2016-01-11 acem primary pharmacology - acem primary pharmacology (1) Flashcards

Question

Give an example if a drug that is distributed in the extracellular water? What is the volume of distribution?

Answer 1

Mannitol, gentamycin larger water soluble molecules 0.2l/kg 14 L

Answer 2

0.08l/kg= 5.6L

Answer 3

Heparin 0.04l/kg Bound to a plasma protein

Answer 4

DDT (insecticide) | 0.2-.35l/kg (14-24l)

Answer 5

0.07l/kg (4.9L) lead and flouride

Answer 6

drugs with large volumes of distribution

Answer 7

Antidepressants Phenothiazines Propanolol Verapamil

Answer 8

``` Theophylline Salicylate Phenobarbitone Lithium Phenytoin Heparin Warfarin ```

Answer 9

Time required to change the amount of drug in the body by 1/2 during elimination or during a constant infusion T1/2=0.7xVd / CL Half life can refer to the drug itself or the active metabolites of the drug

Answer 10

drugs that bind to the same receptor but do not prevent binding of the receptor molecule, may enhance or inhibit action

Answer 11

ligand binding often causes acellerated endoscytosis of reception followed by the degradation of the receptors and their bound ligands

Answer 12

because it is the volume apparently necessary to contain the concentration found in blood, plasma or water Drugs with very high volumes of distribution have much higher concentrations in the extravascular compartment then in the vascular compartment- i.e. not homogenously distributed. Drugs that are completely retained within the vascular compartment have a minimum volume of distrubution

Answer 13

Rate of elimination/concentration, this is additive when more than one organ clears it i.e. CL(liver)= rate of elimination by liver/C kidney generally excretes unchanged drug while liver metabolises

Answer 14

CLx C when clearance is first order | calculated using the area under the time concentration curve (dose/AUC)

Answer 15

capacity limited elimination e.g. phenytoin and ethanol, aspirin also known as dose/concentration and saturatable elimination cannot use auc to measure rate of elimination rate of elimination = vmax x c/ km x c

Answer 16

relevant for drugs that are cleared mainly on the first pass and therefore elimination depends on blood flow to the organ

Answer 17

The fraction of the drug reaching the systemic circulation following administration by any route- IV has greatest bioavailability because it avoids first pass metabolism, extent of absorption (liphophilicity, reverse transporter associated with p glycoprotein)

Answer 18

CL x target concentration (TC)

Answer 19

Drugs are usually administered in order to achieve a steady state where dosing equals elimination. Dosing rate=CL X target concentration (TC) Maintenance dose=dosing rate x dosing interval

Answer 20

Loading doses are required if the half-life of a drug is prolonged and the time taken to reach steady state would otherwise be prolonged If the target concentration is known the clearance will determine the dosing rate Loading dose=Vd X TC(target concentration)

Answer 21

Clearance can pertain to each organ and is additive in effect CLrenal+CLliver+CLother=CLsystemic.

Answer 22

zero order kinetics

Answer 23

Drug elimination pathway becomes saturated at high concentration of drug. Elimination is proportional to concentration of the drug at low concentrations but at high concentrations elimination is constant. e.g. Aspirin, Phenytoin, Ethanol

Answer 24

First order clearance = clearance proportional to concentration

Answer 25

Extraction is chiefly dependent on blood flow through the organ and the drug is almost completely extracted by the organ on first pass Morphine Lignocaine Propanolol

Answer 26

Lipophilic (acyclovir) versus hydrophilic (atenolol) drugs | Bacterial metabolism within the gut (digoxin) Absorption abnormalities in small bowel.

Answer 27

Extraction ratio defines the degree of first pass metabolism. ER=CL liver /Q (Q is hepatic blood flow = 90l/h)

Answer 28

Can occur in gut wall, portal blood, or by excretion in bile. Most important is metabolism by liver.

Answer 29

``` Systemic bioavailability (F) =extent of absorption (f) X (1-ER) ```

Answer 30

Hepatic first pass metabolism can be avoided by sublingual, transdermal and to a lesser extent, rectal administration

Answer 31

Biotransformation is the metabolism of drugs that allows for the renal excretion of lipophilic, un-ionised or partially ionised drugs that would otherwise fail to be effectively excreted and have a prolonged duration of action. Biotransformation transforms a lipophilic molecule into a more polar and therefore more readily excretable product.

Answer 32

Biotransformation can occur in GIT (eg clonazepam, penicillin), lungs, skin, kidneys, but most important site is liver.

Answer 33

Phase 1 reactions Convert the parent drug to a more polar metabolite by introducing or unmasking a functional group such as OH, NH2, SH. Phase 2 reactions The introduced functional group combines with an endogenous substrate to form a highly polar conjugate. Enzymes for phase 2 reactions may be located in microsomes or in the cytosol. Phase 2 reactions can sometimes precede phase 1 reactions.

Answer 34

Phase 1 reactions utilise mixed function oxidases located on the ER of liver cells and other tissues. Require oxygen and NADPH to function. Mixed function oxidases include NADPH-cytochrome P450 reductase and cytochrome P450.

Answer 35

Different P450 isoforms are responsible for metabolism of different drugs. 7 main isoforms account for most metabolism. CYP3A4 is the largest component, responsible for 60% of clinically prescribed drugs metabolised by the liver.

Answer 36

Whase 1 occur on the ER, Phase 2 occur in microsomes and the cytosol

Answer 37

Suxamethonium - genetic defect in pseudocholinesterase, causes suxamethonium to remain active for prolonged periods. Other examples - oxidation of ethanol, acetylation of isoniazid

Answer 38

Enzymes may be induced or inhibited by environmental factors. Charcoal - induction grapefruit juice -inhibition of CYP3A4 (responsible for 60% of drug metabolism)

Answer 39

Phenytoin enhances digoxin metabolism

Answer 40

Barbiturates enhance warfarin metabolism

Answer 41

Cimetidine inhibits warfarin and diazepam metabolism

Answer 42

Cardiac disease can affect drugs that are flow-limited | e.g. Morphine, Verapamil

Answer 43

1. Aqueous diffusion -generally determined by fixed law though if a drug is charged its flux will be influenced by electrical fields. 2. Lipid diffusion - most important limiting factor for drug permeation. Lipid:aqueous partition coefficient determines how readily the molecule moves between acid aqueous and lipid media. The abililty of weak acids and bases to move between aqueous and lipid mediums depends on pH. 3. Special carriers (active transport/facilitated diffusion) - for molecules that are too large or too insoluble - eg peptides, amino acids, glucose 4. Endocytosis and exocytosis for very large molecules -eg vit B12, iron

Answer 44

Passive flux of molecules down a concentration gradient equals the difference in concentration across the membrane (C1- C2) multiplied by the area of the membrane and the permeability coefficient, divided by the thickness of the membrane conc grad x sa x perm coeff /thickness

Answer 45

a neutral molecule that can readily dissociate into an anion and a proton

Answer 46

A neutral molecule that can combine with a proton and form a cation

Answer 47

pKa =the pH at which the concentrations of ionized and and inionized forms are equal

Answer 48

More of a weak acid will be in a lipid soluble from at an acid pH. More of a weak base will be in a lipid soluble form at an alkaline pH This is important for excretion of drugs by the kidney.

Answer 49

pH = pKa + log [base]/[acid]

Answer 50

Consist of a lipophilic group, ester or amide chain and ionisable group (usually a tertiary amine)

Answer 51

Esters: Cocaine (procaine) (benzocaine) Amides: Lignocaine Bupivicaine Prilocaine (etidocaine)

Answer 52

Agents which reversibly block impulse conduction along nerve axons, thereby reducing pain sensation- usually do this by blocking voltage gated sodium channels

Answer 53

Blockade occurs at the intracellular end of the sodium channel

Answer 54

Activated channels have higher affinity for drug therefore drug effect is more marked in rapidly firing fibres. Progressive increase in drug concentration causes increased threshold, reduced action potential amplitude, then failure to produce an action potential.

Answer 55

Local anaesthetic effect is increased by hyperkalaemia and decreased by hypercalcaemia

Answer 56

Large diameter fibres less sensitive than small diameter fibres. (3 successive nodes required for blockade, nodes are further apart in large fibres). Myelinated fibres of the same diameter as unmyelinated fibres tend to become blocked first.

Answer 57

Sensory fibres tend to have a fast firing rate and long action potential therefore are more sensitive to blockade.

Answer 58

Peripheral nerves exposed first -motor nerves tend to be peripheral in large trunks.

Answer 59

2mg/kg IV, 3mg/kg SC, 5mg/kg with adrenaline.

Answer 60

Bupivacaine 2mg/kg SC | Prilocaine 3-5mg/kg IVRA

Answer 61

``` (if procaine = 1) Cocaine =2 Lignocaine =4 Bupivacaine = 16 Prilocaine = 3 ```

Answer 62

Drowsiness, visual and auditory disturbance, restlessness, nystagmus, shivering, convulsions, CNS depression.

Answer 63

If convulsion occurs, the patient should be hyperventilated to induce respiratory alkalosis as this lowers extracellular potassium and favours rested, low affinity sodium channels

Answer 64

Bupivacaine>lignocaine> prilocaine Bipivicaine is most cardiotoxic -Although all local anesthetics potentially shorten the myocardial refractory period, bupivacaine avidly blocks the cardiac sodium channels, thereby making it most likely to precipitate malignant arrhythmias.

Answer 65

Depression of cardiac pacemaker activity, excitability and conduction. Negative inotropic effect and decreased peripheral resistance.

Answer 66

noradrenaline uptake blockade and subsequent vasoconstriction and hypertension.

Answer 67

Prilocaine in high doses liberates the 0-toluidine metabolite that causes methaemoglobinaemia.

Answer 68

Fentanyl and midazolam utilise same microsomal enzymes in liver Halothane, cimetidine and beta blockers decrease hepatic blood flow and therefore reduce metabolism Enzyme inducers such as phenytoin may increase metabolism

Answer 69

most are weak bases, potency depends on how liphophilic it is and therefore depends on the pH of the tissue

Answer 70

Most are in a charged, cationic form and this is the active form at the receptor site, but the uncharged form is required for penetration - hence poor penetration in acidic (infected) tissue

Answer 71

bupivicaine 95%, prilocaine 50%

Answer 72

dose, vascularity of site of injection, drug-tissue binding, presence of vasoconstrictors (more effective for short acting highly lipid soluble drugs), chemical properties of the drug. Local effect is proportional to the amount of drug that penetrates the nerve fibre

Answer 73

Cocaine -medium Lignocaine -medium Bupivacaine - long (up to 12 hours for peripheral nerve blocks) Prilocaine - medium.

Answer 74

Rapidly metabolised by pseudo- cholinesterase therefore half life less than 1 minute.

Answer 75

Slowly hydrolysed by liver enzymes and excreted by kidney: Dosage reduction required in liver disease and reduced hepatic blood flow Prilocaine metabolised most rapidly, lignocaine intermediate, bupivacaine slowest: Prilocaine metabolism produces O- toluidine

Answer 76

Stage of analgesia Stage of excitement Stage of surgical anaesthesia Stage of medullary depression

Answer 77

1. Partial pressure of inspired anaesthetic agent 2. Solubility (blood:gas partition coefficient) The more soluble an agent the longer it takes for its partial pressure in blood to rise therefore the slower the onset of anaesthesia. 2. Pulmonary ventilation Increases the rate of induction of anaesthesia for drugs with high solubility - little effect on drugs with low solubility 3. Pulmonary blood flow Increased flow decreases the rate of induction with soluble agents, little effect with poorly soluble agents. 4. Arteriovenous concentration gradient (tissue:blood solubility coefficient) Gradient between arterial and mixed venous blood determined by uptake of agent by highly perfused organs such as brain, heart, liver, kidneys and gut. Drugs with high tissue:blood solubility coefficient take longer to reach equilibrium.

Answer 78

The partial pressure (% concentration) of an agent which results in immobility of 50% of patients undergoing a surgical incision. For nitrous oxide, MAC>100% means that even if the partial pressure of nitrous oxide is 760mmHg, incomplete anaesthesia is achieved. There may be vast individual differences and the MAC gives no indication where the other 50% lie on the curve.

Answer 79

When steady state is achieved, the partial pressure of an inhaled anaesthetic in the brain equals that in the lung, therefore measurement of steady state alveolar concentration gives a measure of potency

Answer 80

Increase in cellular threshold to firing with subsequent decreased spontaneous and evoked neuronal activity. Ionic basis of effect includes activation of potassium currents to cause hyperpolarisation and opening of cation channels to decrease synaptic transmission. Research suggests that agents interact with lipid membranes to cause distortion of ion channels.

Answer 81

Dose related variable reduction in mean arterial pressure and myocardial oxygen demand. Effects may be masked by nitrous oxide which causes sympathetic stimulation Nitrous oxide causes minimal depressant effects Halothane sensitises the myocardium to catecholamines and is arrhythmogenic.

Answer 82

1. Respiratory depression due to reduced TV and inadequate increased rate. (except nitrous oxide) 2. Increase apneic threshold to pCO2. 3. Decrease ventilatory response to hypoxia. 4. Decrease mucociliary function leading to atelectasis. 5. Most have bronchodilator action.

Answer 83

Increase metabolic rate and blood flow to brain due to reduced cerebrovascular resistance. Hyperventilation reduces this effect.

Answer 84

GUS Reduced renal blood flow and GFR. Uterine relaxation (minimal with nitrous oxide) GIT Reduced hepatic blood flow.

Answer 85

Halothane -1 in 35000 cases of fatal hepatic necrosis. Methoxyflurane -fluoride related nephrotoxicity. Malignant hyperthermia -tachycardia, hypertension, acidosis, hyperkalaemia, muscle rigidity, hyperthermia ,more common if suxamethonium also used -treated with dantrolene. Chronic exposure to Nitrous oxide is associated with megaloblastic anaemia

Answer 86

Nitrous oxide >100 Isoflurane - 1.4 Halothane - 0.75 Methoxyfluorane - 0.16

Answer 87

``` Solubility (blood:gas partition coefficient) : Nitrous oxide - 0.47 Isoflurane -1.4 Halothane - 2.3 Methoxyfluorane - 12 ``` Brain:blood partition coefficient Nitrous oxide ␣ 1.1 Isoflurane - 2.6 Halothane - 2.9 Methoxyfluorane - 2.0

Answer 88

Barbiturates Benzodiazepines Opioids Propofol Ketamine

Answer 89

Phenobarbitone | Thiopentone -ultra short acting barbiturate intravenous anaesthetic

Answer 90

1. Barbiturates bind to components of the GABA receptor and facilitate its action by increasing the duration of chloride channel opening. 2. At high concentrations GABA may directly stimulate the receptor. 3. Also depress actions of other excitatory neurotransmitters and have non-synaptic membrane effects.

Answer 91

GABA receptor consists of 5 alpha, beta and gamma membrane-spanning proteins which can form different pentameric combinations.

Answer 92

Phenobarbitone - neonatal seizures. Thiopentone -anaesthesia Dose Thiopentone 3-5mg/kg

Answer 93

Toxicity CVS Depression at high doses. Dose dependent decreased blood pressure, stroke volume and cardiac output. Respiratory depression. Decreased cerebral metabolism and blood flow. Nystagmus. Reduces hepatic and renal blood flow. Dizziness, fatigue, amnesia, blurred vision. Tolerance. Dependence.

Answer 94

Effects are potentiated by other sedatives such as alcohol or other sedatives-may cause fatal CVS depression. Induction of liver enzymes - decreases effect of warfarin, anticonvulsants, digoxin.

Answer 95

Precaution with liver failure. Readily crosses placenta and enters breast milk. Porphyrias

Answer 96

Phenobarbitone -Orally active, rapidly absorbed. 50% protein bound. Thiopentone - intravenous Highly lipid soluble and rapidly distributed to brain, then redistributed to other tissues. Redistribution from CNS to skeletal muscle and adipose tissue is important process that contributes to termination of CNS effects. Initial redistribution to brain and viscera, then to lean tissues and then to fat Metabolised slowly in liver to water- soluble inactive metabolites that are excreted in urine.

Answer 97

Phenobarbitone plasma half life 4 hours, excretion half life 4-5 days (therefore has a tendency to accumulate) Thiopentone Produces hypnosis in one circulation time. Plasma:brain equilibrium occurs rapidly (

Answer 98

Phenobarbitone 20% excreted unchanged. | Thiopentone - 1% excreted unchanged, metabolised at 12- 16% per hour.

Answer 99

Phenol derivative. Short acting intravenous anaesthetic agent. Presented as an oil in water emulsion.

Answer 100

Potentiates the action of inhibitory neurotransmitters including GABA and glycine.

Answer 101

Sedation 0.5-1mg/kg Usually given in 20mg increments Induction of anaesthesia 2-2.5mg/kg Usually given in 40mg increments. Dose can be repeated as required.

Answer 102

1. Marked hypotension (15- 25%) due to reduced peripheral vascular resistance (direct effect of propofol). Potent negative inotropic effects. No compensatory increase in heart rate. 2. Potent respiratory depression. Brief apnoea common. Infusion produces decreased tidal volume. Some bronchodilation due to direct effect on smooth muscle. 3. Rapid, smooth induction and clear headed recovery. Cerebral blood flow and ICP decrease slightly. 4. General Pain in injection in 25%. Contraindications: Acidosis and possible neurological sequelae in children therefore contraindicated under 3 years. Given as an intravenous fat emulsion - previous vehicle cause hypersensitivity reactions.

Answer 103

Rapid onset (30 seconds) and recovery Distribution half life (t1/2 alpha) : 2-8 minutes, Elimination half life (t1/2 beta): 30- 60 minutes. 90% protein bound. Small volume of distribution.

Answer 104

Rapidly metabolised in liver (10 times faster than thiopentone) and excreted in urine. Duration of effect largely determined by redistribution. Less than 1% excreted unchanged.

Answer 105

Short acting non-barbiturate intravenous anaesthetic agent. Chemically related to PCP Action may involve blockade of glutamic acid (NMDA) receptors. Mechanism of action largely unknown

Answer 106

Characteristic dissociative anaesthesia :amnesia, profound analgesia, normal or slightly increased muscle tone without loss of consciousness or loss of protective reflexes.

Answer 107

1-4mg/kg Administer slowly over 60 seconds to avoid respiratory depression and pressor response

Answer 108

Onset 30 seconds, duration of action 5- 10 minutes. Additional doses can be given without accumulation (Intramuscular 6.5-13mg/kg Onset 2 minutes, duration 20 minutes)

Answer 109

1. CVS: Increased heart rate, blood pressure and cardiac output via inhibition of noradrenaline reuptake -peaks 2-4 minutes after injection, declines after 20 minutes. 2. RS: May increase or decrease respiratory rate for several minutes. Upper airway tone is maintained. 3. CNS Marked increase in cerebral blood flow and intracranial pressure. Nystagmus 4. Emergence phenomena in 12% -disorientation, sensory and perceptual illusions and vivid dreams. Less incidence in children and elderly. Reduced by minimising verbal, tactile and visual stimuli during recovery Interactions Avoid hypertensive agents Contraindications Uncontrolled hypertension, severe cardiovascular disease

Answer 110

Distribution Highly lipid soluble. Rapid distribution to all tissues. Termination of effect due to redistribution from brain to peripheral tissues

Answer 111

Metabolised by liver to 4 different metabolites including norketamine which has one sixth the potency of ketamine Metabolites excreted in urine.

Answer 112

Structure: All bear a structural resemblance to acetylcholine Depolarising Suxamethonium= 2 acetylcholine molecules linked end-to-end. Non- depolarising (NDPMRs) Isoquinolone, tubocurarine, atracurium. Steroid: pancuronium, vecuronium, rocuronium.

Answer 113

1. Binds with the nicotinic receptor at the neuromuscular junction to cause the sodium channel to open and the end plate to depolarise. This results in generalised disorganised contraction. Suxamethonium is not metabolised effectively at the synapse, therefore depolarised membranes remain depolarised and unresponsive to subsequent impulses. 2. Phase 2 block (Desensitising): depolarisation gradually decreases and the membrane becomes repolarised. Membrane cannot become repolarised while suxamethonium is present- essentially this is the same as non-depolarising blockade.

Answer 114

Reversible blockade, act predominantly at nicotinic receptors. Prevents opening of the sodium channel, may also enter ion pore at higher does and cause blockade.

Answer 115

Suxamethonium 1-1.5mg/kg (children relatively resistant) May be given IM Vecuronium 0.1mg/kg

Answer 116

1. CVS: Pancuronium causes a moderate increase in heart rate and cardiac output due to vagolytic action. Vecuronium, rocuronium (and most others) have little or no cardiovascular effects 2. Suxamethonium stimulates all autonomic cholinoceptors to some extent. Bradycardia and negative inotropic effects at low doses and especially after a second dose. Prevented by premedication with atropine and by giving a minimum dose. 3. Hyperkalaemia Due to exaggerated release of potassium from extra- junctional nicotinic receptors. There is an exaggerated release with burns, renal failure. 4. Raised intraocular pressure Raised intragastric pressure Raised intracranial pressure 5. Muscle pain This is the most common side effect Malignant hyperthermia: Tachycardia, tachypnoea, rigidity

Answer 117

Personal or family history of malignant hyperthermia Muscular dystrophy

Answer 118

All are highly polar and inactive orally. Non-depolarising : Rapid initial distribution, small volume of distribution.

Answer 119

Onset of action 30s, duration of action 5-10 minutes due to rapid hydrolysis by pseudo- cholinesterase. This limits the amount of drug reaching the synaptic cleft. Very little plasma cholinesterase at end plate neuromuscular blockade is terminated by diffusion away from the endplate into extracellular fluid. 95% of the population will have a normal pseudo- cholinesterase response. 5% will have prolonged apnoea up to 10 minutes.

Answer 120

Onset of action 2-3 minutes Route of elimination correlates with duration of action. Renal excretion is slow, hepatic excretion fast. Steroid -metabolised to 3 hydroxy, 17 hydroxy and 3,17 hydroxy metabolites that also have clinical effect and may persist. Vecuronium - duration of action 20-35 minutes, minimal cardiovascular effects, hepatic elimination - 85% eliminated into bile. Pancuronium -duration of action 35minutes - 1 hour, mainly excreted by kidney. Rocuronium - very rapid onset of action.

Answer 121

rocuronium

Answer 122

Acts on the sarcoplasmic reticulum of skeletal muscle | Causes reduced release of calcium from the sarcoplasmic reticulum

Answer 123

Malignant hyperthermia can be triggered by general anaesthesia and neuromuscular blockade and is a hereditary impairment of the ability to sequester calcium in the sarcoplasmic reticulum Trigger results in massive release of calcium with prolonged muscle contraction, lactic acidosis and hyperthermia

Answer 124

1. Phenothiazine derivatives: Chlorpromazine 2. Thioxanthene: Thiothixene 3. Butyrophenone derivatives : Haloperidol 4. Miscellaneous: Clozapine, Rispiradone, Olanzapine

Answer 125

Dopamine antagonist ␣ antipsychotic action related to dopamine receptor blockade in mesolimbic and mesofrontal systems. ``` Chlorpromazine Alpha1=5H T2>D2>D1 Haloperidol D2>D1=D4>Alpha1> 5H T2 Clozapine Alpha1 =D4 >5HT2> D2=D1 Rispiridone D2=5HT2 Olanzapine 5HT2>D2=D1=Alpha1> H1 ```

Answer 126

``` Chlorpromazine -low Thiothixene - high Haloperidol - high Clozapine - medium Rispiradone - high Olanzapine - high ```

Answer 127

Haloperidol Oral 1-15mg/day in divided doses. IM - 2-30mg IV - 1-5mg Chlorpromazine PO/IM 25-50mg tds Olanzapine 10mg PO/IM

Answer 128

Toxicity CNS Extrapyramidal effects Extrapyramidal toxicity related to high D2 affinity; manifest as parkinsonism, akathisia, acute dystonic reactions, tardive dyskinesia. ``` Chlorpromazine -high Thiothixene - medium Haloperidol - very high Clozapine - very low Rispiradone - low Olanzapine - very low ``` Sedation: esp chlorpromazine Clozapine -2% incidence of seizures (can also occur with other antipsychotics)

Answer 129

Autonomic effects Antimuscarinic actions. Loss of accommodation, dry mouth, difficulty urinating, constipation : Alpha1 antagonist actions.

Answer 130

Tachycardia, reduced stroke volume, decreased peripheral resistance, orthostatic hypotension Thioridazine causes T wave abnormalities and is associated with prolonged QT, ventricular arrhythmias and sudden death most- chlorpromazine, least: olanzapine and haloperidol

Answer 131

Neuroleptic malignant syndrome Muscle rigidity, reduced sweating, fever, autonomic instability, leukocytosis Marked increases in CK may result in renal failure -use bromocriptine

Answer 132

Amenorrhoea, galactorrhoea, increased or decreased libido, impotence -secondary to blockade of dopamine induced tonic inhibition of prolactin secretion. Clozapine, chlorpromazine may cause agranulocytosis Chlorpromazine - corneal and lens deposits

Answer 133

Orally active. Readily but incompletely absorbed. Chlorpromazine Significant first pass metabolism :bioavailability 30%. Half life 30 hours. Others- Moderate first pass metabolism : bioavailability 65% 95% protein bound, lipid soluble, high distribution volumes

Answer 134

Drowsiness, coma, neuromuscular excitability, convulsions. Miosis and loss of deep tendon reflexes. Hypotension and hypothermia. Activated charcoal effective. Supportive therapy. Avoid adrenaline and lignocaine.

Answer 135

1. Closely related to sodium -inhibits sodium exchange across membranes but no effect on sodium/potassium or sodium/calcium exchange. 2. Effects on neurotransmitters Enhances the action of serotonin. Decreases noradrenaline and dopamine turnover. Augments the synthesis of acetylcholine. 3. Effects on second messengers. Inhibits enzymes responsible for recycling of inositol compounds, resulting in depletion of PIP2, IP3 and DAG.

Answer 136

dose 500mg-1g/day

Answer 137

Renal clearance reduced by diuretics and some NSAIDs. Increased extrapyramidal effects when used with antipsychotics (except newer drugs) May increase the duration of muscle relaxnants.

Answer 138

Tremor (alleviated by propanolol), choreoathetosis, motor hyperactivity, ataxia, dysarthria, aphasia. Mental confusion, drowsiness and seizures at higher levels. Endocrine: Reversible reduction in thyroid function. GUS: Nephrogenic diabetes insipidus, chronic interstitial nephritis, minimal change glomerulonephritis. CVS: Nodal depression and T wave flattening. General Oedema and weight gain.

Answer 139

Clearance increases during pregnancy and falls following delivery. ??dysmorphogenesis - unsettled. Lithium toxicity in newborns characterised by lethargy, cyanosis, poor suck and reflexes

Answer 140

Orally active, completely absorbed in 6-8 hours, peak levels 30 minutes. 100% bioavailability. Distribution Total body water, slow entry into intracellular compartment. Some sequestration into bone.

Answer 141

Not metabolised. Excreted into urine at 20% of the rate of creatinine clearance. Elimination half- life 20 hours.

Answer 142

anorexia, nausea, vomiting, diarrhoea, muscle weakness, lack of cooordination No specific antidote. Clearance increased by osmotic diuresis and urinary alkalinisation. Readily removed by haemodialysis.

Answer 143

tricyclincs- amytriptilline, imipramine Heterocyclics: SSRI: MAOI's Tricyclics Imipramine Amitriptyline Heterocyclics Second generation: Maprotiline (tetracyclic) ,Buproprion Third generation: venlafaxine SSRIs fluoxetine MAOs: Phenelzine, Moclobamide

Answer 144

Blockade of amine (serotonin >>noradrenaline) reuptake pumps. Antimuscarinic actions Alpha1, H1, H2 antagonist >1000mg toxic CNS Sedation, seizures, psychosis, coma Antimuscarinic effects very common Tremor, insomnia CVS Orthostatic hypotension Tachycardia and minor T/ST changes very common Conduction defects (long PR, wide QRS>0.1s, long QT and ST) and arrhythmias also common. GIS Nausea, raised liver enzymes

Answer 145

Buproprion alters noradrenaline neurotransmission by an unknown mechanism. Third generation heterocyclics have additional antagonist of 5HT receptors. Same as TCAs though less pronounced.

Answer 146

Blockade of MAO mediated amine degradation. MAO-A metabolises noradrenaline and serotonin, MAO-B metabolises dopamine. Initial increase in amine leads to down-regulation of receptors.

Answer 147

Anxiety, insomnia, tremor, nausea, rash (may lead to severe vasculitis), decreased libido. SSRI use in combination with MAO may lead to toxic build up of serotonin and serotonin syndrome

Answer 148

TCAs and SSRIs Serotonin syndrome if characterised by hyperthermia, muscle rigidity, myoclonus.

Answer 149

Phenothiazines displace TCAs from protein binding site and potentiate action. Nefazodone can inhibit P450-3A4 and block the metabolism of terfenadine and cisapride. F luoxetine and paroxetine are potent inhibitors of P450-2D6 -desipramine, nortriptiline and flecainide are dependent on same enzyme system for clearance. MAOs : Accumulation of tyramine (fermented foods and drinks) results in hypertension. Moclobamide is relatively short acting compared with older drugs therefore this effect is rare

Answer 150

Incompletely absorbed. Slow gastric emptying due to antimuscarinic effect. Significant first pass metabolism (bioavailability 30- 70%) 80-90% protein bound. High lipid solubility. Large Vd

Answer 151

Incompletely absorbed. Significant first pass metabolism (bioavailability 30- 70%) 80% protein bound. High lipid solubility. Large Vd

Answer 152

Well absorbed orally. Moderate first pass metabolism (bioavailability 50- 70%) 95% protein bound. High lipid solubility. Large Vd

Answer 153

Well absorbed orally.

Answer 154

Tricyclics: Metabolised in liver to active metabolites. Half life 10-40 hours Heterocyclics: Metabolised in liver to active metabolite. Half life 10-40 hours SSRIs Metabolised in liver. Fluoxetine forms an active metabolite, nil with paroxetine. Half life 24-96 hours. MAOs: Metabolised in liver. Acetylation of phenelzine varies between individuals and may persist for several weeks.

Answer 155

Severe antimuscarinic response is common Extension of toxic effects listed plus respiratory depression, metabolic acidosis, heart failure, cardiac arrest

Answer 156

Phenytoin | Carbamazepine Sodium valproate Lamotrigine

Answer 157

Benzodiazepines Gabapentin Vigabatrine Phenobarbitone

Answer 158

Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials. Reduces calcium permeability therefore inhibits calcium related secretory processes. May potentiate the effects of GABA Inhibits release of serotonin and noradrenaline, promotes uptake of dopamine. Inhibits monoamine oxidases.

Answer 159

Prophylaxis and treatment of partial seizures and generalised tonic clonic seizures. Fast atrial and ventricular arrhythmias resulting from digoxin toxicity. Trigeminal neuralgia.

Answer 160

10-15mg/kg not exceeding 50mg/minute then 100mg orally every 8 hours (slow administration due to propylene glycol diluent which may induce cardiac arrhythmias

Answer 161

Dose related CNS: Nystagmus and loss of smooth ocular pursuit. Diplopia and ataxia. Sedation. CVS: Cardiovascular collapse (diluent effect if rapid administration) Idiosyncratic: Chronic use frequently leads to gingival hyperplasia and hirsutism, coarsening of facial features, diminished tendon reflexes and osteomalacia. Rash, fever, rare agranulocytosis.

Answer 162

Protein binding : Phenytoin is displaced by highly protein bound drugs such as sulphonamides, calcium channel blockers. Hypoproteinaemia causes increased free drug. May confuse thyroid function tests due to affinity for TBG. Enzyme inducers: Phenytoin induces liver enzymes and affects the metabolism of other drugs such as warfarin, opioids, neuromuscular blockers, beta blockers Other inducers may reduce phenytoin levels - anticonvulsants, rifampicin, ciprofloxacin Enzyme inhibitors Erythromycin, cimetidine

Answer 163

Orally active. Intramuscular absorption unpredictable. 90% bound to plasma proteins. Maximal effect after IV dose occurs after 30-60 minutes and may persist for 24 hours Accumulates in endoplasmic reticulum of brain, liver, muscle and fat. Therapeutic concentration 10- 20ug/l

Answer 164

Metabolised by liver, excreted in bile, reabsorbed and excreted in urine. Variable order kinetics: Elimination rate is dose dependent - at low doses there is first order kinetics but metabolism is saturated at therapeutic concentrations and small increases in dose quickly lead to toxicity.

Answer 165

Half life 12-36 hours -much higher at high concentrations. 5-7 days to reach steady state.

Answer 166

Overdose Toxicity varies between individuals CNS effects predominate though bradycardia and heart block can also occur

Answer 167

Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials. Also acts pre-synaptically to decrease synaptic transmission. Inhibits reuptake and release of noradrenaline. Interacts with adenosine receptors - ?significance

Answer 168

Skin rash common. Diplopia, ataxia - often mild and reversible. Drowsiness at high concentration. Hyponatraemia and water intoxication rarely. Rare agranulocytosis , leukopenia is common and just requires monitoring.

Answer 169

Induces liver enzymes and affects own metabolism : half-life is typically halved from 40 to 20 hours with continuous therapy. Phenytoin, carbamazepine, barbiturates and lamotrigine induce liver enzymes and reduce levels of each other. Reduces effectiveness of benzodiazepines, pethidine, and warfarin.

Answer 170

Orally active Rate of absorption variable but complete Slow distribution. 70% protein bound. Metabolised in liver -metabolite may have some clinical activity.

Answer 171

Fully ionised at body pH therefore active constituent is the valproate ion.

Answer 172

Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials. Increases levels of GABA - likely insignificant Increases membrane potassium conductance

Answer 173

Dose related nausea vomiting and abdominal pain. Sedation (particularly if used with phenobarbitone) Tremor, weight gain, hair loss. Idiosyncratic hepatotoxicity -may be fatal, more common in children under 2 years, usually occurs within 4 months of starting the drug.

Answer 174

Dose related nausea vomiting and abdominal pain. Sedation (particularly if used with phenobarbitone) Tremor, weight gain, hair loss. Idiosyncratic hepatotoxicity - may be fatal, more common in children under 2 years, usually occurs within 4 months of starting the drug.

Answer 175

Orally active. 80% bioavailability. 90% plasma protein bound. Distribution confined to extracellular water due to ionised status and protein binding.

Answer 176

Clearance is dose dependant - it inhibits its own metabolism at low doses. At higher doses there is increased free valproate. 20% excreted as a direct conjugate of valproate. 80% metabolised in liver and excreted in urine. Half life 9-18 hours.

Answer 177

Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.

Answer 178

Partial seizures. Usually used in add- on therapy but increasingly used alone.

Answer 179

Absence seizures. Generalised tonic- clonic seizures

Answer 180

`Phenytoin, carbamazepine, barbiturates and lamotrigine induce liver enzymes and reduce levels of each other. Reduces effectiveness of benzodiazepines, pethidine, warfarin.

Answer 181

rash- if rash then cease lamortigine as linked to SJS, aseptic meningitis, leukopaenia, dizzyness, headache diplopia

Answer 182

Orally active. 50% protein bound. Linear kinetics. Metabolised by liver and excreted by urine. Half life 24 hours, reduced to 15 hours if taking enzyme inducing drugs.

Answer 183

Reversible inhibitor of GABA aminotransferase which degrades GABA. GABA levels are therefore increased. Indicated for partial seizures. Orally active. Renally excreted. Short (5-8 hour) half life)

Answer 184

Dizziness, drowsiness and weight gain. Agitation and confusion rare

Answer 185

Amino acid analogue of GABA. Despite structural relationship to GABA, does not act on GABA receptors but may alter GABA metabolism. Partial seizures. Usually used in add- on therapy but increasingly used alone.

Answer 186

Does not induce liver enzymes. No significant interactions.

Answer 187

Orally active. Not protein bound. Renally excreted. Short (5-8 hour) half life)

Answer 188

Bind to GABA receptor in CNS Benzodiazepines bind to the gamma subunit and in association with GABA, triggers chloride channel opening and subsequent hyperpolarisation. Benzodiaepines increase the efficacy of GABAergic synaptic transmission -they do not cause chloride channel opening alone.

Answer 189

GABA receptor consists of 5 alpha, beta and gamma membrane-spanning proteins which can form different pentameric combinations.

Answer 190

Diazepam Oral, IV or PR Adult 5-40mg Child 0.1-0.3mg/kg Midazolam IV/IM 0.03-0.2mg/kg (higher dose used for induction of anaesthesia)

Answer 191

Effects potentiated by other sedatives such as alcohol - may cause fatal CVS and respiratory depression.

Answer 192

Orally active. Absorption dependent on lipid solubility. Diazepam most lipid soluble. Oxazepam, lorazepam and temazepam least lipid soluble. They are highly protein bound and CNS uptake dependent is also dependent on lipid solubility.

Answer 193

Peak sedation 15 minutes after IM injection, 4 minutes after IV injection

Answer 194

Redistribution from CNS to skeletal muscle and adipose tissue is important process that contributes to termination of CNS effects.

Answer 195

Metabolised in liver to water-soluble metabolites that are excreted in urine. Metabolites may be more active than parent drug (diazepam forms desmethyldiazepam which is transformed to oxazepam and temazepam)

Answer 196

Diazepam -20-80 hours (metabolite persist much longer) Temazepam -10-40 hours. Midazolam 2-4 hours Elimination may increase up to 6 times in elderly patients in ICU

Answer 197

Reversal of benzodiazepine induced clinical effect. | Reversal of respiratory depression is unpredictable.

Answer 198

Agitation, confusion, dizziness, nausea May precipitate severe withdrawal syndrome if existing physiological dependence. Very likely to induce convulsions if patient has a known seizure disorder or in TCA overdose.

Answer 199

Undergoes significant first pass metabolism if administered orally. Intravenous administration. Rapid onset. 50% protein bound. Small volume of distribution.

Answer 200

Rapid hepatic metabolism to inert metabolites and excreted in urine. Short half life 0.7- 1.3 hours. Infusion may be necessary.

Answer 201

Spinal Dorsal horn pain transmission neurons of spinal cord. Pain transmission: Ventral caudal thalamus Diencephalon Pain modulation: Cortex Midbrain periaqueductal gray area Rostral ventral medulla

Answer 202

Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release. Also causes opening of potassium channels on post synaptic neurons resulting in hyperpolarisation and formation of IPSPs mu1, mu2

Answer 203

``` Analgesia Euphoria Sedation Respiratory depression Tolerance and dependence ```

Answer 204

F ull: Morphine Pethidine Fentanyl | Partial: Codeine

Answer 205

delta 1 delta 2 Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release. This causes spinal analgesia.

Answer 206

morphine and codeine are partial agonists

Answer 207

kappa 1, kappa 2 , kappa 3 Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release.

Answer 208

Phenanthrenes

Answer 209

pethidine, fentanyl, loperamide

Answer 210

mu, delta, kappa

Answer 211

mixture of 253 parts morphine, 23 parts papaverine, 20 parts codeine - sometimes used as a premedication. Essentially identical actions as morphine though greater sedation and relief of anxiety.

Answer 212

stimulates ADH, prolactin and somatotropin, inhibits LH Histamine release- itching and urticaria

Answer 213

increase tone e.g.increased biliary smooth muscle contraction, increased GI smooth muscle contraction

Answer 214

Reduced preload and afterload, reduced anxiety, reduced dyspnoea

Answer 215

respiratory depession | truncal rigidity- reduces thoracic compliance and increases work of breathing- likely supraspinal effect

Answer 216

rhinorrhea, lacrimation, yawning, chills, piloerection, hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhoea, and anxiety. Onset 6-10 hours, Peak 36-48 hours, Lasts 5 days

Answer 217

Rapid absorption orally but high (and unpredictable) first pass metabolism therefore low bioavailability. Variable protein binding. Concentrates in highly perfused organs. Structure determines how readily the drug crosses the blood/brain barrier -codeine and fentanyl cross quite readily, morphine less so.

Answer 218

Metabolised in liver and excreted in urine. Morphine, codeine - metabolised in liver to active metabolites that may have greater activity than parent drug. Excreted in urine. Small amount excreted in bile. Metabolites may accumulate in renal failure.

Answer 219

Less efficacious - partial agonist at mu and delta receptors only. Few side effects due to low potency. Constipation is prominent.

Answer 220

The structure of codeine protects it from first pass effects and increases ability to cross the blood brain barrier. 10% is metabolised to morphine

Answer 221

One tenth as potent as morphine.

Answer 222

Metabolite 50% as active as parent drug - and is associated with seizures. Halothane and enflurane decrease clearance by 50%.

Answer 223

highly selective mu agonist only

Answer 224

CNS toxicity: Little hypnosis or sedation Potent respiratory depression Truncal rigidity Marked muscle rigidity at high doses. Peripheral toxicity: Bradycardia with little effect on cardiac output or blood pressure. Obtunds the cardiovascular response to intubation. Minimal histamine release. Halothane and enflurane decrease clearance by 50%.

Answer 225

IV or transdermal 33% bioavailability given PO More lipid soluble than morphine therefore crosses the blood/brain barrier more readily. Rapid onset of action. 50-80 times more potent than morphine. Small dose has a shorter duration of action (1-1.5 hours) - larger doses 4-6 hours.

Answer 226

converted to morphine by tissue esterases

Answer 227

Centrally acting analgesic with some opioid properties. Not structurally related to opioids Weak mu agonist actions Noradrenaline inhibition and serotonin reuptake inhibition.

Answer 228

Mild to moderate pain | Dose PO/IV 50-100mg tds- rapidly orally absorbed

Answer 229

Similar CNS and peripheral side effects No respiratory depression except at high doses No cardiac effects No histamine release Does not suppress opioid withdrawal symptoms Increased risk of seizures Avoid with SSRIs and MAOs due to actions on serotonin Increased tramadol metabolism with enzyme inducers such as tramadol

Answer 230

Orally active, equivalent potency, longer duration of action Tolerance and dependence develop and resolve more slowly and symptoms are milder.

Answer 231

Antagonist action at opioid receptors. More potent action at mu receptors than delta or kappa. Inert if no agonist present. Antagonist action results in reversal of opioid induced effects in 1-3 minutes.

Answer 232

naloxone: Extensive first pass metabolism therefore IV only. Short half life 1-2 hours (duration of action usually 20 minutes) therefore frequent dosing required in overdose naltrexone: Longer half life than naloxone (10 hours) and will block the effects of injected heroin for 48 hours

Answer 233

No specific receptor. Affects broad range of molecular processes including neurotransmission, enzyme action, electron transport chain, ion transport. Enhances the action of GABA Inhibits the action of glutamate

Answer 234

Intoxication. Myocardial depression. Smooth muscle relaxation.

Answer 235

Increased alcohol metabolism leads to increased NADH/NAD+ ratio, resulting in reduced gluconeogenesis, hypoglycaemia, ketoacidosis and promotion of TG synthesis from FFA. Accumulation of acetaldehyde promotes inflammation. Nutritional deficiency is due to reduced intake and reduced absorption due to small bowel injury - reduces free radical scavengers such as glutathione Increased gastric and pancreatic secretion, alteration of mucosal barriers resulting in gastritis.

Answer 236

CNS: Nystagmus. Generalised symmetrical peripheral neuropathy. Gait disturbance and ataxia. Dementia. Wernicke-Korsacoff syndrome - paralysis of external ocular muscles, ataxia, acute confusion, memory loss. CVS toxicity Dilated cardiomyopathy, ventricular hypertrophy, fibrosis. Atrial and ventricular arrhythmias. Hypertension. Blood: Mild anaemia due to folate deficiency. Immune system: Higher rates of infection Foetal alcohol syndrome: Poor growth, microcephaly, poor coordination, flattened facial features, minor joint abnormalities, congenital heart defects. Cancer: Mouth, pharynx, larynx, oesophagus, liver. Interactions: Additive effect with other sedatives. Acute use tends to inhibit enzymes, chronic use induces. Additive effect with hypoglycaemics and vasodilators.

Answer 237

Small, water soluble molecule rapidly absorbed from GIT. Vd approximates TBW. Concentration in CNS rises quickly due to large blood flow.

Answer 238

90% metabolised by liver, 10% excreted by lungs and urine. Metabolism follows zero order kinetics at approximately 1 standard drink per hour. Ethanol converted to acetaldehyde by alcohol dehydrogenase in liver and stomach and by mixed function oxidase. MFO activity increases in alcoholism. Acetaldehyde converted to acetate by aldehyde dehydrogenase. Acetete converted to carbon dioxide and water.

Answer 239

Inhibition of aldehyde dehydrogenase therefore aldehyde accumulates. Flushing, throbbing, headache, nausea, vomiting, sweating, hypotension, confusion within a few minutes of alcohol consumption.

Answer 240

Interactions Inhibits the metabolism of phenytoin, warfarin, isoniazid. Other drugs including metronidazole, cephalosporins may have disulfiram like effects.

Answer 241

Orally active. Rapidly and completely absorbed Slow elimination

Answer 242

No specific receptor. Affects broad range of molecular processes including neurotransmission, enzyme action, electron transport chain, ion transport. Enhances the action of GABA. Inhibits the action of glutamate.

Answer 243

Visual disturbance predominates -may take 30 hours to be present. Formaldehyde may be detectable on breath.

Answer 244

Charcoal ineffective Supportive Intravenous ethanol- higher affinity for alcohol dehydrogenase therefore less formate. Haemodialysis effective

Answer 245

Toxicity is probably related to the formation of formate. Visual disturbances (snowstorm sensation) is typical. CVS and CNS depression, metabolic acidosis.

Answer 246

Small, water- soluble molecule rapidly absorbed from GIT. Vd approximates TBW. Concentration in CNS rises quickly due to large blood flow.

Answer 247

Charcoal ineffective. Supportive. Intravenous ethanol -higher affinity for alcohol dehydrogenase. Consider alcohol dehydrogenase inhibitor - 4- methylpyrazole. Haemodialysis effective.

Answer 248

Transient excitation followed by CNS depression. Severe high anion gap metabolic acidosis after 4-12 hours. Renal insufficiency due to deposition of oxalate.

Answer 249

Converted to toxic aldehydes and oxalate by alcohol dehydrogenase.

Answer 250

Alteration of function of chloride channels in cell membranes Inhibition of mast cell degranulation Likely inhibits mediator release from other cells Used for asthma prevention through MDI or inhaler toxicity: Reversible dermatitis, myositis or gastroenteritis in 2%

Answer 251

Inhibits phosphodiesterase at high concentrations resulting reduced degradation of cAMP and high intracellular cAMP. Increased intracellular cAMP leads to smooth muscle relaxation. Increased cAMP in the heart leads to calcium influx and positive chronotropic and inotropic action Inhibition of respiratory mucosal adenosine receptors which cause contraction of smooth muscle and histamine release Blockade of cardiac adenosine receptors leading to increased catecholamine release Possible anti-inflammatory action.

Answer 252

Loading dose should be given slowly as rapid loading results in transient toxic plasma levels. Dose Orally 3-4mg/kg tds Tends to be avoided IV due to toxicities but can be given as an intravenous loading dose followed by infusion

Answer 253

Therapeutic and toxic effects closely related to blood level. Therapeutic range 5-20mg/l Anorexia, nausea, vomiting, headache at 15mg/l Seizures or arrhythmias at >40mg/l Interactions : Clearance enhanced by liver enzyme inducers -phenytoin, phenobarbitone. Clearance reduced by propanolol, macrolides, cimetidine, OCP, calcium channel blockers.

Answer 254

Absorption Well absorbed orally. Distribution Volume of distribution is proportional to lean body weight. Rapid intravenous loading causes transient toxic plasma levels

Answer 255

Metabolised by liver (therefore reduced dose in liver disease, heart failure). Variable order kinetics Elimination rate is dose dependent -at low doses there is first order kinetics but metabolism is saturated at therapeutic concentrations and small increases in dose quickly lead to toxicity. Children clear theophylline most rapidly -poor in neonates and young infants

Answer 256

B2 receptor agonists Stimulation of adenylyl cyclase results in increased cAMP Inhibits release of mediators Bronchodilation due to smooth muscle relaxation. Inhibition of mediator release from mast cells. Inhibition of microvascular leakage. Increase mucociliary transport.

Answer 257

Intravenous/SC Adults Loading dose 200ug then 5-20ug/min Children Loading dose 7.5ug/kg then 5ug/kg/hr

Answer 258

Predictable beta agonist actions Tachycardia, palpitations, nausea, dizziness, tremor are common May cause an initial reduced pO2 due to ventilation/perfusion mismatch Hypokalaemia - especially high doses in combination with methylxanthines and diuretics Hyperglycaemia and possible ketoacidosis in diabetics Excessive use may result in tolerance

Answer 259

Metabolised by liver. 28% excreted unchanged by kidney Half life 4 hours. Salmeterol has long duration of action due to high lipid solubility rather than long duration of action

Answer 260

Muscarinic antagonist | Comtetitively inhibits the action of acetylcholine at muscarinic receptors

Answer 261

Predictable antimuscarinic effects though poor systemic absorption minimises this

Answer 262

Absorption Poor systemic absorption Quaternary ammonium structure leads to poor penetration into CNS. 10% of dose reaches airways, 90% swallowed. Onset 1-3 minutes. Peak effect 1-2 hours. 90% excreted unchanged in faeces Half life 3 hours.

Answer 263

``` Carbon monoxide 52% Sulphur oxides 14% Hydrocarbons 14% Nitrogen oxides 14% Particles 4% ```

Answer 264

Colourless, tasteless, odourless by product of incomplete combustion Combines reversibly with haemoglobin to form carboxyhaemoglobin 220 times more avid binding than oxygen An individual breathing air containing 0.1% CO (1000ppm) would have a carboxyhaemoglobin level of 50%

Answer 265

Removal of source ABC Oxygen Room air at 1atm, elimination half life of CO 320 minutes 100% oxygen at 1atm elimination half life 80 minutes 100% oxygen at 2atm elimination half life 20 minutes

Answer 266

Chlorinated hydrocarbons: DDT Lindane Organophosphates and carbamates: Parathion Malathion Naturally-derived insecticides: Pyrethrum

Answer 267

Alcohols - edrophonium. Carbamates - neostigmine, physostigmine Organo- phosphates - parathion, malathion. Interact with acetylcholinesterase and therefore blocks the hydrolysis of acetylcholine.

Answer 268

Alcohols - short lived reversible binding lasting 2- 10 minutes. Carbamates -2 step hydrolysis to form a covalent bond, lasts 30mins-6hours Organophosphates - initial hydrolysis results in a phosphorylated active site. This undergoes aging that involves strengthening of the phosphorus-enzyme bond that may last for hundreds of hours.

Answer 269

Effects are similar to direct acting cholinomimetics. At the NMJ, therapeutic effects prolong and intensify the physiological action of acetylcholine resulting in increased strength of contraction. Higher does may result in fibrillation.

Answer 270

Alcohols (edrophonium): Diagnosis of myasthenia gravis = tensilon test. Carbamates (neostigmine, physostigmine): Reversal of non- depolarising neuromuscular blockade. Myasthenia gravis Glaucoma Paralytic ileus Urinary retention Organo-phosphates (parathion, malathion): Glaucoma

Answer 271

Muscarinic agonists: nausea, vomiting, diarrhoea, salivation, sweating, vasodilation, bronchoconstriction. Nicotinic agonists: CNS stimulation, convulsions, coma, flaccid paralysis, hypertension and cardiac arrhythmias. Organophosphates may also cause delayed neurotoxicity

Answer 272

Carbamates - absorption poor due to permanent charge and lipid insolubility. Physostigmine has better absorption due to tertiary amine group. Organophosphates - well absorbed from skin, lung, gut, conjunctiva and distributed into CNS. Distribution: Carbamates - distribution in CNS negligible. Physostigmine is widely distributed. Organophosphates - widely distributed including the CNS.

Answer 273

Carbamates: majority of the dose is excreted in the urine. Organo-phosphates: Malathion is rapidly metabolised to inactive products and therefore relatively safe. Parathion is metabolised less effectively and is therefore more toxic.

Answer 274

Atropine: found in Atropa belladonna (deadly nightshade) and datura stramonium Hyoscine: found in hyoscyamus niger

Answer 275

Tertiary amines - pirenzepine, tropicamide Quaternary amines - propantheline, glycopyrrolate, ipratropium, benztropine.

Answer 276

Competitive antagonist of acetylcholine at muscarinic receptors. Reversible blockade. No distinction between M1,2 and 3 Salivary, bronchial and sweat glands are the most sensitive.

Answer 277

Mydriasis Cycloplegia Decreased lacrimal secretion Tachycardia (note - may cause initial bradycardia at low dose) Increased contractility Arterial constriction (Dilation - high dose direct effect) Venoconstriction (Dilation - high dose direct effect) Bronchiolar smooth muscle relaxation Decreased mucus secretion Gut relaxation Contraction of sphincters Decreased salivary, gastric and pancreatic secretion. Bladder wall relaxation Bladder sphincter contraction Uterus smooth muscle relaxation Decreased sweating Drowsiness, confusion, hallucinations, dysarthria

Answer 278

Bradycardia due to increased vagal tone, including cardiac arrest -Atropine Cholinomimetic (direct or indirect) poisoning -Atropine Mydriasis -Tropicamide, Atropine Motion sickness -Hyoscine Bronchodilation -Ipratropium Diarrhoea - Atropine Urinary urgency -Oxybutynin

Answer 279

In adults, toxic effects are an extension of the clinical effect. Children are sensitive to hyperthermic effects that are centrally mediated. Produce very similar effects to LSD in high doses though delusions tend to be bizarre. Effects are very long acting (several days). Delerium, fluctuating level of awareness, difficulty in thinking and marked loss of memory are particularly characteristic. Contraindications Glaucoma.

Answer 280

Absorption Naturally occurring agents: Well absorbed from gut, skin and conjunctival membranes. Synthetic agents (quaternary amines) : only 10-30% absorbed orally. Distribution: Naturally alkaloid esters of tropic acid - widely distributed. Synthetic antimuscarinic agents (quaternary amines) - mostly peripheral distribution.

Answer 281

Metabolised in liver and excreted in urine | Half life 4 hours

Answer 282

Cholinesterase regenerator: The Acetylcholinesterase enzyme has two parts to it. An acetylcholine molecule bound at both ends to both sites of the enzyme, is cleaved in two to form acetic acid and choline. In organophosphate poisoning, an organophosphate binds to just one end of the acetylcholinesterase enzyme [ the esteric site ], blocking its activity. Pralidoxime is able to attach to the other half [ the unblocked, anionic site ] of the acetylcholinesterase enzyme.It then binds to the organophosphate, the organophosphate changes conformation, and loses its binding to the acetylcholinesterase enzyme. The conjoined poison / antidote then unbinds from the site, and thus regenerates the enzyme, which is now able to function again. After some time though, some inhibitors can develop a permanent bond with cholinesterase, known as aging, where oximes such as pralidoxime can not reverse the bond

Answer 283

Hydrolysis of phosphorylated acetylcholinesterase Slows aging process Pralodoxime is only effective if aging has not occurred

Answer 284

Pralidoxime is initially administered intravenously in a dose of 1 to 2 g. Signs of recovery appear rapidly. If the symptoms reappear, then an infusion of 2.5% is infused at a rate of 0.5 g/hour.

Answer 285

herbicide Paraquat forms a potent free radical that accumulates in the lung: Oedema, alveolitis, progressive fibrosis

Answer 286

50-500mg/kg

Answer 287

Initial gastrointestinal symptoms Delayed onset respiratory distress Death may occur after several weeks Oxygen aggravates pulmonary effects

Answer 288

Inhibition of enzymes of oxidative phosphorylation Shock Arrhythmias Encephalopathy Peripheral neuropathy Pancytopenia

Answer 289

absorbed: All mucosal surfaces Widely distributed | Excreted by kidney

Answer 290

inorganic oxides: Inhibition of enzymes, interferes with essential cations, alters membrane structure Inorganic oxides and salts: Anaemia, peripheral neuropathy, nephropathy, hypertension Organic: Encephalopathy

Answer 291

Inorganic oxides and salts: Gastrointestinal and respiratory tracts Organic: All mucosal surfaces Excretion: Organic -Metabolised by liver to lead, excreted in urine and faeces

Answer 292

Inhibition of enzymes and membrane alterations Elemental: Behavioural disturbance (erethism) Gingivostomatitis Peripheral neuropathy pneumonitis Inorganic: (Hg+ less toxic than Hg2+) ATN Organic: CNS effects, birth defects

Answer 293

Elemental: Respiratory tract Inorganic: Gastrointestinal tract Skin Organic: All mucosal surfaces Tend to concentrate in soft tissues, especially kidney

Answer 294

Elemental: Converted to Hg2+ Excreted in urine and faeces Inorganic: Excreted in urine

Answer 295

Nausea Epigastric pain Abdominal cramps Constipation Diarrhoea Black stools

Answer 296

Seen commonly in young children (10 tablets can be lethal) Necrotising gastroenteritis with vomiting, abdominal pain and bloody diarrhoea Shock Improvement followed by severe metabolic acidosis, coma and death Treated with desferrioxamine

Answer 297

Used for iron poisoning Avidly binds to iron Competes for iron binding with haemosiderin and ferritin Iron-chelator complex is excreted in urine

Answer 298

Flushing Gastrointestinal symptoms ARDS

Answer 299

1. CNS: Psychosis, sedation, seizures, coma Antimuscarinic Sympathomimetic: Tremor, insomnia ``` 2. CVS: Orthostatic hypotension Conduction defects (long PR, wide QRS>0.1s, long QT and ST), arrhythmias. ``` 3. Respiratory depression and apnoea. 4. Metabolic acidosis

Answer 300

1. Salicylism: tinnitus, reduced hearing, vertigo. 2. Hyperventilation, fever, dehydration 3. Metabolic acidosis due to salicylic acid dissociation, deranged carbohydrate metabolism and reduced renal function. 4. Respiratory alkalosis due to central stimulation of respiratory centre Eventual renal and respiratory failure

Answer 301

12-16meq/L | Na+ + K+) - (HCO3- + Cl-

Answer 302

``` Methanol Ethylene glycol Lactic acid Cyanide Carbon monoxide Salicylates Metformin ```

Answer 303

``` Alcohols: ethanol intoxication methanol ingestion ethylene glycol ingestion acetone ingestion isopropyl alcohol ingestion ``` Sugars: mannitol sorbitol glucose (in those with insulin resistance, such as diabetics) Lipids: Hypertriglyceridemia Proteins: Hypergammaglobinemia (M. Waldenström)

Answer 304

2 x [Na mmol/L] + [glucose mmol/L] + [urea mmol/L]

Answer 305

Causes include: lactic acidosis ketoacidosis chronic renal failure (accumulation of sulfates, phosphates, urea) ``` intoxication: organic acids (salicylates, ethanol, methanol, formaldehyde, ethylene glycol, paraldehyde, INH) sulfates, metformin (Glucophage) massive rhabdomyolysis ```

Answer 306

``` U - ureterosigmoidostomy S - saline administration (in the face of renal dysfunction) E - endocrine (Addisons, spironolactone, triamterene, amiloride, primary hyperparathyroidism) D - diarrhea C - carbonic anhydrase inhibitors A - ammonium chloride R - renal tubular acidosis P - pancreatitis ```

Answer 307

no, not effective for most drugs

Answer 308

``` Molecular weight Water solubility Protein binding Endogenous clearance Volume of distribution (small) ```

Answer 309

``` Amphetamines, cocaine Benzodiazepines Phenothiazines Digoxin Opioids Quinidine Tricyclics ```

Answer 310

``` Ethylene glycol Methanol Salicylate Theophylline Procainamide ```

Answer 311

Withdrawal - agents with short half lives produce rapidly evolving severe withdrawal. Longer half life produces gradual, less severe withdrawal. Withdrawal similar to alcohol - agitation, nausea and vomiting reduced seizure threshold, delirium, psychosis.

Answer 312

Inhibits phosphodiesterase at high concentrations resulting reduced degradation of cAMP in high intracellular cAMP. Possible inhibition of adenosine receptors.

Answer 313

Causes release of catecholamines from central and peripheral nerves. Produces insidious onset central euphoriant effect. Withdrawal characterised by pronounced and long lasting craving.

Answer 314

Inhibition of dopamine and noradrenaline reuptake Produces marked increased mental alertness and euphoria then may progress to delusions and psychosis. Short acting compared with amphetamines but magnified effect.

Answer 315

Cause central increased catecholamine neurotransmitter release Produces marked increased mental alertness and euphoria then may progress to delusions and psychosis Withdrawal - lethargy, increased appetite, depression Methamphetamine - speed Methyeledoxymethamphetamine - ecstasy

Answer 316

The psychedelic effects of LSD are attributed to its strong partial agonist effects at 5-HT2A receptors but exact mechanism unknown. LSD affects a large number of the G protein-coupled receptors, including all dopamine receptor subtypes, and all adrenoreceptor subtypes, as well as many others. Mechanism unknown ␣ interacts with several serotonin receptor subtypes. Produces dizziness, weakness, tremors, nausea and prominent visual illusions and other perceptive abnormalities. Also causes pupillary dilation, tachycardia and increased blood pressure.

Answer 317

Related to ketamine. May act at opioid, dopamine or glutamate receptors. NMDA antagonist, D2 partial agonist, nAchR antagonist. Produces detachment, disorientation, distortion of body image, nystagmus (vertical and horizontal), sweating, tachycardia, hypertension. Overdose can be fatal (in contrast with LSD).

Answer 318

Produce very similar effects to LSD in high doses though delusions tend to be bizarre. Effects are very long acting (several days). Delirium, fluctuating level of awareness, difficulty in thinking and marked loss of memory are particularly characteristic.

Answer 319

Contains several cannaboids including tetrahydrocannabinol (THC). Stimulates a specific receptor located in basal ganglia, substantia nigra, globus pallidus, hippocampus and brain stem. May also have a non-specific membrane effect. Produces euphoria and characteristic uncontrollable laughter, alteration of time sense, sharpened vision followed by extreme relaxation and dream like states. Tachycardia and conjunctival reddening are characteristic. Therapeutic use likely to increase due to antiemetic and analgesic actions

Answer 320

Large surface area available to adsorb many drugs and poisons. 1 gram has a surface area of 1000m2 Manufactured by heating charcoal under pressure. Most effective in a 10:1 ratio of charcoal to poison.

Answer 321

does not bind: Ions - lithium, potassium, cyanide Heavy metals - iron Hydrocarbons Acids/alkalis Alcohols: ethanol, methanol

Answer 322

Balanced polyethylene glycol-electrolyte solution: used for iron, enteric coated medications, foreign bodies.

Answer 323

acetylcysteine

Answer 324

pralidoxime

Answer 325

bicarbonate

Answer 326

desferrioxamine

Answer 327

digibind, digoxin antibodies

Answer 328

flumazenil

Answer 329

physostigmine

Answer 330

Reduced synthesis of eicosanoid mediators: Irreversible inhibition of cyclooxygenase Reduced synthesis of thromboxane A2 Reduced synthesis of prostaglandins Central blockade of CNS response to IL1 in causing fever

Answer 331

Antiplatelet action lasts for the lifespan of the platelet - thromboxane A2 stimulates platelet aggregation and granule release Antiinflammatory Analgesic Antipyretic

Answer 332

1. Therapeutic range 0-10mg/kg Gastritis, ulceration Impaired haemostasis 2. Anti-inflammatory range 50mg/kg Salicylism: tinnitus, reduced hearing, vertigo. 3. Toxic range 50-150mg/kg hyperventilation, fever, dehydration, metabolic acidosis 4. Serious intoxication >150mg/kg Respiratory alkalosis due to central stimulation of respiratory centre Renal compensation for respiratory alkalosis. Metabolic acidosis due to salicylic acid dissociation, deranged carbohydrate metabolism and reduced renal function. Eventual renal and respiratory failure

Answer 333

Displaces from protein binding (phenytoin, methotrexate) Decreased activity of spironolactone Decreased tubular secretion of penicillin

Answer 334

Orally active Rapidly absorbed. Acidity of stomach keeps aspirin in nonionised form that is more readily absorbed Bound to albumin in low doses. As serum concentration rises, increasing fraction is unbound

Answer 335

Hydrolysed to acetic acid and salicylate by blood and tissue esterases. Salicylate conjugated by liver and excreted by kidney. Demonstrates variable order kinetics ␣ metabolism is saturable and small further increases in aspirin dose results in large rise in salicylate levels. Half life 3-5 hours at low dose, 12 hours at anti- inflammatory doses Alkalinisation of the urine increases rate of excretion of free salicylate Haemodialysis indicated in severe toxicity

Answer 336

Reduced synthesis of eicosanoid mediators Reversible inhibition of cyclooxygenase (COX1, COX2 or both) Reduced synthesis of thromboxane A2 Reduced synthesis of prostaglandins Prostaglandins are important mediators of inflammation Inhibition of mediator release from leukoctes Decreased sensitivity of vessels and pain sensors to bradykinin and histamine Central blockade of CNS response to IL1 in causing fever

Answer 337

Gastritis, ulceration and minor gastrointestinal disturbance Impaired haemostasis Nephrotoxicity and reduced renal function in those with renal disease Hepatotoxicity and increased liver enzymes in those with hepatic disease Oedema, especially if pre- existing heart failure Visual disturbances Aseptic meningitis

Answer 338

Warfarin: risk of fatal haemorrhage due to displacement from albumin Lithium/digoxin: increased plasma levels Antihypertensives: reduced effect

Answer 339

NSAID/aspirin sensitive asthma 3rd trimester of pregnancy: may cause closure of the fetal ductus arteriosus, fetal renal impairment, inhibition of platelet aggregation and delay labour and birth

Answer 340

Orally active Rapidly absorbed. Absorption slowed by food Highly protein bound

Answer 341

Metabolised by liver to inactive metabolites. Excreted in urine and bile Half life 2 hours

Answer 342

10mg/kg in 2 divided doses slow release formulation available may impair feritlity

Answer 343

Mostly excreted unchanged Half life 12 hours

Answer 344

Indomethacin, ketoprofen and diclofenac inhibit lipoxygease and therefore reduce formation of leukotrienes ketoprofen Half life 2 hours

Answer 345

May antagonise the actions of prostaglandins PGE2 and PGF2alpha at uterine receptors

Answer 346

Potent prostaglandin inhibitor 28 times more potent than aspirin PR more rapid T 1/2 4 hours

Answer 347

Patent ductus arteriosus Gout Preterm labour (though may cause closure of the ductus, renal toxicity, delayed labour, impaired haemostasis Dose 50-200mg/day in 2- 3 divided doses

Answer 348

Short-term management of post operative pain Equally effective as 10mg morphine/100mg pethidine IM or panadeine forte Dose 10-30mg IM every 6 hours for a maximum of 5 days

Answer 349

Para-aminophenol derivative Weak prostaglandin inhibitor Probably has COX3 antagonist actions in the CNS

Answer 350

Toxic symptoms include vomiting, abdominal pain, hypotension, sweating, central stimulation with exhilaration and convulsions in children, drowsiness, respiratory depression, cyanosis and coma. Hypokalaemia and ECG changes have also been noted In adults, hepatotoxicity may occur after ingestion of a single dose of paracetamol 10 to 15 g 25 g is potentially fatal. Symptoms during the first two days of acute poisoning by paracetamol do not reflect the potential seriousness of the intoxication. Major manifestations of liver failure such as jaundice, hypoglycaemia and metabolic acidosis may take at least three days to develop.

Answer 351

Alcohol and enzyme inducers :increased risk of toxicity

Answer 352

Orally active | Peak blood levels 30- 60 minutes Food intake delays paracetamol absorption. Partially protein bound

Answer 353

Metabolised in liver In adults at therapeutic doses, paracetamol is mainly conjugated with glucuronide or sulfate. Also metabolised to a toxic metabolite (cyp3a4 and cyp2a1) that is detoxified by conjugation with glutathione Excreted in the urine Elimination half- life varies from one to three hours. Overdose Activated charcoal IV fluids If 15g or more ingested, acetylcysteine

Answer 354

Paracetamol is metabolised in the liver, mainly by conjugation with glucuronide and sulfate. It is also metabolised by cytochrome P450 to form a reactive, potentially toxic, metabolite. This metabolite is normally detoxified by conjugation with hepatic glutathione, to form nontoxic derivatives. In paracetamol overdosage, the glucuronide and sulfate conjugation pathways are saturated, so that more of the toxic metabolite is formed. As hepatic glutathione stores are depleted, this toxic metabolite may bind to hepatocyte proteins, leading to liver cell damage and necrosis.

Answer 355

Acetylcysteine is a sulfydryl (SH) group donor, and may protect the liver from damage by restoring depleted hepatic reduced glutathione levels, or by acting as an alternative substrate for conjugation with, and thus detoxification of, the toxic paracetamol metabolite.

Answer 356

8 hours or less since overdose ingestion. Initial dose 150 mg/kg over 15 minutes, followed by continuous infusion of 50 mg/kg in glucose 5% 500 mL over four hours and 100 mg/kg in glucose 5% 1 L over 16 hours. If more than eight hours have elapsed since the overdosage was taken, the antidote may be less effective. Rumack-Matthew nomogram gives indication of likelihood of toxicity as a function of time since ingestion and plasma levels

Answer 357

Nausea and vomiting Allergic reactions Tachycardia, chest pain Contraindications: Asthma, renal and hepatic failure - administer with caution

Answer 358

Binds to intracellular tubulin, therefore inhibiting leucocyte migration and phagocytosis (also anti- mitotic) Inhibits formation of leukotriene B4 Inhibits urate crystal deposition

Answer 359

Acute gouty arthritis Dose 0.5-1mg then 0.5mg every 2 hours until pain is relieved or diarrhoea occurs Do not exceed 8mg

Answer 360

Diarrhoea (80% in 8-12 hours) Nausea and vomiting Bone marrow suppression (especially in overdose) inhibition of B12 absorption

Answer 361

Hepatic or renal disease Cardiac disease Gastrointestinal disease

Answer 362

Toxic dose >0.5mg/kg Latent period- 2-12 hours: Burning throat pain, bloody diarrhoea, dehydration Second phase 24-72 hours: Shock, renal failure, muscular weakness and ascending paralysis, bone marrow suppression, DIC, multiorgan failure

Answer 363

Rapidly absorbed | Bioavailability 25- 50%

Answer 364

Metabolised by liver, excreted in bile and urine. Some enterohepatic circulation Half life 4 hours

Answer 365

Activated charcoal | Supportive measures

Answer 366

Xanthine oxidase inhibitor Urate formed from amino acids and purines Xanthine oxidase is required for formation of urate therefore its inhibition will decrease production

Answer 367

``` May precipitate acute gout unless given with colchicine or probenicid Rash Nausea and vomiting Bone marrow depression Impaired renal function Impaired hepatic function ```

Answer 368

80% absorbed not bound to plasma proteins Metabolised by xanthine oxidase which it also inhibits Half life 1-2 hours

Answer 369

Sympathetic preganglionic fibres terminate in ganglia in paravertebral chains. Post ganglionic fibres then pass to the organs

Answer 370

Parasympathetic fibres: some terminate in parasympathetic ganglia (ciliary, pterygopalatine, submandibular, otic, pelvic), majority terminate in organs.

Answer 371

All pre-ganglionic autonomic All parasympathetic post-ganglionic All somatic motor

Answer 372

Acetylcholine synthesised in cytoplasm from acetyl-CoA (made in mitochondria) and choline (transported from extracellular fluid by sodium dependent carrier) - enzyme=choline acetyltransferase. Hemicholiniums block choline carrier

Answer 373

Acetylcholine transported from cytoplasm to storage vesicle by proton antiporter. Vesamicol blocks antiporter.

Answer 374

Calcium influx causes the vesicle to fuse with the terminal membrane and release acetylcholine into the synaptic cleft. Synaptobrevin, SNAP and syntaxin required. Botulinum toxin blocks release by enzymatic removal of 2 amino acids from synaptobrevin.

Answer 375

Acetylcholine degraded by acetylcholinesterase into acetate and choline.

Answer 376

Most post-ganglionic sympathetic

Answer 377

Tyrosine carried into cell by sodium dependent carrier. Converted to DOPA by tyrosine hydroxylase. DOPA converted to Dopamine by DOPA decarboxylase. Metyrosine inhibits action of tyrosine hydroxylase.

Answer 378

Dopamine transported into vesicle by a carrier. Reserpine blocks carrier.

Answer 379

Calcium influx causes the vesicle to fuse with the terminal membrane and release noradrenaline into the synaptic cleft. ATP and dopamine beta hydroxylase are also released into the cleft. Tyramine and amphetamines are capable of noradrenaline release by a displacement process that is not calcium dependent. Release can be blocked by bretylium and guanethadine

Answer 380

Noradrenaline diffuses away from the cleft or is transported back into the cytoplasm or into the post-junctional cell. Noradrenaline is then metabolised by MAO and COMT. Reuptake is blocked by cocaine and tricyclic antidepressants.

Answer 381

CNS, sympathetic postganglionic, some pre-synaptic

Answer 382

IP3, DAG, increased calcium

Answer 383

heart, smooth muscle, endothelium, some pre- synaptic

Answer 384

Inhibit adenylyl cyclase, open potassium channels, stimulates release of EDRF.

Answer 385

Exocrine glands, vessels, eye, lungs, GIT, bladder IP3, DAG, increased calcium

Answer 386

Postganglionic neurons, some pre-synaptic cholinergic terminals Open sodium and potassium channels, depolarisation

Answer 387

Skeletal muscle endplates | Open sodium and potassium channels, depolarisation

Answer 388

mostly smooth muscle IP3, DAG, increased calcium

Answer 389

pre-synaptic terminals, platelets, lipocytes, smooth muscle inhibition of adenylyl cyclase, reduced cAMP

Answer 390

heart, brain, lipocytes plus presynaptic stimulation of adenylyl cyclase, increased cAMP

Answer 391

heart, lungs, smooth muscle stimulation of adenylyl cyclase, increased cAMP

Answer 392

lipocytes stimulation of adenylyl cyclase, increased cAMP

Answer 393

B1, B2 (acellerate) | M2 (decellerate)

Answer 394

B1, A1, B2 (increase) | M2 (decrease)

Answer 395

relax a2, b2 contracts M3 sphincters contract a1, relax m3

Answer 396

1. B2, A 2. B2, A 3. B3 4. A2

Answer 397

1. B2 2. M3 3. A1 4. M3

Answer 398

relax: b2 contract: A, M3

Answer 399

1) A1 | 2) A, M

Answer 400

Choline esters: Acetylcholine (both), Methacholine (muscarinic), Carbachol (both), Bethanecol (muscarinic) Alkaloids: Pilocarpine (muscarinic), Nicotine (nicotinic), Lobeline (nicotinic), Muscarine (muscarinic).

Answer 401

1. Glaucoma: pilocarpine, methacholine, carbachol. 2. Paralytic ileus: bethanechol 3. Urinary retention: bethanechol 4. Antimuscarinic drug intoxication.

Answer 402

Choline esters: Poorly absorbed orally. Alkaloids: Well absorbed orally and transcutaneously. Distribution: Choline esters Hydrophilic therefore poorly distributed in CNS Alkaloids: Nicotine very lipid soluble therefore widely distributed in CNS

Answer 403

Choline esters: Hydrolysed in GIT (acetylcholine more than others, carbachol and methacholine negligible) Alkaloids: Renally excreted, increased by acidification of the urine.

Answer 404

catecholamine and non-catecholamine Catecholamines: Adrenaline, Noradrenaline, Isoprenaline, Dopamine Dobutamine Non-catecholamines: Ephedrine Phenylephrine, Amphetamine Indirect acting sympathomimetics: Cocaine Tyramine

Answer 405

agonist: Phenylephrine A1>A2>>>>>B antagonist: prazocin

Answer 406

Agonist: Clonidine A2>A1>>>>>B antagonist: Yohimbine

Answer 407

agonist: Dobutamine B1>B2>>>>A antagonist: Betaxolol

Answer 408

agonist: Terbutaline/Salbutamol (B2>>B1>>>>A) antagonist: Butoxamine

Answer 409

agonist: isoprenaline antagonist: propranolol

Answer 410

D1=D2>>B>>A

Answer 411

Number and function of adrenoceptors may be regulated to modify physiological response. Desensitisation may occur after exposure over a period of time and results in lesser response to further stimulation. Mechanisms: 1. Receptor sequestration -rapid and transient event decrease in receptor availability. 2. Down-regulation -reduced receptors due to reduced synthesis. 3. Receptor phosphorylation - resulting in impaired binding

Answer 412

Sympathomimetic drugs are based on a benzene ring structure with an ethylamine side chain. Substitutions made on the terminal amino group, benzene ring or the alpha or beta carbons modify the affinity of binding at specific receptors. Catecholamine formed by substitution with hydroxy groups on the benzene ring this increase potency but decreases bioavailability and decreases duration of action by making the drug subject to inactivation by COMT. Substitution on the amino group increases beta receptor activity. Substitution at the alpha carbon blocks oxidation by MAO. Substitution on the beta carbon is important for storage.

Answer 413

Adrenaline, Noradrenaline, Isoprenaline, Dopamine, Dobutamine.

Answer 414

Ephedrine, Phenylephrine, Amphetamine.

Answer 415

Adrenaline: Non-selective alpha and beta- adrenergic agonist. Noradrenaline: Non-selective alpha agonist, B1 greater than B2. Isoprenaline: Selective beta agonist Potent beta agonist, little alpha agonist effect. Dopamine: D1 and D2 agonist with beta and alpha actions at high doses. Dobutamine: B1 selective agonist. (Dobutamine is a racemic mixture -the positive isomer has B1 agonist and A1 antagonist actions, the negative isomer has A1 agonist actions - the net effect is positive inotrope action with little peripheral effect hence less reflex tachycardia)

Answer 416

Relatively pure alpha agonist with limited beta action

Answer 417

Some direct non-selective action on adrenoceptors, also causes release of stored catacholamines.

Answer 418

Causes release of stored catecholamines

Answer 419

Methyldopa - centrally acting A2 agonist. Clonidine - centrally acting A2 agonist). causes centrally mediated reduction in TPR (clonidine also causes bradycardia)

Answer 420

Adrenaline: Rise in systolic blood pressure due to positive inotropic and chronotropic effects via B1 receptors. Total peripheral resistance and hence diastolic blood pressure may fall due to vasodilation mediated by B2 receptors. Bolus doses tend to have mainly peripheral vasoconstrictor effect whereas infusions have the effect described above Noradrenaline: Rise in systolic blood pressure due to positive inotropic and chronotropic effects via B1 receptors. Total peripheral resistance and diastolic pressure also increase due to alpha effect and lack of B2 mediated vasodilation

Answer 421

Isoprenaline: Marked increase in cardiac output due to positive inotropic and chronotropic effect mediated by B1 receptors. Total peripheral resistance and diastolic blood pressure fall due to vasodilation mediated by beta receptors. Systolic pressure typically falls by a small amount though may rise. Dopamine: Reduction in TPR mediated by D1 receptors on blood vessels and pre-synaptic D2 receptors that result in reduced noradrenaline secretion. Most important effects are renal vasodilation. At higher doses, dopamine acts on beta receptors then alpha receptors to cause vasoconstriction and has an adrenaline-like action. Dose: Renal 0.5-2ug/kg/min Beta 2-10ug/kg/min Alpha >10ug/kg/min

Answer 422

Increased stroke volume and cardiac output mediated by B1 receptors. Less chronotropic effects. Mild vasodilation, sometimes vasoconstriction.

Answer 423

Phenylephrine: Marked increase in peripheral vascular resistance and decrease in venous capacitance mediated by alpha receptors and resulting in hypertension, and reflex vagally-induced mild bradycardia. Ephidrine: Mainly used as a nasal decongestant, mild central stimulant effect. Amphetamine: Marked central stimulant effect on mood and alertness. Appetite suppressant. Some efficacy in ADHD. Most have marked central stimulant effect, especially amphetamine.

Answer 424

Poor bioavailability after oral administration due to catechol structure and subsequent inactivation by COMT found in gut and liver Poor distribution to CNS due to catechol structure. Metabolised by COMT and MAO and excreted in the urine.

Answer 425

Orally active, longer duration of action. Readily enters CNS, especially amphetamine. Significant fraction excreted unchanged. Weak base therefore excretion enhanced by acidification of the urine.

Answer 426

Cocaine Inhibition of noradrenaline reuptake at noradrenergic synapses Widely distributed and readily enters CNS, short duration of action

Answer 427

Phentolamine imidazoline derivative. Phenoxy- benzamine Prazosin (Piperazinyl quiazoline)

Answer 428

1. Phentolamine: Non selective mixed A1 and A2 antagonist. Reduction in peripheral vascular resistance mediated by blockade of alpha receptors. This may result in a reflex tachycardia. Antagonism of pre- synaptic A2 receptors may cause noradrenaline release. (Also inhibits response to 5HT and H1/H2) 2. Phenoxybenzamine: A1 selective antagonist. (also blocks Ach, H1, 5HT). Blockade of catecholamine induced vasoconstriction. 3. Prazosin: Potent A1 antagonist. Decreased total peripheral resistance due to relaxation of arterial and venous smooth muscle mediated by alpha 1 blockade.

Answer 429

Phentolamine: Reflex tachycardia due to greater release of noradrenaline and its action on beta receptors Phenoxybenzamin: Postural hypotension and reflex tachycardia. Inhibition of ejaculation, fatigue, sedation. Prazosin: Less reflex tachycardia 1st dose hypotension Tends to cause salt and water retention Dizziness Palpitations Headache No effect on lipids

Answer 430

Phentolamine: Poorly absorbed orally. Duration of action determined by half life and rate of dissociation from the receptor. Phenoxybenzamine: Well absorbed orally. Prazosin: Well absorbed orally Highly protein bound

Answer 431

Extensively metabolised by liver | 50% bioavailability. Half-life 3 hours.

Answer 432

1. Propanolol: Non-selective beta antagonist No action at alpha or muscarinic receptors 2. Metoprolol: B1 selective 3. Atenolol: B1 selective. 4. Esmolol B1 selective 5. Labetolol: Mixed B1 antagonist and alpha antagonist 6. Carvedilol: Mixed non-selective beta blocker and alpha antagonist

Answer 433

The following beta blockers also act as membrane stabilisers by sodium channel blockade Acebutolol Betaxolol Labetolol Metoprolol Pindolol Propanolol

Answer 434

CVS Negative inotropic and chronotropic effect on the heart. (including slowed AV conduction and increased PR interval) Increased peripheral vascular resistance due to unopposed alpha effects. Antagonism of the release of renin (B1) resulting in reduced TPR RS Increased airway resistance (largely avoided by B1 selective agents but not completely). Eye Decreased aqueous humour production leading to reduced intraocular pressure. Metabolic and endocrine: Inhibition of catecholamine induced lipolysis and glycogenolysis via B2 receptors. Impair the recovery from hypoglycaemia as this is usually mediated by catecholamines. Masking of clinical signs of hypoglycaemia and impaired recovery from hypoglycaemia Increased VLDL, decreased HDL

Answer 435

Sedation, sleep disturbance, depression, psychotic episodes.

Answer 436

Calcium antagonists - leading to severe hypotension, bradycardia, congestive cardiac failure

Answer 437

Absorption Well absorbed orally. Distribution Large volume of distribution. Propanolol: Lipid soluble Readily crosses BBB Metoprolol: Moderate lipid solubility Atenolol: Low lipid solubility Esmolol: Low lipid solubility

Answer 438

Extensive first pass metabolism Excreted in urine Variable between individuals Low bioavailability Half life 3-6 hours Dose reduction required in hepatic failure

Answer 439

1. Metoprolol: Extensive first pass metabolism Low bioavailability, Half life 3-4 hours 2. Atenolol: Less extensive first pass metabolism Low bioavailability. Half life 6-9 hours 3. Esmolol: Rapidly hydrolysed by esterases in red blood cells. Half life 10 minutes.

Answer 440

ganglion blocking agent: Competitive antagonist at nicotinic cholinoceptors on sympathetic and parasympathetic postganglionic neurons. Causes pooling of blood in capacitance vessels. Abandoned due to side effects ␣ sympathoplegia (excessive orthostsaic hypotension, sexual dysfunction) and parasympathoplegia (constipation, urinary retention, glaucoma, blurred vision, dry mouth) IV administration

Answer 441

Inhibitor of noradrenaline release from postganglionic sympathetic neurons: Guanethidine is transported across the nerve membrane by uptake 1. Concentrated in transmitter vesicles where it replaces noradrenaline causing depletion of noradrenaline stores. Causes reduced cardiac output due to bradycardia and relaxation of capacitance vessels. Postural hypotension common. Overdosage may result in severe hypotension or shock. May induce hypertensive crisis in those with phaechromocytoma due to release of noradrenaline. Effects are attenuated when TCAs are coadministered due to their effect on blocking reuptake. Very large volume of distribution and long half life.

Answer 442

Reserpine blocks carrier mediated transport of dopamine into the vesicle. Results in depletion of dopamine, noradrenaline, and serotonin in central and peripheral neurons. Causes antihypertensive effect by reduction in cardiac output and total peripheral resistance. Effects are largely irreversible and last for several days.

Answer 443

1. Centrally acting alpha agonist. Inhibition of dopa decarboxylase and depletion of noradrenaline A2 actions greater than A1 2. Centrally mediated reduction in total peripheral resistance with variable reduction in heart rate and cardiac output. 3. Mild to moderate hypertension. Pregnancy induced hypertension Dose 0.5-3g/day in divided doses 0.25-1g IV over 20 minutes.

Answer 444

CVS May cause postural hypotension and bradycardia. CNS Sedation and loss of concentration Depression Nightmares. Endocrine: Lactation -mediated by inhibiting action on dopaminergic mechanisms in the hypothalamus. Other: Positive Coombs test is 25%. Interactions May result in lithium toxicity if co-administered

Answer 445

1. Absorption Orally active. Occasional IV use occasional. Distribution Active transport into brain 2. Extensive first pass metabolism. Metabolised in liver ␣ likely production of an active metabolite. Most is renally excreted. Antihypertensive effect in 4-6 hours, clinical effect may last 24 hours due to active metabolite.

Answer 446

1. Centrally acting partial agonist at alpha receptors, causing reduced sympathetic tone and increased parasympathetic tone. Preference for A2 2. Reduction in blood pressure and mild bradycardia. 3. Hypertension

Answer 447

Sedation, dry mouth. Depression. Reactive hypertensive crisis if rapidly withdrawn.

Answer 448

Orally active, bioavailability 75%. Distribution Lipid soluble and rapidly enters the brain. Half life 8-12 hours

Answer 449

1. carbonic anhydrase inhibitor: Carbonic anhydrase most prominent in the luminal membrane of the PCT 2. Profound depression of bicarbonate reabsorption in the proximal tubule Reduced production of bicarbonate by the ciliary body 3. Glaucoma Urinary alkalinisation Metabolic alkalosis Acute mountain sickness Epilepsy Dose 250mg-1g/24hours

Answer 450

Toxicity: Hyperchloraemic metabolic acidosis Renal stones Renal potassium wasting Skin reactions Interactions : Salicylates - increased risk of metabolic acidosis Phenytoin - reduced excretion of phenytoin resulting in toxic levels Contraindications: Hepatic failure - acetazolamide will decrease the urinary loss of ammonia.

Answer 451

Well absorbed orally Increased urinary pH within 30 minutes