Pharmacology: Pharmacodynamics: Mechanism of Actions: Chlorpromazine is readily absorbed from the gastro-intestinal tract but is subject to considerable first-pass metabolism in the gut wall. It is also extensively metabolized in the liver and is excreted in the urine and faeces in the form of numerous active and inactive metabolites; there is evidence of enterohepatic recycling. Owing to the first-pass effect, plasma concentrations following oral administration are much lower than those following intramuscular administration. Moreover, there is very wide intersubject variation in plasma concentrations of Chlorpromazine and its metabolites, and their therapeutic effect. Patch of metabolism of Chlorpromazine include hydroxylation and conjugation with glucuronic acid, N-oxidation, oxidation of a sulfur atom, and dealkylation. Although the plasma half-life of Chlorpromazine has been reported to be only a few hours, it has a very prolonged terminal elimination phase of up to about 3 weeks. Its duration of therapeutic effect can range from a few days to several weeks or possibly longer.
Chlorpromazine is very extensively bound to plasma proteins. It is widely distributed in the body and crosses the bloodbrain barrier to achieve higher concentrations in the brain than in the plasma. Chlorpromazine and its metabolites also cross the placental barrier and excreted in milk (see Precautions).
A review of the literature on the absorption and fate of Chlorpromazine; blood and urinary studies by and large favour a fairly short sojourn of the bulk of Chlorpromazine in the body. For the blood studies, this is in the range of 2 to 3 days, and for urinary studies up to about 18 days. There is no doubt, however, that Chlorpromazine brings about changes that can persist much longer than this, after drug discontinuation. The exact relationship of persisting therapeutic effects to administered Chlorpromazine is uncertain. There is the possibility that minute amounts of Chlorpromazine and/or metabolites persist at active sites in slowly reversible or relatively irreversible ways. It also seems that some Chlorpromazine is stored in adipose tissue and slowly mobilized after stopping Chlorpromazine administration.