Pharmacology

The typical antipsychotics share a similarity in pharmacotherapeutic and adverse-effect profiles. They are all dopamine receptor antagonists; this blockade in the limbic system is thought to be primarily responsible for the antipsychotic activity of these agents. Dopaminergic antagonism in the basal ganglia also occurs, causing disinhibition of cholinergic neurons; this in turn may lead to various involuntary movement disorders, termed extrapyramidal side effects, as discussed below.1 In addition to blocking dopaminergic receptors, these typical antipsychotics also block, to varying degrees, a-adrenergic (principally a .), muscarinic, and histaminic receptors. a.-Adrenergic antagonism leads to orthostatic hypotension and reflex tachycardia due to peripheral vasodilatation. Anticholinergic activity at muscarinic sites leads to hyperthermia, tachycardia, pupillary dilatation, dry mouth, urinary retention, and constipation. Histamine blockade results in central nervous system sedation..,2 Generally speaking, drugs of higher potency (i.e., low milligram-per-day dosage) tend to cause significant dopaminergic antagonism and thus are more likely to cause extrapyramidal effects; examples include haloperidol, fluphenazine, and thiothixene. Drugs of lower potency (i.e., high milligram-per-day dosage) are less likely to cause extrapyramidal effects, but are more likely to cause sedation and orthostatic hypotension, due to strong antihistaminic and anticholinergic/muscarinic effects; examples include chlorpromazine and thioridazine. 2,3 It should be emphasized, however, that all typical antipsychotics could cause some degree of extrapyramidal symptoms, sedation, orthostatic hypotension, and various anticholinergic effects.

The newer, atypical antipsychotic agents, in addition to featuring varying degrees of antagonistic activity at dopaminergic, a-adrenergic, histaminic, and cholinergic/muscarinic receptor sites, block serotonergic sites with varying affinity. 14 These drugs exhibit greater clinical efficacy in that they also improve negative symptomatology and cognitive dysfunction, and they are less likely to cause extrapyramidal effects and thus are more attractive than the typical antipsychotics. There is evidence that these newer agents also are effective in neuroleptic treatment-resistant patients who are so labeled due to treatment failures with the typical antipsychotic agents.1

Pharmacokinetically, all antipsychotic agents are similar, given well-controlled, therapeutic situations. Bioavailability is erratic and peak plasma levels occur 2 to 6 h after oral administration, although clinical effects are seen within the first 30 to 60 min. 34 Those agents available for parenteral administration achieve higher plasma levels, resulting in a more rapid onset of action, than do the oral preparations; 2 none of the new atypical antipsychotics are available in injectable form. Protein binding, lipophilicity, and volume of distribution are uniformly high for all antipsychotics, rendering dialysis an ineffective means of treating toxicity. Elimination is via hepatic metabolism—both hepatic microsomal enzyme oxidation and enterohepatic circulation—followed by renal excretion, to varying degrees. 24 The newer atypical antipsychotics all carry warnings regarding use in patients with concomitant hepatic disease, and only quetiapine does not carry such precautions in renal disease, due to trivial excretion of unchanged drug by the kidney. Plasma-level monitoring can establish compliance, but is not generally recommended with the antipsychotics, in either therapeutic or toxicologic assessment situations.24

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