Pharmacology

Question 1

What is the definition of a receptor?

Answer 1

The cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular or systemic response

Question 2

What is the definition of potency?

Answer 2

Potency is the concentration (EC50) or dose (ED50) of a drug to produce 50% of the drugs maximal effect

Question 3

What is the definition of relative potency?

Answer 3

A variant where instead of using units to describe the dose required to reach a certain end point, one ends up using a ratio of equivalent doses

Question 4

What is the definition of efficacy?

Answer 4

E(max) is the maximum effect which can be expected from the drug. (When this magnitude is reached, increasing the dose will not increase the magnitude of the effect)

Question 5

What is the definition of intrinsic activity/maximal agonist effect of a drug?

Answer 5

The maximal efficacy as a fraction of the maximal efficacy produced by a full agonist of the same type acting through the same receptors in the same condition

Question 6

What actually is a ligand?

Answer 6

Usually a small molecule, but they range from ions and small peptides to dissolved proteins

Question 7

What actually is a receptor?

Answer 7

A large protein with a 3D structure

Question 8

What does it mean that a ligand and a receptor have molecular complementarity?

Answer 8

The shape and chemical properties of their binding sites are matching to permit high-affinity selective binding

Question 9

What are the chemical bonds that make up ligand and receptor binding and give four examples?

Answer 9

1. Van de Waals forces - monoclonal antibodies and their targets
2. Hydrophobic attraction - suggamadex and rocuronium
3. Hydrogen bonding - local anaesthetic to a voltage gated sodium channel
4. Electrostatic attraction - acetylcholine and its receptor

Question 10

What is a pharmacophore?

Answer 10

The ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target

Question 11

Think systematically

List the different drug-receptor interactions and give some examples

Answer 11

Extracellular
- Soluble extracellular enzymes (dabigatran, perindopril)
Cell Surface
- Cell surface molecules (abciximab)
- Transmembrane non-enzymes (cytokines, interferon gamma)
- Transmembrane proteins with active domains eg receptor kinases (insulin)
- Ligand-gated ion channels (nicotine, suxamethonium)
- Voltage-gated ion channels (lignocaine, verapamil)
- G-protein coupled receptors (dobutamine, metoprolol)
Intracellular
- Soluble intracellular enzymes (GTN)
- Nuclear receptors (corticosteroids, thyroxine)
- Nucliec acids (azithromycin)

Question 12

What are ion channels?

Answer 12

They are pore-like transmembrane proteins that alter the local permeability of the cell membrane to ions. Typically, these are fairly selective to which ion they open for

Question 13

How do ligand-gated ion channels work?

Answer 13

The binding of a ligand opens the pore, and without the ligand the channel is closed.

Classic examples are acetylcholine and suxamethonium.
Endogenous ligands include serotonin, GABA, glycine and glutamate

Question 14

How do voltage-gated ion channels work?

Answer 14

The channels are closed and undergo a conformational change when the transmembrane voltage difference reaches some threshold voltage.

Question 15

How do G-protein coupled receptors work?

Answer 15

The G-protein coupled receptor is bound to a GTP-ase protein, which hydrolyses GTP into GDP. When bound to GTP, these proteins become activated, which then allows them to regulate the activity of second messenger systems and amplify the signal of receptor activation

A G-protein is a receptor with seven transmembrane regions, which have their extracellular domain as the receptor. They are made of seven helix domains that stretch back and forth across the membrane

Question 16

How do nuclear receptors work?

Answer 16

These receptors, when activated, will bind directly to some sort of ‘response elements’ in the promoter regions of their specific genes. Once it binds to the ligand, the receptor will usually undergo a conformational change which recruits other proteins into a huge multimeric complex, or instead destabilises and deactivates such a complex

These are usually hormone receptors, and their role is to regulate gene transcription. They work slowly.

Question 17

What are the two different types of nuclear receptors and how do they work?

Answer 17

Steroid
Generally found in extranuclear cytoplasm, when bound to an agonist they move intranuclear and do their work
Non-steroid
Often intranuclear, found in a heterodimer (bound to other intranuclear receptors and transcription factors)

Question 18

What is an agonist?

Answer 18

A ligand that binds to a receptor and alters the receptor state resulting in a biological response

Question 19

What are the 3 different types of agonist?

Answer 19

Full agonist
reaches the maximal response capability of the system
Partial agonist
does not reach the maximal response capability of the system even at a full receptor occupancy
Inverse agonist
a ligand that by binding to the receptors, reduces the fraction of them in an active conformation

Note: A partial agonist acts as an antagonist in the presence of a full agonist (if they compete for the same receptors)

Question 20

What does an allosteric modulator do?

Answer 20

Increases or decreases the action of a primary agonist whilst having no effect on its own

Question 21

What are spare receptors?

Answer 21

They are receptors that exist wherever a full agonist can cause a maximal response when occupying only a fraction of the total receptor population

Question 22

What is an antagonist?

Answer 22

A drug that reduced the action of another drug

Question 23

What are the 5 different types of antagonist?

Answer 23

Competitive antagonist
competes for the same binding site with an agonist, their binding is mutually exclusive
Non-competitive antagonist
can prevent the action of an agonist without any effect of the binding of the agonist to the receptor
Insurmountable antagonist
can reduce the maximum effect of the agonist, and this inhibitory effect is not affected by increasing agonist concentration
Irreversible antagonist
is insurmountable but it does not have to be non-competitive
Physiological antagonist
non-competitive but it does not have to be insurmountable e.g. something that depresses what the agonist is trying to illicit

Question 24

How does a competitive antagonist effect efficacy and potency?

Answer 24

The efficacy is not affected but the potency is increased

Question 25

What is the Schild equation used for?

Answer 25

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

Question 26

What is the Schild equation?

Answer 26

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

Question 27

What is a second messenger?

Answer 27

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

Question 28

What are the characteristic features of a second messenger?

Answer 28

• 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

Question 29

Where can a second messenger act?

Answer 29

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

Question 30

What are the 5 broad types of second messengers?

Answer 30

• 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

Question 31

What is cAMP?

Answer 31

Cyclic adenosine monophosphate is a cyclic nucleotide secondary messenger

Question 32

How is cAMP produced and degraded?

Answer 32

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

Question 33

What is cAMPs main targets?

Answer 33

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

Question 34

What is the main action of cAMP?

Answer 34

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

Question 35

What are nucleotides made of?

Answer 35

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

Question 36

What are the observable effects of cAMP?

Answer 36

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

Question 37

What is cGMP?

Answer 37

Cyclic guanosine monophospate is a cyclic nucleotide secondary messenger

Question 38

How is cGMP produced and degraded?

Answer 38

• 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

Question 39

What are the main downstream targets of cGMP and briefly tell me their effects?

Answer 39

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

Question 40

What does PKG do and how does that affect the net effect of cGMP?

Answer 40

• 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

Question 41

What are the clinically relevant effects of cGMP?

Answer 41

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

Question 42

Describe the points on the graph including the axis labels, what each line represents and what the dotted lines represent

Answer 42

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

Question 43

What do the lines on this graph represent?

Answer 43

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

Question 44

What is the definition of volume distribution?

Answer 44

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

Question 45

What is volume distribution used for?

Answer 45

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

Question 46

How do you work out the volume distribution?

Answer 46

Dose / Plasma concentration

Question 47

What are the units of volume distribution?

Answer 47

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

Question 48

What is V-initial/Vc? What affects V-initial?

Answer 48

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

Question 49

What is V-extrap? What is it used for?

Answer 49

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

Question 50

What is V-area?

Answer 50

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

Question 51

How do you calculate Varea?

Answer 51

Question 52

What is V-ss? How do you work it out?

Answer 52

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

Question 53

What are the main molecule factors that influence the volume distribution?

Answer 53

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

Question 54

What are the main patient features that affect volume distribution?

Answer 54

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

Question 55

How do these things affect Vd?
* Molecule size
* Molecule charge
* pKa
* Lipid solubility
* Water solubility

Answer 55

• 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

Question 56

What is the definition of half life?

Answer 56

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

Question 57

What is the equation for half life?

Answer 57

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

Question 58

How is half life related to Vd and clearance?

Answer 58

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

Question 59

How many half lives does it take for a drug to be roughly 97% eliminated?

Answer 59

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

Question 60

How would doubling the dose of a drug affect the half life?

Answer 60

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

Question 61

How does first or zero order kinetics affect half life?

Answer 61

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

Question 62

What is first order kinetics vs zero order kinetics?

Answer 62

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

Question 63

How does concentration affect first order and zero order kinetics?

Answer 63

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

Question 64

What is Michaelis-Menten kinetics?

Answer 64

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

Question 65

What is non-linear elimination kinetics?

Answer 65

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)

Question 66

What is the pharmacology of first order kinetics?

Answer 66

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

Question 67

What does this graph show?

Answer 67

Question 68

What equation can you use to estimate the concentration of the drug at any given time using the semi-logarithmic concentration/time graph?

Answer 68

Question 69

What is the pharmacology mechanism behind Michaelis Menten elimination kinetics?

Answer 69

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

Question 70

What is the equation of Michaelis Menten kinetics?

Answer 70

Question 71

How does Michaelis Menten elimination kinetics affect the doses we give to patients?

Answer 71

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

Question 72

How is Michealis Menden elimination kinetics relevant to therapeutic index? At what value does it become a narrow index?

Answer 72

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

Question 73

How do you calculate the dose rate?

Answer 73

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

Question 74

How do you calculate the maintenance dose rate?

Answer 74

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

Question 75

How do you calculate the loading dose?

Answer 75

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

Question 76

How do you achieve maintenance dosing in continuous infusions? How long does this take?

Answer 76

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

Question 77

How do you achieve maintenance dosing in regular dosing? How long does it take?

Answer 77

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

Question 78

Why do you need loading dose?

Answer 78

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

Question 79

How do you calculate the loading dose?

Answer 79

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.

Question 80

How does oral vs IV administration affect dosing?

Answer 80

• 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

Question 81

What are the factors that affect dosing intervals?

Answer 81

• 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

Question 82

What is the bioavailability?

Answer 82

The fraction of the dose which reaches systemic circulation intact

Question 83

What is absolute vs relative bioavailability?

Answer 83

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

Question 84

How is bioavailability measured?

Answer 84

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)

Question 85

What does bioequivalent mean?

Answer 85

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

Question 86

What factors affect bioavailability?

Answer 86

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

Question 87

What is morphine’s bioavailiability?

Answer 87

Morphine is a drug that has poor bioavailability

Question 88

How is phenytoin’s volume distribution affected and by what?

Answer 88

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

Question 89

How is gentamicin cleared and how does this affect its administration?

Answer 89

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

Question 90

How is Vancomycin effected by sepsis and why?

Answer 90

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

Question 91

What sort of molecules are easily renally excreted? What happens to drugs that aren’t?

Answer 91

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

Question 92

Biotransformation reactions can be split into two phases. Phase I and Phase II. What are they?

Answer 92

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

Question 93

Where do biotransformations occur?

Answer 93

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

Question 94

What is the first pass effect?

Answer 94

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

Question 95

What cellular organelles house a lot of drug metabolising enzymes?

Answer 95

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

Question 96

How are microsomes formed and what are their characteristic properties?

Answer 96

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

Question 97

What two key enzymes are important for oxidative drug metabolism? What do they need to do it?

Answer 97

NADPH-cytochrome P450 oxidoreductase
and
Cytochrome P450

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

Question 98

What happens in the oxidation reaction with cytochrome P450?

Answer 98

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

Question 99

There are numerous P450 isoforms, which is the most important one?

Answer 99

CYP3A4 metabolises over 50% of prescribed drugs

Question 101

What happens if P450 enzyme is induced?

Answer 101

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

Question 102

What are some classic P450 drug substrates?

Answer 102

Beta blockers
Warfarin
Oral contraceptives
Statins
Theophylline
Amiodarone
SSRIs
Opioids

Question 103

List some P450 inhibitors

Answer 103

INHIBITORS
Sulphonamides
Isoniazid
Cemetidine
K etoconazole
Fluconazole
Alcohol
Ciprofloxacin
Erythromycin
Sodium valproate
.
Chloramphenicol
Omeprazole
Metronidazole**

Question 104

List some P450 Inducers

Answer 104

Inducers
Sulphonylureas
Carbamazepine
Rifampicin
Alcohol - chronic
Phenytoin

Question 105

What are the phases of clinical trials?

Answer 105

• 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

Question 106

What is a cardiac arrythmia?

Answer 106

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

Question 107

What are some factors that can precipitate or exacerbate arrhythmias?

Answer 107

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

Question 108

What is the classification of anti-arrhythmics called? What are it’s groups? Give examples for each

Answer 108

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

Question 109

What is a use-dependent or state-dependent drug?

Answer 109

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

Question 110

How do class 1 antiarrhythmics work? What are the subclasses of class 1? - Give an example for each

Answer 110

• 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

Question 111

How do class 2 anti-arrhythmics work? Give an example

Answer 111

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

Question 112

How do class 3 anti-arrhythmics work? Give an example

Answer 112

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

Question 113

How do class 4 anti-arrhythmics work?

Answer 113

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

Question 114

What are the cardiac effects of amiodarone?

Answer 114

• 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

Question 115

What are the extracardiac effects of Amiodarone?

Answer 115

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

Question 116

What are the toxic effects of amiodarone?

Answer 116

• 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

Question 117

What is the pharmacokinetics of amiodarone?

Answer 117

• 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

Question 118

What are the cardiac effects of verapamil?

Answer 118

• 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

Question 119

What are the extracardiac effects of verapamil?

Answer 119

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

Question 120

What are the effects of verapamil toxicity?

Answer 120

• 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

Question 121

What are the pharmacokinetics of verapamil?

Answer 121

• 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

Question 122

What are some other anti-arrhythmics that don’t fit into the conventional classification?

Answer 122

• Adenosine
• Digoxin
• Magnesium
• Potassium

Question 123

What is the mechanism of action of adenosine?

Answer 123

• 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.

Question 124

What is the half-life of adenosine and what are the usual doses?

Answer 124

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

Question 125

What are the toxic effects of adenosine?

Answer 125

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

Question 126

What are the pharmacokinetics of digoxin?

Answer 126

• 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.

Question 127

What are the pharmacodynamics of digoxin?

Answer 127

• 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, is has cardioselective parasympathetic effects by sensitising the baroreceptors, causing central vagus stimulation, and facilitation of muscarinic transmission at the nerve ending-myocyte synapse

Question 128

What happens during digoxin toxicity?

Answer 128

• 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.

Question 129

What extracardiac effects does digoxin have?

Answer 129

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

Question 130

How do potassium and digoxin interact?

Answer 130

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

Question 131

How do calcium and magnesium interact with digoxin?

Answer 131

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

Question 132

What receptors does adrenaline bind to? What effect does this have?

Answer 132

• 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

Question 133

What receptors does noradrenaline bind to? What effect does this have?

Answer 133

• 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

Question 134

What is dopamine and what are the effects of using it?

Answer 134

• 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

Question 135

What are the tissues where alpha 1 receptors are and the actions they produce?

Answer 135

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

Question 136

What are the tissues where alpha 2 receptors are and the actions they produce?

Answer 136

• 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

Question 137

What are the tissues where beta 1 receptors are and the actions they produce?

Answer 137

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

Question 138

What are the tissues where beta 2 receptors are and the actions they produce?

Answer 138

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

Question 139

What are the tissues where beta 3 receptors are and the actions they produce?

Answer 139

Bladder - relaxes detrusor muscle

Question 140

What are the tissues where delta 1 and 2 receptors are and the actions they produce?

Answer 140

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

Question 141

What are the three drug groups traditionally used in angina?

Answer 141

Organic nitrates
Calcium channel blockers
Beta blockers

Question 142

What are the pharmacokinetics of nitrates?

Answer 142

• 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

Question 143

What is the pharmacodynamics of nitrates mechanism of action in smooth muscle?

Answer 143

• 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.

Question 144

What are the pharmacodynamics of vascular effects of nitrates?

Answer 144

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.

Question 145

How do nitrates affect the veins and how does this effect cardiac output?

Answer 145

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

Question 146

What are the indirect effects of nitrates and what does this lead to?

Answer 146

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.

Question 147

How do nitrates affect the arteries and how does this add to side effects?

Answer 147

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.

Question 148

How do nitrates affect other smooth muscle organs?

Answer 148

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.

Question 149

What are the effects of nitrates on the action of platelets?

Answer 149

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.

Question 150

What are the acute adverse effects of nitrates?

Answer 150

Orthostatic hypotension
Tachycardia
Throbbing headache

Question 151

What are the contraindications to nitrates?

Answer 151

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

Question 152

How does tolerance of nitrates occur?

Answer 152

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

Question 153

What are the nitrate effects in angina of effort?

Answer 153

• 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

Question 154

What are the nitrate effects in variant angina?

Answer 154

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

Question 155

What are the nitrate effects in unstable angina?

Answer 155

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

Question 156

What are the different ways of administrating nitrates?

Answer 156

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

Question 157

What is the pharmacokinetics of calcium channel blockers?

Answer 157

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

Question 158

What is the mechanism of action of calcium channel blockers?

Answer 158

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.

Question 159

What are the smooth muscle effects of calcium channel blockers?

Answer 159

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

Question 160

Name some calcium channel blockers

Answer 160

Dihydropyridines
* Amlodipine
* Nifedipine

Miscellanous
* Diltiazem
* Verapamil

Question 161

How do dihydropyridines and other calcium channel blockers affect smooth muscle differently?

Answer 161

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

Question 162

How do calcium channel blockers affect cardiac muscle?

Answer 162

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

Question 163

How do the different calcium channel blockers differ with regards to their actions on the heart?

Answer 163

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

Question 164

Why is skeletal muscle not affected by calcium channel blockers?

Answer 164

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

Question 165

What are the toxic effects for calcium channel blockers?

Answer 165

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

Question 166

What are the half-lives of the following calcium channel blockers?
* Amlodipine
* Nifedipine
* Diltiazem
* Verapamil

Answer 166

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

Question 167

What are the mechanisms of the clinical effects of calcium channel blockers?

Answer 167

• 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

Question 168

What is the effect of CCBs in overt heart failure?

Answer 168

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

Question 169

What is the mechanism of action of beta blockers in angina?

Answer 169

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.

Question 170

What are the contraindications to the use of beta blockers?

Answer 170

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

Question 171

What are some adverse effects of beta blockers?

Answer 171

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

Question 172

What is the mechanism and site of action of propranolol?

Answer 172

• 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

Question 173

What are the pharmacodynamics of propranolol?

Answer 173

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

Question 174

How does the mechanism of metoprolol compare to that of propranolol?

Answer 174

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

Question 175

What are the pharmacodynamics of metoprolol?

Answer 175

• 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

Question 176

What are the pharmacodynamics of atenolol?

Answer 176

• 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

Question 177

What are the pharmacodynamics of nadolol and carteolol?

Answer 177

• 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

Question 178

What are the pharmacokinetics and pharmacodynamics of betaxolol and bisoprolol?

Answer 178

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

Question 179

What are the mechanisms of action of labetalol, carvedilol and nebivolol?

Answer 179

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

Question 180

What are the pharmacodynamics of esmolol?

Answer 180

• 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

Question 181

What is a ‘diuretic’ vs a ‘natiuretic’ vs an ‘aquaretic’?

Answer 181

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

Question 182

Where is carbonic anhydrase present in the kidney and what is its function?

Answer 182

• 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.

Question 183

What are some examples of carbonic anhydrase inhibitors and how do they cause diuresis?

Answer 183

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

Question 184

What are the pharmacokinetics of carbonic anhydrase inhibitors?

Answer 184

• 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

Question 185

What are the pharmacodynamics of carbonic anhydrase inhibitors?

Answer 185

• 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.

Question 186

What are some of the non-diuretic clinical indications for carbonic anhydrase inhibitors?

Answer 186

• 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.

Question 187

What are the adverse effects of carbonic anhydrase inhibitors?

Answer 187

• 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

Question 188

What are the pharmacodynamics of SGLT2 inhibitors?

Answer 188

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

Question 189

How does Angiotensin II affect SGLT2 inhibitors?

Answer 189

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

Question 190

What are the pharmacokinetics of SGLT2 inhibitors?

Answer 190

• They are rapidly absorbed by the GI tract.
• The elimination half-life of dapagliflozin is 10-12 hours
• Up to 70% of the give 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

Question 191

Give some examples of SGLT2 inhibitors?

Answer 191

Dapagliflozin
Canagliflozin
Empagliflozin
Ipragliflozin

Question 192

On a very basic level, how do loop diuretics work?

Answer 192

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

Question 193

What are the pharmacokinetics of loop diuretics?

Answer 193

• The are rapidly absorped.
• They are eliminated by the kindey 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.

Question 194

What are the pharmacodynamics of loop diuretics?

Answer 194

• 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

Question 195

How can loop diuretics be used in hypercalcaemia?

Answer 195

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.

Question 196

How can NSAIDs interfere with loop diuretics? What group of patients does this effect?

Answer 196

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

Question 197

How do loop diuretics affect pulmonary congestion and left ventricular filling?

Answer 197

• 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

Question 198

Apart from acute pulmonary oedema and other oedematous conditions, what are the other clinical indications of furosemide?

Answer 198

• 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

Question 199

What are the adverse effects of loop diuretics?

Answer 199

• 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

Question 200

What are the pharmacokinetics of thiazides?

Answer 200

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.

Question 201

What are the pharmacodynamics of thiazides?

Answer 201

• 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

Question 202

What are the main clinical indications for thiazide diuretics?

Answer 202

HTN
HF
Nephrolithiasis due to idiopathy hypercalciuria
Nephrogenic diabetes insipidus

Question 203

What are the adverse effects of thiazides?

Answer 203

• 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

Question 204

Name some thiazide diuretics

Answer 204

Bendroflumethiazide
Hydrochlorothizaide
Indapamide
Chlorothiazide

Question 205

Name some potassium-sparing diuretics

Answer 205

Spironolactone
Amiloride
Eplerenone

Question 206

Briefly, how do potassium-sparing diuretics work?

Answer 206

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).

Question 207

What are the pharmacokinetics of spironolactone?

Answer 207

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)

Question 208

What are the pharmacokinetics of eplerenone and how are these different from spironolactone?

Answer 208

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.

Question 209

What are the pharmacodynamics of potassium-sparing diuretics?

Answer 209

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.

Question 210

What are the clinical indications of K+ sparing diuretics?

Answer 210

• 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

Question 211

What are the adverse effects of K+ sparing diuretics?

Answer 211

• 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.

Question 212

What are some contraindications to potassium sparing diuretics?

Answer 212

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

Question 213

How do osmotic diuretics work?

Answer 213

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

Question 214

What is an example of an osmotic diuretic?

Answer 214

Mannitol

Question 215

What are the pharmacokinetics of mannitol?

Answer 215

• 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

Question 216

What are the pharmacodynamics of mannitol?

Answer 216

• 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.

Question 217

What are the clinical indications of mannitol?

Answer 217

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.

Question 218

What is the dose of mannitol in reducing ICP and how quick does it work?

Answer 218

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

Question 219

When could mannitol be using in dialysis?

Answer 219

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

Question 220

What are the adverse effects of mannitol?

Answer 220

• 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, hyerkalaemia 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 impariment, 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

Question 221

What are indirect thrombin inhibitors? Name some. How do they work?

Answer 221

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.

Question 222

What is the chemical make up of heparin? What is it’s mechanism of action

Answer 222

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.

Question 223

How does antithrombin work? How does heparin effect it?

Answer 223

• 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)
• Herpain functions as a cofactor for the reaction wihtout being consumed. Once the complex is formed, heparin is released intact for renewed binding to more antithrombin.

Question 224

How is HMWH different from LMWH?

Answer 224

• 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

Question 225

How do you monitor heparin effect?

Answer 225

• 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.

Question 226

What are the adverse effects of heparin?

Answer 226

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

Question 227

What are the contraindications to heparin?

Answer 227

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

Question 228

What is the dosing for continuous IV administration of heparin?
Whats the ideal anti-Xa level?

Answer 228

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

Question 229

What is the prophylactic dose of enoxaparin?
What is treatment dose of enoxaparin? What level of anti-factor Xa does this aim for?

Answer 229

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.

Question 230

What is the prophylactic and treatment dose of dalteparin?

Answer 230

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

Question 231

What are the pharmacokinetics of fondaparinux?

Answer 231

• 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

Question 232

What are the pharmacokinetics of warfarin?

Answer 232

• 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 unirary excretion of unchanged drugs

Question 233

What is the mechanism of action of warfarin?

Answer 233

• 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.

Question 234

How long does warfarin take to work? Why?

Answer 234

• 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.

Question 235

Why is warfarin not used to treat patient in an active hypercoagulable state? i.e. bridging

Answer 235

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

Question 236

What are the adverse effects of warfarin?

Answer 236

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.

Question 237

What is the administration and dosage of warfarin?

Answer 237

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.

Question 238

What is the INR?

Answer 238

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

Question 239

What is the recommended INR in warfarin?

Answer 239

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

Question 240

Occasionally patients exhibit warfarin resistance, defined as progression or recurrence of a thrombotic event whilst in target range. We may raise their INR target or swtich anticoagulation. What diseases is this seen in?

Answer 240

Patients with advanced cancers, typically of GI origin

Question 241

What are the pharmacokinetic mechanisms for drug interactions with warfarin? Which drugs interact with the pharmacokinetics?

Answer 241

They mainly involve cytochrome P450 CYP2C9 enzyme induction, enzyme inhibitiona nd reduced plasma protein binding.

Question 242

What are the pharmacodynamic mechanisms for drug interactions with warfarin? Which drugs interact with the pharmacodynamics?

Answer 242

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)

Question 243

What is the chemical make-up of warfarin?

Answer 243

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

Question 244

How do metronidazole, fluconazole and trimethoprim and sulfamethoxazole interact with warfarin?

Answer 244

They stereoselectively inhibit the metabolic transformation of S-warfarin

Question 245

How do amiodarone, disulfiram and cimetidine interact with warfarin?

Answer 245

They inbibit metabolsim of both R-warfarin and S-warfarin

Question 246

How do aspirin, hepatic disease and hyperthyroidism augment warfarin’s effects?

Answer 246

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

Question 247

How do third-egenration cephalosporins (cefixime, ceftazadine, cefotaxime) interact with warfarin?

Answer 247

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

Question 248

How do barbiturates and rifampicin interact with warfarin?

Answer 248

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

Question 249

How does cholesytramine interact with warfarin?

Answer 249

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

Question 250

What things cause pharcodynamic reductions of anticoagulant effects of warfarin?

Answer 250

• 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

Question 251

What are some drugs with no significant effect of anticoagulant effect of warfarin?

Answer 251

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

Question 252

How can excessive anticoagulant effect of warfarin by reversed?

Answer 252

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

Question 253

What are some oral direct factor Xa inhibitors (DOACs)?

Answer 253

Rivaroxaban, apixaban, edoxaban.

Question 254

How do DOACs work?

Answer 254

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

Question 255

What are the pharmacokinetics of rivaroxaban?

Answer 255

• 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 ecreted 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

Question 256

What are the pharmacokinetics of apixaban?

Answer 256

• 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

Question 257

What are the pharmacokinetics of edoxaban?

Answer 257

• 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

Question 258

What are the clinical indications for DOACs?

Answer 258

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

Question 259

What are the dosing regimens for rivaroxaban?

Answer 259

• 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

Question 260

What are the dosing regimens for apixaban?

Answer 260

• 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

Question 261

How can you reverse direct factor Xa inhibitors?

Answer 261

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

Question 262

What are the pharmacodynamics and pharmacokinetics of dabigatran?

Answer 262

• 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

Question 263

What are the clinical indications and doses for Dabigatran?

Answer 263

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

Question 264

What is the reversal of dabigatran?

Answer 264

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

Question 265

How do fibrinolytic drugs work?

Answer 265

• They rapidly lysae thrombi by catalysing the formation of the serine protease plasmn 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

Question 266

What is the chemistry of streptokinase?

Answer 266

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

Question 267

What is the chemistry of urokinase?

Answer 267

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

Question 268

How do tissue plasminogen activators (t-PAs) work? Name some and tell me about them

Answer 268

• 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 half0life, it can be given as an IV bolus

Question 269

What are the indications of fibrinolytic drugs?

Answer 269

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

Question 270

What is the dosing regimen for streptokinase?

Answer 270

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

Question 271

What is the dosing regimen for urokinase?

Answer 271

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

Question 272

What is the dosing regimen for alteplase (t-PA)?

Answer 272

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

Question 273

What is the dosing regimen for Tenecteplase?

Answer 273

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

Question 274

Platelet function is regulated by three categories of substances. Name them and tell me whats in each one

Answer 274

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.

Question 275

How do the different antiplatelets work?

Answer 275

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

Question 276

What are the pharmacodynamics of aspirin?

Answer 276

• 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.

Question 278

What are the adverse effects of ticlopidine?

Answer 278

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

Question 279

What are the clinical indications and dosing regimens for clopidogrel?

Answer 279

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

Question 280

How long does clopidogrel take to work and how long is it effective for?

Answer 280

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

Question 281

What does vitamin K do?

Answer 281

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

Question 282

Where can people get vitamin K from? What type of vitamin is it?

Answer 282

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.

Question 283

What are the two natural forms of vitamin K and where are they found?

Answer 283

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

Question 284

What are the pharmacokinetics of vitamin K?

Answer 284

• 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.

Question 285

IV administration of vitamin K should be slow. Why?

Answer 285

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

Question 286

What are the two different subtypes of the anti-cholinergics?

Answer 286

Muscarinic and nicotinic subgroups

Question 287

Where do anti-nicotinics have their effect in the CNS?

Answer 287

Ganglion blockers and neuromuscular junction blockers make up the antinicotinic drugs

Question 288

How many different subtypes of muscarinic receptors are there? How are they classified? Where are they?

Answer 288

• 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

Question 289

What is an example of an antimuscarinic drug?

Answer 289

Atropine
Glycopyrrolate
Hyoscine

Question 290

What is the source and chemistry of atropine?

Answer 290

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

Question 291

What is the absorption of antimuscarinics?

Answer 291

• Natural alkaloids and msot 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)

Question 292

What is the distribution of antimuscarinics?

Answer 292

• 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

Question 293

What is the metabolism and excretion of atropine?

Answer 293

• 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.

Question 294

What is the mechanism of action of atropine?

Answer 294

• 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.

Question 295

The effectiveness of antimuscarinic drugs varies with the tissue and with the source of agonist. What tissues are most sensitive to atropine? What about the source of the agonist?

Answer 295

• 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

Question 296

How does atropine work on muscarinic receptors compared to nicotinic receptors?

Answer 296

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

Question 297

Does atropine distingiush between M1, M2 and M3 receptors?

Answer 297

No.

Question 298

What are the dominant effectors systems of M1, M2 and M3 receptors? What are some anatagonists that are specific for those receptors?

Answer 298

• M1 - increase IP3 and DAG - Pirenzepine, dicyclomine
• M2 - decrease cAMP, increase potassium channel current - Gallamine
• M3 - increase IP3 and DAG 0 oxybutynin, tolterodine, solifenacin

Question 299

What are some of the organ system effects of anti-muscarinics?

Answer 299

• CNS - reduce the tremor of Parkinson’s disease; reduce vestibular disturbances, especially motion sickness; slow long-lasting sedative effects on the brain - can caue 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

Question 300

Right, more on atropines effect on the heart. How does it cause the tachycardia? Does this happen straight away? How does it affect the ventricles and the atrium?

Answer 300

• The SA node is very sensitive to muscarinic receptor blockage. Moderate to high therpeutic 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.

Question 301

How do antimuscarinics act on bloods vessels?

Answer 301

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.

Question 303

What are some therapeutic applications of antimuscarinics?

Answer 303

• 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

Question 304

What are some antimuscarinic drugs used in ophthalmology, their half lives and usual concentration?

Answer 304

• 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

Question 305

What is the half-life of tiotropium, umeclidinium and aclidinium and dose intervals?

Answer 305

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

Question 306

Which antimuscarinics are used in overactive bladder? What is their mechanism of action?

Answer 306

• 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.

Question 307

What routes can be used to give oxybutynin?

Answer 307

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.

Question 308

How can ati-muscarinics be used to treated BPH?

Answer 308

• 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 reduced urinary frequency

Question 309

Mushroom poisoning has traditionally been divided into rapid-onset and delayed-onset types. Tell me about these

Answer 309

• 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.

Question 310

What are some adverse effects of atropine?

Answer 310

• 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

Question 311

How do you treat an overdose of atropine?

Answer 311

• 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

Question 312

What are the symptoms of and how would you treat an overdose of quaternary antimuscarinic drugs?

Answer 312

• 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.

Question 313

What are some contraindications of antimuscarinic drugs?

Answer 313

• 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

Question 314

How do ganglion-blocking drugs work? Why are they not really used?

Answer 314

• 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

Question 315

The neurophysiological state produced by general anaesthetics is characterised by five primary effects. What are they?

Answer 315

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

Question 316

Where in the neurons do anaesthetics have their effects? What effects do they have?

Answer 316

• Anaesthetics affect neurons at various cellular locations, but the primary focus has been on teh 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.

Question 317

Regarding inhaled anathestics, a clear distinction should be made between volatile and gaseous anathestics. What is the different and give me some examples?

Answer 317

• Volatile anaesthetics (halothane, isoflurane, desflurane, sevoflurane) have low vapor pressures and thus high bioling 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.

Question 318

What are the principle molecular targets of anaesthetic agents?

Answer 318

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.

Question 319

What are some factors that control uptake and distribution of inhaled anaesthetics?

Answer 319

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

Question 320

The driving force for uptake of an inhaled anaesthetic into the body involved inspired concentration and alveolar concentration. How? and how can we alter it?

Answer 320

• 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 macimum partial pressure that can be achieved in the alveoli as well as the rate of rise of the partial pressure in the alevoli

Question 321

How can we change induction of inhaled anaesthetic agents? How does this change alveolar concentration?

Answer 321

• 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 rpessure 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

Question 322

Apart from partial pressure, what is another parameter under control of the anaesthetist that directly determines the rate of rise of F_A/F_I? How? Is this different for different anaesthetics?

Answer 322

• 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.

Question 323

What is determined by the blood:gas partition co-efficient?

Answer 323

• 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 glood:gas partition coefficient.

Question 324

How is the effect of increased ventilation affected by the blood:gas partition coefficient?

Answer 324

• 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

Question 325

How does solubility affect the uptake of inhaled anaesthetic?

Answer 325

• 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 comapred 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.

Question 326

The blood:gas coefficient for nitrous oxide in 0.47, what does this mean? what would change with a larger blood:gas coefficient?

Answer 326

• The blood:gas coefficient os 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

Question 327

How does cardiac output affect the uptake of inhaled anaesthetic?

Answer 327

• 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.

Question 328

How does cardiac output effect the distribution of inhaled anaesthetic?

Answer 328

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

Question 329

How does the alveolar-venous partial pressure difference affect distribution of inhaled anaesthetic agents?

Answer 329

• 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

Question 330

During the induction phase of anaesthesia (and the initial phase of the maintenance period), the tissues that exert greatest influence on the arteriovenous anaesthetic concentration gradient are which? why?

Answer 330

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 solutbility in highly perfused tissues, venous blood concentration initially is very low, and equilibrium with the alveolar space is achieved slowly

Question 331

How does the drug distribution change when going from the induction phase to the maintenance phase of inhaled anaesthetics?

Answer 331

• During maintenance, the drug cotninues 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 that 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.

Question 332

What is the MAC?

Answer 332

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

Question 333

The combination of what determines the rate of rise of F_A/F_I characteristic of each drug?

Answer 333

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

Question 334

When is the anaesthetic state achieved using inhaled anaesthetics?

Answer 334

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

Question 335

How does the alveolar - venous partial pressure difference change with different anaesthetics and why?

Answer 335

• 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.

Question 336

What is the MAC, blood:gas and brain:blood partition coefficient of nitrous oxide?

Answer 336

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

Question 337

What is the metabolism, onset and recovery of nitrous oxide?

Answer 337

• No metabolism
• Incomplete anaesthetic
• Rapid onset and recovery

Question 338

What is the MAC, blood:gas and brain:blood partition coefficient of desflurane?

Answer 338

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

Question 339

What is the metabolism, volatility and recovery of desflurane?

Answer 339

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

Question 340

What is the MAC, blood:gas and brain:blood partition coefficient of sevoflurane?

Answer 340

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

Question 341

What is the metabolism, onset and recovery of sevoflurane?

Answer 341

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

Question 342

What is the MAC, blood:gas and brain:blood partition coefficient of isoflurane?

Answer 342

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

Question 343

What is the metabolism, onset and recovery of isoflurane?

Answer 343

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

Question 344

What is the MAC, blood:gas and brain:blood partition coefficient of enflurane?

Answer 344

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

Question 345

What is the metabolism, onset and recovery on enflurane?

Answer 345

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

Question 346

What is the MAC, blood:gas and brain:blood partition coefficient of halothane?

Answer 346

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

Question 347

What is the metabolism, rate of onset and recovery of halothane?

Answer 347

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

Question 348

What does the time to recovery from inhalation anaesthesia depend on?

Answer 348

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

Question 349

One of the most important factors governing the rate of recovery is the blood:gas partition coefficient of the anaesthetic agent. Why?

Answer 349

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.

Question 350

Two features differentiate the recovery phase from the induction phase. What are they?

Answer 350

• 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 by 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.

Question 351

How does the solubility of inahled anaesthetics effect their elimination?

Answer 351

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

Question 352

What is the speed of elimination of the different inhaled anaesthetics? Why?

Answer 352

• 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.

Question 353

What are the patient and procedure factors that can effect rate of elimination of inhaled anaesthetics?

Answer 353

• 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 anasethesia may be rapid even with the more soluble agents, recovery is slow after prolonged administration of halothane or isoflurane

Question 354

How can ventilation change the rate of elimination of inhaled anaesthetic?

Answer 354

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

Question 355

How does anaesthetic metobolism effect the rate of elimination of inhaled anaesthetics? Give an example

Answer 355

• 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.

Question 356

In terms of the extent of hepatic metabolism of inhaled anaesthetics, what is the rank oder?

Answer 356

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

Question 358

How do inhaled and IV anaesthetics affect the metabolic activity of the brain? What effect does this have?

Answer 358

• 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 anaetshetics 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.

Question 359

How does the MAC affect the cerebral blood flow?

Answer 359

• 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.

Question 360

When is an increase in cerebral blood flow undesirable? What can you do about this?

Answer 360

• 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 reesponse; 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

Question 361

How can nitrous oxide effect cerebral blood flow and ICP? How?

Answer 361

• 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.

Question 362

Traditionally, anaesthetic effects on the brain produce four stages or levels of increasing depth of CNS depression (Guedel’s signs). What are they?

Answer 362

• 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 3 - 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

Question 363

How do volatile inhaled anaesthetics effect cardiac contractility? What effect does this have? How do they affect vasular resistance? Why is this relevant?

Answer 363

• 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.

Question 364

How does nitrous oxide effect myocardial function?

Answer 364

• 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

Question 365

How do inhaled anaesthetics effect heart rate?

Answer 365

• 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.

Question 366

How do inhaled anaesthetics effect myocardial oxygen consumption?

Answer 366

• 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.

Question 367

Why might some volatile anaesthetics cause arrhythmias?

Answer 367

• 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.

Question 368

How do inhaled anaesthetics affect bronchodilation and airways? What effect does this have on asthmatic patients?

Answer 368

• 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.

Question 369

How do inhaled anaesthetics affect resp rate and tidal volume?

Answer 369

• 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.

Question 370

How do volatile anaesthetics affect the apneic threshold? How can you change this?

Answer 370

• 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.

Question 371

How do inhaled anaesthetics effect mucociliary function? What are the effects of this?

Answer 371

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.

Question 372

What are the renal effects of inhaled anaesthetics?

Answer 372

• 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

Question 373

What are the hepatic effects of inhaled anaesthetics?

Answer 373

• 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

Question 374

How do inhaled anaesthetics effect uterine smooth muscle?

Answer 374

• 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

Question 375

Do inhaled anaesthetic agents have nephrotoxicity?

Answer 375

• 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

Question 376

Does nitrous oxide have haematotoxicity?

Answer 376

• 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.

Question 377

How are inhaled anaesthetics related to carbon monoxide?

Answer 377

• 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.

Question 378

What is malignant hyperthermia? What causes it?

Answer 378

Malignant hyperthermia is a heritable 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.

Question 379

What are the clinical characteristics of malignant hyperthermia?

Answer 379

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.

Question 380

What is the underlying cellular basis of malignant hyperthermia?

Answer 380

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

Question 382

What are the characteristics of malignant hyperthermia?

Answer 382

• 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

Question 383

How can you test for genetic susceptibility of malignant hyperthermia?

Answer 383

• 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

Question 384

What is the most likely cause of hepatic dysfunction following surgery and general anaesthsia?

Answer 384

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

Question 385

What is the incidence of halothane hepatitis

Answer 385

1 in 20,000-35,0000

Question 386

What do most local anaesthetics consist of? What types have a shorter or longer duration of action?

Answer 386

• 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.

Question 387

Are local anaesthetics acids or bases? How are they available clinically? Why?

Answer 387

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

Question 388

How do local anaesthetics exist in the body? How are the proportions of these forms governed?

Answer 388

• 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:

Question 389

Why can pK_a be used as an effective way to consider the tendency for compounds to exist in a charged or uncharged form?

Answer 389

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.

Question 390

What is the pK_a of most local anaesthetics? What does this mean for its chemistry? Which one is different?

Answer 390

• 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

Question 391

Why is the issue of ionisation of local anaesthetics important? Why is this complicated?

Answer 391

• 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.

Question 392

What are the chemical and clinical situations that can effect the effectiveness of local anaesthetics?

Answer 392

• 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.

Question 393

Systemic absorption if injected local anaesthetic from the site of administration is determined by several factors. What are they?

Answer 393

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 bnding also serves to increase the duration of action

Question 394

How does application of local anaesthetics to a vascular vs non-vascular area effect its absorption?

Answer 394

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.

Question 395

When local anaesthetic is used for major conduction blocks, the peak serum levels will vary as a function of the specific shite of injection. Where is the highest and lowest?

Answer 395

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

Question 396

What are the effects of vasoconstrictors being used with the local anaesthetics?

Answer 396

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.

Question 397

As local anesthetic is usually injected directly at the site of the target organ, distribution within this compartment plays an essential role with respect to achievement of clinical effect. What factors affect this? How is this shown in CSF?

Describe the solution terms !

Answer 397

• 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.

Question 398

The peak blood levels achieved during major conduction anaesthesia will be minimally affected by the concentration of anaesthetic or the speed of injection. The disposition of these agents can be well approximated by a two-compartment model. Describe this…

Answer 398

• 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.

Question 399

What is the uptake of local anaesthetic into the lungs? Why?

Answer 399

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.

Question 400

Where are local anaesthetics excreted? How does it differ between amide and ester types?

Answer 400

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

Question 401

How are local anaesthetics excreted?

Answer 401

• 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.

Question 402

How are ester-type local anaesthetics metabolised?

Answer 402

• 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

Question 403

How are the amide local anaesthetics metabolised?

Answer 403

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

Question 404

There is considerable variation in the rate of liver metabolism of individual amide compounds. Tell me the fastest to the slowest…

What does this mean in terms of toxicity?

Answer 404

Prilocaine > lidocaine > mepivacaine > ropivacaine, bupivacaine, levobupivacaine (slowest)

Toxicity from amide-type local anaesthetics is more likely to occur in patients with hepatic disease.

Question 405

Decreased hepatic elimination of local anaesthetics would be anticipated in patients with reduced hepatic blood flow. What does this mean about the general anaesthetics used and the elimination of local anaesthetic?

Answer 405

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.

Question 406

If the sodium current is blocked over a critical length of the nerve, propagation across the blacked area is no longer possible. What is the critical length in myelinated nerves?

Answer 406

2 - 3 nodes of Ranvier

Question 407

What is the mechanism of action of local anaesthetic?

Answer 407

• 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.

Question 408

The blockade of sodium channels by most local anaesthetics is dependent on what?

Answer 408

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

Question 409

How does elevated extracellular calcium and potassium affect local anaesthetic?

Answer 409

• 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 teh inactivated state, enhancing the effect of local anaesthetics.

Question 410

Local anaesthetics bind to the sodium channel with low affinity and poor specificity, and there are multiple other sites for which their affinity is nearly the same as that for sodium channel binding. What are they?

Answer 410

• 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 aggregeation, and the microcirculation, as well as modulation of inflammation

Question 411

What is the t_1/2 Distribution (min) of:
Bupivacaine
Lidocaine
Mepivacaine
Prilocaine
Ropivacaine

Answer 411

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

Question 412

What is the t_1/2 Elimination (hours) of:
Bupivacaine
Lidocaine
Mepivacaine
Prilocaine
Ropivacaine

Answer 412

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

Question 413

What is the volume of distribution at steady stae per 70kg body weight (L) of:
Bupivacaine
Lidocaine
Mepivacaine
Prilocaine
Ropivacaine

Answer 413

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

Question 414

What is the clearance (L/min) of:
Bupivacaine
Lidocaine
Mepivacaine
Prilocaine
Ropivacaine

Answer 414

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

Question 415

Nerve fibres differ significantly in their susceptibility to local anaesthetic blockade. Tell me how?

Answer 415

• 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.

Question 416

Are sensory or motor fibers more susceptible to local anaesthetic blockade? Why? Give some examples

Answer 416

• 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

Question 417

In addition to the effect of intrinsic vulnerability to local anaesthetic block, the anatomic organisation of the peripheral nerve bundle may impact the onset and suscepibility of its components. How?

Answer 417

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.

Question 418

What are the usual routes of administration of local anaesthetics?

Answer 418

• Topical application (nasal mucose, 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.

Question 419

In clinical practice, there is generally an orderly evolution of block components. What is it? Give an example

Answer 419

• 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.

Question 420

Several benefits may be derived from addition of vasoconstrictor to a local anaesthetic in a block. Tell me some:

Answer 420

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.

Question 421

When incorporated into a spinal anaesthetic, adrenaline may not only contribute to prolongation of the local anaesthetic but also has a direct analgesic effect. How?

Answer 421

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

Question 422

What are the untoward effects of inclusion of adrenaline in blocks?

Answer 422

• 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.

Question 423

Local anaesthetics are sometimes used systemically in chronic pain. How does this work?

Answer 423

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

Question 424

Local anaesthetic toxicity derives from two distinct processes. What are they?

Answer 424

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

Question 425

What are the systems involved local anaesthetic toxicity?

Answer 425

• CNS toxicity
• Cardiotoxicity

Question 426

What are the CNS toxicity clinical features of local anaesthetic?

Answer 426

• 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.

Question 427

How do local anaesthetics cause their CNS toxic effects? What is the classic pattern they follow?

Answer 427

• 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

Question 428

When large doses of a local anaesthetic are required, what can you do to provide some prophylaxis against local anaesthetic-induced CNS toxicity?

Answer 428

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

Question 429

It seizures do occur from local anaesthetic toxicity, what is critical to prevent and how will you do that?

Answer 429

• 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.

Question 430

Seizures induced by local anaesthetics should be rapidly controlled to prevent patient harm and exaceration of acidosis. What do you use to control them?

Answer 430

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.

Question 431

Which local anaesthetic has the highest risk of cardiotoxicity?

Answer 431

Bupivacaine

Question 432

What do you use to reverse bupivocaine toxicity? How does that work?

Answer 432

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”

Question 433

How do local anaesthetics cause localised neural injury?

Answer 433

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.

Question 434

What are some transient neurological symptoms that can occur with neuraxial administration of local anaesthetic?

Answer 434

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

Question 435

What is bupivacaine used for?

Answer 435

• Based on concerns for cardiotoxicity, bupivacaine is often avoided for techniques that demand high volumes of concentrated anaesthetic.
• In contracts, 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.

Question 436

What is the risk of prilocaine with system toxicity? Why?

Answer 436

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

Question 437

What does EMLA stand for? What is it made of?

Answer 437

Eutectic Mixture of Local Anaesthetics.
This formulation, containing 2.5% lidocaine and 2.5% prilocaine, permits anaesthetic penetration of the keratinised layer of skin, producing localised numbness

Question 438

What are some amide local anasethetics?

Answer 438

Lidocaine, bupivacaine, prilocaine, articaine, ropivacaine

Question 439

What are some ester type local anasethetics?

Answer 439

Chloroprocaine
Cocaine
Procaine
Tetracaine
Benzocaine

Question 440

Suxamethonium is the only clinically useful depolarising muscle relaxant. It’s mechanism of action is split into two phases. Tell me about the mechanism of action of Phase 1.

Answer 440

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.

Question 441

How do neuromuscular blocking drugs work and what are they often used with and for?

Answer 441

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.

Question 442

The mechanism of neuromuscular transmission at the motor end plate is simialar to that described for preganglionic cholinergic nerves. What is the process of it?

Answer 442

• The arrivial 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

Question 443

What is the magnitude of the end plate potential related to? What is the outcome of the different potentials?

Answer 443

• 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

Question 444

At least two additional types of acetylcholine receptors are found within the neuromuscular apparatus. What and where are they? What do they do?

Answer 444

• One type is located on the presynaptic motor axon temrinal, and activation of these receptors mobilises additional transmitted 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.

Question 445

Skeletal muscle relaxation and paralysis can occur from interruption of function at several sites along the pathway from the CNS to myelinated somatic nerves, unmyelinated motor nerve terminals, the motor end place, and the intracellular muscle contractil apparatus itself.
Blockade of end plate function cna be accomplished by two basic mechanisms. What are they?

Answer 445

• 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

Question 446

What is the chemistry of the different types of neuromuscular blocking drugs?

Answer 446

• All of the available neuromuscular blocking drugs bear a structural resemblance to acetylcholine. For example, succinylcholine is two acetylcholine molecules liked end-to-end
• In contrast to the linear structure of succinylcholine and other depolarising drugs, the non-depolarising agents (e.g. pancuronium) concerl 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

Question 447

What are the modes of administration of neuromuscular blocking drugs?

Answer 447

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

Question 448

What is the distribution and elimination of non-depolarising relaxant drugs? e.g. pancuronium, rocuronium

Answer 448

• 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

Question 449

What effects the duration and half-life on non-depolarising relaxant drugs?

Such an pancuronium and rocuronium

Answer 449

• 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.

Question 450

What are some steroid derivative non-depolarising muscle relaxant drugs and how are they metabolised?

Answer 450

• 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 usuaully 40-80% as potent as the parent drug

Question 451

What are the intermediate-acting steroid muscle relaxants and how are they eliminated?

Answer 451

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

Question 452

What is atracurium? How is it metabolised and why is it not really used anymore?

Answer 452

• 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.

Question 453

What is cisatracurium? How is it different to atracurium?

Answer 453

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.

Question 454

What is the duration of action on succinylcholine/suxamethonium? Why?

Answer 454

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

Question 455

How is suxamethonium metabolised and eliminated?

Answer 455

• 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

Question 456

How do the circulating levels of plasma cholinesterase influence the duratio of action of succinylcholine?

Answer 456

• 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.

Question 457

What is the dibucaine number? What is it used for and how?

Answer 457

• 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%

Question 458

What is the elimination, clearance and approximate duration of action of atracurium?

Answer 458

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

Question 459

What is the elimination, clearance and approximate duration of action of Cisatracurium?

Answer 459

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

Question 460

What is the elimination, clearance and approximate duration of action of Pancuronium?

Answer 460

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

Question 461

What is the elimination, clearance and approximate duration of action of Rocuronium?

Answer 461

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

Question 462

What is the elimination, clearance and approximate duration of action of suxamethonium?

Answer 462

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

Question 463

What is the mechanism of action of non-depolarising muscle relaxants (eg. rocuronium)?

Answer 463

• 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, msucle realxants interfere with the mobilisation of acetylcholine at the nerve ending and cause fade of evoked nerve twitch contractions.

Question 464

How does the potency of a non-depolarising relaxant effect its onset and duration?

Answer 464

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

Question 465

What is the principle behind the reversal of residual blockade by cholinesterase inhibitors?

Answer 465

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)

Question 466

What is the different between the effect of neostigmine on rocuronium vs suxamethonium?

Answer 466

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

Question 467

What is the initial excitatory effect on skeletal muscle of rocuronium vs suxamethonium?

Answer 467

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

Question 468

What is the response to a tetenic stimulus in rocuronium vs suxamethonium?

Answer 468

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

Question 469

What is the post-tetanic facilitation of rocuronium vs suxamethonium?

Answer 469

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

Question 470

What is the rate of recovery when using rocuronium vs suxamethonium?

Answer 470

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

Question 471

Suxamethonium is the only clinically useful depolarising muscle relaxant. It’s mechanism of action is split into two phases. Tell me about the mechanism of action of Phase 1.

Answer 471

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.

Question 472

What is phase 2 of the mechanism of action of suxamethonium?

Answer 472

• 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.

Question 473

The standard approach for monitoring the effects of muscle relaxants during surgery uses peripheral nerve stimulation to elicit motor responses. What are the three most commonly used patterns?

Answer 473

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

Question 474

How is single-twitch stimulation used to monitor the level of muscle relaxant during surgery?

Answer 474

• 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.

Question 475

How is trial of four stimulation used to monitor the level of muscle relaxant during surgery?

Answer 475

• 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.

Question 476

How does the trial of four ratio compare in non-depolarising and depolarising muscle relaxants?

Answer 476

• 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.

Question 477

What TOF ratio is required for resumption of spontaneous ventilation?

Answer 477

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.

Question 478

What is tetanic stimulation in regards to measuring muscle relaxants?

Answer 478

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

Question 479

How does tetanic stimulation effect non-depolarising muscle relaxants?

Answer 479

• 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

Question 480

The reappearance of the first response to twitch stimulation after tetanic stimulation reflects the duration of profound (clinical) neuromuscular blockade. How do you determine the posttetanic count? What does it mean?

Answer 480

• 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 cound of 2 suggests no twitch response (by TOF) for about 20-30 minutes, and a post-tetanic count of 5 correlates to a no-twict response (by TOF) of about 10-15 minutes

Question 481

The double-burst stimulation pattern is another mode of electrical nerve stimulation developed with the goal of allowing for manual detction of residual neuromuscle blockade. When is it used? What is it?

Answer 481

• It is used with 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.

Question 482

What is the order of muscles to be relaxed after administration of non-depolarising relaxant drugs?

Answer 482

• 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 ton recover

Question 483

Of the currently available nondepolarising muscle relaxants, which one has the msot rapid onset time? What is it?

Answer 483

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

Question 484

What is the dose, pattern and duration of action of suxamethonium?

Answer 484

• 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.

Question 485

What are the cardiovascular effects of non-depolarising muscle relaxants?

Answer 485

• 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.

Question 486

What are the cardiac effects of suxamethonium?

Answer 486

• 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.

Question 487

What are some adverse effects of suxamethonium?

Answer 487

• Hyperkalaemia - during administration of sux, porassium 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 fasciulations 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.

Question 488

What are the drugs that muscle relaxants interact with?

Answer 488

• Anaesthetics
• Antibiotics
• Local anaesthetics
• Anti-arrhythmics

Question 489

What are the interactions between anaesthetics and muscle relaxants? Which ones have the most effect?

Answer 489

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

Question 490

What are the important mechanisms of interaction between anaesthetics and muscle relaxants?

Answer 490

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 postjunctional membrane to depolarisation

Question 491

How do antibiotics and muscle relaxants interact?

Answer 491

• 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. mechanism of this prejunction effect appears to be blockade of specific P-type calcium channels in the motor nerve terminal.

Question 492

How do local anaesthetics interact with muscle relaxants?

Answer 492

• 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 msucle contractions as a result of blockade of the nicotinic receptor ion channels.

Question 493

Several diseases can diminish or augment the neuromuscular blockade produced by non-depolarising muscle relaxants. What are they and how do they effect it?

Answer 493

• Myasthenia gravis enhances the neuromuscular blockade produced by these drugs.
• Advanced age is assoicated 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 doase 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.

Question 494

How can you reverse non-depolarising muscle relaxants? (not including Sugammadex)

Answer 494

• 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, there cholinesterase inhibitors also increase the release of this transmitted from the motor nerve terminal.
• In contrast, edrophonium antagonises neuromsucular 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.

Question 495

What is sugammadex? How does it work?

Answer 495

• 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 diffase away from the neuromuscular junction back into the circulation, where it is quickly bound by free sugammadex.

Question 496

Currently, three dose ranges are recommended for sugammadex. What are they and for what?

Answer 496

• 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.

Question 497

How is sugammadex excreted?

Answer 497

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

Question 498

What are the adverse effects and drug interactions of sugammadex?

Answer 498

• 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.

Question 499

What is the chemistry of IV anaesthetics that allows then to have rapid onset of action?

Answer 499

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

Question 500

What effects the termination of the effect of a single bolus of IV anaesthetics? What does this mean for their duration of action?

Answer 500

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.

Question 501

What are some common IV anaesthetics?

Answer 501

Thiopental, midazolam, propofol, ketamine

Question 502

Why is propofol a good IV anaesthetic?

Answer 502

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.

Question 503

What can be used to create TIVA (total IV anaesthesia (no gas))?

Answer 503

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.

Question 504

What is the induction dose of:
* diazepam
* ketamine
* midazolam
* propofol
* thiopental

Answer 504

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

Question 505

What is the duration of action of:
* diazepam
* ketamine
* midazolam
* propofol
* thiopental

Answer 505

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

Question 506

What is the chemistry of propofol?

Answer 506

• 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%.

Question 507

What is the mechanism of action of propofol?

Answer 507

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

Question 508

What are the pharmacokinetics of propofol?

Answer 508

• 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 eliminaiton of up to 30% of a bolus dose of the drug.

Question 509

What is the recovery of propofol like? Why?

Answer 509

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

Question 510

What is the duration of action of propofol and why?

Answer 510

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.

Question 511

What is the context-sensitive half-time of a drug? What is it used for?

Answer 511

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.

Question 512

What is the context-sensitive half-life of propofol? What does this mean for its recovery?

Answer 512

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

Question 513

What are the CNS effects of propofol?

Answer 513

• 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.

Question 514

How does propofol effect cerebral blood flow and metabolic rate for oxygen, ICP and intraocular pressure? How does this compare to thiopental?

Answer 514

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.

Question 515

What are the cardiovascular effects of propofol?

Answer 515

• 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.

Question 516

What effects the effect propofol has on systemic blood pressure?

Answer 516

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.

Question 517

What are the respiratory effects of propofol?

Answer 517

Propofol is a potent respiratory depressant and generally produces apnoea afer an induction dose.
A maintenance infusion reduced 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.

Question 518

How does propofol effect upper airway reflexes compared to thiopental? What is this useful for?

Answer 518

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

Question 519

Is propofol painful to give?

Answer 519

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

Question 520

What is the induction dose of propofol? What factors require you to reduce or increase the induction dose of propofol?

Answer 520

• 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)

Question 521

When used for sedation of mechanically ventilated patients in the ICU or for sedation during procedures, what is the required plasma concentration of propofol and what is the infusion rate required for this?

Answer 521

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

Question 522

Give a example of a barbiturate used for induction of general anaesthesia?

Answer 522

Thiopental

Question 523

What are the pharmacodynamics of the anaesthetic effect of barbiturates?

Answer 523

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

Question 524

Is thiopental metabolised?

Answer 524

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

Question 525

What is the elimination half-time and recovery after a single bolus of thiopental?

Answer 525

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.

Question 526

What are the CNS effects of barbiturates (thiopental)?

Answer 526

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

Question 527

How do barbiturates effect cerebral blood flow, colume and ICP?

Answer 527

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.

Question 528

The ability of barbiturates to decrease ICP and CMRO₂ is useful in the management of which patients?

Answer 528

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).

Question 529

What are the cardiovascular effects of barbiturates (thiopental)?

Answer 529

• The decrease in systemic blood pressure associated with administration of barbiturates for induction of anaesthetsia 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

Question 530

The depressant effects on systemic blood pressure caused by barbiturates (thiopental) are increased in what cohort of patients? Why?

Answer 530

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.

Question 531

What are the respiratory effects of barbiturates (thiopental)?

Answer 531

• 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.

Question 532

How does suppression of laryngeal reflexes and cough reflexes vary between thiopental and propofol?

Answer 532

Suppression of laryngeal and cough reflexes 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.

Question 533

What is the dosage of thiopental for induction of anaesthesia and how long does it take for the anaesthesia to work?

Answer 533

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

Question 534

What are some benzodiazepines commonly used in the perioperative period?

Answer 534

Midazolam, lorazepam, and less frequently, diazepam.

Question 535

What are the pharmacokinetics of benzodiazepines in the anaesthesia setting?

Answer 535

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.

Question 536

How is the effect-site equilibration time different between midazolam, propofol and thiopental? What does this mean clinically?

Answer 536

• 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.

Question 537

How do the benzodiazepines context-sensitive half-time vary? What does this mean clinically?

Answer 537

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

Question 538

How do benzodiazepines affect the CNS system?

Answer 538

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

Question 539

How can the CNS effects of benzodiazepines be terminated?

Answer 539

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

Question 540

What are the cardiovascular effects of benzodiazepines? How does it vary between them?

Answer 540

• 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.

Question 541

What are the respiratory effects of benzodiazepines?

Answer 541

• 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.

Question 542

What is the dosage and clinical uses of midazolam for anaestatic-based things? In both adults and children

Answer 542

• 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)

Question 543

How does the onset and amnesia effects vary between midazolam and diazepam?

Answer 543

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

Question 544

How does the onset of unconsciousness and awakening time vary between using midazolam as general anaesthetic and propofol and thiopental?

Answer 544

• 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

Question 545

What is the chemistry of ketamine?

Answer 545

• 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.

Question 546

What is the characteristic stat observed after an induction dose of ketamine?

Answer 546

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

Question 547

What is the mechanism of action of ketamine?

Answer 547

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

Question 548

What are the pharmacokinetics of ketamine?

Answer 548

• 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-solubl inactive metabolites that are excreted in urine

Question 549

What happens with the airway, eyes, lacrimation and salivation if ketamine is administered as the sole anaesthetic?

Answer 549

• If ketamine is aadministered 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

Question 550

What are the CNS effects of ketamine? When should it not be used?

Answer 550

• 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.

Question 551

Unpleasant emergence reactions after administration are the main factor limiting ketamine’s use. What are they?

Answer 551

• 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.

Question 552

What are the cardiovascular effects of ketamine?

Answer 552

• 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.

Question 553

What are the respiratory effects of ketamine?

Answer 553

• 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.

Question 554

What is the dose of ketamine?

Answer 554

• 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

Question 555

What is the metabolism of benzodiazepines?

Answer 555

• 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.

Question 556

What is the half-lives of the phase 1 metabolites of benzodiazepines?

Answer 556

• 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.

Question 557

What is the time to peak blood levels and the half-lives of major metabolites of alprazolam?

Answer 557

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

Question 558

What is the time to peak blood levels and the half-lives of major metabolites of diazepam?

Answer 558

• 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

Question 559

What is the time to peak blood levels and the half-lives of major metabolites of lorazepam?

Answer 559

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

Question 560

What is the time to peak blood levels and the half-lives of major metabolites of temazepam?

Answer 560

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

Question 561

What molecules do the benzodiazepines, barbiturates and other sedatives bind to?

Answer 561

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.

Question 562

What is the structure of the GABA_A receptor? Where do benzodiazepines bind to?

Answer 562

• A major inform 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 locate 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.

Question 563

What effect do Benzodiazepines have after they’ve bound to the GABA_A receptor?

Answer 563

• 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.

Question 564

How do barbiturates work and how does their mechanism of action different from benzos?

Answer 564

• 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.

Question 565

The GABA_A receptor-chloride ion channel macromolecule is very versatile. Three types of ligang-benzodiazepine receptor interactions have been reported there. What are they?

Answer 565

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.

Question 566

What are the general effects of benzodiazepines on patterns of normal sleep?

Answer 566

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

Question 567

What is drug tolerance?

Answer 567

Decreased responsiveness to a drug following repeated exposure.

Question 568

What is physiological dependence?

Answer 568

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

Question 569

What is the half-life of flumenazil? What is it used for and how does it do that?

Answer 569

• 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

Question 570

What are the pharmacokinetics of ethanol?

Answer 570

• 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.

Question 571

What is the volume of distribution of ethanol?

Answer 571

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

Question 572

How does ethanol effect men and women differently? Why?

Answer 572

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

Question 573

What kinetics does the rate of alcohol oxidation usually follow?

Answer 573

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.

Question 574

What level of alcohol can be metabolised and at what rate?

Answer 574

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

Question 575

What is the primary pathway for the metabolism of alcohol? What happens during it?

Answer 575

• 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.

Question 576

Where is ADH located for alcohol metabolism? How does this vary between men and women?

Answer 576

• 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.

Question 577

What system is induced during chronic alcohol consumption? What happens during this?

Answer 577

• 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)

Question 578

How is acetaldehyde formed from alcohol metabolised?

Answer 578

• 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.

Question 579

How does disulfiram work?

Answer 579

• 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.

Question 580

At what different blood alcohol concentrations do which clinical effects occur?

Answer 580

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

Question 581

The CNS is markedly affected by acute alcohol consumption. What symptoms does it cause?

Answer 581

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

Question 582

How does alcohol have its effects on the CNS?

Answer 582

• 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

Question 583

How does ethanol effect the heart?

Answer 583

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

Question 585

How does ethanol effect smooth muscle?

Answer 585

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.

Question 586

What molecules cause the tissue damage caused by chronic alcohol ingestion?

Answer 586

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.

Question 587

What are the specific mechanisms implicated in tissue damage caused by chronic alcohol consumption?

Answer 587

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

Question 588

What causes death linked to alcohol consumption?

Answer 588

• liver disease
• cancer
• accidents
• suicide

Question 589

What is the most common medical complication of alcohol abuse? What proportion of chronic drinkers get this?

Answer 589

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

Question 590

What is the pathogenesis of alcohol liver disease?

Answer 590

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.

Question 591

How does alcohol affect the pancreas?

Answer 591

• 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 promots the formation of protein plugs and calcium carbonate-containing stones.

Question 592

Chronic alcohol drinkers, when forced to reduce or discontinue alcohol, experience a withdrawal syndrome, which indicates the existence of physical dependence. What are the symptoms of this? What determines the intensity of the withdrawal syndrome?

Answer 592

• 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.

Question 593

What are the characteristics of psychological dependence on alcohol?

Answer 593

• 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.

Question 594

What mechanisms underly the seizures that occur in alcohol withdrawal?

Answer 594

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

Question 595

What mechanism is believed to play a significant role in tolerance and withdrawal? Why?

Answer 595

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

Question 596

What neurotransmitters does ethanol effect? How?

Answer 596

• 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.

Question 597

Consumption of large amounts of alcohol over extended periods (usually years) often leads to neurologic deficits. What is the most common neurologic abnormality?

Answer 597

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.

Question 598

What is a relatively uncommon but important neurotoxic effect of chronic alcohol intake? Tell me about it

Answer 598

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.

Question 599

What are the cardiovascular complications of chronic alcohol consumption?

Answer 599

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

Question 600

How does alcohol cause cardiomyopathy?

Answer 600

• 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-regularion of voltage-gated calcium channels.

Question 601

How does the prognosis of alcoholic dilated cardiomyopathy differ from idiopathic dilated cardiomyopathy? Why?

Answer 601

• Patients with alcohol-induced dilated cardiomyopathy do significantly worse than patients with idiopathi 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

Question 602

How does chronic alcohol consumption cause arrythmias?

Answer 602

• 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

Question 603

How does chronic alcohol consumption cause HTN?

Answer 603

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

Question 604

How does moderate alcohol consumption effect coronary heart disease?

Answer 604

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.

Question 605

What receptor is potentially linked with the hallucinatory effects in the brain? What do these receptors do?

Answer 605

Serotonin receptors, such as 5-HT_2A receptor and potentially 5-HT_2C.

These receptors module 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.

Question 606

How is the serotonin receptors used in the mechanism of action of second-generation antipsychotic drugs (clozapine)

Answer 606

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.

Question 607

What are some of the classes of antipsychotic drugs and examples for each?

Answer 607

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

Question 608

How are antipsychotics absorbed?

Answer 608

• 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%

Question 609

What is the general volume of distribution of anti-psychotics? Why? What is their general duration of action? Why?

Answer 609

• 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.

Question 610

How long does it take for chlorpromazine to be excreted?

Answer 610

• 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.

Question 611

What is the average time for relapse in stable patients with schizophrenia who discontinue their drugs? What is the exception to this?

Answer 611

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

Question 612

How are antipsychotic drugs metabolised?

Answer 612

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

Question 613

Five dopaminergic systems or pathways are important for understanding schizophrenia and the mechanism of action of antipsychotic drugs. What are they?

Answer 613

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 neurone and releasing dopamine into the pituitary portal circulation. Dopamine released by these neuorns 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

Question 614

There are five dopamine receptors, consisting of two separate families. What are they and what do they do? How do they relate to antipsychotics?

Answer 614

• 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

Question 615

What is the mechanism of action of first-generation antipsychotic agents? How many receptors do they need to occupy to be effective?

Answer 615

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 stratal D₂ receptors is required for efficacy.

Question 616

How does the percentage of D₂ receptors occupied to achieve efficacy by first-generation and second-generation antipsychotics differ? Why?

Answer 616

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.

Question 617

What are some of the adverse pharmacologic effect of antipsychotics on the autonomic nervous system? Give the manifestation and the mechanism

Answer 617

Muscarinic cholinoreceptor blockade - loss of accommodation, dry mouth, difficulty urinating, constipation

α-Adrenoreceptor blockade - orthostatic hypotension, impotence, failure to ejaculate

Question 618

What are some of the adverse pharmacologic effect of antipsychotics on the central nervous system? Give the manifestation and the mechanism

Answer 618

** Dopamine-receptor blockade** - Parkinson’s syndrome, akathisia, dystonia

Supersensitivity of dopamine receptors - tardive dyskinesia

Muscarinnic blockade - toxic-confusional state

Question 619

What is an adverse pharmacologic effect of antipsychotics on the endocrine system? Give the manifestation and the mechanism

Answer 619

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

Question 620

What are the psychiatric indications of antipsychotics?

Answer 620

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

Question 621

What type of drug is chlorpromazine?

Answer 621

An aliphatic phenothiazine

Question 622

What type of drug is haloperidol? What are its advantages and disadvantages?

Answer 622

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

Question 623

What type of drug is clozapine? What are its advantages and disadvantages?

Answer 623

• 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

Question 624

What type of drug is risperidone? What are its advantages and disadvantages?

Answer 624

• 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

Question 625

What type of drug is olanzapine? What are its advantages and disadvantages?

Answer 625

• 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

Question 626

What is the usual range of daily doses for antipsychotic use of haloperidol, clozapine, olanzapine, quetiapine, risperidone and aripiprazole?

Answer 626

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

Question 627

Why does tardive dyskinesia happen with antipsychotics? Is it easier to treat early or late?

Answer 627

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.

Question 628

If agranulocytosis is going to occur secondary to clozapine, when does it usually happen? How do we monitor for it?

Answer 628

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.

Question 629

What is neuroleptic malignant syndrome? What are the symptoms and pathologies associated with it?

Answer 629

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.

Question 630

What blood test apart from leukocytes is elevated in neuroleptic malignant syndrome?

Answer 630

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

Question 631

What is the cause of neuroleptic malignant syndrome?

Answer 631

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

Question 632

How do you treat neuroleptic malignant syndrome?

Answer 632

• 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.

Question 633

What usually happens after an overdose of antipsychotics?

Answer 633

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

Question 634

What is the absorption, distribution, metabolism and excretion of lithium?

Answer 634

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.

Question 635

What is the target plasma concentration and dosage of lithium?

Answer 635

Target plasma concentration 0.6-1.4mEq/L

Dosage - 0.5mEq/kg/day in divided doses

Question 636

Lithium directly inhibits its two signal transduction pathways. What are they are what are the consequences of this?

Answer 636

• 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 othat are facilitated by the accumulation of β-catenin via GSK-3 inhibition modulate energy metabolism, provide neuroprotection, and increase neuroplasticity.

Question 637

What electrolyte is lithium closely related to? Why?

Answer 637

• 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

Question 638

What enzymes are affected by lithium? What are the enzyme functions and the action of lithium on them?

Answer 638

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

Question 639

When is a lithium level ideally taken?

Answer 639

Usually 10-12 hours after the last dose

Question 640

How long after starting lithium should a level be checked?

Answer 640

• 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.

Question 641

The decision to use lithium as prophylactic treatment for bipolar depends on many factors. What are they?

Answer 641

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 diagnosed ones are probably candidates for maintenance treatment.

Question 642

What are some drugs that interact with lithium? How?

Answer 642

• 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

Question 643

What are the adverse effects of lithium? How do you treat them?

Answer 643

• 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

Question 644

What are the two hypotheses for the pathophysiology of major depression?

Answer 644

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

Question 645

What is the neurotrophic hypothesis of depression pathophysiology?

Answer 645

• 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.

Question 646

What is the monoamine hypothesis of depression?

Answer 646

• 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.

Question 647

What are some neuroendocrine factors in the pathophysiology of depression?

Answer 647

• 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.

Question 648

There are currently six available SSRIs. What are they? Are they lipophilic or lipophobic?

Answer 648

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

Question 649

Two classes of antidepressant act as combined serotonin and noradrenaline reuptake inhibitors. What are they?

Answer 649

Selective serotonin-noradrenaline reuptake inhibitors and Tricyclic antidepressants

Question 650

Give some SNRI examples. What can they be used for apart from for depression?

Answer 650

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.

Question 651

How do the mechanism of actions of SNRIs and TCAs differ and how are they similar?

Answer 651

• 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.

Question 652

Apart from SSRIs, and SNRIs. What are the other type of antidepressants and give examples of them? What are they used for?

Answer 652

• 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

Question 653

The antidepressants share several pharmacokinetic features. What are they?

Answer 653

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.

Question 654

What is fluoxetine metabolised into? What is the half-life of this metabolite?

Answer 654

• 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

Question 655

What is the bioavailability of citalopram, escitalopram, fluoxetine, paroxetine and sertraline?

Answer 655

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

Question 656

What is the bioavailability of duloxetine and venlafaxine?

Answer 656

Duloxetine - 50%
Venlafaxine - 45%

Question 657

What is the bioavailability of amitriptyline, trazadone and mirtazepine?

Answer 657

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

Question 658

What is the half-lives of venlafaxine and desvenlafaxine?

Answer 658

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

Question 659

What are the pharmacokinetics of tricyclic antidepressants?

Answer 659

• 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.

Question 660

What are the pharmacodynamics of SSRIs?

Answer 660

• 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

Question 661

What are the pharmacodynamics of SNRIs? How do they differ between themselves?

Answer 661

• 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.

Question 662

How do SNRIs differ from TCAs? Why does this mean they’re used more?

Answer 662

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.

Question 663

What are the pharmacodynamics of TCAs?

Answer 663

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

Question 664

How do the different TCAs effect sertraline transporters and noradrenaline transporters differently?

Answer 664

• 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.

Question 665

Mirtazapine has a complex pharmacokinetic mechanism. Tell me about it

Answer 665

• 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.

Question 666

What are some of the clinical uses of antidepressants?

Answer 666

• 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

Question 667

What is the difference between panic disorder and GAD?

Answer 667

• 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

Question 668

What is the usual therapeutic dose for citalopram, escitalopram, fluoxetine, paroxetine and sertraline?

Answer 668

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

Question 669

What are the usual therapeutic doses for venlafaxine and desvenlafaxine?

Answer 669

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

Question 670

What is the usual therapeutic dose for mirtazepine?

Answer 670

15-45mg/day

Question 671

What are the adverse effects of SSRIs?

Answer 671

• 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

Question 672

What are the adverse effects of SNRIs?

Answer 672

• 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.

Question 673

What are the adverse effects of TCAs?

Answer 673

• 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.

Question 674

What are the symptoms, level required to achieve suicide and treatment of TCA overdose?

Answer 674

• 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.

Question 675

What are the symptoms of MAOI overdose?

Answer 675

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

Question 676

What is the clinical presentation of serotonin syndrome?

Answer 676

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

Question 677

What are the precipitating drugs for serotonin syndrome?

Answer 677

SSRIs
SNRIs
MAOIs
Linezolid
Tramadol
Ondansetron
Sumatriptan
MDMA
LSD

Question 678

How do you treat serotonin syndrome?

Answer 678

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