Pharmacology (MRCP) Flashcards
On administration of an unknown dose of a new antipsychotic, a 55-yearold
man develops extra pyramidal symptoms. The dose at which this effect
appears would be established in which phase of clinical trials?
A. Phase 1
B. Phase 2
C. Preclinical phase
D. Phase 3
E. Phase 4
A. The dose at which side-effects develop is often determined at phase 1 of clinical trials. The
pathway that a drug must follow before approval and marketing starts with animal studies, where
the molecule is demonstrated to have specifi c actions. These extensive, preclinical animal studies
must be carried out on at least two different animal species. Mutagenicity, carcinogenicity, and organ
system toxicity are studies at this phase. A new drug under investigation then enters human trials.
The fi rst phase consists of determining if the drug is safe on human subjects. It is administered to a
small group of volunteers and safety, tolerability, and pharmacokinetics of the drug are ascertained.
In phase 2, effectiveness in comparison to placebo is studied in hundreds of patients with the target
disease to see if it works at all against the disease. In phase 3, the drug undergoes extensive doubleblind,
randomized controlled trials to determine how well it works and what are the common sideeffects.
Phase 4 takes place if all the previous phases are successfully crossed—the drug undergoes
the approval process by regulatory bodies and postmarketing surveillance ensues. Less common
side-effects, which sometimes could lead to a drug’s withdrawal, can be picked up when large-scale
prescribing takes place during postmarketing surveillance.
Haloperidol is more potent than chlorpromazine. Potency of a therapeutic
formulation refers to
A. Strength of binding to receptors
B. Duration of action at receptors
C. Size of the dose required to produce an effect
D. Elimination half-life of a drug
E. Proportion of available receptors occupied by a drug
C. Potency of a drug with receptor-binding action refers to the amount of the drug needed
to produce a particular effect compared to another standard drug with similar receptor profi le
(‘vigour’). Affi nity refers to the ability of the drug to bind to its appropriate receptor (‘affection’).
Effi cacy refers to how well the drug produces the expected response, that is the maximum
clinical response produced by a drug (‘productivity’). Effi cacy depends on affi nity, potency, duration
of receptor action in some cases, and kinetic properties such as half-life, among other factors.
Haloperidol is more potent than chlorpromazine as approximately 5 mg of haloperidol is required
to achieve the same effect as 100 mg of chlorpromazine. These drugs, however, are equal in the
maximal clinical response achievable using them, that is equally effi cacious but not equipotent.
Absorption of orally administered drugs is affected by which of the following A. Intestinal transit B. Co-administered drugs C. P-glycoprotein D. Presence of food E. All of the above
E. After oral administration, a drug may be incompletely absorbed. This is mainly due to lack
of absorption from the intestine related to the presence of inhibitory factors such as food or gastric
acid, or to changes in intestinal motility; for example having diarrhoea or vomiting can affect drug
absorption. Inherent properties of certain drugs can also affect their absorption, for example highly
hydrophilic drugs cannot cross the lipid cell membrane, while highly lipophilic drugs will struggle to
cross the water layer in extracellular space. Presence of reverse transporters, such as P-glycoprotein,
can affect drug absorption. P-glycoprotein pumps certain drug molecules actively out into the gut
lumen from gut cells. Inhibition of P-glycoprotein and gut wall metabolism, for example by grapefruit
juice, can increase absorption of certain (mostly non-psychotropic) medications.
Which of the following conditions predisposes to a higher rate of transport
through the blood–brain barrier?
A. Presence of ionized drug molecules
B. Presence of protein-bound drug molecules
C. Presence of water-soluble drug molecules
D. Presence of infl amed meninges
E. All of the above
D. The blood–brain barrier poses a special challenge to the transit of drug molecules into
the brain, which is very important to ensure the activity of most psychotropics. The blood–brain
barrier is a structural and functional barrier comprised of capillary endothelium of brain, which
possesses tight junctions, acting in unison as a single sheet or membrane. These junctions are
disrupted when meningitis or other infl ammation affects the structure. The ability of a drug
to pass the blood–brain barrier depends on its molecular size, lipid solubility, and ionic status.
Unionized molecules that are freely available and less protein bound are transported across the
barrier easily. In general, the higher the lipid water partition coeffi cient, the greater the ability
to cross the barrier. Exceptionally, there are a few molecules that pass the barrier effectively in
spite of having a low lipid–water partition coeffi cient. These have specifi c carrier mechanisms, for
example amino acid transport system (this is stereo specifi c, so that L amino acids but not
D amino acids are easily transferred). L-dopa and valproate have specifi c carrier mechanisms.
Some areas of brain lack this barrier—subfornical organ, area postrema, and median eminence.
These circumventricular organs allow transfer of many compounds from blood to brain. This may
have a survival benefi t as certain toxic substances stimulate the area postrema and induce nausea
and vomiting.
A 72-year-old patient with bipolar illness experiences more side-effects
when taking the same medication that he was prescribed 30 years ago,
when he was 42 years old. Which of the following is a possible explanation?
A. Reduced proportion of body fat
B. Increased liver enzyme activity
C. Increased renal clearance of drugs
D. Increased protein-binding fraction
E. All of the above
A. Pharmacokinetic changes in old age are pertinent when considering initiation, dosing,
and coadministration of medications in the elderly. In general, the ability to absorb an orally
administered medication is not greatly affected, but elderly patients have less body fat, and so
lipid-soluble drugs may be distributed to brain tissue more avidly. However, this effect is not
universal for all drugs. Protein binding and hepatic metabolism are reduced in elderly people,
especially when malnourished. Renal function invariably drops with age. Note that this question is
non-specifi c with respect to the prescribed drug.
Which one of the following has partial agonistic activity as a major therapeutic mechanism? A. Propranalol B. Olanzapine C. Lithium D. Pindolol E. Carbamazepine
D. Pindolol is a partial agonist at β-receptor sites. In addition, it is a 5-HT1A antagonist
and has been studied as an augmenting agent with antidepressants. The fi nal common pathway
of action of most psychotropics is interference with neurotransmitter function. In general,
neurotransmitters are released from a presynaptic neurone, occupy a receptor in a postsynaptic
neurone, and bring about a change in the activity of the postsynaptic neurone. If a drug acts in
a similar fashion to a neurotransmitter and brings about a similar change in the postsynaptic
neurone, then it is called an agonist. This is often due to the intrinsic activity of the drug molecule
on the specifi c receptors. Certain drugs occupy the receptors and do not have any intrinsic
activity; they simply stop the neurotransmitter from carrying out its routine function. These
drugs are called antagonists for the particular receptor. Certain other drugs have a degree of
intrinsic activity; thus, when there is no indigenous neurotransmitter in the vicinity, they can
produce a degree of effect similar to the neurotransmitter but if these molecules are allowed to
compete with the indigenous neurotransmitters, this becomes counter productive. They block
the full action that could be provided by the neurotransmitter. Hence, these are called partial
agonists. Propranalol is a β-agonist with both β1- and β2-antagonistic properties. Olanzapine
is predominantly a serotonin (5-HT2A) and dopamine antagonist (D2). Carbamazepine is a
membrane-stabilizing agent while the mechanism of action of lithium is thought to be mediated
via the second messenger inositol system. The anxiolytic buspirone is a partial agonist at 5-HT1A
autoreceptors. Aripiprazole is also a partial agonist at dopamine receptors.
A 44-year-old in-patient, recently started on clozapine, develops
exacerbation of chronic sinusitis and appears excessively drowsy.
All of the following remedial measures might interfere with clozapine
metabolism except
A. Coffee
B. Quitting smoking
C. Amoxicillin
D. Erythromycin
E. Ciprofl oxacin
C. Amoxicillin is largely cleared through the kidneys and does not interfere with clozapine
metabolism. Clozapine undergoes hepatic metabolism via CYP1A2, CYP3A4, and CYP2D6.
Ciprofl oxacin and other fl uoroquinolone antibiotics can inhibit CYP1A2 and affect clozapine
levels. Smoking induces CYP1A2 and quitting it will lead to a rebound inhibition effect on the
enzyme appearing after 2 to 4 weeks. Byproducts of tobacco smoking, particularly the polycyclic
aromatic hydrocarbons, are the major offenders in this regard. The metabolic inductive effects
are not specifi c to tobacco smoking as they can also be expected from marijuana smoking.
Erythromycin inhibits CYP3A4; this may lead to increase in clozapine levels. Caffeine has the
opposite effect of smoking on clozapine metabolism. It inhibits CYP1A2 enzyme, leading to
higher clozapine levels.
Imipramine is a tricyclic antidepressant. Which one of the following
is true with respect to imipramine?
A. It acts synergistically with ECT.
B. Imipramine has no effect in atypical depression.
C. Imipramine and CBT are equally effective in severe depression.
D. Imipramine decreases non-REM sleep.
E. Imipramine is not toxic in overdose.
A. Imipramine seems to be synergistic with ECT; it is shown to be more effective than SSRIs
in preventing relapse following ECT in depressed patients (Lauritzen et al., 1996). Monoamine
oxidase inhibitors have been shown to be more effective than tricyclics in atypical depressive
disorders with biological features such as increased sleep and increased appetite. Though
imipramine may not be as effective as MAOIs, it has been shown to be better than placebo in
atypical depression. An often-quoted study that undertook head-to-head comparison of CBT and
imipramine is the National Institute of Mental Health Depression Study (Elkin et al., 1989). In this
study 16 weeks of CBT, imipramine, interpersonal therapy (IPT), and placebo were compared.
Among the less-severely depressed patients, comparable proportions achieved remission in all
three active treatment arms; but among the more-depressed patients, imipramine was superior
to CBT in terms of remission rates achieved. Imipramine alters sleep structure considerably; it
reduces REM (rapid eye movement) sleep and increases NREM (non-REM) sleep. All tricyclics
are toxic in overdose; tertiary amines such as amitriptyline and imipramine produce longer-acting
metabolites and have higher toxic potential than secondary amines.
Use of stimulants is relatively contraindicated in which of the following
patients with ADHD?
A. 9-year-old child with a family history of ADHD
B. 9-year-old child with a family history of psychosis
C. 9-year-old child with ADHD and treatment-emergent tics
D. 19-year-old with signifi cant residual symptoms of ADHD
E. All of the above
C. Treatment-emergent tics and dyskinesias are often self-limited over 7 to 10 days in
children taking stimulants. In some cases, if the severity of tics necessitates a dose reduction,
adjustments can be made in the medication dosage. In severe cases, atomoxetine could be
prescribed after stopping stimulants. Methylphenidate may also worsen already existing tics in
one-third of patients. In most of these cases tics are variable, depending on the plasma levels.
They resolve immediately on clearance of the drug. In the rest, tics are triggered by the treatment
and persist for several months. It is appropriate to continue treating an adult with residual,
disabling symptoms of ADHD. Though stimulants can exacerbate psychosis, a family history
of psychosis is not a contraindication. Family history of ADHD does not adversely infl uence
stimulant prescription.
Which one of the following is not a dose-dependent side-effect of olanzapine? A. Agranulocytosis B. Akathisia C. Galactorrhoea D. Parkinsonism E. Sedation
A. Olanzapine can induce agranulocytosis, similar to clozapine albeit at much lower
frequency. Atypicality of atypical antipsychotics does not exist as a dichotomous entity from
typical drugs. At high doses, most atypical agents lose their atypicality and produce extrapyramidal
symptoms and galactorrhoea. Large weight gains with increased appetite occur during the fi rst
6 months of treatment, irrespective of the dose used. The risk of weight gain continues over time,
probably reaching a peak after 9 months, after which it slows down but continues as long as
one takes the drug. Weight gain is associated with increased total cholesterol. Olanzapine is also
associated with dose-dependent sedation, though tolerance usually develops for this effect.
An anxious patient who has not responded to initial doses of clozapine
titration wants to know about the dose-dependent side-effects of clozapine.
Which one of the following is defi nitely not a dose-related risk?
A. Seizures
B. Hypersalivation
C. Sedation
D. Agranulocytosis
E. Anticholinergic effects
D. Agranulocytosis is not dose dependent; it is idiosyncratic. A reduction in dose of
clozapine cannot help a patient who has developed agranulocytosis. Clozapine-associated
seizures are clearly dose related. When doses of clozapine below 300 mg/day are used, the
seizure rate remains 1%; further doses between 300 and 600 mg/day increase the seizure rate
to 2.7%, and doses above 600 mg/day have a rate of 4.4%. Slower dose titration, using a lower
dose, and the addition of anticonvulsant agent such as valproic acid can reduce the frequency of
seizures. Anticholinergic effects, such as tachycardia and constipation, may be dose dependent,
and are often noted in overdoses. Similar to sialorrhoea, clozapine-related tachycardia is often
seen in early phases of treatment, and tolerance develops in due course.
Acetyl cholinesterase and butyryl cholinesterase are two enzymes
metabolizing acetylcholine. Which one of the following antidementia
drugs has signifi cant effects on both enzymes?
A. Galantamine
B. Rivastigmine
C. Ginkgo biloba
D. Memantine
E. Donepezil
B. Donepezil and galantamine are selective inhibitors of acetylcholinesterase enzyme.
Rivastigmine affects both butyryl and acetyl cholinesterase. Galantamine also affects nicotinic
receptors. However, these differences do not translate into signifi cant clinical differences in
effi cacy or tolerability. Memantine is an N-methyl-D-aspartic acid (NMDA) antagonist and hence
is thought to be a neuroprotective agent. Tacrine was one of the foremost anticholinesterases
introduced but is no longer used due to hepatotoxic effects. Tacrine inhibits both acetyl and
butyrylcholinesterases. Ginkgo biloba is widely used in Germany as a cognitive enhancer. Its
mechanism of action is unclear.
A 66-year-old lady being treated for tremors by her neurologist develops
insomnia, increased nocturnal myoclonus, and disruptive nightmares
following the prescription of a particular medication. The most likely
causative agent is
A. Bromocriptine
B. Levodopa
C. Propranolol
D. Pramipexole
E. Selegeline
B. Levodopa is used to treat symptoms of Parkinson’s disease. Levodopa is associated with
increase in libido; in some cases secondary mania is reported. It can cause disruptive nightmares
and forced reminiscences. It is a stimulating medication and can produce initial insomnia and
nocturnal myoclonus. It is also associated with belpharospasms. Bromocriptine and pramipexole
are dopamine agonists while selegeline is a monoamine oxidase B (MAO-B) inhibitor used in
treating Parkinson’s disease.
A patient treated for severe Parkinson’s disease develops troublesome
psychotic symptoms attributed to levodopa. The neurologist is reluctant to
reduce or stop levodopa given her deterioration in the past when this was
attempted. The most appropriate drug to treat her psychotic symptoms is
A. Olanzapine
B. Risperidone
C. Quetiapine
D. Paliperidone
E. Bromocriptine
C. Psychosis is common in patients with Parkinson’s disease. This may be due to the use of
dopaminergic medications such as levodopa or unrelated to the pathology of Parkinson’s disease.
Lewy body dementia can result in psychotic features and prominent parkinsonism, in which
case antipsychotic treatment may be required. In such cases and in levodopa-induced psychosis,
quetiapine has been used as the treatment of choice as it has a very low extrapyramidal sideeffects
profi le. Clozapine is also equally useful and generally regarded as the gold standard. In
Parkinson’s disease-related psychosis even low doses of atypical antipsychotics can result in good
effi cacy.
Which one of the following drugs denatures the monoamine oxidase enzyme, rendering it ineffective to metabolize even low amounts of tyramine? A. Selegiline B. Moclobemide C. Tranylcypromine D. Reboxetine E. None of the above
C. Tyramine is predominantly metabolized by MAO-A enzyme present in gut wall and
liver, apart from brain and other tissues. Drugs which irreversibly inhibit MAO-A affect tyramine
metabolism. These include tranylcypromine and phenelzine. Drugs such as selegiline are
irreversible MAO-B selective inhibitors; they do not have the same effect on tyramine as MAO-A
inhibitors. Moclobemide is a reversible, somewhat competitive MAO-A selective inhibitor. Thus,
when the relative amount of tyramine in the vicinity increases, the moclobemide molecule makes
way for tyramine from the MAO-A enzyme site. Reboxetine is not an MAO inhibitor.
Tyramine is present in certain food substances and can cause hypertensive
crises if consumed by a patient on monoamine oxidase inhibitors. Choose
the site of action of tyramine from the following options
A. Presynaptic storage vesicles
B. Reuptake channels
C. α1 adrenergic receptors
D. β adrenergic receptors
E. α2 autoreceptors
A. Tyramine is a monoamine naturally occurring in many food substances. Generally,
most ingested tyramine undergoes a complete breakdown in the periphery due to the action
of MAO-A enzyme in gut mucosa and liver. When a patient is taking MAO-A inhibitor drugs,
tyramine escapes such degradation and enters the brain through amino acid transport. It uses
the norepinephrine reuptake channels, and gains entry to presynaptic neurones. Here, tyramine
stimulates release of all bound monoamines, especially norepinephrine, leading to a hypertensive
reaction. This is called the cheese reaction as tyramine is abundant in mature cheeses.
Which one of the following antidepressants can block the neuronal uptake
of tyramine and potentially reduce the risk of tyramine–MAOI interaction?
A. SSRIs
B. Moclobemide
C. L-tryptophan
D. Tricyclic antidepressants
E. Levothyroxine
D. As tyramine gains entry to presynaptic neurones via the norepinephrine transporter,
blocking this reuptake transporter can prevent tyramine action, at least theoretically. Tricyclic
antidepressants act via blockade of this transporter. Hence the incidence of cheese reaction
due to tyramine is less in those who are on tricyclic antidepressants before the commencement
of MAO-A inhibitors. However, such combination is not advisable as the potential to cause
serotonin syndrome is very high. SSRIs and L-tryptophan can increase the risk of serotonin
syndrome many fold when coprescribed with MAO-A inhibitors.
Which one of the following mood stabilizers can potentiate GABA transmission by increasing GABA release, reducing GABA metabolism, and increasing GABA receptor density? A. Lithium B. Carbamazepine C. Lamotrigine D. Valproate E. Vigabatrin
D. The mechanism of action of lithium remains speculative. Valproate increases
gamma-aminobutyric acid (GABA) release and reduces GABA metabolism. It increases
neuronal responsiveness to GABA and also increases GABAB receptor density. Carbamazepine
prolongs sodium channel inactivation, leading to a secondary increase in calcium channel
inactivation. This is linked to reduced glutamatergic neurotransmission. Carbamazepine also has
adenosine antagonistic properties. Lamotrigine acts via membrane stabilization while vigabatrin
is a GABA transaminase inhibitor.
Which one of the following benzodiazepines has partial agonistic action
at some receptors, leading to fewer withdrawal symptoms?
A. Diazepam
B. Triazolam
C. Lorazepam
D. Clonazepam
E. Chlordiazepoxide
D. Clonazepam has partial agonistic action at certain benzodiazepine receptors, leading to
fewer withdrawal symptoms. Clonazepam is a high-potency drug (0.25 mg clonazepam is equated
to 5 mg diazepam); it is shown to be effective in panic disorder and social phobia (but is not
recommended for long-term therapy). In bipolar type 1 disorder, clonazepam may result in a
prolonged remission phase and reduced depressive relapses when used as an adjuvant to lithium
or lamotrigine, respectively.
A patient presents with recurrent episodes of feeling detached and unreal.
A pharmacological agent that can worsen the above symptoms is
A. Clozapine
B. Caffeine
C. Lamotrigine
D. Clonazepam
E. Valproate
D. Caffeine can worsen depersonalization. Experimental induction of depersonalization
and derealization has been tried using caffeine. SSRIs are used in treating established cases of
depersonalization disorder. However, paradoxically, some times initiation or discontinuation
of SSRIs can produce depersonalization experiences. Lamotrigine and clonazepam are used in
treating symptoms of depersonalization
A 64-year-old man with schizophrenia is being treated for cirrhotic liver.
Unfortunately, he develops a relapse of psychotic symptoms and needs a
change in his antipsychotic prescription. The safest option with regard to
his hepatic status is
A. Amisulpride
B. Olanzapine
C. Clozapine
D. Risperidone
E. Chlorpromazine
A. Most psychotropic medications undergo hepatic metabolism. Notable exceptions are
amisulpride, paliperidone, lithium, acamprosate, and gabapentin. These medications are largely
renally excreted without much hepatic degradation. Hence in patients with hepatic failure, the
antipsychotic of choice from the given list is amisulpride. Note that certain benzodiazepines, such
as oxazepam, undergo glucuronide conjugation (phase 2 metabolism) reaction but no oxidation
(phase 1 metabolism) in the liver. Oxazepam can be used in treating alcohol withdrawal in a
patient with signifi cantly low hepatic reserve
The mechanism of action of St John’s wort is A. Serotonin antagonism B. Norepinephrine agonism C. MAO inhibition D. Multiple reuptake inhibition E. Membrane stabilization
D. St John’s wort has been shown to be an effective antidepressant in mild to moderate
cases. It increases photosensitivity of skin but other adverse effects are limited. It is thought
to act by inhibiting reuptake of multiple monoamines, including serotonin, norepinephrine,
and dopamine. It also inhibits GABA and glutamate reuptake but the effects of these are
unknown. It is a potent inducer of hepatic CYP450 enzymes, leading to a fall in plasma levels of
carbamazepine, oral contraceptives, and warfarin if coprescribed.
Which one of the following acts via opiate receptors and could be
a potential agent to prevent relapse of alcohol use?
A. Naloxone
B. Acamprosate
C. Disulfi ram
D. Naltrexone
E. Bupropion
D. Opioid receptor antagonists are tested as adjuncts for the treatment of alcohol
dependence. They can reduce alcohol craving and alcohol consumption. If naltrexone is used in
maintaining abstinence, the number of relapses is reduced and the severity of relapses, if they
occur, is considerably less. Naloxone is a parenterally administered opioid antagonist, used to
reverse the effects of exogenously administered opioids. Acamprosate, bupropion, and disulfi ram
do not act via an opioid mechanism.
A 44-year-old man with bipolar disorder treated with lithium develops
chronic back pain. His GP wants to prescribe a NSAID analgesic and
asks you to choose a NSAID with the least potential to interact with
lithium. You will choose
A. Ibuprofen
B. Diclofenac
C. Aspirin
D. Ketorolac
E. Indomethacin
C. Aspirin (and sulindac, to some extent) has comparatively lesser potential to interact with
lithium compared to most other NSAIDs. NSAIDs can reduce renal lithium clearance via their
effects on fl uid balance. This can lead to renal toxicity if the coadministration is suffi ciently long.
Indometacin is suspected to be worse compared to other NSAIDs in this regard, though careful
monitoring of lithium levels is warranted even with use of COX-2 inhibitors such as rofecoxib.
Lithium excretion is decreased by medications such as thiazides, angiotensin-converting enzyme
inhibitors, and, to a lesser extent, frusemide (furosemide). Lithium clearance is increased by other
medications with diuretic effects such as acetazolamide, mannitol, and caffeine
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
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.
Atomoxetine is useful in children with ADHD. The mechanism of action is by A. Norepinephrine reuptake inhibition B. Serotonin potentiation C. GABA potentiation D. Membrane stabilization E. Acetylcholine synthesis
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.
A 30-year-old known heroin user is brought to A&E after an overdose
of heroin, with a GCS of 3, a respiratory rate of four breaths per minute,
and pinpoint pupils. On administration of naloxone he develops running
nose, diarrhoea and profuse sweating, and multiple joint aches. The most
likely explanation is
A. Residual symptoms of toxicity
B. Allergic reaction to naloxone
C. Effect of coadministered cocaine
D. Precipitated opioid withdrawal
E. None of the above
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.
A 30-year-old known heroin user develops opioid intoxication which
reverses on administration of naloxone. He takes a self-discharge
against medical advice. He was brought back within a few hours of this
self-discharge with signs suggestive of opioid intoxication, but without any
history of additional opioid intake. The most likely explanation is
A. Inappropriate dose of naloxone
B. Inappropriate route of administration of naloxone
C. Short half-life of naloxone
D. Reduced opioid tolerance on administering naloxone
E. None of the above
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
Naloxone can be life-saving in cases of opioid toxicity. The commonest
route of administration of naloxone for this purpose is
A. Subcutaneous
B. Intramuscular
C. Transtracheal
D. Intrathecal
E. Intravenous
E. Naloxone is commonly administered via intravenous injections in the UK. It can also be
administered intramuscularly or via subcutaneous injections.
Lofexidine is useful in managing symptoms of opiate withdrawal.
The mechanism of action of lofexidine is by
A. Agonism of α2 autoreceptors
B. Direct opioid antagonism
C. Partial opioid agonism
D. Direct dopamine blockade
E. Spinal opiate receptor blockade
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.
Fluoxetine increases the clinical effi cacy of clozapine through which of
the following pharmacokinetic mechanism?
A. Increased plasma protein binding
B. Increased intestinal absorption
C. Inhibition of hepatic metabolism
D. Reduced renal clearance
E. Improved blood–brain barrier penetration
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.
Tyramine can produce the ‘cheese reaction’ in patients taking MAO
inhibitors. Which one of the following is true with respect to the
moclobemide–tyramine interaction?
A. Moclobemide does not cause cheese reaction with tyramine
B. Moclobemide causes cheese reaction at the same frequency as phenelzine
C. Moclobemide does not act on the same enzyme that metabolizes tyramine
D. Large consumption of tyramine can produce the cheese reaction with moclobemide
E. All of the above
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.
Which one of the following is a partial opioid agonist with a low intrinsic activity? A. Naloxone B. Naltrexone C. Methadone D. Buprenorphine E. None of the above
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
A 12-year-old child treated for ADHD with stimulants develops tics, which
persist even on withdrawal of stimulants. Which of the following offers a
potential to treat both tics and ADHD symptoms simultaneously?
A. Clonidine
B. Lofexidine
C. Bromocriptine
D. Atomoxetine
E. Risperidone
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.
A 40-year-old male develops impotence secondary to antidepressant
therapy. After trying various options, you are considering sildenafi l.
The mechanism of action of sildenafi l is by
A. Phosphodiesterase inhibition
B. Acetylcholine stimulation
C. Increasing nitric oxide production
D. Blockade of sympathetic discharge
E. None of the above
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.
Buspirone is an anxiolytic with no immediate effect on acute
administration, unlike diazepam. This is due to
A. Short half-life of buspirone
B. Longer time required to achieve steady state
C. Buspirone follows fi rst-order kinetics
D. Buspirone is a GABA partial agonist
E. Buspirone acts via the serotonin system
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
Most diuretics interact with lithium to produce signifi cant changes in
plasma lithium levels. Which one of the following diuretics is useful in
treating polyuria, a common side-effect of lithium?
A. Amiloride
B. Triamterene
C. Chlorthiazide
D. Frusemide
E. None of the above
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
A 30-year-old woman was diagnosed with paranoid schizophrenia.
She has been hospitalized and is prescribed antipsychotics. Which one
of the following treatment-emergent conditions is known to be associated
with the risk of suicide?
A. Akathisia
B. Anticholinergic symptoms
C. Dystonia of the laryngeal muscles
D. Neuroleptic malignant syndrome
E. Tardive dyskinesia
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.
For typical neuroleptics, the antipsychotic effect on positive psychotic symptoms is strongly correlated with A. D2 occupancy B. Half-life C. D4 occupancy D. 5-HT antagonism E. None of the above
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.
Memantine is an antidementia drug licensed for moderately severe
Alzheimer’s dementia. The mechanism by which memantine acts is
A. Inhibition of NMDA receptor
B. Inhibition of calcium ion channels
C. Stimulation of GABA output
D. Stimulation of glutamate release
E. Mimicking the effects of acetylcholine
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
Phenytoin and lithium are said to have narrow therapeutic indices.
The term therapeutic index refers to
A. Ratio between median toxic and median effective dose
B. Rate of production of toxic effects at a constant dose
C. Duration of persistence of toxic effects after the onset
D. Proportion of patients who experience a specifi c side-effect
E. None of the above
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.
The lower incidence of extrapyramidal side-effects due to clozapine
compared to haloperidol is possibly related to
A. Duration of D2 receptor occupancy
B. Glutamate blockade
C. GABA release at basal ganglia
D. Intrinsic partial agonistic activity at the D2 receptor
E. All of the above
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
The volume of distribution of a drug depends on all of the following except A. Protein binding B. Lipid solubility C. Tissue binding D. Half-life E. None of the above
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.
Drug A is an anticonvulsant, metabolized to inactive metabolites by the
CYP450 system. Drug B, which induces CYP450, is expected to produce
which one of the following if coadministered with drug A?
A. Reduced concentration of inactive metabolites
B. Reduced effi cacy of drug A
C. Increased metabolism of drug A resulting in increased effi cacy
D. Increased concentration of drug A in plasma
E. None of the above
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.
Glucuronyl transferase acts on an antidepressant drug A and converts
it into a more water-soluble component with less potency but a higher
concentration in bile. This process is called
A. Conjugation
B. Oxidation
C. Saponifi cation
D. Depolarization
E. Enzyme induction
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
Metabolism of psychotropic drugs include phase 1 and phase 2 reactions.
All of the following are phase 2 reactions except
A. Glucuronidation
B. Methylation
C. Oxidation
D. N acetylation
E. Sulfation
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.
Breastfeeding is contraindicated when certain psychotropics are
administered. The characteristic features of such psychotropics
that are secreted in breast milk include all except
A. High lipid solubility
B. High degree of ionization
C. Poor protein binding
D. Low acidic property
E. All of the above
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.
A 25-year-old postgraduate student is suffering from initial insomnia
during his fi nal year of study. He is asking for a hypnotic that will cause
least disturbance to his sleep architecture. The best choice is
A. Diazepam
B. Chloral hydrate
C. Zolpidem
D. Promethiazine
E. Temazepam
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
Selegiline is used as an antiparkinsonian agent. Its mechanism of action is A. Dopamine receptor agonism B. Increased dopamine synthesis C. COMT inhibition D. MAO-A inhibition E. MAO-B inhibition
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
Which of the following antidepressants is most selectively serotonergic? A. Fluoxetine B. Paroxetine C. Citalopram D. Clomipramine E. Venlafaxine
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.
Which one of the following antipsychotics is strongly implicated in deaths due to QTc prolongation? A. Quetiapine B. Olanzapine C. Pimozide D. Risperidone E. Aripiprazole
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.
Which one of the following anticonvulsants follows zero-order
kinetics on dose increase within therapeutic range?
A. Gabapentin
B. Phenytoin
C. Ethosuximide
D. Valproate
E. Lamotrigine
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.
A patient suffering from gastritis is prescribed several psychotropic
medications. She wants to know which part of her body will absorb
most of these orally administered drugs. The correct answer is
A. Oral mucosa
B. Large intestine
C. Oesophagus
D. Stomach
E. Small intestine
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.
A patient started on antidepressant treatment for a fi rst episode of
depression stopped the medication abruptly after an initial response.
Which one of the following medications, if prescribed, has the highest
chance of causing the most troublesome discontinuation reaction?
A. Mirtazapine
B. Mianserin
C. Fluoxetine
D. Paroxetine
E. Moclobemide
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.
A patient started on paroxetine after the fi rst episode of depression
stopped the medication abruptly following an initial response. Apart
from short half-life, higher incidence of discontinuation reaction following
paroxetine is attributed to
A. Cholinergic rebound
B. Poor plasma protein binding
C. High blood–brain barrier penetration
D. Higher addictive potential
E. None of the above
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.
The tricyclic antidepressant which is most lethal on overdose is A. Dosulepin B. Imipramine C. Lofepramine D. Clomipramine E. Nortriptyline
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.
A patient develops neuroleptic malignant syndrome secondary to
antipsychotic prescription. Which one of the following properties
of antipsychotics predicts a lower risk of producing neuroleptic
malignant syndrome?
A. High anticholinergic property
B. High sedative effect
C. Strong dopamine blockade
D. α adrenergic blockade
E. High potency
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
Which one of the following agents produces dysphoria, myoclonus,
fl u-like symptoms, ataxia, hyperacusis, and anxiety on withdrawal?
A. Opioids
B. Benzodiazepines
C. Cannabis
D. Procyclidine
E. Amphetamines
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.
