Chlorpromazine has also been used in porphyria and as part of tetanus treatment. It still is recommended for short-term management of severe anxiety and psychotic aggression. Resistant and severe hiccups, severe nausea/emesis, and preanesthetic conditioning are other uses.
Phenothiazine; Antipsychotic
Chlorpromazine is a major tranquilliser. It is a phenothiazine, which has antipsychotic actions, the exact basis for which are not fully understood. Its clinical properties include alleviating anxiety, tension and agitation, potentiating CNS depressants including analgesics, narcotics and sedatives; an antiemetic action. Chlorpromazine is a dopamine inhibitor. It inhibits prolactin-release-inhibitory factor, considered to be dopamine, thereby stimulating the release of prolactin. The turnover of dopamine in the brain is also increased. The antagonism of central dopaminergic function may be related to the therapeutic effect in psychotic conditions. Chlorpromazine can produce alpha-adrenergic blockade which may produce hypotension. Chlorpromazine also has a tendency to produce elevated serum glucose and cholesterol levels. Absorption:
Chlorpromazine is readily absorbed from the gastrointestinal tract but is subject to
considerable first-pass metabolism in the gut and the liver. Following oral administration,
peak plasma levels are reached in 1-4 hours; following intramuscular injection, peak plasma
levels usually occur in 15 - 30 minutes. Oral absorption is erratic and incomplete with
10 - 80% of the oral dose reaching the systemic circulation. There is wide inter-subject
variation.
Distribution:
Chlorpromazine is widely distributed to the body tissue. It crosses the blood-brain barrier
and achieves higher concentrations in the brain than in the plasma. The average volume of
distribution of chlorpromazine is quite large, ranging from 10 - 35 L/Kg (mean 22 L/Kg). It is
highly protein-bound (90 - 99%). Chlorpromazine has been detected in urine for up to one
year after discontinuation of chronic administration.
Metabolism:
Chlorpromazine metabolism is complex. There is extensive first pass metabolism after oral
administration, accounting for a low oral bioavailability of unchanged drug, especially at low
oral doses. Over 150 metabolites have been postulated of which about half have been
detected in blood and urine. Major metabolic pathways are hepatic and include
demethylation, N-oxidation, sulphoxidation, deamination and conjugation. The metabolites
of clinical importance appear to be 7- hydroxychlorpromazine, 3- hydroxychlorpromazine,
desmethylchlorpromazine and chlorpromazine N-oxide, all of which are biologically active;
and chlorpromazine sulphoxide, which is not biologically active. Chlorpromazine is almost
completely metabolised with less than 1% excreted in the urine as unchanged drug. Serum
levels of unchanged drug and clinical effect do not correlate well. A therapeutic serum level
is usually between 100-300ng/mL and toxic effects appear by 750ng/mL but routine serum
level monitoring is not necessary. Serum levels in chronic dosing may be lower than those
reached after acute dosing.
Excretion:
Chlorpromazine and its metabolites are removed from the body significantly in the urine, in
small amounts in faeces and in lesser amounts in sweat and hair. Average urinary excretion
in 24 hours ranges from 43 - 65% of the daily dose. There is a wide variation in the
elimination half lives proposed by various groups, and also wide inter-patient variation.
There may be several elimination phases consisting of an early phase of 2 - 3 hours, an
intermediate phase of 15 hours and a late phase of up to 60 days.
ORAL Intractable hiccup: Adult: Initially, 25-50 mg 3-4 times daily for 2-3 days; if unresponsive, may admin 25-50 mg via IM lnj. If still necessary, 25-50 mg in 500- 1000 ml of NS may be given via slow IV infusion. Child: 1-12 yr: 500 mcglkg every 4-6 hr. Max: >5 yr: 75 mg daily; 1-5 yr: 40 mg daily. Elderly: lnitially,1/3-1/2 the normal adult dose. Psychoses: Adult: 25 mg tid; may be given as a single 75 mg dose at night. Maintenance: 25-100 mg tid increased to 1 g daily as required in psychotic patients. Child: 1-12 yr: 500 mcg/kg every 4-6 hr. Max: >5 yr: 75 mg daily; 1-5 yr: 40 mg daily. Elderly: Initially, 1/3-1/2 the normal adult dose. INTRAMUSCULAR Psychoses: Adult: 25-50 mg repeated every 6-8 hr. Substitute w/ oral therapy as soon as possible. ChIld: 1-12 yr: 500 mcg/ kg every 4-6 hr. Max: >5 yr: 75 mg daily; 1-5 yr: 40 mg daily. Elderly: Initially,1/3-1/2 the normal adult dose. Nausea & vomiting: Adult: Initially, 25 mg via IM inj, followed by 25-50 mg every 3-4 hr until vomiting stops. Child: 1-12 yr: 500 mcg/kg every 4-6 hr. Max: >5 yr: 75 mg daily; 1-5 yr: 40 mg daily. Elderly: Initially,1/3-1/2 the normal adult dose. RECTAL Psychoses: Adult: 100 mg every 6-8 hr as suppositories.
Interactions resulting in decreased chlorpromazine levels Food, alcohol and benztropine can reduce the absorption of chlorpromazine. Antacids can slow the absorption of chlorpromazine. Lithium and chronic administration of barbiturates can lead to increased clearance of chlorpromazine. Interactions resulting in increased chlorpromazine levels Tricyclic antidepressants decrease the clearance of chlorpromazine and may lead to increased serum levels. Administration of chlorpromazine with CYP1A2 inhibitors, in particular strong (such as ciprofloxacin and fluvoxamine) or moderate (such as oral contraceptives and vemurafenib) inhibitors leads to an increase in chlorpromazine plasma concentrations. Therefore, patients may experience any chlorpromazine dose-dependent adverse drug reaction. Interactions in which other drugs are affected by chlorpromazine Chlorpromazine can increase the depressant action of central nervous system depressants such as benzodiazepines, anaesthetic drugs, opioids, barbiturates and lithium. Chlorpromazine may reduce serum phenytoin levels, may reduce propranolol clearance and may antagonise antidiabetic agents and levodopa, increase valproic acid levels, antagonise the effects of amphetamines, diminish the effect of oral anticoagulants and interact with anticholinergic drugs such as orphenadrine to produce hypoglycaemia. Phenothiazines such as chlorpromazine are potent inhibitors of CYP2D6. Co-administration of chlorpromazine with amitriptyline, a CYP2D6 substrate, may lead to an increase in the plasma levels of amitriptyline. Monitor patient for dose-dependent adverse reactions associated with amitriptyline. Chlorpromazine can oppose the effects of adrenaline to produce a paradoxical fall in blood pressure. It can also oppose the effects of guanethidine and clonidine. Thiazide diuretics may accentuate the orthostatic hypotension that may occur with phenothiazines. Interaction with quinidine may lead to additive myocardial depression. Interaction with MAOIs may lead to additive hypotensive effects. Interactions with suxamethonium, organophosphorus insecticides and atrophine or related drugs are also a possibility. Chlorpromazine may lower the convulsive threshold; dosage adjustments of anticonvulsants may be necessary.
Hypersensitivity; preexisting CNS depression, coma, bone-marrow supression; phaeochromocytoma; lactation. Parkinson’s disease; CV disease; renal or hepatic impairment; cerebrovascular & resplratoty disease; jaundice; DM; hypothyroidism; paralytic ileus; prostatic hyperplasia or urinary retention; epilepsy or history of seizures; myasthenia gravis; pregnancy; elderly (especially w/ dementia), & debilitated patients. Avoid direct sunlight.
Tardive dyskinesia (on long-term therapy). Involuntary movements of extremities may also occur. Dry mouth, constipation, urinary retention, mydriasis, agitation, insomnia, depression & convulsions; postural hypotension, ECG changes. Allergic skin reaction, amenorrhoea, gynaecomastia, wt gain. Hyperglycaemia & raised serum cholesterol. Agranulocytosis. Instantaneous deaths associated w/ ventricular tachyarrhythmias. Marked elevation of body temp w/ heat stroke. Neuroleptic malignant syndrome, extrapyramidal dysfunction.
use during pregnancy has been linked to severe limb reduction defects. Effects of antipsychotic use in lactating mothers are mostly unknown. However, the use of chlorpromazine has been reported to result in drowsiness and lethargy in breastfed infants.
The symptoms of overdosage with chlorpromazine include CNS depression progressing from drowsiness to coma with areflexia; patients with early or mild intoxication may experience restlessness, confusion and excitement. Other symptoms include hypotension, tachycardia, hypothermia, pupillary constriction, tremor, muscle twitching, spasm or rigidity, convulsions, muscular hypotonia, difficulty in swallowing and breathing, cyanosis and respiratory and/or vasomotor collapse, possibly with sudden apnoea. Polyuria has also been noted which may result in dehydration. Deaths in young children have followed ingestion of 350 to 800 mg of chlorpromazine. Acute toxicity has been determined in animals. LD50 values range from 15 mg/kg (intra-venous, rabbit) to 75 mg/kg (oral, mouse).
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.
.png&w=384&q=75)