Antipsychotic agents hepatic effects

Chlorpromazine is the best known representative of the aliphatic phenothiazines. Although it is considered to be a low potency agent it is still frequently used. It is one of the most sedative antipsychotic agents and is therefore very effective in the treatment of agitated and violent patients. Extrapyramidal effects are seen with a rather low incidence. However it displays marked anticholinergic activity. There have been reports of hepatotoxicity, also in patients with previously normal hepatic function, due to chlorpromazine. Alimemazine and triflupro-mazine are other representatives from this group. 

Tricyclic antidepressants are notorious for their risk to be involved in drug-drug interactions. Additive anticholinergic effects can be expected in combination with antihistamines, antipsychotics and anticholinergic-type anti-Parkinson agents. Hepatic enzyme-inducing agents increase their hepatic metabolism while enzyme inhibitors may potentiate the effects of tricyclics. Concomitant use with monoamine oxidase inhibitors will produce hypertension, hyperpyrexia and convulsions. 

Contraindications for antipsychotic therapy are few they may include Parkinson s disease, hepatic failure, hypotension, bone marrow depression, or use of CNS depressants. Overdoses of antipsychotics are rarely fatal, except for thioridazine, which is associated with major ventricular arrhythmias, cardiac conduction block, and sudden death. For other agents gastric lavage should be attempted even if several hours have elapsed since the drug was taken, because gastrointestinal motility is decreased and the tablets may still be in the stomach. Moreover, activated charcoal effectively binds most of these drugs and can be followed by a saline cathartic. The hypotension often responds to fluid replacement or pressor agents such as norepinephrine. 

This agent has a broad spectrum of activity encompassing several neurotransmitter systems. In this light, clozapine is similar to such phenothiazines as CPZ and thioridazine (519). It is also subject to a hepatic first-pass effect, which produces metabolites with low or unknown pharmacological activity. It has an elimination half-life ranging from 6 to 33 hours and a volume of distribution (V 5 l /kg) lower than most other antipsychotics. This last quality indicates less drug is sequestered in tissue sites. Plasma levels of the parent compound at or above 350 ng/mL may be associated with a better clinical response ( 66, 520). Plasma levels are lower in men than women, especially male smokers (329). 

A mutual increase in serum levels of both thioridazine and paroxetine is evident when these agents are combined. Paroxetine has also been shown to increase haloperidol and perphenazine serum levels, with associated extrapyramidal side-effects. The mechanism is presumably via inhibition of hepatic enzymes. With respect to the second-generation antipsychotic drugs (SCAs), paroxetine at a dose of 20 mg/daily produces a 3-9-fold elevation in plasma risperidone. If paroxetine is administered with clozapine, mean plasma concentrations of clozapine and norclozapine may increase significantly (by about 30%). 

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