbations

Answer 1076

* It is given via aerosol inhalation * It lasts for 12-24 hours * Toxicity causes tremor and tachycardia * Overdose causes arrhythmias

Answer 1077

* It alters gene expression * It reduced mediators of inflammation and can be powerful prophylaxis of exacerbations * They do not relax airway smooth muscle directly but reduce bronchial hyperactivity and reduce the frequency of asthma exacerbations if taken regularly * Their most important action is inhibition of the infiltration of asthmatic airways by lymphocytes, eosinophils and mast cells.

Answer 1078

* Its duration is hours * It is limited by aerosol application * It can cause candidiasis infection and vocal cord changes * Some examples include beclomethasone, budesonide, ciclesonide, fluticasone * Inhaled steroids have less systemic effects that oral steroids

Answer 1079

* The mechanism of action is uncertain, it is thought it does phosphodiesterase inhibition, thereby increasing concentrations of intracellular cAMP and in some tissues cGMP and adenosine receptor antagonist, dilating airway smooth much and reducing release of histamine from airway mast cells. * It causes bronchodilation, cardiac stimulation and increased skeletal muscle strength (diaphragm) working in the same way as caffeine

Answer 1080

* It is given orally * Its duration is 8-12 hours but extended release preparations are often used

Answer 1081

* Montelukast and zafirlukast * They block leukotriene D₄ receptors * They block the airways response to exercise and antigen challenge

Answer 1082

* It is used in the prophylaxis of asthma, especially in children and in aspirin-induced asthma * It give orally and tis duration is hours * It has minimal toxicities

Answer 1083

* It is a potent atropine analog that is poorly absorbed after aerosol administration and is therefore relatively free of systemic atropine-like effects. * It is a muscarinic antagonist that competitively inhibits the action of acetylcholine at muscarinic receptors. * In the airways, acetylcholine is released from efferent endings of the vagus nerve, and muscarinic antagonists block the contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity.

Answer 1084

* Tiotropium, aclidinium and umeclidinium * These drugs bind to M₁, M₂ and M₃ receptors with equal affinity, but dissociate most rapidly from M₂ receptors, expressed on the efferent nerve ending. * This means that they do not inhibit the M₂-receptor-mediated inhibition of acetylcholine release and thus benefit from a degree of receptor selectivity.

Answer 1085

* A single dose of 19mcg of tiotropium or 62.6mcg of umeclinidium has a 24 hour duration of action * Inhalation of 400mcg of aclidinium has a 12-hour duration of action and is thus taken twice daily

Answer 1086

Inhaled corticosteroids and much more effective but people are concerned about side effects and it is harder for children to take inhalers compared to oral medications

Answer 1087

10mg for adults and 4mg for children OD

Answer 1088

* They irreversibly block the H⁺/K⁺/-ATPase pump in active parietal cells of stomach * They cause long-lasting reduction of stimulated and nocturnal acid secretion

Answer 1089

* It is used for peptic ulcers, GORD and erosive gastritis * Their half-lives are much shorter than their duration of action * They have a low toxicity * Reduction of stomach and may reduce absorption of some drugs and increase that of others

Answer 1090

* They are D₂-receptor blockers and remove inhibition of acetylcholine neurons in enteric nervous system. * Within the gastrointestinal tract, activation of dopamine receptors inhibits cholinergic smooth muscle stimulation; blockade of this effect is believed to be the primary pro-kinetic mechanism of action of these agents * These agents increase oesophageal peristaltic amplitude, increase lower oesophageal sphincter pressure, and enhance gastric emptying but have no effect on small intestine or colonic motility. * Metoclopramide and domperidone also block dopamine D2 receptors in the chemoreceptor trigger zone of the medulla (area postrema), resulting in potent anti-nausea and antiemetic action.

Answer 1091

* It is used as an anti-emetic and for gastric paresis * It should not be used in patients with Parkinsonism symptoms due to block of CNS D₂ receptors * The most common adverse effects of metoclopramide involve the central nervous system. * Restlessness, drowsiness, insomnia, anxiety, and agitation occur in 10–20% of patients, especially the elderly. * Extrapyramidal effects (dystonias, akathisia, parkinsonian features) due to central dopamine receptor blockade occur acutely in 25% of patients given high doses and in 5% of patients receiving long-term therapy. * Elevated prolactin levels (caused by both metoclopramide and domperidone) can cause galactorrhea, gynecomastia, impotence, and menstrual disorders. * Domperidone is extremely well tolerated. Because it does not cross the blood-brain barrier to a significant degree, neuropsychiatric and extrapyramidal effects are rare.

Answer 1092

* **Bulk-forming laxatives** - methylcellulose, psyllium, increases volume of colon contents, stimulate evacuation * **Stimulants** - Senna, stimulates activity, may cause cramping * **Stool surfactants** - docusate, lubricate stool, ease passage * **Magnesium hydroxide and other non-absorbable salts and sugars**: movicol, osmotic agents increases water content of stool, usually causes evacuation within 4-6 hours, sooner in large doses, can cause toxicity in renal impairment

Answer 1093

* It activates μ-opioid receptors in enteric nervous system * This slow motility in the gut with negligible CNS effects * It can cause mild cramping but little or no CNS toxicity

Answer 1094

* Selective 5-HT₃-receptor antagonists have potent antiemetic properties that are mediated in part through central 5-HT3- receptor blockade in the vomiting center and chemoreceptor trigger zone but mainly through blockade of peripheral 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves. * The antiemetic action of these agents is restricted to emesis attributable to vagal stimulation (eg, postoperative) and chemo- therapy; other emetic stimuli such as motion sickness are poorly controlled. * It lasts for 4-9 hours duration of action * It undergoes extensive hepatic metabolism and is eliminated by renal and hepatic excretion.

Answer 1095

* They may inhibit eicosanoid inflammatory mediators * Sulfasalazine causes sulfonamide toxicity and may cause GI upset, myalgias, arthralgias, myelosuppression

Answer 1096

* Examples include azathioprine and 6-mercaptopurine * They are purine antimetabolites that have immunosuppressive properties * The bioavailability of azathioprine (80%) is superior to 6-MP (50%). * After absorption, azathioprine is rapidly converted by a non-enzymatic process to 6-MP. * 6-Mercaptopurine subsequently undergoes a complex biotransformation via competing catabolic enzymes (xanthine oxidase and thiopurine methyltransferase) that produce inactive metabolites and anabolic pathways that produce active thioguanine nucleotides. * Azathioprine and 6-MP have a serum half-life of less than 2 hours; however, the active 6-thioguanine nucleotides are concentrated in cells resulting in a prolonged half-life of days. * The prolonged kinetics of 6-thioguanine nucleotide results in a median delay of 17 weeks before onset of therapeutic benefit from oral azathioprine or 6-MP is observed in patients with IBD.

Answer 1097

* An example is infliximab * It binds to TNF and prevents it from binding to its receptors * It causes suppression of several aspects of immune function, especially T_H1 lymphocytes * It can cause infusion reactions, reactivation of latent TB, increased risk of dangerous systemic fungal and bacterial infections

Answer 1098

* It reduces cholesterol secretion not bile and concentration of endogenous hepatocyte bile salts * It dissolves gallstones and reduces hepatic inflammation and fibrosis

Answer 1099

* It is a somatostatin analog and may alter portal blood flow and variceal pressures * It is used for patients with bleeding varices or at high risk of repeat bleeding * It reduces endocrine and exocrine pancreatic activities and can cause GI upset

Answer 1100

* Examples include cimetidine, ranitidine, famotidine, and nizatidine * All are rapidly absorbed from the intestine. Nizatidine has little first-pass metabolism, the others have first-pass hepatic metabolism resulting in a bioavailability of approx 50% * They are cleared by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion. * They exhibit competitive inhibition at the parietal cell H₂ receptor and suppress basal and meal-stimulated acid secretion in a linear, dose-dependent manner. * The volume of gastric secretions and the concentration of pepsin are also reduced. * First, histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to the parietal cell H2 receptor. * Second, direct stimulation of the parietal cell by gastrin or acetylcholine has a diminished effect on acid secretion in the presence of H2-receptor blockade.

Answer 1101

* PPIs are administered as inactive prodrugs. * To protect the acid-labile prodrug from rapid destruction within the gastric lumen, oral products are formulated for delayed release as acid-resistant, enteric-coated capsules or tablets. * After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. The bioavailability of all agents is decreased approximately 50% by food; hence, the drugs should be administered on an empty stomach. * The PPIs are lipophilic weak bases (pKa 4–5) and, after intestinal absorption, diffuse readily across lipid membranes into acidified compartments (eg, the parietal cell canaliculus). * The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold. There, it rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H+/K+- ATPase, irreversibly inactivating the enzyme.

Answer 1102

* When given to a fasting patient, they inactivate acid pumps that are actively secreting, but they have no effect on pumps in quiescent, non-secreting vesicles. * Because the half-life of a single injection of the intravenous formulation is short, acid secretion returns several hours later as pumps move from the tubulovesicles to the canalicular surface. * Thus, to provide maximal inhibition during the first 24–48 hours of treatment, the intravenous formulations must be given as a continuous infusion or as repeated bolus injections.

Answer 1103

* The H₂ antagonists exhibit competitive inhibition at the parietal cell H₂ receptor and suppress basal and meal-stimulated acid secretion in a linear, dose-dependent manner. * They are highly selective and do not affect H1 or H3 receptors. * The volume of gastric secretion and the concentration of pepsin are also reduced.

Answer 1104

* In contrast to H₂ antagonists, PPIs inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion, the proton pump. * In standard doses, PPIs inhibit 90–98% of 24-hour acid secretion. When administered at equivalent doses, the different agents show little difference in clinical efficacy.

Answer 1105

* The brainstem “vomiting center” is a loosely organised neuronal region within the lateral medullary reticular formation and coordinates the complex act of vomiting through interactions with cranial nerves VIII and X and neural networks in the nucleus tractus solitarius that control respiratory, salivatory, and vasomotor centers. * High concentrations of muscarinic M1, histamine H1, neurokinin 1 (NK1), and serotonin 5-HT3 receptors have been identified in the vomiting center

Answer 1106

1. The “chemoreceptor trigger zone” or area postrema is located at the caudal end of the fourth ventricle. This is outside the blood-brain barrier and is accessible to emetogenic stimuli in the blood or cerebrospinal fluid. The chemoreceptor trigger zone is rich in dopamine D2 receptors and opioid receptors, and possibly serotonin 5-HT3 receptors and NK1 receptors. 2. The vestibular system is important in motion sickness via cranial nerve VIII. It is rich in muscarinic M1 and histamine H1 receptors. 3. Vagal and spinal afferent nerves from the gastrointestinal tract are rich in 5-HT3 receptors. Irritation of the gastrointestinal mucosa by chemotherapy, radiation therapy, distention, or acute infectious gastroenteritis leads to release of mucosal serotonin and activation of these receptors, which stimulate vagal afferent input to the vomiting center and chemoreceptor trigger zone. 4. The central nervous system plays a role in vomiting due to psychiatric disorders, stress, and anticipatory vomiting prior to cancer chemotherapy.

Answer 1107

* The antiemetic properties of phenothiazines are mediated through inhibition of dopamine and muscarinic receptors. Sedative properties are due to their antihistamine activity. The agents most commonly used as antiemetics are prochlorperazine, promethazine, and thiethylperazine. * The antiemetic properties of olanzapine may be attributable to inhibition of dopamine D₂ and serotonin 5-HT_1c and 5-HT₃ receptors. * Antipsychotic butyrophenones also possess antiemetic proper- ties due to their central dopaminergic blockade. The main agent used is droperidol, which can be given by intra- muscular or intravenous injection. In antiemetic doses, droperidol is extremely sedating.

Answer 1108

* Hyoscine (scopolamine), a prototypic muscarinic receptor antagonist, is one of the best agents for the prevention of motion sickness. * However, it has a very high incidence of anticholinergic effects when given orally or parenterally. * It is better tolerated as a transdermal patch.

Answer 1109

* Methotrexate is an antimetabolite that has beneficial effects in a number of chronic inflammatory diseases, including Crohn’s disease and rheumatoid arthritis, and in cancer. * Methotrexate may be given orally, subcutaneously, or intramuscularly. * Reported oral bioavailability is 50–90% at doses used in chronic inflammatory diseases. * Intramuscular and subcutaneous methotrexate exhibit nearly complete bioavailability.

Answer 1110

* The principal mechanism of action is inhibition of dihydrofolate reductase, an enzyme important in the production of thymidine and purines. * At the high doses used for chemotherapy, methotrexate inhibits cellular proliferation. * However, at the low doses used in the treatment of IBD (12–25 mg/wk), the anti-proliferative effects may not be evident. * Methotrexate may interfere with the inflammatory actions of IL-1. * It may also stimulate increased release of adenosine, an endogenous anti-inflammatory autacoid. * Methotrexate may also stimulate apoptosis and death of activated T lymphocytes.

Answer 1111

* Examples of drugs with large volumes of distribution (>5 L/kg) include antidepressants, antipsychotics, antimalarials, opioids, propranolol, and verapamil. * Drugs with a relatively small Vd (<1 L/kg) include salicylate, ethanol, phenobarbital, lithium, valproic acid, and phenytoin.

Answer 1112

* Dissolution of tablets or gastric emptying time may be slowed so that absorption and peak toxic effects are delayed. * Drugs may injure the epithelial barrier of the gastrointestinal tract and thereby increase absorption. * If the capacity of the liver to metabolize a drug is exceeded, the first-pass effect will be reduced and more drug will be delivered to the circulation. With a dramatic increase in the concentration of drug in the blood, protein-binding capacity may be exceeded, resulting in an increased fraction of free drug and greater toxic effect. * At normal dosage, most drugs are eliminated at a rate proportional to the plasma concentration (first-order kinetics). If the plasma concentration is very high and normal metabolism is saturated, the rate of elimination may become fixed (zero-order kinetics). This change in kinetics may markedly prolong the apparent serum half-life and increase toxicity.

Answer 1113

* Many toxins depress the central nervous system (CNS), resulting in obtundation or coma. They may die as a result of **airway obstruction** by the flaccid tongue, aspiration of gastric contents into the tracheobronchial tree, or respiratory arrest. These are the most common causes of death due to overdoses of narcotics and sedative-hypnotic drugs * **Cardiovascular toxicity** is also frequently encountered in poisoning. Hypotension may be due to depression of cardiac contractility; hypovolemia resulting from vomiting, diarrhea, or fluid sequestration; peripheral vascular collapse due to blockade of α-adrenoceptor-mediated vascular tone; or cardiac arrhythmias. * **Cellular hypoxia** may occur despite adequate ventilation and oxygen administration when poisoning is due to cyanide, hydrogen sulfide, carbon monoxide, and other poisons that interfere with transport or utilization of oxygen. * **Seizures, muscular hyperactivity, and rigidity may result in death**. Seizures may cause pulmonary aspiration, hypoxia, and brain damage. Hyperthermia may result from sustained muscular hyperactivity and can lead to muscle breakdown and myoglobinuria, renal failure, lactic acidosis, and hyperkalaemia. Drugs and poisons that often cause seizures include antidepressants, isoniazid (INH), diphenhydramine, cocaine, and amphetamines.

Answer 1114

* Hypertension and tachycardia are typical with amphetamines, cocaine, and antimuscarinic (anticholinergic) drugs. * Hypotension and bradycardia are characteristic features of overdose with calcium channel blockers, β blockers, clonidine, and sedative hypnotics. * Hypotension with tachycardia is common with tricyclic antidepressants, trazodone, quetiapine, vasodilators, and β agonists.

Answer 1115

* Rapid respirations are typical of salicylates, carbon monoxide, and other toxins that produce metabolic acidosis or cellular asphyxia. * Hyperthermia may be associated with sympathomimetics, anticholinergics, salicylates, and drugs producing seizures or muscular rigidity. * Hypothermia can be caused by any CNS-depressant drug, especially when accompanied by exposure to a cold environment.

Answer 1116

* Constriction of the pupils (miosis) is typical of opioids, clonidine, phenothiazines, and cholinesterase inhibitors (eg, organophosphate insecticides), and deep coma due to sedative drugs. * Dilation of the pupils (mydriasis) is common with amphetamines, cocaine, LSD, and atropine and other anticholinergic drugs. * Horizontal nystagmus is characteristic of intoxication with phenytoin, alcohol, barbiturates, and other sedative drugs. * The presence of both vertical and horizontal nystagmus is strongly suggestive of phencyclidine poisoning.

Answer 1117

* The skin often appears flushed, hot, and dry in poisoning with atropine and other antimuscarinics. * Excessive sweating occurs with organophosphates, nicotine, and sympathomimetic drugs. * Cyanosis may be caused by hypoxaemia or by methemoglobinemia. * Icterus may suggest hepatic necrosis due to acetaminophen or Amanita phalloides mushroom poisoning.

Answer 1118

* Abdominal examination may reveal ileus, which is typical of poisoning with antimuscarinic, opioid, and sedative drugs. * Hyperactive bowel sounds, abdominal cramping, and diarrhea are common in poisoning with organophosphates, iron, arsenic, theophylline, A phalloides, and A muscaria.

Answer 1119

* Nystagmus, dysarthria, and ataxia are typical of phenytoin, carbamazepine, alcohol, and other sedative intoxication. * Twitching and muscular hyperactivity are common with atropine and other anticholinergic agents, and cocaine and other sympathomimetic drugs. * Muscular rigidity can be caused by haloperidol and other antipsychotic agents, and by strychnine or by tetanus. * Generalized hypertonicity of muscles and lower extremity clonus are typical of serotonin syndrome. * Seizures are often caused by overdose with antidepressants (especially tricyclic antidepressants and bupropion), cocaine, amphetamines, theophylline, isoniazid, and diphenhydramine. * Flaccid coma with absent reflexes and even an isoelectric electroencephalogram may be seen with deep coma due to sedative-hypnotic or other CNS depressant intoxication and may be mistaken for brain death.

Answer 1120

Anion gap = (Na⁺ + K⁺) – (HCO₃^– + Cl^–)

Answer 1121

* Normally, the sum of the cations exceeds the sum of the anions by no more than 12–16 mEq/L. * A larger than expected anion gap is caused by the presence of unmeasured anions (lactate, etc) accompanying metabolic acidosis. * This may occur with numerous conditions, such as diabetic ketoacidosis, renal failure, or shock-induced lactic acidosis. * Drugs that may induce an elevated anion gap metabolic acidosis include aspirin, metformin, methanol, ethylene glycol, isoniazid, and iron

Answer 1122

* Drugs that may cause hyperkalaemia despite normal renal function include potassium itself, β blockers, digitalis glycosides, potassium-sparing diuretics, and fluoride. * Drugs associated with hypokalaemia include barium, β agonists, caffeine, theophylline, and thiazide and loop diuretics.

Answer 1123

Substances that are often associated with an abnormal osmol gap include acetone, ethanol, ethylene glycol, isopropyl alcohol, methanol, and propylene glycol.

Answer 1124

* Widening of the QRS complex duration (to more than 100 milliseconds) is typical of overdose of tricyclic antidepressants and other drugs that block the sodium channel in cardiac conducting tissue. * The QTc interval may be prolonged in many poisonings, including antidepressants and antipsychotics, lithium, and arsenic * Variable atrioventricular (AV) block and a variety of atrial and ventricular arrhythmias are common with poisoning by digoxin and other cardiac glycosides. * Hypoxaemia due to carbon monoxide poisoning may result in ischaemic changes on the electrocardiogram.

Answer 1125

Note in the table, almost all of the drugs not useful begin with A-D apart from metoprolol and opioids

Answer 1126

* Owing to its large surface area, activated charcoal can adsorb many drugs and poisons. * It is most effective if given in a ratio of at least 10:1 of charcoal to estimated dose of toxin by weight. * Charcoal does not bind iron, lithium, or potassium, and it binds alcohols and cyanide only poorly. It does not appear to be useful in poisoning due to corrosive mineral acids and alkali. * Repeated doses of oral activated charcoal may enhance systemic elimination of some drugs (including carbamazepine, dapsone, and phenobarbital) by a mechanism referred to as “gut dialysis,” although the clinical benefit is unproved.

Answer 1127

* Acute ingestion of more than 150–200 mg/kg (children) or 7 g total (adults) is considered potentially toxic. * A highly toxic metabolite is produced in the liver

Answer 1128

* Initially, the patient is asymptomatic or has mild gastrointestinal upset (nausea, vomiting). * After 24–36 hours, evidence of liver injury appears, with elevated aminotransferase levels and hypoprothrombinaemia. * Fulminant liver failure may ensue, leading to metabolic acidosis, hypoglycaemia, encephalopathy, and death. * Renal failure may also occur. * With acute massive ingestion and very high serum levels, metabolic acidosis can occur in the absence of liver failure. * Rarely, acetaminophen ingestion can cause 5-oxoprolinuria due to glutathione depletion.

Answer 1129

* The severity of poisoning is estimated from a serum acetaminophen concentration measurement. * If the level is greater than 150 mg/L approximately 4 hours after ingestion, the patient is at risk for liver injury. (Chronic alcoholics or patients taking drugs that enhance P450 production of toxic metabolites may be at risk with lower levels.) * The antidote acetylcysteine acts as a glutathione substitute, binding the toxic metabolite as it is produced. It is most effective when given early and should be started within 8–10 hours if possible. * Liver transplantation may be required for patients with fulminant hepatic failure.

Answer 1130

* At the doses usually used by stimulant abusers, euphoria and wakefulness are accompanied by a sense of power and well-being. * At higher doses, restlessness, agitation, and acute psychosis may occur, accompanied by hypertension and tachycardia. * Prolonged muscular hyperactivity or seizures may contribute to hyperthermia and rhabdomyolysis. Body temperatures as high as 42°C (107.6°F) have been recorded. * Hyperthermia can cause brain damage, hypotension, coagulopathy, and renal failure.

Answer 1131

* Treatment for stimulant toxicity includes general supportive measures as outlined earlier. * There is no specific antidote. * Seizures and hyperthermia are the most dangerous manifestations and must be treated aggressively. * Seizures are usually managed with intravenous benzodiazepines (eg, lorazepam). * Temperature is reduced by removing clothing, spraying with tepid water, and encouraging evaporative cooling with fanning. For very high body temperatures (eg, >40–41°C), neuromuscular paralysis (eg, with vecuronium) is used to abolish muscle activity quickly.

Answer 1132

* The classic anticholinergic (technically, “antimuscarinic”) syndrome is remembered as “red as a beet” (skin flushed), “hot as a hare” (hyperthermia), “dry as a bone” (dry mucous membranes, no sweating), “blind as a bat” (blurred vision, cycloplegia), and “mad as a hatter” (confusion, delirium). * Patients usually have sinus tachycardia, and the pupils are usually dilated. * Agitated delirium or coma may be present. * Muscle twitching is common, but seizures are unusual unless the patient has ingested an antihistamine or a tricyclic antidepressant. * Urinary retention is common, especially in older men.

Answer 1133

* Treatment for anticholinergic syndrome is largely supportive. * Agitated patients may require sedation with a benzodiazepine or an antipsychotic agent (eg, haloperidol or olanzapine). * The specific antidote for peripheral and central anticholinergic syndrome is physostigmine, which has a prompt and dramatic effect and is especially useful for patients who are very agitated. * Physostigmine is given in small intravenous doses (0.5–1 mg) with careful monitoring, because it can cause bradycardia and seizures if given too rapidly. * Physostigmine should not be given to a patient with serious tricyclic antidepressant overdose because it can aggravate cardiotoxicity, resulting in heart block or asystole. * Catheterisation may be needed to prevent excessive distention of the bladder.

Answer 1134

* Tricyclic antidepressants (eg, amitriptyline, desipramine, dox- epin) are among the most common prescription drugs involved in life-threatening drug overdose. * Ingestion of more than 1 g of a tricyclic (or about 15–20 mg/kg) is considered potentially lethal.

Answer 1135

* Tricyclic antidepressants are competitive antagonists at muscarinic cholinergic receptors, and anticholinergic findings (tachycardia, dilated pupils, dry mouth) are common even at moderate doses. * Some tricyclics are also strong α blockers, which can lead to vasodilation. * Centrally mediated agitation and seizures may be followed by depression and hypotension. * Most important is the fact that tricyclics inhibit the cardiac sodium channel, causing slowed conduction with a wide QRS interval and depressed cardiac contractility. This cardiac toxicity may result in serious arrhythmias, including ventricular conduction block and ventricular tachycardia.

Answer 1136

* Treatment of tricyclic antidepressant overdose includes general supportive care. * Endotracheal intubation and assisted ventilation may be needed. * Intravenous fluids are given for hypotension, and dopamine or norepinephrine is added if necessary. * Many toxicologists recommend norepinephrine as the initial drug of choice for tricyclic-induced hypotension. * The antidote for cardiac toxicity (manifested by a wide QRS complex) is sodium bicarbonate: a bolus of 50–100 mEq (or 1–2 mEq/kg) provides a rapid increase in extracellular sodium that helps overcome sodium channel blockade.

Answer 1137

* Antipsychotic drugs include the older phenothiazines and butyrophenones, as well as newer so-called “atypical” drugs. * All of these can cause CNS depression, seizures, and hypotension. * Some can cause QT prolongation. * The potent dopamine D₂ blockers are also associated with parkinsonian movement disorders (dystonic reactions) and in rare cases with the neuroleptic malignant syndrome, characterised by “lead-pipe” rigidity, hyperthermia, and autonomic instability

Answer 1138

Newer antidepressants (eg, fluoxetine, paroxetine, citalo- pram, venlafaxine) are mostly SSRIs and are generally safer than the tricyclic antidepressants and monoamine oxidase inhibitors, although they can cause seizures.

Answer 1139

* Acute ingestion of more than 200 mg/kg is likely to produce intoxication. * Poisoning can also result from chronic overmedication; this occurs most commonly in elderly patients using salicylates for chronic pain who become confused about their dosing. * Poisoning causes uncoupling of oxidative phosphorylation and disruption of normal cellular metabolism.

Answer 1140

* The first sign of salicylate toxicity is often hyperventilation and respiratory alkalosis due to medullary stimulation. * Metabolic acidosis follows, and an increased anion gap results from accumulation of lactate as well as excretion of bicarbonate by the kidney to compensate for respiratory alkalosis. * Arterial blood gas testing often reveals a mixed respiratory alkalosis and metabolic acidosis. * Body temperature may be elevated owing to uncoupling of oxidative phosphorylation. * Severe hyperthermia may occur in serious cases. * Vomiting and hyperpnea as well as hyperthermia contribute to fluid loss and dehydration. * With very severe poisoning, profound metabolic acidosis, seizures, coma, pulmonary oedema, and cardiovascular collapse may occur. * Absorption of salicylate and signs of toxicity may be delayed after very large overdoses or ingestion of enteric coated tablets.

Answer 1141

* General supportive care is essential. * After massive aspirin ingestions (eg, more than 100 tablets), aggressive gut decontamination is advisable, including gastric lavage, repeated doses of activated charcoal, and consideration of whole bowel irrigation. * Intravenous fluids are used to replace fluid losses caused by tachypnea, vomiting, and fever. * For moderate intoxications, intravenous sodium bicarbonate is given to alkalinise the urine and promote salicylate excretion by trapping the salicylate in its ionized, polar form. * For severe poisoning (eg, patients with severe acidosis, coma, and serum salicylate level >90–100 mg/dL), emergency haemodialysis is performed to remove the salicylate more quickly and restore acid-base balance and fluid status.

Answer 1142

* In overdose, β blockers inhibit both β1 and β2 adrenoceptors; selectivity, if any, is lost at high dosage. * The most toxic β blocker is propranolol. As little as two to three times the therapeutic dose can cause serious toxicity. * This may be because propranolol in high doses may cause sodium channel-blocking effects similar to those seen with tricyclic antidepressants, and it is lipophilic, allowing it to enter the CNS.

Answer 1143

* Bradycardia and hypotension are the most common manifestations of toxicity. * Agents with partial agonist activity (eg, pindolol) can cause tachycardia and hypertension. * Seizures and cardiac conduction block (wide QRS complex) may be seen with propranolol overdose.

Answer 1144

* General supportive care. * The usual measures used to raise the blood pressure and heart rate, such as intravenous fluids, β-agonist drugs, and atropine, are generally ineffective. * Glucagon is a useful antidote that—like β agonists—acts on cardiac cells to raise intracellular cAMP but does so independent of β adrenoceptors. * It can improve heart rate and blood pressure when given in high doses (5–20 mg intravenously).

Answer 1145

* Calcium antagonists can cause serious toxicity or death with relatively small overdoses. * These channel blockers depress sinus node automaticity and slow AV node conduction. * They also reduce cardiac output and blood pressure. * Serious hypotension is mainly seen with nifedipine and related dihydropyridines, but in severe overdose all of the listed cardiovascular effects can occur with any of the calcium channel blockers.

Answer 1146

* Treatment requires general supportive care. * Since most ingested calcium antagonists are in sustained-release form, it may be possible to expel them before they are completely absorbed; initiate whole bowel irrigation and oral activated charcoal as soon as possible, before calcium antagonist-induced ileus intervenes. * Calcium, given intravenously in doses of 2–10 g, is a useful antidote for depressed cardiac contractility but less effective for nodal block or peripheral vascular collapse. * Other treatments reported to be helpful in managing hypotension associated with calcium channel blocker poisoning include high-dose insulin (0.5–1 unit/kg/h) plus glucose supplementation to maintain euglycemia; glucagon; veno-arterial extracorporeal membrane oxygenation (ECMO-VA); and methylene blue.

Answer 1147

* Stimulation of muscarinic receptors causes abdominal cramps, diarrhoea, excessive salivation, sweating, urinary frequency, and increased bronchial secretions. * Stimulation of nicotinic receptors causes generalised ganglionic activation, which can lead to hypertension and either tachycardia or bradycardia. * Muscle twitching and fasciculations may progress to weakness and respiratory muscle paralysis. * CNS effects include agitation, confusion, and seizures. * The mnemonic DUMBELS (diarrhoea, urination, miosis and muscle weakness, bronchospasm, excitation, lacrimation, and seizures, sweating, and salivation) helps recall the common findings. * Blood testing may be used to document depressed activity of red blood cell (acetylcholinesterase) and plasma (butyrylcholinesterase) enzymes, which provide an indirect estimate of synaptic cholinesterase activity.

Answer 1148

* General supportive care should be provided. * Precautions should be taken to ensure that rescuers and health care providers are not poisoned themselves by exposure to contaminated clothing or skin. This is especially critical for the most potent substances such as parathion or nerve gas agents. * Antidotal treatment consists of atropine and pralidoxime. * Atropine is an effective competitive inhibitor at muscarinic sites but has no effect at nicotinic sites. * Pralidoxime given early enough may be capable of restoring the cholinesterase activity and is active at both muscarinic and nicotinic sites; however, studies are conflicting regarding its effect on clinical outcome.

Answer 1149

* Vomiting is common in patients with digitalis overdose. * Hyperkalaemia may be caused by acute digitalis overdose or severe poisoning, whereas hypokalaemia may be present in patients as a result of long-term diuretic treatment. (Digitalis does not cause hypokalemia.) * A variety of cardiac rhythm disturbances may occur, including sinus bradycardia, AV block, atrial tachycardia with block, accelerated junctional rhythm, premature ventricular beats, bidirectional ventricular tachycardia, and other ventricular arrhythmias.

Answer 1150

* General supportive care should be provided. * Atropine is often effective for bradycardia or AV block. * The use of digoxin antibodies has revolutionised the treatment of digoxin toxicity; they should be administered intravenously in the dosage indicated in the package insert. * Symptoms usually improve within 30–60 minutes after antibody administration. * Digoxin antibodies may also be tried in cases of poisoning by other cardiac glycosides (eg, digitoxin, oleander), although larger doses may be needed due to incomplete cross-reactivity.

Answer 1151

* Patients with ethanol or other sedative-hypnotic overdose may be euphoric and rowdy (“drunk”) or in a state of stupor or coma (“dead drunk”). * Comatose patients often have depressed respiratory drive. * Depression of protective airway reflexes may result in pulmonary aspiration of gastric contents, leading to pneumonia. * Hypothermia may be present because of environmental exposure and depressed shivering. * Ethanol blood levels greater than 300 mg/dL usually cause deep coma, but regular users are often tolerant to the effects of ethanol and may be ambulatory despite even higher levels. * Patients with GHB overdose are often deeply comatose for 3–4 hours and then awaken fully in a matter of minutes.

Answer 1152

* General supportive care should be provided. * With careful attention to protecting the airway (including endotracheal intubation) and assisting ventilation, most patients recover as the drug effects wear off. * Hypotension usually responds to intravenous fluids, body warming if cold, and, if needed, dopamine. * Patients with isolated benzodiazepine overdose may awaken after intravenous flumazenil, a benzodiazepine antagonist. However, this drug is not widely used as empiric therapy for drug overdose because it may precipitate seizures in patients who are addicted to benzodiazepines or who have ingested a convulsant drug (eg, a tricyclic antidepressant). * There are no antidotes for ethanol, barbiturates, or most other sedative-hypnotics.

Answer 1153

* Somatropin * Mechanism of action: Recombinant form of human GH - acts through GH receptors to increase production of IGF-I * Effects: Restores normal growth and metabolic GH effects in GH-deficient individuals * increases final adult height in some children with short stature not due to GH deficiency

Answer 1154

* Clinical actions: Replacement in GH deficiency * increased final adult height in children with certain conditions associated with short stature * wasting in HIV infection * short bowel syndrome * SC injection * Toxicity: Pseudotumor cerebri, slipped capital femoral epiphysis, edema, hyperglycemia, progression of scoliosis, risk of asphyxia in severely obese patients with Prader-Willi syndrome and upper airway obstruction or sleep apnea

Answer 1155

* Octreotide * Agonist at somatostatin receptors * Inhibits production of GH and, to a lesser extent, of TSH, glucagon, insulin, and gastrin

Answer 1156

* Acromegaly and several other hormone-secreting tumors * acute control of bleeding from oesophageal varices * SC or IV injection * long-acting formulation injected IM monthly * Toxicity: Gastrointestinal disturbances, gallstones, bradycardia, cardiac conduction problems

Answer 1157

* Bromocriptine * Activates dopamine D2 receptors * Suppresses pituitary secretion of prolactin and, less effectively, GH * dopaminergic effects on CNS motor control and behavior

Answer 1158

* Uses: Treatment of hyperprolactinemia * acromegaly * Parkinson’s disease * Administered orally or, for hyperprolactinemia, vaginally * Toxicity: Gastrointestinal disturbances, orthostatic hypotension, headache, psychiatric disturbances, vasospasm and pulmonary infiltrates in high doses

Answer 1159

* Desmopressin * Relatively selective vasopressin V2 receptor agonist * Acts in the kidney collecting duct cells to decrease the excretion of water * acts on extrarenal V2 receptors to increase factor VIII and von Willebrand factor

Answer 1160

* Uses: Pituitary diabetes insipidus * pediatric primary nocturnal enuresis * hemophilia A and von Willebrand disease * Oral, IV, SC, or intranasal * Toxicity: Gastrointestinal disturbances, headache, hyponatremia, allergic reactions

Answer 1161

* Levothyroxine, liothyroxine * Activation of nuclear receptors results in gene expression with RNA formation and protein synthesis * maximum effect seen after 6–8 weeks of therapy * Toxicities: symptoms of hyperthyroid

Answer 1162

* Examples include methimazole, propylthiouracil * Inhibit thyroid peroxidase reactions * block iodine organification * inhibit peripheral deiodination of T4 and T3 (primarily PTU)

Answer 1163

* Rapid-acting: Lispro, aspart, glulisine, inhaled regular * Short-acting: Regular * Long-acting: Detemir, glargine, degludec

Answer 1164

* Glipizide, Glyburide, Glimepiride, Gliclazide * Insulin secretagogues: Close K+ channels in beta cells and increase insulin release * Effects: Reduce circulating glucose in patients with functioning beta cells

Answer 1165

* Orally active * Duration 10–24 h * Toxicity: Hypoglycemia, weight gain

Answer 1166

* Metformin * Activates AMP kinase and reduces hepatic and renal gluconeogenesis * This decreases circulating glucose

Answer 1167

* Oral * Maximal plasma concentration in 2–3 h * Toxicity: Gastrointestinal symptoms, lactic acidosis (rare) * Cannot use if impaired renal/hepatic function, congestive heart failure (CHF), hypoxic/acidotic states, alcoholism

Answer 1168

* Examples include: Exenatide, liraglutide, albiglutide, dulaglutide * Mechanism: Analogs of GLP-1: Bind to GLP-1 receptors * Effects: reduce post-meal glucose excursions, increase glucose- mediated insulin release, lower glucagon levels, slow gastric emptying, decrease appetite

Answer 1169

* Parenteral (SC) * Toxicity: Nausea, headache, vomiting, anorexia, mild weight loss, pancreatitis

Answer 1170

* Examples: Sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin * Mechanism of action: Block degradation of GLP-1, raise circulating GLP-1 levels * Effect: Reduces post-meal glucose excursions: Increases glucose-mediated insulin release, lowers glucagon levels, slows gastric emptying, decreases appetite

Answer 1171

* Oral * Half-life ~12 h * 24-h duration of action * Toxicity: Rhinitis, upper respiratory infections, headaches, pancreatitis, rare allergic reactions

Answer 1172

* Examples: Canagliflozin, dapagliflozin, empagliflozin * Mechanism of action: Block renal glucose resorption * Effects: Increase glucosuria, lower plasma glucose levels

Answer 1173

* Oral * Half-life ~10–14 h * Toxicity: Genital and urinary tract infections, polyuria, pruritus, thirst, osmotic diuresis, constipation