PROCHLORPERAZINE MALEATE

Indications

• Psychoses
• Schizophrenia
• Severe anxiety
• Nausea and vomiting
• Prevention of nausea and vomiting in migraine
• Labyrinthine disorders

Dosage

Adults: For psychosis, 12.5 mg by deep intramuscular injection as required; orally, initially 4 mg daily adjusted according to response, then increased by 2-4 mg at intervals of not less than 1 week, maximum 16 mg per day. For nausea and vomiting

Mechanism of action

Prochlorperazine's mechanism of action is primarily through its anti-dopaminergic effects, particularly by blocking D2 dopamine receptors in the brain. This blockade inhibits dopaminergic signaling in the mesolimbic system, contributing to its antipsychotic and antiemetic properties. Additionally, it affects serotonin type 3 (5-HT3) receptors at the chemoreceptor trigger zone (CTZ), further aiding in the prevention of nausea and vomiting.

Pharmacodynamics

As an antipsychotic agent, prochlorperazine promotes postsynaptic inhibition of dopaminergic neurons. It has strong antiemetic activity, displaying efficacy similar to ondansetron in preventing nausea and vomiting. Prochlorperazine also exhibits weak anticholinergic effects, moderate sedation, and strong extrapyramidal side effects. It can cause sedation and muscle relaxation through its blockade of alpha-1 adrenergic receptors and displays anti-anxiety effects.

Pharmacokinetics

Prochlorperazine is well absorbed after oral administration, with peak plasma concentrations typically reached in 1 to 2 hours. It has a plasma half-life of approximately 6 to 8 hours, with metabolism occurring primarily in the liver through cytochrome P450 enzymes. The drug is excreted mainly in urine as metabolites, with only a small fraction excreted unchanged. Caution is advised in patients with hepatic or renal impairment, as these conditions can affect drug clearance.

Contra-indications

• CNS depression
• comatose states
• history or family history of congenital QT prolongation
• phaeochromocytoma

Adverse effects

• drowsiness
• extrapyramidal symptoms
• blurred vision
• muscle spasms
• hypotension
• dry mouth
• constipation
• urinary retention
• heatstroke
• confusion
• delirium

Interactions

• pimozide
• other antipsychotics
• tricyclic antidepressants
• drugs prolonging the QT interval
• certain antihistamines
• antiarrhythmics
• drugs causing electrolyte disturbances, especially diuretics

Precautions

• caution in elderly patients
• monitor ECG in patients receiving large doses or co-administered with pimozide
• caution in hepatic impairment
• caution in renal impairment
• monitor for signs of neuroleptic malignant syndrome

Pregnancy

Prochlorperazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is classified as Category C.

Breast-feeding

Prochlorperazine is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• oral tablets
• oral suspension
• buccal tablets
• deep intramuscular injection

Mechanism of action

The mechanism of action of prochlorperazine has not been fully determined, but may be primarily related to its anti-dopaminergic effects. Prochlorperazine blocks the D2 dopamine receptors in the brain, which are somatodendritic autoreceptors. Inhibition of D2 receptor signaling results in the blockade of postsynaptic dopamine receptors in the mesolimbic system and an increased dopamine turnover. Nausea and vomiting are proposed to arise from peripheral or central stimulation of serotonin type 3 (5-HT3) and dopamine type 2 receptors, the predominant receptors expressed at the chemoreceptor trigger zone (CTZ). Prochlorperazine exerts antiemetic effects and was shown to inhibit apomorphine-induced vomiting by blocking D2 dopamine receptors in the CTZ.. The principal pharmacologic effects of prochlorperazine are similar to those of chlorpromazine. Prochlorperazine has weak anticholinergic effects, moderate sedative effects, and strong extrapyramidal effects. Prochlorperazine has strong antiemetic activity. The development of phenothiazine derivatives as psychopharmacologic agents resulted from the observation that certain phenothiazine antihistaminic compounds produced sedation. In an attempt to enhance the sedative effects of these drugs, promethazine and chlorpromazine were synthesized. Chlorpromazine is the pharmacologic prototype of the phenothiazines. The pharmacology of phenothiazines is complex, and because of their actions on the central and autonomic nervous systems, the drugs affect many different sites in the body. Although the actions of the various phenothiazines are generally similar, these drugs differ both quantitatively and qualitatively in the extent to which they produce specific pharmacologic effects. /Phenothiazine General Statement/ In the CNS, phenothiazines act principally at the subcortical levels of the reticular formation, limbic system, and hypothalamus. Phenothiazines generally do not produce substantial cortical depression; however, there is minimal information on the specific effects of phenothiazines at the cortical level. Phenothiazines also act in the basal ganglia, exhibiting extrapyramidal effects. The precise mechanism(s) of action, including antipsychotic action, of phenothiazines has not been determined, but may be principally related to antidopaminergic effects of the drugs. There is evidence to indicate that phenothiazines antagonize dopamine-mediated neurotransmission at the synapses. There is also some evidence that phenothiazines may block postsynaptic dopamine receptor sites. However, it has not been determined whether the antipsychotic effect of the drugs is causally related to their antidopaminergic effects. Phenothiazines also have peripheral and/or central antagonistic activity against alpha-adrenergic, serotonergic, histaminic (H1-receptors), and muscarinic receptors. Phenothiazines also have some adrenergic activity, since they block the reuptake of monoamines at the presynaptic neuronal membrane, which tends to enhance neurotransmission. The effects of phenothiazines on the autonomic nervous system are complex and unpredictable because the drugs exhibit varying degrees of alpha-adrenergic blocking, muscarinic blocking, and adrenergic activity. The antipsychotic activity of phenothiazines may be related to any or all of these effects, but it has been suggested that the drugs' effects on dopamine are probably most important. It has also been suggested that effects of phenothiazines on other amines (eg, gamma-aminobutyric acid [GABA]) or peptides (eg, substance P, endorphins) may contribute to their antipsychotic effect. Further study is needed to determine the role of central neuronal receptor antagonism and of effects on biochemical mediators in the antipsychotic action of the phenothiazines and other antipsychotic agents. /Phenothiazine General Statement/ Although the exact mechanism(s) of action has not been conclusively determined, phenothiazines have an antiemetic effect. The

Pharmacodynamics

Prochlorperazine is an antipsychotic agent that works to promote postsynaptic inhibition of dopaminergic neurons. It also exerts its anti-emetic actions via anti-dopaminergic effects, where it displays similar efficacy as ondansteron, a 5HT-3 receptor antagonist and anti-emetic, in preventing delayed nausea and vomiting. Prochlorperazine was shown to inhibit histaminergic, cholinergic and alpha-1 adrenergic receptors. The blockade of alpha-1 adrenergic receptors may result in sedation, muscle relaxation, and hypotension. It displays anti-anxiety effects as well. Compared to other phenothiazine derivatives, prochlorperazine is less sedating and has a weak propensity for causing hypotension or potentiating the effects of CNS depressants and anesthetics. Other than its primary action on D2 receptors, one study showed that prochlorperazine may inhibit the P2X7 receptor in human macrophages, leading to inhibition of calcium ion influx.