Pharmacology (MRCP) Flashcards

Question

``` Stimulants are useful in ADHD. The symptom that best responds to stimulants is A. Insomnia B. Hyperactivity C. Inattention D. Motor tics E. Conduct disturbance ```

Answer 1

B. Stimulants such as methylphenidate are more effective in treating hyperactivity than inattention due to ADHD. Methylphenidate is available in two forms—immediate release and sustained release forms. The immediate release form starts to act within 20 to 60 minutes after administration and acts for up to 2 to 4 hours, while the sustained release form acts up to 12 hours, obviating the need for divided doses.

Answer 2

A. Atomoxetine is the fi rst non-stimulant drug to be approved for ADHD. It has a tricycliclike structure; it is classifi ed as a phenylpropanolamine derivative. It acts through selective inhibition of the presynaptic norepinephrine transporter. It has a half-life of approximately 5 hours and is metabolized through the CYP2D6 pathway. Drugs such as fl uoxetine, paroxetine or bupropion are CYP2D6 inhibitors and may raise atomoxetine levels. Atomoxetine is used for patients who fi nd stimulants too activating or who experience other intolerable side-effects. Atomoxetine has been associated with cases of severe liver injury in a few patients. It must be avoided in patients taking MAOI.

Answer 3

D. Naloxone is an opioid antagonist. It can precipitate acute withdrawal when administered to patients who are actively taking opioid drugs. Symptoms of acute opioid withdrawal include a strong urge to seek the drug, feeling of temperature change, pain, and abdominal distress. Patient may also have confusion, drowsiness, vomiting, and diarrhoea. When opioid antagonists that act for a long duration, such as naltrexone, are prescribed to encourage abstinence and maintain remission in opioid users it is absolutely essential that the use of street drugs has been completely stopped for at least a period of 5 to 7 days. If not, acute withdrawal symptoms will be precipitated. Naloxone produces opioid antagonism that lasts less than 1 hour, whereas naltrexone-induced withdrawal can persist for more than 24 hours.

Answer 4

C. Naloxone produces opioid antagonism that lasts less than 1 hour, as its plasma halflife is between 1 and 2 hours. In opioid overdose, naloxone is administered intravenously and repeated at 2- to 3-minute intervals until the desired response is achieved. In order to maintain recovery in signifi cant overdoses, it is often necessary to continue naloxone by infusion or repeated administration. As this has not happened in the patient described in this question, signs of intoxication have returned

Answer 5

E. Naloxone is commonly administered via intravenous injections in the UK. It can also be administered intramuscularly or via subcutaneous injections.

Answer 6

A. Lofexidine is an analogue of clonidine, and licensed only in the UK for use in opiate detoxifi cation. It is an α2 adrenoceptor agonist, similar to clonidine but it causes signifi cantly less hypotension. Action of lofexidine peaks at 3 hours and its elimination half-life is 12–15 hours. It is administered in divided doses to achieve the desired peak effect coincidental with the peak of withdrawal effects. It is used for 1 to 3 weeks in opiate detoxifi cation, with or without substituting a tapering dose of prescribed opiates. α2 agonism leads to increased autoreceptor activity and resultant reduction in sympathetic stimulation, which mediates the withdrawal symptoms when administration of opioids is suddenly stopped.

Answer 7

C. SSRIs, especially fl uoxetine, inhibit CYP2D6 enzyme involved in the metabolism of clozapine. This results in an increase in clozapine levels, leading to additional therapeutic advantage. This combination strategy has been tried in patients whose psychotic symptoms are refractory to clozapine. Therapeutic use of this interaction should be considered only when compliance is assured, maximal dosing has been achieved, and despite this the serum level is below 350 ng/ml. It should be attempted cautiously and with regular monitoring of plasma levels. When adding an SSRI, the dose of clozapine should be reduced in anticipation of the likely rise in plasma concentrations—an approximately twofold dose reduction is suggested for fl uoxetine and paroxetine.

Answer 8

D. Moclobemide acts on the same MAO-A enzyme that metabolizes tyramine, but the effect of moclobemide on this enzyme is reversible, leading to a lesser propensity of moclobemide to cause the tyramine reaction. When an unusually large consumption of tyraminecontaining products occurs, moclobemide can produce the cheese reaction similar to other MAO inhibitors. Due to the reversible and partly competitive nature of MAO-A blockade by moclobemide, normal activity of existing MAO-A returns within 16 to 48 hours of the last dose of moclobemide. Therefore, the dietary restrictions are less stringent, reducing the avoidance of foods with a high concentrations of tyramine to a period from 1 hour before to 2 hours after taking moclobemide. These foods must be avoided only for 3 days after the last dose of moclobemide, unlike other MAO inhibitors where several days of diet is needed even after withdrawing the medication.

Answer 9

D. Buprenorphine is a partial μ-opioid agonist. It has a slow onset of action and dissociates rather slowly from the μ-receptor. It has very poor oral bioavailability and so is administered sublingually. The half-life of buprenorphine is only 3 to 5 hours but its action is rather prolonged due to slow dissociation of the drug molecule from the receptor—this phase lasts for more than 24 hours. Due to its partial agonistic action, the propensity to cause respiratory depression is lower than that of heroin. When overdose occurs, naloxone must be given at a higher dose and in continuous infusion to reverse the toxicity

Answer 10

A. Clonidine is a central α2 agonist. As the α2 receptor is an autoreceptor, which on stimulation reduces sympathetic output, clonidine acts as sympatholytic drug. It is useful in some patients with tics and in Tourette’s syndrome. As many drug withdrawal states are mediated by sympathetic overdrive, clonidine can potentially be used in opioid, alcohol, or benzodiazepine withdrawal though this is not a licensed indication. In children with ADHD, clonidine can be used as a third-line agent after stimulants and atomoxetine. However, it is rarely used for pure ADHD symptoms; it is commonly used when ADHD is accompanied by motor tics. Clonidine can cause signifi cant hypotension.

Answer 11

A. Sexual arousal in a man results in the release of nitric oxide (NO) in vascular endothelium, mediated by autonomic nervous signals. NO acts as a second messenger and stimulates the synthesis of cyclic guanosine monophosphate (cGMP). This initiates a chain reaction, which results in corpus cavernosal relaxation and an increase in blood fl ow into the penis. This is followed by erection. Once produced, cGMP is cleared by the action of an intracellular enzyme called phosphodiesterase-5 (PDE-5). When PDE-5 is inhibited, the concentration of cGMP increases intracellularly, leading to prolonged tumescence and turgidity of the penis. Hence sexual arousal is required for PDE-5 inhibitors to have an effect on performance. Sildenafi l acts as a PDE-5 inhibitor, allowing an increase in cGMP and enhancing the vasodilatory effects of NO. Hence it is sometimes referred to as an NO enhancer, but it does not have a direct effect on NO synthesis.

Answer 12

E. Buspirone is an azapirone which, by partial agonistic action on the 5-HT1A receptor, suppresses activity in presynaptic serotonergic neurones. This in turn reduces the serotonin activity, leading to down-regulation of various 5-HT receptors. This is related to anxiolytic activity but with no hypnotic effect. Though buspirone is equieffective to diazepam, patients taking buspirone improve more slowly. This is related to the inherent mode of action, which depends on receptor down-regulation rather than producing a direct receptor action. Patients who are switched from benzodiazepines to buspirone do not do as well as those without previous exposure to benzodiazepines

Answer 13

A. Amiloride is useful in some cases of lithium-induced polyuria. Polyuria is the most common adverse effect of lithium, occurring in 25% of patients. This polyuria is related to the antagonistic effects of lithium on antidiuretic hormone, leading to diuresis. Conservative management includes fl uid replacement, decreasing the dosage of lithium, and single daily dosing of lithium. Potassium-sparing diuretics, such as triamterene and amiloride, or thiazide diuretics are also useful. Unlike thiazides and frusemide, amiloride does not reduce lithium clearance; instead it may increase lithium excretion

Answer 14

A. Akathisia is the commonest movement disorder associated with antipsychotic prescription. It is more commonly acute, with onset within 48 to 96 hours of administration of the antipsychotics. It is unclear whether akathisia results from dopamine antagonism or dysfunction of other neurotransmitters such as serotonin, acetyl choline, and norepinephrine. Akathisia is often mistaken for anxiety or worsening of psychotic agitation. Akathisia can vary in severity over time, making assessment diffi cult. Akathisia is associated with suicidality, absconsion, aggression, and non-compliance. Tardive dyskinesia develops late in the course of antipsychotic treatment and as such is not associated with absconsion from in-patient units, as more often than not the patients do not recognize having troublesome movement disorders. Neuroleptic malignant syndrome and laryngeal dystonia are life-threatening syndromes, often requiring immediate medical attention.

Answer 15

A. D2 occupancy in typical antipsychotics correlates with their antipsychotic effi cacy and propensity to cause extrapyramidal side-effects. This was demonstrated in a landmark positron emission tomography (PET) study by Kapur et al., where haloperidol produced therapeutic effect at around 65% occupancy; extrapyramidal side-effects occurred when the occupancy was around 78%. For atypicals, both 5-HT2A blockade and D2 occupancy are correlated with clinical effi cacy. Clozapine and quetiapine occupy less than half of D2 receptors but still are effi cacious as antipsychotics.

Answer 16

A. Memantine has moderate affi nity for the NMDA receptor and acts as a voltagedependent and non-competitive antagonist. Calcium-mediated excitotoxicity could be due to overstimulation of NMDA receptors by glutamate. Memantine may protect cells against excess glutamate by partially blocking NMDA receptors associated with abnormal transmission of glutamate, while physiological transmission remains unaffected

Answer 17

A. Therapeutic index is a measure that relates the dose of a drug required to produce a desired effect to that which produces an undesired effect. In animal studies, the therapeutic index is usually defi ned as the ratio of the median toxic dose to the median effective dose for some therapeutically relevant effect. The therapeutic index of a drug in humans cannot be measured directly and the value itself does not have much clinical use; instead, drug trials often reveal a range of usually effective doses and a range of possibly toxic doses, from which a safe therapeutic range is determined, for example 1.0 to 1.2 for lithium which when exceeded results in toxic effects.

Answer 18

A. Clozapine has a hit-and-run profi le at D2 receptors. The occupancy is around 40% and the time course of occupancy is comparatively shorter than typical antipsychotics. Quetiapine has a similar mode of action to that of clozapine. Clozapine and quetiapine bind more loosely to D2 receptors than dopamine itself whereas haloperidol and risperidone bind to these receptors more tightly. It is suggested that antipsychotics with low binding affi nity and fast dissociation rates, such as clozapine and quetiapine, are more responsive to endogenous changes in dopamine than those that bind more tightly and dissociate from the receptor more slowly. This is because baseline dopamine levels are interspersed with task- or stress-induced, several-fold increases in dopamine from normal physiological level

Answer 19

D. Volume of distribution is a measure of the apparent space in the body available to contain an administered drug. It can be calculated as a ratio of the administered dose (intravenous) and plasma (or blood) concentration at time = 0, that is when administration occurred. Hence, the higher the plasma concentration, the lower the volume of distribution and vice versa. Volume of distribution can vastly exceed any physical volume in the body because it is an apparent, not an actual, volume necessary to contain a drug homogeneously at the concentration found in the plasma. Drugs with very high volumes of distribution have higher concentrations in extravascular tissue than in the vascular compartment, while those that are contained fully in the vascular compartment have a smaller volume of distribution limited by the volume of plasma component. The apparent volume of distribution depends on properties of the drug molecule, such as lipid solubility and protein binding. Tissue binding decreases the plasma concentration and makes the apparent volume larger. Plasma protein binding increases plasma concentration and makes the apparent volume smaller. Half-life is a secondary measurement calculated from the volume of distribution and clearance rates, but volume of distribution itself does not depend on half-life of a drug. If the rate of clearance is slower or the volume of distribution is more extensive, the half-life will be longer.

Answer 20

B. The cytochrome P450 (CYP450) enzyme system is responsible for much of the phase 1 metabolism of drugs. Phase 1 metabolism includes oxidation, reduction, and hydrolysis, as a result of which a molecule (active or inactive) suitable for conjugation is produced. The phase 2 metabolism involves conjugation reactions such as glucuronidation, as a result of which polar compounds (mostly inactive), which are excretable in bile or urine, are formed. Induction and inhibition of the activity of the CYP450 system can result in various potential drug interactions. The most important enzymes in the CYP family involved in the metabolism of psychotropic drugs are CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP3A4 is responsible for the metabolism of more than 90% of psychotropic drugs that undergo hepatic biotransformation. In this question, if the CYP system is induced then the metabolic breakdown of drug A will be increased, producing more inactive metabolites. This will reduce the effi cacy of drug A.

Answer 21

A. Conjugation refers to phase 2 metabolism of administered drugs. These take place after oxidation-type reactions in phase 1. Enzymes such as transferases carry out conjugation, which usually results in inactive metabolites (or, rarely, active compounds, e.g. morphine). It is not essential that a drug must undergo phase 1 metabolism in order to undergo phase 2 metabolism, for example oxazepam undergoes direct phase 2 reactions

Answer 22

C. Oxidation is not a phase 2 reaction—it is a phase 1 reaction. Various types of phase 2 reactions include glucuronidation, acetylation, sulfation, and glutathione conjugation. Hydrolysis and hydroxylation are considered to be other phase 1 reactions.

Answer 23

B. Most prescribed drugs transfer into breast milk except very large molecules such as heparin and insulin, but the amount transferred is negligent for most drugs. The mechanism of transfer is passive diffusion through the lipid cell membrane of the lactating glands. Factors such as low plasma protein binding and high lipid solubility aid a drug in reaching high concentrations in breast milk. As milk is slightly more acidic than plasma, weakly basic drugs transfer more readily into breast milk, become ionized in the acid medium, and so get ‘trapped’. Unionized molecules cross biological membranes more easily than charged particles (ions). If a breastfeeding mother must take psychotropics and the drug is a relatively safe one, it is recommended that the drug is taken 30–60 minutes after nursing and 3–4 hours before the next feed, if possible.

Answer 24

C. Zolpidem is a non-benzodiazepine hypnotic of the imidazopyridine class. It is rapidly absorbed and has a short elimination half-life (mean 2.5 hours). It decreases sleep-onset latency, reduces disruptive midnight awakenings but has less consistent effects on total sleep time. It does not affect the REM distribution and unlike benzodiazepines, which increase stage 2 NREM at the expense of deep sleep NREM, zolpidem does not increase stage 2. It is unclear if zolpidem produces clinically signifi cant rebound as yet but dependence is thought to be low compared to other hypnotics

Answer 25

E. Two types of monoamine oxidase have been recognized: monoamine oxidase A predominantly metabolizes norepinephrine and serotonin; monoamine oxidase B predominantly metabolizes dopamine. Selegiline is a selective inhibitor of monoamine oxidase B that retards the breakdown of dopamine and so it prolongs the antiparkinsonism effect of levodopa as an adjunctive therapy for patients with fl uctuating response to levodopa. Some studies have found it to be effective for treating depression but only at very high doses at which selective MAO-B inhibition effect is taken over by non-specifi c inhibition

Answer 26

C. Citalopram (and escitalopram) is the most selective inhibitor of serotonin reuptake, with negligible effects on the reuptake of other monoamines such as norepinephrine or dopamine. It does not have any clinically signifi cant effect on histaminergic, GABAergic, or acetylcholinergic transmission. Paroxetine has clinically signifi cant anticholinergic activity. Fluoxetine weakly inhibits norepinephrine reuptake and binds to 5-HT2C receptors. Sertraline weakly inhibits both norepinephrine and dopamine reuptake, without any additional clinical advantage.

Answer 27

C. Prolongation of the QT interval of the ECG is associated with the development of torsade de pointes, a ventricular arrhythmia that can cause syncope and may progress to ventricular fi brillation and sudden death. The average QTc interval is approximately 400 ms. A QTc interval of 500 ms or greater is considered to be a high risk factor for torsades de pointes, though the prediction of arrhythmia is not simply linearly dependent on QT measure. An elevated risk of serious adverse cardiac events or sudden cardiac death has been documented for thioridazine, clozapine, droperidol, pimozide, and sertindole. These are considered higher-risk antipsychotics in terms of serious cardiac effects. Haloperidol, quetiapine, risperidone, chlorpromazine, and trifl uoperazine have a tendency to extend the QT interval even at therapeutic doses, but their link with sudden cardiac death is not yet clarifi ed. Amisulpride, aripiprazole, olanzapine, sulpride, and zotepine have not been linked with an elevated risk of sudden cardiac death or QTc prolongation. Typical neuroleptics that have lower potency, such as thioridazine and chlorpromazine, are more cardiotoxic than high-potency drugs such a haloperidol. The major effects on the electrocardiogram include prolongation of the QT and PR intervals, T wave blunting or inversion, and ST segment depression. Sudden death noted in antipsychotic recipients may also be due to seizures during sleep, sudden asphyxiation, temperature dysregulation (for example malignant hyperthermia), and neuroleptic malignant syndrome.

Answer 28

B. Drugs can undergo two different types of clearance when administered. When a constant fraction of a drug is cleared per unit time, it is called fi rst-order kinetics. This means that when the amount of drug in plasma or dose of administered drug increases, the clearance proportionately increases as a stable fraction of plasma concentration. When the system facilitating such clearance of drugs becomes saturated, drugs follow zero-order kinetics. Here a constant amount, not a fraction, of the drug is cleared per unit time. This means that irrespective of the amount of drug in plasma or dose of drug administered, only a fi xed unit of drug is cleared by the body. Thus, increasing the dose might result in serious toxicity in this case. Certain drugs have a propensity to undergo zero-order kinetics, even at therapeutic dose levels. Phenytoin metabolism is dose dependent, wherein smaller therapeutic doses follow fi rst-order kinetics while higher doses follow zero-order kinetics. Gabapentin is not metabolized by liver and undergoes fi rst-order renal clearance. Valproate follows fi rst-order kinetics even in wide therapeutic dose levels. Lamotrigine, too, shows fi rst-order linear kinetics and it is metabolized predominantly through glucuronidation.

Answer 29

E. The small intestine has the largest surface area for drug absorption in the GI tract, and its membranes are more permeable than oral epithelium, oesophagus, or stomach. Hence most drugs are absorbed primarily in the small intestine. Gut mucosa harbours many metabolic enzymes that can breakdown active drug molecules and reduce the bioavailability of administered drugs.

Answer 30

D. The abrupt discontinuance of SSRI use is associated with a discontinuation syndrome. This is characterized by fatigue, light headedness, nausea, headache, anxiety, insomnia and poor concentration, fl u like symptoms, and electric shock-like paresthesias. In most cases, at least 6 weeks of treatment have elapsed before a discontinuation reaction takes place. The symptoms are self-resolving within 3 weeks in most cases. It is suggested that those who tolerate SSRIs poorly on initiation are more likely to develop discontinuation symptoms. Fluoxetine is the SSRI least likely to be associated with this syndrome, because it has a metabolite that is active with a half-life of more than a week. Shorter half-life medications, such as paroxetine, are associated with more discontinuation symptoms. Other classes of antidepressants, such as venlafaxine and tricyclics, are also associated with discontinuation reactions.

Answer 31

A. Paroxetine has a half-life of nearly 21 hours, which is short compared to fl uoxetine, which has a prolonged duration of action due to an active metabolite that remains in the body for many days. In addition, paroxetine is more anticholinergic than most other SSRIs. Too rapid a discontinuation of any drug with signifi cant anticholinergic properties may lead to a cholinergic rebound. The symptoms are characterized by acetylcholine excess—nausea, vomiting sweating, stomach cramps, diarrhoea, anxiety, agitation, and insomnia. In some cases delirium can result. This rebound is more common with tricyclics than SSRIs, except in the case of paroxetine which has signifi cant anticholinergic effects.

Answer 32

A. Dosulepin or dothiepin together with amitriptyline has been associated with most cases of fatal tricyclic antidepressant overdose. The ingestion of large quantities of tricyclics in overdose results in complex changes in the normal pharmacokinetics observed at therapeutic doses. Due to anticholinergic effects, gastric emptying is delayed and a sustained slow absorption takes place. Respiratory depression produces acidosis, which reduces protein binding and increases the active free fraction of the toxic drug. The toxic effects of tricyclics are due mainly to an increased sympathetic drive, adrenergic blockade, arrythmogenic effect on myocardium, and anticholinergic action.

Answer 33

A. Many treatment variables are associated as risk factors for neuroleptic malignant syndrome (NMS). Nearly all dopamine antagonists have been associated with NMS, although high-potency conventional antipsychotics are associated with a greater risk compared with lowpotency agents and atypical antipsychotics. Intramuscular administration, rapid tranquilization, and faster titration rates are associated with higher incidence. Drugs with an intrinsic anticholinergic property have a lower propensity to cause NMS. Atypical agents produce atypical NMS, where the classic rigidity or hyperthermia component of NMS may be conspicuously absent. The risk of NMS is not related to α adrenergic blockade or sedative property of an antipsychotic drug

Answer 34

B. Benzodiazepine withdrawal symptoms include anxiety, inner tension, dizziness, insomnia, and anorexia. More severe withdrawal symptoms include nausea and vomiting, severe tremor, muscle weakness, postural hypotension, and tachycardia with psychological symptoms of dysphoria, depressive pessimistic thoughts, and obsessive ruminations. Myoclonus, pain symptoms, ataxia, kinaesthetic hallucinations, depersonalization, and hyperacusis are also noted. The withdrawal symptoms can develop after only 4 weeks of continuous use. Clonazepam, carbamazepine, and long-acting benzodiazepines themselves have been used in the management of withdrawal symptoms.

Answer 35

B. Typical neuroleptics vary in their potential to cause anticholinergic symptoms. As a general rule, high-potency medications such as haloperidol produce less anticholinergic effects compared to low-potency drugs such as chlorpromazine and thioridazine. Peripheral anticholinergic effects include dry mouth, blurred vision, constipation, and urinary retention. Central anticholinergic effects, such as confusion and delirium, are seen especially in overdose of low-potency agents and in the elderly

Answer 36

D. Severe sweating incongruent to room temperature is associated with TCAs, SSRIs, and venlafaxine. This is a socially disabling side-effect. Drugs such as terazosin, cyproheptadine, benztropine, and oxybutynin have been tried anecdotally to treat this symptom but none of these has been recommended for routine use. The mechanism by which SSRIs increase sweating is unknown but is hypothesized to be through activation of the sympathetic nervous system or by action on the hypothalamus.

Answer 37

A. The most commonly used anticholinergic drugs for extrapyramidal symptoms in patients taking antipsychotics are trihexyphenidyl (benzhexol), benztropine, biperiden, and procyclidine. Orphenadrine is an antihistaminergic agent with prominent anticholinergic action. Benztropine also has some antihistaminergic effects. All these agents are antimuscarinic. Trihexyphenidyl (benzhexol) is the most stimulating of all anticholinergics.

Answer 38

C. Benztropine is the least stimulating anticholinergic agent and so it is least associated with drug-abuse potential. Benztropine reaches peak plasma concentrations in 2 to 3 hours after oral administration and acts for 1 to 12 hours. Benztropine is available as an intramuscular preparation and this is preferred when available in acute dystonia.

Answer 39

A. Trihexyphenidyl is suspected to have some dopaminergic activities which produce stimulating effects. It has a higher abuse potential than other anticholinergic drugs.

Answer 40

. Lithium-induced tremor is frequently postural in nature and occurs at 8 to 12 Hz frequency. It is most notable in outstretched hands. If troublesome, the tremor can be reduced by giving lithium in divided doses or using a sustained release formulation wherein peaks and troughs in plasma level are better managed. A reduction in tremors can be noted if the patient’s anxiety is better managed and caffeine intake is reduced. β-blockers, such as propranolol, have been used to reduce lithium-induced tremor. If the tremors turn coarse, suspect lithium toxicity. Procyclidine can alleviate extrapyramidal symptoms but it has no effects on lithium-induced tremors.

Answer 41

A. Donepezil is an anticholinesterase drug widely used in patients with a moderate degree of Alzheimer’s dementia. It is administered orally once daily. The half-life of donepezil is 70 hours in the elderly and steady-state levels are achieved within about 2 weeks. The half-life of rivastigmine, another antidementia drug, is 1 hour, but it dissociates slowly from cholinesterase enzyme, thus a single dose is therapeutically active for 10 hours. Rivastigmine is taken twice daily. Galantamine is an alkaloid (extracted from daffodils (Narcissus pseudonarcissus) and snow drops (Galanthus nivalis)); it has an elimination half-life of nearly 6 hours, and so is administered twice daily. A sustained release preparation is now available.

Answer 42

D. Alcohol (ethanol) is metabolized via an oxidation reaction catalysed by alcohol dehydrogenase. This results in formation of acetaldehyde, which is further broken down to acetyl-coenzyme A by aldehyde dehydrogenase. Disulfi ram is a non-competitive, irreversible aldehyde dehydrogenase inhibitor. So when alcohol is taken together with disulfi ram this leads to accumulation of acetaldehyde. A high level of acetaldehyde is associated with nausea, throbbing headache, vomiting, hypertension, fl ushing, sweating, thirst, dyspnoea, tachycardia, chest pain, vertigo, and blurred vision. The accumulation of acetaldehyde occurs almost immediately after the ingestion of alcohol in those who take disulfi ram; the reaction can last from 30 minutes to 2 hours. The initiation of disulfi ram should not take place unless the patient has abstained from alcohol for at least 12 hours. Its half-life is estimated to be 60 to 120 hours. The effect of disulfi ram treatment can last as long as 1 or 2 weeks after the last dose of disulfi ram. Most fatal reactions occur in persons who are taking more than 500 mg a day of disulfi ram and who consume more than 90 g of alcohol.

Answer 43

A. Cigarette smoking occurs at a very high rate in patients with schizophrenia. Many reasons have been proposed as to why such high rates of smoking are seen in schizophrenia patients. One suggestion is that patients smoke as a form of self-medication with nicotine, which may help to regulate a dysfunctional mesolimbic dopamine system. Nicotine can increase dopamine release in the prefrontal cortex and reduce negative symptoms to some extent. Nicotine could enhance cognitive performance for certain tasks. Antipsychotic medications could block the dopamine reward pathway, necessitating an increase in nicotine concentrations needed to produce reward effects from smoking. Smoking may decrease the plasma levels of typical antipsychotic drugs via induction of the CYP450 enzymes system, providing some relief from extrapyramidal side-effects, but most patients who smoke start smoking even before onset of the illness.

Answer 44

B. Acamprosate is a structural analogue of GABA and taurine. Its mechanism of action is thought to be antagonism of glutamatergic N-methyl-D-aspartate (NMDA) receptors. It should only be started after the individual has been successfully weaned off alcohol; this is not because of alcohol–acamprosate interaction but the effi cacy of acamprosate is demonstrated only in individuals who have been successfully detoxifi ed from alcohol. The concomitant intake of alcohol and acamprosate does not affect the pharmacokinetics of either alcohol or acamprosate, but if the patient relapses more than once while on acamprosate the treatment must be reconsidered. Administration of disulfi ram does not affect the pharmacokinetics of acamprosate; though this is practiced at certain centres, no strong evidence exists to support the combination. Bupropion, used to aid abstinence from smoking, is started 2 weeks before a target date is set to quit smoking.

Answer 45

C. Dantrolene sodium is used to treat rigidity and hyperthermia in patients with neuroleptic malignant syndrome (NMS). Dantrolene binds to a calcium channel called ryanodine receptor in skeletal muscle, leading to a fall in intracellular calcium concentration and reduced contraction. It is usually administered via the intravenous route; it reduces muscle spasm in most patients with neuroleptic malignant syndrome. Dantrolene is not a stand-alone treatment for NMS; it must be accompanied by resuscitation, fl uid replacement, and cardiac and respiratory support. Rigidity is relieved usually within minutes to hours of administration. Dantrolene can also be used in other cases of life-threatening muscle rigidity, for example catatonia and serotonin syndrome.

Answer 46

E. Haloperidol is chemically a butyrophenone. Fluphenazine, perphenazine, and trifl uperazine are piperazine phenothiazines. Chlorpromazine is an aliphatic phenothiazine while thioridazine is a piperidine phenothiazine. Thiothixene is a thioxanthene antipsychotic; pimozide is a diphenyl butyl piperidine. Loxapine is a dibenzoxapine. Many of these typical antipsychotics are rarely used in current practice

Answer 47

B. Lamotrigine is an anticonvulsant increasingly being used to prevent recurrent depressive episodes in bipolar disorder. Lamotrigine is thought to act via blockade of voltage-sensitive sodium channels, with secondary effect on calcium transport. Lamotrigine has weak effects on the serotonin system

Answer 48

B. Lithium produces hypokalaemia-like changes on the electrocardiogram (ECG). This is related to displacement of intracellular potassium by the lithium ion. T-wave fl attening or inversion is the commonest ECG change reported. These changes commonly disappear after stopping lithium. Lithium depresses the sinoatrial node; this can lead to sinus dysrhythmia, heart block, and syncope. Hence lithium is contraindicated in persons with sick sinus syndrome. Cardiac effects of lithium are more pronounced in those who have pre-existing cardiac problems, on diuretic treatment, and in those with renal impairment

Answer 49

A. Lamotrigine is associated with rash, which is benign in about 8% of patients started on lamotrigine within the fi rst 4 months of treatment. In a small but signifi cant proportion of patients (nearly 0.1%) this may be an early manifestation of Stevens–Johnson syndrome or toxic epidermal necrolysis. So lamotrigine must be discontinued whenever a rash is reported during treatment. Unfortunately, this discontinuation is not always suffi cient to prevent the life threatening-hypersensitivity reaction, Steven–Johnson syndrome. The chances of developing a rash increases if lamotrigine is started at a higher than recommended dose or titrated at a faster than recommended speed. Coadministration of valproate can also increase the incidence of rash.

Answer 50

A. The electrical stimulus delivered via ECT must be strong enough to reach the seizure threshold of the patient. Each individual has a different seizure threshold with nearly 40-fold variability among patients. During the course of ECT treatment itself, the seizure threshold could increase in the range of 25 to 200%. Older men generally have a higher threshold than the young. Amnesia related to ECT is proportional to the degree to which the administered electricity dose is high in relation to patients’ seizure thresholds. Incidence of cognitive disturbance is higher when a patient receives thrice-weekly ECT compared to twice-weekly treatments.

Answer 51

B. Bupropion resembles amphetamine in its structure—it is a monocyclic aminoketone. Bupropion is a norepinephrine and dopamine reuptake inhibitor. Its side-effects profi le is different from that of SSRIs in that it causes very low incidence of sexual dysfunction or sedation and produces some weight loss. It does not cause signifi cant discontinuation reactions. It is currently licensed to help people quit smoking, but is not licensed as an antidepressant in the UK. Bupropion is contraindicated in patients with a history of eating disorder; it can cause signifi cant changes in appetite. Bupropion has a high propensity to cause seizures.

Answer 52

D. In the UK, duloxetine is marketed to treat stress urinary incontinence (SUI) in women under the name Yentreve® (Eli Lilly and Company). The female urethra has a rhabdosphincter of circularly arranged striated muscles. Generally, relaxation of this sphincter allows micturition. The sphincter is innervated by neurones from the sacral spinal cord (S2–S4). Duloxetine blocks the reuptake of serotonin and norepinephrine at this site to stimulate contraction of the rhabdosphincter, leading to an increase in the tone of the urethral sphincter. The increased muscle tone inhibits involuntary urine loss. To treat stress incontinence, a dose of 40 mg twice daily (80 mg/day) is recommended. In depression a dose of 60 mg/day given once daily is often used. Duloxetine can also help neuropathic pain, where a higher dose of up to 120 mg has been used.

Answer 53

C. Lamotrigine is mainly metabolized via glucuronidation and does not have much effect on other prescribed medications, but valproate has been observed to double the plasma levels of lamotrigine. The elimination half-life of lamotrigine in healthy young adults is approximately 25 to 30 hours. In patients taking valproate this is prolonged to 60 hours. As a result, when lamotrigine is initiated for patients who are taking valproate, the starting dose should be approximately 50% of the normal starting dose of lamotrigine. Some suggest that if valproate is started for a patient who is already on lamotrigine, one must consider obtaining a baseline lamotrigine plasma concentration. The lamotrigine dose may have to be reduced during the valproate dose titration. As a result of this interaction, the incidence of lamotrigine-induced rash seems to be more common in those taking the combination. Phenytoin, carbamazepine, and oral contraceptives may reduce the half-life of lamotrigine.

Answer 54

A. Lithium can aggravate psoriasis. The induction of psoriasis without pre-existing disease is less common than exacerbation of existing disease. Not all patients with pre-existing psoriasis have a fl are when starting lithium and psoriasis is not considered to be a contraindication to taking lithium for mania or depression. Similarly, other drugs such as β-blockers, antimalarials, and indometacin can aggravate psoriasis. Psoriasis that has fl ared with lithium appears to be more resistant to standard treatment modalities. Some preliminary evidence suggests that supplemental inositol or omega-3-fatty acids may improve symptoms in patients with psoriasis during lithium treatment. Histological studies on the skin lesions induced or aggravated by lithium are equivocal; some support the lesions to be consistent with psoriasis, although others have claimed the features as non-specifi c and refer to as psoriasiform dermatitis.

Answer 55

C. Ployuria, one of the most common side-effects of lithium, is related to tubular concentrating defect that is resistant to vasopressin. This results in nephrogenic diabetes insipidus. Vasopressin receptor expression is reduced by lithium, leading to a failure of facilitation of water movement. It is thought that taking lithium in a single dose prevents, or at least limits, renal tubular impairment. The most likely reason for the reduction of thirst and polyuria is the less frequent stimulation of the thirst centre by the lithium salts in once-a-day doses. However, some studies have shown that the benefi cial effect of single dosage is seen only in those who received multiple doses for a short time. It is possible that long-term, multiple-dose administration results in irreversible changes in tubular mechanisms. Patient adherence can be improved by a single-dosing schedule of lithium; however, once-a-day schedules have not been shown to be conclusively superior with respect to glomerular damage or renal failure.

Answer 56

E. On pharmacokinetic grounds, oxazepam may be preferable to chlordiazepoxide in cirrhotic patients since the elimination of oxazepam is not greatly altered in cirrhosis. In general, longer-acting benzodiazepines, such as chlordiazepoxide or diazepam, are preferred as they produce a smoother withdrawal course with less breakthrough or rebound symptoms, but they may lead to excess sedation for patients with hepatic dysfunction/cirrhosis. Shorter-acting benzodiazepines, such as oxazepam, may result in greater discomfort and more discharges against medical advice, because alcohol withdrawal symptoms tend to recur when the plasma drug levels drop. Shorter-acting agents, such as lorazepam or oxazepam, require more frequent dosing. They may be more useful for symptom-triggered regimens than fi xed-dose regimens of alcohol detoxifi cation.

Answer 57

D. Anticholinergic drugs may exacerbate some symptoms of tardive dyskinesia (TD). Traditionally, long-term anticholinergic prescriptions are thought to promote the onset of TD, though the evidence in support of this notion is minimal. Tardive dyskinesia is a troublesome sideeffect of antipsychotics. It is more common in older patients and those with neurological diseases. The risk of tardive dyskinesia is estimated as 3–5% per year of exposure (at least for the fi rst 5 years) with conventional antipsychotics. The appearance of symptoms usually takes more than 3 months, the risk increasing proportionally with duration of treatment. In elderly patients this increases to be as high as 25% within the fi rst year of exposure to typical antipsychotics. Women, children, and patients with primary mood disorders or learning disabilities are also at higher risk. Some studies report an increased risk associated with diabetes and comorbid substance use.

Answer 58

B. Serotonin is released from platelets in response to vascular injury. It promotes vasoconstriction and platelet aggregation. Platelets do not possess the synthetic machinery to produce serotonin and so depend on uptake via 5-HT transporters on their membrane. SSRIs inhibit the serotonin transporter, leading to a hyposerotonergic state in platelets. This reduces the ability to form clots, with subsequent increase in the risk of bleeding. Thus, SSRIs cause a functional impairment of platelet aggregation (thrombasthenia), but not a reduction in platelet number. This can cause easy bruising or prolonged bleeding in those with gastric ulcers or bleeding diathesis. Some authors recommend gastroprotection when SSRIs are coadministered with NSAIDs.

Answer 59

A. Varenicline is a partial agonist at the α4β2 unit of the nicotinic acetylcholine receptor. It is shown to assist smoking cessation by relieving nicotine withdrawal symptoms and reducing the rewarding properties of nicotine. It is advised to choose a quitting date and start taking the tablets 1 week before the date. Generally, varenicline is started at 0.5 mg daily, increasing to 0.5 mg twice daily after 3 days. The fi nal dose is 1 mg twice daily for up to 12 weeks

Answer 60

E. All of the listed drugs except α1-blockers are associated with erectile dysfunction. Parasympathetic activity during arousal triggers the release of nitric oxide, which increases the levels of the intracellular cyclic guanosine monophosphate (cGMP). Increases in cGMP cause penile vascular and trabecular smooth muscle relaxation, leading to increase in blood fl ow. The rapid fi lling of the cavernosal spaces compresses venules leading to reduction in venous outfl ow. This process effectively raises intracavernosal pressure, resulting in erection. α1 adrenergic blockers can enhance erectile function by reducing the sympathetic tone and relaxing trabecular smooth muscle cells. Nearly 25% of cases of erectile dysfunction are related to medication side-effects. Many prescribed drugs, including β-blockers, H2 antagonists, diuretics, antiepileptics, antidepressants, and antiparkinsonian medications, can cause erectile dysfunction. In addition, street drugs such as cannabis, cocaine, alcohol, ecstasy, and opiates can also lead to impotence

Answer 61

B. The vasodilatation required to bring on erection is mediated by nitric oxide (NO). Nitric oxide enables vascular smooth muscle relaxation via production of a second messenger, called cGMP. Men suffering from erectile dysfunction (ED) may have successful erection if the availability of cGMP is prolonged or increased. This can be achieved by modulating an enzyme called phosphodiesterase (PDE-5). Normally PDE-5 terminates the action of cGMP by converting it into inactive form (GMP). By inhibiting PDE-5, sildenafi l lengthens the life of cGMP and helps to achieve erection. There are nine different types of PDE found in different tissues of the body; for example coronary tissues have the PDE-3 type receptors; PDE-5 receptors are found in platelets and various muscle tissues; and PDE-6 receptors are found in the retina. Sildenafi l has some propensity to act on PDE-6, apart from its primary action on PDE-5; this explains defects in colour vision experienced by some patients taking sildenafi l. As sildenafi l does not produce new cGMP directly, it cannot act as an aphrodisiac. Hence it cannot help patients with reduced arousal due to other causes such as depression.

Answer 62

D. Naloxone is an opioid antagonist and has no analgesic activities. Naltrexone is a longeracting opioid antagonist with no clinically useful analgesic actions. Nomifensine is not an opioid; it is a cyclic antidepressant with norepinephrine and dopamine reuptake inhibition. It was withdrawn from the clinical market due to hepatotoxicity and renal damage, in addition to fears regarding abuse potential. Propoxyphene has mild to moderate analgesic properties but its metabolite, norpropoxyphene, is devoid of clinically useful analgesia. Codeine, on the other hand, is a strong analgesic and breaks down to morphine which has potent analgesic activity. Codeine is ineffective as an analgesic at usual doses in 7 to 10% of the white population with low activity CYP2D6 alleles. It is reported that in those with ultrarapid CYP2D6 metabolism, codeine intake may result in an increase in morphine production, occasionally resulting in opioid intoxication.

Answer 63

C. There are three important types of opioid receptors; most analgesic effects are associated with μ receptors. The δ and κ receptors also contribute to the analgesic effect to some extent. Morphine and codeine mainly act via μ receptors to produce clinical analgesia. Opioids are coupled to Gi proteins that decrease cAMP. When opioids bind to μ receptors, hyperpolarization of the nociceptive neurone (sensory neurone for pain) takes place via opening of K+ channels and inhibition of the Ca2+ channels. This reduces neuronal activity and reduces the transmission of pain signals via ascending pathways to the brain.

Answer 64

B. Methylxanthines include caffeine and theophylline. They have CNS stimulatory properties. At therapeutic doses, these drugs block adenosine receptors; at higher concentrations inhibition of the phosphodiesterase enzyme takes place. Adenosine is released from neurones and glia. It acts via G-protein-coupled receptors (A1, A2A, A2B, and A3). A1 receptors have inhibitory role while A2 receptors have stimulatory properties. A1 receptor antagonism may enhance cognition and facilitate arousal. At higher doses where inhibition of phosphodiesterase occurs, intracellular levels of cAMP increase.

Answer 65

C. Livedo reticularis refers to a characteristic purple mottling of the skin see in patients taking amantadine. It is usually seen as a lacy, net-like pattern of vascular change on the legs. It is also associated with vasculitis such as lupus. Mostly, the livedo reticularis disappears when the drug is discontinued, usually within several weeks. The appearance of livedo does not always warrant the cessation of the drug. The common side-effects of levodopa include insomnia, postural hypotension, gastrointestinal disturbances, tremors, mood changes, and fatigue. Bromocriptine can cause postural hypotension, nausea, oedema, confusion, dry mouth, and depression. Tolcapone is a COMT inhibitor and can cause abdominal pain, back pain, constipation, nausea, diarrhoea, and liver failure

Answer 66

D. Tiagabine is an add-on antiepileptic drug developed by modifying a GABA uptake inhibitor called nipecotic acid. Tiagabine is a potent inhibitor of GABA uptake into both neurones and glial cells. It acts via selective inhibition of the GABA transporter, GAT-1. Through this mechanism, tiagabine enhances GABAA receptor-mediated tonic inhibition. Vigabatrin is a selective and irreversible GABA-transaminase inhibitor. Topiramate produces its antiepileptic effect through several mechanisms such as modifi cation of Na+-dependent and/or Ca2+- dependent action potentials, enhancement of GABA-mediated Cl– fl uxes into neurones, and inhibition of kainate-mediated conductance at AMPA glutamate receptors. Gabapentin is a structural analogue of GABA and though originally designed as a GABA-mimetic, its mechanism of action is still unknown.

Answer 67

A. Melatonin has not been demonstrated to have clinically signifi cant antidepressant properties. Ropinirole is a dopamine agonist; it acts via the stimulation of postsynaptic dopamine D2-type receptors within the basal ganglia. Agomelatine is a novel agent promoted as a melatonergic antidepressant; its main antidepressant effect is mediated via 5-HT2C antagonism, which may modulate noradrenergic and dopaminergic neurotransmission. L-tryptophan is a serotonin precursor and is not considered as melatonergic drug. Modafi nil is not used as an antidepressant; it acts via an infl uence on dopamine-dependent adrenergic signalling, though the exact mechanism is still unclear.

Answer 68

D. Buprenorphine and naloxone act via opioid receptors; they are not indicated in sleep disorders such as narcolepsy. Antidepressants, including fl uoxetine and tricyclics such as imipramine, can help cataplexy (sudden loss of muscle tone) in narcolepsy. Modafi nil is a drug with stimulant properties and it is used to promote wakefulness in narcolepsy and allied disorders.

Answer 69

D. Pindolol acts as a partial agonist at 5-HT1A receptors. Several controlled studies in the past have shown that the addition of pindolol to SSRI therapy rapidly potentiates the effects of these antidepressants. However, despite the rapidity of improvement with the combination, most studies found no overall advantage at the end of the study period. Systematic review of randomized controlled trials does not support the use of pindolol and β-blockers are not licensed for the treatment of depression. Pentazocine is a partial agonist at kappa opiate receptors; it has some psychotomimetic properties but is not used as an antidepressant. In fact, it may induce depression. Tramadol is an opioid analgesic with no antidepressant effects.

Answer 70

E. The mean elimination half-life of atomoxetine after oral administration is 5.2 hours. In poor metabolizers (CYP2D6 polymorphism) the mean elimination half-life is more than 20 hours, due to reduced clearance. Nearly 80% of atomoxetine is excreted in the urine. Atomoxetine does not affect the cytochrome P450 2D6 enzyme system. The effects of atomoxetine last longer than would be expected from its half-life; hence, once-daily administration is effective.

Answer 71

C. Antidepressant combinations involving MAOIs require close monitoring due to the risk of serotonergic and hypertensive side-effects. Phenelzine is supposed to be the safest MAO-A inhibitor in combination therapy for depression. It is a derivative of hydrazine similar to isonaizid, but the latter is mainly used as an antituberculosis drug and has only a weak antidepressant action. Selegeline is an MAO-B inhibitor

Answer 72

``` visual pigments • noradrenergic • muscarinic cholinergic • serotonergic • GABA B ```

Answer 73

Nicotinic GABA A Glycine

Answer 74

Na+, K+, Ca2+

Answer 75

``` Glutamic acid -->glutamic acid decarboxylase GABA -->GABA transaminase (GABAT) Glutamic acid + Succinic semialdehyde ```

Answer 76

``` NMDA R-> ligand gated ion Ca Quisqualate-> ligand gated ion Kainate (Glu 5-7, KA1-2)-> ligand gated ion AMPA, AP4 Glu 1-4-> ligand gated ion Metabotropic glutamate recetor-> GPCR ```

Answer 77

NMDA receptors are coupled intracellularly to GlyR and also to a binding site for PCP (phencyclidine) PCP and σ opiate receptor activation antagonises the excitatory effects of NMDA activation but does not affect Q or K receptors NMDA receptors have a very high conductance, and are usually blocked by a Mg2+ ion under certain conditions, such as activation of AMPA receptors, which conduct the bulk of glutamate transmission, the magnesium ion leaves the channel, so unblocking it and allowing calcium influx this influx of calcium activates cellular enzymes that bring about changes in neuronal l excitability and synaptic function

Answer 78

``` Acetyl coenzyme A + choline -->Choline acetyltransferase acetylcholine -->Cholinesterase Choline + Acetic (ethanoic) acid ```

Answer 79

M1 and M3 activate a G protein that stimulates PLC activity, and thereby resulting in the release of intracellular Ca2+ M2 receptors activates Gi proteins which inhibit adenylate cyclase, and open K+ and close Ca2+ channels Agonists-> muscarine, pilocarpine, arecholine, methacholine, carbachol Antagonists-> atropine, scopolamine, TCA

Answer 80

``` L-tyrosine (T hydroxylase) L DOPA (3,4-dihydroxyphenylanine) Dopamine (aromatic-L-amino-acid decarboxylase) Noradrenaline (D B-hydroxylase) Normetanephrine (COMT) MHPG VMA (vanillyl mandelic acid) ```

Answer 81

‘indirectly acting sympathomimetic amines’ such as AMPHETAMINE, TYRAMINE and EPHEDRINE release NA quickly enough to bind with postsynaptic receptors antihypertensive agents such as DEBRISOQUINE, BETHANIDINE and GUANETHIDINE inhibit NA release from storage, but do not cross the blood brain barrier

Answer 82

tertiary- amitriptyline: higher affinity for the 5HT uptake site, and are more potent antagonists of a1 adrenoreceptors and muscarinic cholinergic receptors. More sedating and cause more anticholinergic side effects Secondary- nortriptyline, despiramine

Answer 83

MAO A mainly, which is more effective in the breakdown of NA and 5HT

Answer 84

D1-> caudate, nucleus accumbens, olfactory tubercle D2-> basal ganglia, limbic, cerebral cortex D3-> limbic, nucleu accumbens, hypothalamus D4-> limbic and frontal D5-> extra-striatal

Answer 85

CLOZAPINE is one order more potent at D4 than D2 or D3

Answer 86

primarily pure D2 antagonist

Answer 87

anticholinergics such as BENZTROPINE, BENZHEXOL , and ORPHENADRINE inhibit the uptake of DA and also block cholinergic receptors

Answer 88

``` L-Tryptophan ->tryptophan hydroxylase 5-HTP ->5-hydroxytryptophan decarboxylase = amino acid decarboxylase 5-HT ->MAOA 5-HIAA (5-hydroxyindolacetic acid) ```

Answer 89

5HT1A pre and post hippocampus, raphe 5HT2A post, limbic and PF&medial frontal cortex 5HT2C post, wide in forebrain, midbrain and choroid plexus 5HT3 post, widespread, amygdala and limbic

Answer 90

5HT 1A receptor agonists are anxiolytic ( | BUSPIRONE)

Answer 91

seen in drugs such as CLOZAPINE and RISPERIDONE may improve negative symptoms •5HT2A receptors are linked to sexual dysfunction •5HT2A antagonists improve slow wave sleep •5HT 2C antagonists appear to be anxiolytic and play a role in food intake •5HT 3 receptors are linked with nause

Answer 92

Paroxetine

Answer 93

Citalopram

Answer 94

Bind to y2 subunit enhance GABA + other NE, 5HT do not work in the absence of GABA the BZ 2 receptor may mediate anti-anxiety effects of BZDs

Answer 95

sx usually in 2-3 days (Lorazepam), within 7 days for long acting lasts 3-10 days, peak 7-8 anxiety, restlessness, apprehension, insomnia, nausea, tremor, muscle tension, sweating, hyperacusis. uncommon- metallic taste, rare- tinnitus, perceptual disturbances (illusions, macropsia, micropsia, occasionally hallucinations.)

Answer 96

>60 yrs, passive-dependent personality (Peter Tyrer) Short or medium duration Concurrent use of lithium, neuroleptics, some tricyclics, buproprion History of withdrawal, seizures, delirium, alcohol Long duration of treatment Rapid withdrawal from high dose

Answer 97

delayed ejaculation, nocturnal eneuresis, induce myocardial depression and precipitate heart failure, asthma, fatigue, cold extremities, sleep disturbances, poor glucose tolerance, exacerbation of psoriasis

Answer 98

1. activation of inhibitory autoreceptors in the cell bodies of cells in the midbrain, which reduces cell body firing and attenuates the increase in neurotransmission caused by the drug 2. after several days, the autoR on NA and 5HT cell bodies become subsensitive> this frees NA and 5HT neurones from inhibitory feedback control, and restroes the firing rate to normal levels despite the presence of increased synaptic levels of NA and 5HT 3. The antidepressant effects are probably due to long term potentiation of NA and 5HT neuro-transmission

Answer 99

Clomipramine

Answer 100

1. Autonomic: anticholinergic, a1 adrenoreceptor blocking effects, histamine H1 R 2. Cardiovascular-> tachyC, hypotension, PR/QTc, ST depression and flattened T waves, negatively ionotropic, cardiac conduction defect, heart block, cardiac arrythmia 3. Neurological: fine tremor, incoordination, headache, muscle twitching, epileptic seizures 4. Hematological: agranulocytosis, leucopenia, eosinophillia, eosinophilia, thrombocytopenia 5. Dermatological: rashes, photosensitisation 6. Other- mild cholestatic jaundice, hyponatremia, testicular enlargement, black tongue

Answer 101

``` agranulocytosis severe liver damage narrow angle glaucoma prostatic hypertrophy post MI heart block ``` ``` caution in: epilepsy (TCAs lower seizure t hreshold) elderly coronary thrombosis ECT (cardiac events ```

Answer 102

malaise, headache, nausea, abdo pain, diarrhea, restlessness, insomnia, anxiety due to cholinergic hyperfunction

Answer 103

-ve 5HT2 receptor | +5HT1 post, and -ve 5HT1A pre

Answer 104

increased coaguation

Answer 105

1. Altered mental state 2. Autonomic dysfunction 3. Neuromuscular hyperactivity

Answer 106

MAO-A and B- bind covalent linkage

Answer 107

1. Food and drink containing tyramine cheeses, extract with meat/yeast (Bovril, Oxo, Marmite) smoked, pickled fish hung poultry and game some red wines 2. Drugs adrenalin, NA sympathomimetics, L-DOPA opiates, alcohol Barbiturates, insulin and oral hypoglycemics Antidepressants (need drug free period for 2 weeks)

Answer 108

liver disease pheochromocytoma CCF

Answer 109

``` NaSSA antag a2 and heteroR ++serotoinin stimulates 5HT1A blocks pre 2a autoR and enhances NA ++affinity for 5HT1 blocks 5HT2A//C and 5HT3 R, therefore prevents side effects anxiety, agitation, nausea and sexual potent H1 R antagonist ```

Answer 110

Trazodone (weak 5HT re-uptake inhibitor | antag at 5HT2 R blocks post a1 R sedating

Answer 111

DA R blockade in HPA Increased prolactin Amenorrhea, glactorrhea, impotence, infertility

Answer 112

idiosyncratic response to neuroleptics incidence 0.5-1% usually within 10 days of treatment Risks: organic brain, hypermetabolic, agitation, dehydration, recent dose increase Ix: CPK >1000, increased WCC, abnormal LFTs 1. Motor: hypertonicity, dysphagia, dyspnea, 2. mental- akinetic mutism, stupor, fluctuating consciousness, 3. autonomic sx- unstable BP, tachyC, excessive sweating, hyperthermia, hypersalivation, urinary incontinence Treatment: 1. stop AP immediately, 2. bromocriptine, 3. dantrolene (muscle rigidity), 4. general supportive treatment on a medical ward. 5. Rehydration 6. Sedation with short acting Benzo 7. Other treatments: anti-muscarinic, propranolol, ECT, plasmaphoresis Complications: pneumonia, PE, rhabdomyolysis leading to renal failure, arrythmias, cardiac arrest, strokem cardiogenic shock, hepatic failure, E coli, mortality 20% due to renal failure and rhabdomyolysis

Answer 113

Success not related to gender or age, wait at least 5-14 days, use structurally dissimilar agents, start low, avoid depot

Answer 114

levels rise-> when more water absorbed, more lithium | absorbed competitively with sodium, so less sodium, more lithium

Answer 115

if problematic can use thiazide diuretic and reduce dose by 50%, or use Amiloride 5mg without need to reduce lithium dose.

Answer 116

Rare-> distal tubule becomes resistance to influence of ADH, possibly due to blockage of ADH-sensitive adenylate cyclase

Answer 117

Thyroid gland enlargement-> 5%, shrinks if thyroxine given, returns to normal after lithium stopped Hypothyroidism-> 3-4% , females > males, due to interference with thyroid production

Answer 118

GABA agonist, blocks neuronal sodium channels and also affects calcium channels facilitates some aspects of brain 5HT function agranulocytosis: rare 1 in 10 000- 1 in 125 000 leucopenia- usually first few weeks Interactions: increased metabolism- TCA, BZD, haloperidol, oral contraceptives, thyroxine, warfarin , anticonvulsants increased levels- SSRIs, erythomycin, isoniazid, some MAOIs decreased effect of other Ca2+ channel blockers- felodipine, nicardipine neurotoxicity with lithium

Answer 119

mechanism unclear GABA transaminase inhibitor increased GABA release, GABA B R density, neuronal responsiveness to GABA, potassium conductance Reduced- GABA breakdown, turnover, sodium influx Rare acute hepatitis contraI in pre-existing liver diease, pregnant or nursing mothers

Answer 120

inhibition of glutamate release prolongs the slow inactivated state of voltage dependent sodium ion channels for partial seizures, and secondaru generalised tonic clonic seizures can be used as sole treatment or adjunctive SE: rashes, STS, drowsiness, hepatic dysturbance, visual disturbance, GI upset, confusion