Cytochrome P450 1A2 (CYP1A2) is primarily responsible for clozapine metabolism. Agents that induce cytochrome CYP1A2, such as tobacco cigarette smoke, will increase the metabolism of clozapine. Tobacco smokers may require twice the dose of clozapine compared to non-smokers to achieve similar blood levels. Agents that inhibit CYP1A2 (e.g. theophylline, ciprofloxacin, fluvoxamine) and smoking cessation can decrease the metabolism of clozapine and may produce clinical toxicity. Clozapine plasma concentrations can rise 1.5 times in the 2–4 weeks following smoking cessation and in some instances by 50–70% within 2–4 days. If baseline plasma concentrations are higher – particularly over 1 mg/L – the plasma concentration may rise dramatically due to non-linear kinetics. If patients smoking more than 7–12 cigarettes/day while taking clozapine decide to quit, the dose may need to be reduced by 50%.
Agranulocytosis occurs in about 1% of patients who take clozapine during the first few months of treatment and the risk of developing it is highest about 3 months into treatment. Patients who have agranulocytosis with clozapine should not receive it again. Patients taking clozapine should be enrolled in a monitoring programme. This requires weekly blood tests for 18 weeks and then monthly blood tests while on clozapine. Clozapine is indicated for schizophrenia in patients who are non-responsive to other neuroleptic agents.
Tyramine is physiologically metabolised by monoamine oxidase A (MAO-A) (Flockhart, 2012). In humans, if monoamine metabolism is compromised by the use of monoamine oxidase inhibitors (MAOIs) and foods high in tyramine are ingested, a hypertensive crisis can result, as tyramine can cause the release of stored monoamines, such as dopamine, norepinephrine (noradrenaline) and epinephrine (adrenaline). The physiological effects of tyramine include peripheral vasoconstriction, increased cardiac output, increased respiration, elevated blood glucose and release of norepinephrine. MAO-A deaminates serotonin in the central nervous system and dietary monoamines in the gastrointestinal system. MAO-B is found predominantly in liver and muscle and deaminates dopamine and phenylethylamine. The first generation of MAOI drugs are non-specific, inhibit both isoforms of MAO and this inhibition is considered irreversible. The second generation drugs, termed RIMA for reversible inhibitor monoamine (such as selegiline), are selective in inhibition, reversible and carry little risk of a hypertensive effect in low dosage, as in the treatment of Parkinson disease.
All currently available effective anti-psychotics block dopamine (D2) receptors. Atypical anti-psychotics, such as clozapine, olanzapine, risperidone and quetiapine, also antagonise serotonin (5-HT2) receptors, which influences the drug activity. There is also some evidence to suggest that differential blockade of other dopamine receptors (such as D1) may influence therapeutic and adverse effects.
Tricyclic anti-depressants, in addition to inhibiting reuptake of norepinephrine (noradrenaline) and serotonin, also block alpha1-adrenergic, serotonergic, histaminergic and cholinergic receptors.
Clinical
Excess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome, but is better described as a spectrum of toxicity – serotonin toxicity (Isbister et al., 2007). It can occur from an overdose, drug interaction or adverse drug effect involving serotonergic agents.
Serotonin toxicity is characterised by neuromuscular excitation (hyper-reflexia, clonus, myoclonus, rigidity), autonomic stimulation (hyperthermia, tachycardia, sweating, tremor, flushing) and changed mental state (anxiety, agitation, confusion). Serotonin toxicity can be mild (serotonergic features that may or may not concern the patient); moderate (toxicity that causes significant distress and deserves treatment, but is not life-threatening); or severe (a medical emergency characterised by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure).
There are several drug mechanisms that cause excess serotonin, but severe serotonin toxicity only occurs with combinations of drugs acting at different sites, most commonly including a monoamine oxidase inhibitor and a serotonin reuptake inhibitor. Less severe toxicity occurs with other combinations, overdoses and even single-drug therapy in susceptible individuals. Serotonin syndrome is a clinical diagnosis; serum serotonin concentrations do not correlate with clinical findings and severity, and no laboratory test confirms the diagnosis. Treatment should focus on cessation of the serotonergic medication and supportive care. Some anti-serotonergic agents have been used in clinical practice, but the preferred agent, dose and indications are not well defined.
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