Antipsychotics, General

Antipsychotics, General is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles

Epidemiology

According to the AAPCC’s 2007 report, antipsychotic/sedative hypnotic agents were the fourth leading cause of fatal overdoses in the United States.1

Pathophysiology

Antipsychotic agents exert their therapeutic effect largely by binding to dopamine receptors in the CNS, which tends to mitigate the positive symptoms of schizophrenia. Dopamine receptor blockade is also associated with the development of movement disorders, and the newer neuroleptic agents attempt to address this by modulating serotonergic tone. Most antipsychotics affect multiple receptors in the nervous, endocrine, and cardiovascular systems, which accounts for a wide range of toxic symptoms. In general, the older “typical” agents in the phenothiazine class tend to have more cardiac toxicity, with varying degrees of sodium channel blockade (wide QRS) and potassium channel blockade (QTc prolongation). Furthermore, these agents tend to have more significant extrapyramidal effects. The newer or “atypical” antipsychotics tend to exhibit less cardiac toxicity, but they often have pronounced α1-antagonism, causing hypotension. The atypicals are also associated with the idiosyncratic development of other medical problems. For example, olanzapine has been associated with the development of fatal diabetic ketoacidosis (DKA),2 and clozapine was briefly withdrawn from the market because a small percentage of patients developed agranulocytosis.3

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General Principles

Epidemiology

According to the AAPCC’s 2007 report, antipsychotic/sedative hypnotic agents were the fourth leading cause of fatal overdoses in the United States.1

Pathophysiology

Antipsychotic agents exert their therapeutic effect largely by binding to dopamine receptors in the CNS, which tends to mitigate the positive symptoms of schizophrenia. Dopamine receptor blockade is also associated with the development of movement disorders, and the newer neuroleptic agents attempt to address this by modulating serotonergic tone. Most antipsychotics affect multiple receptors in the nervous, endocrine, and cardiovascular systems, which accounts for a wide range of toxic symptoms. In general, the older “typical” agents in the phenothiazine class tend to have more cardiac toxicity, with varying degrees of sodium channel blockade (wide QRS) and potassium channel blockade (QTc prolongation). Furthermore, these agents tend to have more significant extrapyramidal effects. The newer or “atypical” antipsychotics tend to exhibit less cardiac toxicity, but they often have pronounced α1-antagonism, causing hypotension. The atypicals are also associated with the idiosyncratic development of other medical problems. For example, olanzapine has been associated with the development of fatal diabetic ketoacidosis (DKA),2 and clozapine was briefly withdrawn from the market because a small percentage of patients developed agranulocytosis.3

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