Which one of the following has partial agonistic activity as a major therapeutic mechanism?
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 specific 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 auto-receptors. Aripiprazole is also a partial agonist at dopamine receptors.
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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:
C. Amoxicillin is largely cleared through the kidneys and does not interfere with clozapine metabolism. Clozapine undergoes hepatic metabolism via CYP1A2, CYP3A4, and CYP2D6. Ciprofloxacin and other fluoroquinolone 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 specific 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. 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.
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Use of stimulants is relatively contraindicated in which of the following patients with ADHD?
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 influence stimulant prescription.
Which one of the following is not a dose-dependent side-effect of olanzapine?
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 first 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.
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