Prochlorperazine

Prochlorperazine belongs to the phenothiazine group which have a piperazine group at position 10 of the phenothiazine molecule. This entails a greater risk of inducing extrapyramidal side effects but less tendency to produce sedation or autonomic side effects such as hypotension, unless unusually large doses are employed.

Prochlorperazine has a wide range of activity arising from its depressant actions on the CNS and its alpha-adrenergic blocking and weaker anti-muscarinic properties. It inhibits dopamine and prolactin-release-inhibitory factor, thus stimulating the release of prolactin. The turnover of dopamine in the brain is increased. There is evidence that the antagonism of central dopaminergic function is related to the therapeutic effect in psychotic conditions.

Prochlorperazine has sedative properties but tolerance to the sedation usually develops rapidly. Prochlorperazine has anti-emetic, anti-pruritic, serotonin-blocking, and weak antihistamine properties and slight ganglion-blocking activity. It inhibits the heat regulating centre, can relax smooth muscle and has membrane stabilising and hence local anaesthetic properties. Its actions on the autonomic system produce vasodilatation, hypotension and tachycardia. Salivary and gastric secretions are reduced.

The pharmacokinetics of prochlorperazine in man have been little studied because of its difficulty to assay. The low and variable bioavailability is largely due to extensive metabolism of the drug in the gut wall and liver, to sulphoxide.

Prochlorperazine is well absorbed from the GI tract but is subject to considerable first pass metabolism from the gut wall. It is also extensively metabolised in the liver and is excreted in the urine and bile.

Plasma concentrations following oral administration are much lower than those following intramuscular injection, and are subject to wide inter-subject variation. There is no simple correlation between plasma concentrations of prochlorperazine and its metabolites, and therapeutic effect.

Parenteral (intramuscular) administration can increase the availability of the active drug by four to ten times. There is a marked interindividual variation in pharmacokinetics following intravenous administration but no evidence of dose dependent pharmacokinetics; mean terminal half life is of the order of 6.85 hours.

A few generalisations can be made. The phenothiazine group of drugs to which prochlorperazine belongs is highly lipophilic, highly membrane or protein bound and will accumulate in the brain, lung and other tissues with a high blood supply; it also enters the foetal circulation quite easily. This apparent high volume of distribution would confirm that the liver is not the only site of metabolism.

Prochlorperazine may be metabolised by hydroxylation and conjugation with glucuronic acid, N-oxidation, oxidation of the sulfur atom and dealkylation. Plasma half-life is reported to be only a few hours but elimination of the metabolites may be very prolonged. Prochlorperazine is extensively bound to plasma proteins, widely distributed in the body (it crosses the blood/brain barrier) and its metabolites cross the placental barrier and are excreted in milk. The rate of metabolism and excretion decreases in old age.

Not applicable.