MRCPsych Paper A Question Bank

Bioavailability (F) is defined as the fraction of an administered dose of unchanged drug that reaches the systemic circulation. For intravenous administration, bioavailability is by definition 100% (F=1). For oral medications, bioavailability is reduced by incomplete absorption and first-pass metabolism in the gut wall and liver. This is particularly relevant in psychopharmacology where many psychiatric medications undergo significant first-pass metabolism.

First-pass metabolism occurs when a drug absorbed from the gastrointestinal tract is metabolised by the liver before reaching the systemic circulation. For example, chlorpromazine has an oral bioavailability of only 10-25% due to extensive first-pass metabolism, explaining why intramuscular doses are substantially lower than oral doses. The BNF reflects this in its dosing recommendations.

Factors affecting oral bioavailability include the drug's lipophilicity, molecular size, degree of ionisation at gut pH, presence of food, gastrointestinal motility, and hepatic enzyme activity. CYP450 enzyme polymorphisms can significantly alter first-pass metabolism and thus bioavailability. The Maudsley Prescribing Guidelines emphasise that switching between oral and parenteral formulations requires dose adjustment to account for bioavailability differences.

Remember: Bioavailability is the fraction of unchanged drug reaching systemic circulation - IV administration gives 100% bioavailability by definition.

CYP1A2 is significantly induced by polycyclic aromatic hydrocarbons in tobacco smoke (not nicotine itself), and is the primary enzyme responsible for clozapine metabolism. This is one of the most clinically important drug interactions in psychiatry. Smoking induces CYP1A2, increasing clozapine clearance and reducing plasma levels. Conversely, smoking cessation leads to reduced CYP1A2 activity and potentially dangerous rises in clozapine levels.

The Maudsley Prescribing Guidelines recommend that clozapine doses should be reduced by approximately 30-50% when a patient stops smoking, with close monitoring of plasma levels. This interaction is mediated by the hydrocarbons in smoke rather than nicotine, so nicotine replacement therapy does not affect CYP1A2 activity. This distinction is important when patients are admitted to smoke-free wards.

Other CYP1A2 substrates include olanzapine, theophylline, and caffeine. CYP1A2 is also inhibited by fluvoxamine, which can dramatically increase clozapine levels and cause toxicity. The combination of fluvoxamine and clozapine requires very careful dose adjustment. NICE guidelines for psychosis recommend regular plasma level monitoring when factors affecting clozapine metabolism change.

Remember: CYP1A2 is induced by smoking (not nicotine) - smoking cessation can cause dangerous clozapine level rises requiring 30-50% dose reduction.

CYP2D6 is the enzyme responsible for converting codeine (a prodrug) to its active metabolite morphine via O-demethylation. Fluoxetine and its active metabolite norfluoxetine are potent CYP2D6 inhibitors. When fluoxetine inhibits CYP2D6, codeine cannot be converted to morphine, rendering it ineffective as an analgesic. This is a clinically significant pharmacokinetic drug interaction frequently encountered in psychiatric practice.

CYP2D6 is notable for its genetic polymorphism. Approximately 7-10% of Caucasians are poor metabolisers (PMs) lacking functional CYP2D6, while 1-2% are ultra-rapid metabolisers (UMs) with multiple gene copies. PMs will not benefit from codeine regardless of CYP2D6 inhibitors, while UMs may produce dangerously high morphine levels. The MHRA has issued warnings about codeine in ultra-rapid metabolisers, particularly in children.

CYP2D6 also metabolises many psychiatric medications including tricyclic antidepressants, venlafaxine, risperidone, haloperidol, and aripiprazole. Fluoxetine's inhibition of CYP2D6 persists for weeks after discontinuation due to norfluoxetine's long half-life (4-16 days). The Maudsley Prescribing Guidelines recommend awareness of CYP2D6 interactions when co-prescribing.

Remember: CYP2D6 converts codeine to morphine - fluoxetine potently inhibits CYP2D6, blocking this conversion and rendering codeine ineffective.