Fluoxetine increases the clinical efficacy of clozapine through which of the following pharmacokinetic mechanism?
C. SSRIs, especially fluoxetine, 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 fluoxetine and paroxetine.
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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?
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 tyramine containing 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?
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 is a central α2 agonist. As the α2 receptor is an auto-receptor, 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 significant hypotension.
A 40-year-old male develops impotence secondary to antidepressant therapy. After trying various options, you are considering sildenafil.
The mechanism of action of sildenafil is by:
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 flow 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. Sildenafil 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.
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