22 - C. Other antidepressants

C. Other antidepressants

© SPMM Course C. Other antidepressants The MAOIs are all rapidly absorbed. For the irreversible MAOIs the half-life does not correlate with duration of action as the effects on the MAO enzyme are irreversible and new enzyme needs to be synthesized for restoration of normal activity - a minimum of 5 to 7 days. Hence, it is recommended that for drugs that can interact fatally with MAOIs (irreversible) - the safest recommendation is to wait 2 weeks before starting. The combination of MAOIs and pethidine (meperidine) can produce either a depressive (pronounced sedation due to opioid toxicity) or excitatory reaction (related to serotonin excess: agitation, hyperpyrexia and cardiovascular collapse, coma, and death). Pethidine, in particular, has a serotonin releasing property and some reuptake inhibition property. Pethidine must never be used in the presence of MAOIs because of the risk of this fatal excitatory interaction. Morphine has fewer propensities to cause this interaction. Amphetamine also induces serotonin release, while methylphenidate does not. The latter is relatively safe in terms of serotonin toxicity with MAOIs. Venlafaxine has low protein binding; it has t1/2 around 3.5 hours. Venlafaxine is well absorbed per orally. An extended-release formulation of venlafaxine is available, facilitating once daily administration. The metabolite O-desmethyl venlafaxine (ODV) has a half-life of 9 hours. It is metabolized by hepatic cytochrome P450 (CYP) 2D6. Venlafaxine has no enzyme-inducing properties. Duloxetine has t1/2 of about 12 hours – it is extensively metabolized by hepatic enzymes CYP450 and highly protein bound. Trazodone and nefazodone undergo extensive hepatic metabolism, and one major metabolite is m-chlorophenylpiperazine which stimulates 5-HT receptors. Trazodone is readily absorbed and has a half-life of 5 to 9 hours. Trazodone is a weak inhibitor of serotonin reuptake and antagonist of serotonin 5-HT2A and 5-HT2C receptors. The active metabolite of trazodone is mchlorophenylpiperazine (mCPP) is 5-HT2C agonist with t1/2 around 14 hrs. mCPP can cause migraine, anxiety, and weight loss. Trazodone has an acute sedative effect, which is useful in the treatment of agitation, anxiety, and insomnia. Antianxiety effects of trazodone appear earlier than antidepressant effects. Trazodone can increase levels of digoxin and phenytoin and warfarin. CYP 3A4 inhibitors can increase mCPP by reducing its breakdown leading to an increase in side effects. Buspirone has a short half-life of 2-11 hours. Hence it is given three times daily. Buspirone has an active metabolite called 1-pyrimidinylpiperazine (1-PP) – which has some degree of activity