Phenothiazine Derivatives: Chlorpromazine and its mechanism of action

Gambar 1. Chlorpromazine 3D conformer

Major use

Chlorpromazine hydrochloride (CPH) belongs to antipsychotic drugs, also called neuroleptics; and it is mainly used for the treatment of neurological disorders.CPH has sedative, hypotensive and antiemetic properties. CPH, which is an aliphatic phenothiazine, was first synthesized in 1952. It was extensively studied and used as a model for a big class of neuroleptic agents. Haloperidol, thioridazine, lozapine, promethazine, and many other drugs belong to the same Class. Chlorpromazine (CPZ), marketed under the trade names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar disorder, attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. It can be given by mouth, by injection into a muscle, or into a vein.

Kinetic data

Absorption: the oral absorption is diverse and unpredictable depending on the metabolism either within the gastrointestinal lumen or during absorption through the bowel wall.

Bioavailability: approximately 32% (range 10 to 69%). The best bioavailability is achieved through parenteral administration.

Distribution: CPH appears to be concentrated in brain against the plasma gradient, and brain levels have been estimated to be 5 times greater than plasma concentrations. In the fatal cases, high amounts of CPH were also found in liver and kidney.

Time to peak blood concentration: peak CPH plasma levels are normally seen within 2 to 3 h of a single oral dose, with a rapid fall-off in plasma concentration during the following 3 to 6 h.

Plasma protein binding: CPH is extensively bound to tissues (particularly in the brain) and plasma protein (mostly albumin).

Passage of blood brain barrier: free (my own conclusion based on high brain concentrations at fatal cases, AK). 
 

Mechanism of action

The antipsychotic activity of CPH and other neuroleptic drugs is closely associated with their capacity to block D2 dopamine receptors in the brain. Dopamine functions as a neurotransmitter, activating dopamine receptor. Neuroleptic drugs can block also other neurotransmitter receptors, such as histamine (H1 and H2), alpha-adrenergic (alpha1 and alpha2), muscarinic, and serotonin receptors.

Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). Additionally, Chlorpromazine is a weak presynaptic inhibitor of Dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use).

Metabolism

Extensively metabolized in the liver and kidneys. It is extensively metabolized by cytochrome P450 isozymes CYP2D6 (major pathway), CYP1A2 and CYP3A4. Approximately 10 to 12 major metabolite have been identified. Hydroxylation at positions 3 and 7 of the phenothiazine nucleus and the N-dimethylaminopropyl side chain undergoes demethylation and is also metabolized to an N-oxide. In urine, 20% of chlopromazine and its metabolites are excreted unconjugated in the urine as unchanged drug, demonomethylchlorpromazine, dedimethylchlorpromazine, their sulfoxide metabolites, and chlorpromazine-N-oxide. The remaining 80% consists of conjugated metabolites, principally O-glucuronides and small amounts of ethereal sulfates of the mono- and dihydroxy-derivatives of chlorpromazine and their sulfoxide metabolites. The major metabolites are the monoglucuronide of N-dedimethylchlorpromazine and 7-hydroxychlorpromazine. Approximately 37% of the administered dose of chlorpromazine is excreted in urine.

References:

Jose JG and Yielding KL: Photosensitive cataractogens, chlorpromazineand methoxypsoralen, cause DNA repair synthesis in lens epithelial cells. Invest Ophthalmol Vis Sci 17:687, 1978.

Richard H., 1998. Pharmacological Treatment of Schizophrenia 

Chlorpeomazine Hydrochloride. Written by Ada Kolman, March 2006; revised March 2007 (Ada.kolman@telia.com)

QUESTION BOX:

1.    Mengapa bioavailabilitas CPZ paling baik pada penggunaan parenteral? 2.    Bagaimana pengaruh ikatan protein terhadap bioavailabilitas obat ini? 3.    Mengapa CPZ tidak mengalami perubahan ketika di ekskresi lewat urin?

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