CHLORPROMAZINE ContentsPharmacologyIndicationsContraindicationsPrecautionsAdverse EffectsOverdoseDosageResearch

PHARMACOLOGY

Antipsychotic-Antiemetic

Chlorpromazine is an aliphatic phenothiazine. Phenothiazines are bought to elicit their antipsychotic and antiemetic effect via interference with central dopaminergic pathways in the mseolimbic and medullary chemorceptos trigger zone of the brain, respectively. Extrapyramidal side effects are a result of interaction with dopaminergic pathways in the basal ganglia. Although often termed dopamine blockers, the exact mechanism of dopamigergic interference responsible for the drugs antipsychotic activity has not been determined.

The aliphatic phenothiazines are highly sedating which is often apparent

Pharmacokinetics

Chlorpromazine, and many other phenothiazine derivatives, are very lipothilic molecules that readily bind with membrane and proteins. Appoximately 95-98% of the drug is bound in the splasm; 85% of the drug is bound to the plasma proteins albumin. Renal disease may cause this range to expand significantly. Highest concentrations of the drug can be found in the brain, lung, and other tissues that receives a high supply of blood.

The drug can also enter fetal circulation and breast milk. Chlorpomazine is able to cross the placental barrier and it has been shown

that drug doses than 500mg daily in late pregnancy are associated with an increased incidence of respiratory distress in newborns.

The elderly also have a slower rate of metabolism, but it seems that children have the highest.

Bioavalibility: Only about 32% of the administered dose is avilable to the systemic circulation in the active form. Over time and multiple administrations, bioavilability may drop to 2)%. Peak concentration are achieved in 1 to 4 hours (range 1.5-8 hours), after an oral dose absorbed from the intramuscular injection site with the peak plasma concentration occurring 6-24 hours after administration of the drug.

The oral bioavailability is estimated to be 30-50% that of intramuscular doses and about 10% that of intravenous doses due to extensive first pass metabolism in the liver. Its elimination half-life is 16-30hours (8-35 hours, although it is as short as 2 hours or as long as 60 hours in some individuals), due to high lipophilicity, high membrane-biding, and high protein-binding.

It has many active metabolites (more than 100 metabolites being theoretically possible) with greatly varying halflives and pharmacological profiles. A number of the metabolites may contribute to the pharmacological effects of chlorpromazine including 7-hydroxychlorpromazine, chloropromazine –N-oxide, 3 – hydroxychlorpromazine and desmethychlorpromazine.) although the metabolic chrlopromazine –N-oxide does not possess activity in vitro, it can exert an indirect pharmacological effect in vivo by reverting back to chlopromazine.

The major routes of metabolism include hydroxylation, N-oxidation, sulphoxidation, demethylation, deamination and conjugation.

The cytochrome P450 isoenzymes 1A2 and 2D6 are needed for metabolism of chlorpromozine. CYP 2D6 is the main ezymes catalyzing 7-hydroxylation of chlorpromazine, the reactionbeing particulary catalyzed by CYP 1A2.Often, due to their high lipohilic character, these and other metabolites may be detected in the urin up 18 months. After discontinuation of use. Most metaboliies lack any sort of antipsychotic activity, but few are biological active. These include 7-hydroxychlorpromazine, mesoridazine, 9-hydroxyresperiodone, 9-hydroxyreperidone, and a few N-demethylated metabolites.Pharmacodynamics and Central effectsChlorpromazine is very effective very effective antogonist of D2 dopamine receptors and similar receptors, such as D3 and D5. Unlike most other drugs of this genre, it also has a high affinity for D1 receptors. Blcoking these receptors cause diminished neurotransmitter binding in the foramen, resulting in many different effects.

Dopamine, unable to bind with a receptors, causes a feedback loop that cause dopaminergic neurons to release more dopamine. Therefore, upon first taking the drug, patients will experience an increase in activity of dopaminergic neural activity. Eventually, dopamine production of the neurons will drop substantially and dopamine will be removed from the synaptic cleft. At this point, neural activity decreases greatly; the continual blockage of receptors only compounds this effect.

Chlorpromazine acts as an antoganist (blocking agent) on different postsynaptic receptors

Dopamine receptors (subtypes D1, D2, D3, and D4) which account for its different antispsychotic properties on productive and unprodictive symptoms; in the mesolimbic system accounts for the antipsychotic effect whereas the blockage in the nigrostriatal system produces the extrapyramidal efefcts serotonin receptots (5-HT1 and 5-HT1), with anxiolytic, and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties),

Histamine receptors (H1 receptors, accounting for sedation, antiometic effect, vertigo, fall in blood pressure and weight gain),

α1- and α2-adrenergic receptors (antisympathomimetic properties, lowering of blood pressure, reflux tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkisonism-controversal), and

M1 and M2 muscarinic acetylecholine receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).

Chlorpromazine and other typical antipsychotics are primarily blockers of D2 receptors. In fact a almost perfect correlation exists between the therapeutic dose of a typical antipsychotic and the drug’s affinity for the correlation exists between the therapeutic dose of a typical antipsychotic and the drug’s affinity for the D2 receptor.

Therefore, a larger dose is required if the drug’s affinity for the D2 receptors is relatively weak. A correlation exists between average clinical potency and affinity of the antipsychotics for dopaminc receptors. Chloropromazine tends to have greater effect at serotonin receptors than at D2 receptors, which is notably the opposite effect of the other typical antis antipsychotics.

Therefore, chlorpomazine with respect to its effects on dopamic and serotonin receptors is similar to the atypical antipsychotics than the typical antipsychotics.

Additionally, chlorpromazine is a presynaptic inhibitor of dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonina efffects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use).

Chlorpromazine could also achieved glutamatergic effects via inhibitory effects on NMDA receptors at the Zn site.

Peripheral effects Chlorpromazine is an antogonist to H1 receptors (provoking antiallergic

effects), H2 receptors (reduction of forming of gastric juice), M1 and M2 receptors (dry mouth, reduction in forming of gastric juice) and some 5- HT receptors (different anti-allergic/gastrointestinal actions).

The concept of “dirty drugs” and “clean drugs”

at the start of therapy, with time some tolerance to this effect develops.

Chlorpromazine has strong alpha-adrenergic blocking activity and can cause orthostatic hypotension. Infrequently prolongation of the QT interval may occur. Chlorpromazine has moderate anticholinergic activity manifested as occasional dry mouth, blurred vision, urinary retention and constipation.

Chloropromazine increases prolactin secretion due to its dopamine receptor blooking action in the pituitart and hypothalamus. Galactorrhea and gynecomastia have occurred

PHARMACOKINETICS

Chlorpromazine is readily absorbed from the gastrointestinal tract, however its bioavailability is variable due to considerable first pass metabolism by the liver.

Liquid concentrates may have greater bioavailability than tablets.

Food does not appear to affect bioavailability consistently.

I.M. administration by passes much of the first pass effect and higher plasma concentrations are achieved.

The onset of action after i.m administration is usually 15 to 30 minutes and after oral administration 30 to 60 minutes. Rectally administration chlorpromazine usually takes longer to act than oral.

Chropromazine is highly bound to plasma proteins (>90%), principlally albumin. It is not dialysable. It is distributed widely throughout the body, crossinf the blood brain barrier, the placenta and is distributed into milk. Volume of distribution is about 20 L/kg.

Chlorpromazine is metabolized extensively and at least 12 different metabolites are known. Less than 1% excreted unchanged. Most metabolites are excreted in the urine as unconjugated or conjugated forms. The terminal half-life of chropromazine is variable at ap[proximateky 30 hours.

INDICATIONS

The management of psychotic disorders including manifestations of manic depressive illness, manic phase and severe behavioral problems in children, nausea and vomiting due to stimulation of the chemoreceptor trigger zone.

Recent global review of data supports its effectiveness as an antipsychotic. Chlorpromazine formerly was the drug of choice to treat LSD (and other

psychedelic/hallucinogen) intoxication in a hospital setting, resulting in it gaining an erroneous reputation as the LSD antidote. Now reperidone is more commonly used in such situations.Other Uses

Porphyria Tetanus treatment Svere anxiety Aggressive episodes Resistant and severe hicups Severe nausea/emeis Preanesthetic conditoning Amphetamine overdose Appetite stimulant in eating disorder

Off-label and controversial uses Severe migraine Nausea in opioid-treated cancer patients and prolonged the analgesic action opioid Opiod withdrawal in newborns Antianalgesic properties Chlorpromazine: it has a unique action is cholera, reducing the loss water by

approximately 30 percent. In Germany, the brand of chlorpromazine drug Propahenin had asitional indications

for insomnia and itching skin disease. Some jurisdiction in the United States use Chlropromazine as a sedative/tranquilizer

prior to carrying out a death sentence by lethal injecetion. (Methods of Execution).

Contraindications

Comatose of depressed states due to CNS depressants; Blood dycrasias; bone marrow depression, liver damage. Hypersentivity to cchlorpromazine. Cross allergenicity with other phenothiazines may occur.

Should be avoided in children or adolescent with signs or symptoms suggestive of Reye’s Syndrome.

Its antiemetic effect may mask the sign and its CNS effects may be confused with the signs of Reye’s Syndrome or other encephalapathies.

PRECAUTIONS Phenothiazines should be used with caution in patients

with cardiovascular disease. Chlopromazine is an alpha-adrenergic blocking agent

and increase pulse rate and transient hypotension have both been reported in some patients receiving these drugs.

Hypotension, which is typically orthostatic, may occur especially in elderly and in alcoholic patients.

This effect may be additive with other agents that cause a lowering of blood pressure.

If chlorpromazine should cause severe hypotension, most patients will respond to cautions expansion of the intravascular volume with sodium chloride.

If vasopressor drugs are needed, the drugs of choice are alphareceptor agonists such as phenylephrine or methoxomine.

Chlorpromazine has direct negative inotropic action. It prolongs PR and QT intervals, blunts the T wave and depresses the S-T segment.

These changes apear to be reversible and related to disturbance in replorization. Give phenothiazines cautiously to patients with heart disease.

Most reported cases of agranulcytosis associates with the administration of phenothiazine derivatives have occurred between the fourth and tenth week of treatment.

Therefore observe patients on prolonged therapy with particular care during that time for the appearance of such as sore throat, fever and weakness. It these symptoms appear, discontinue the drug and perform WBC and differential counts.

Chlorpromazine should be used with caution in patients who have impaired liver function or alcohol liver disease. CNS depression may be potentiated.

If bilirubinemia, or icterus occur, discontinue the drug and perform liver function tests.

Phenothiazines have been associated with retinopathy.Discontinue chropromazine if retinal changes are observed.

Regular opththalmologic exams are recommended. Use chlorpromazine cautiously in patients with a history

of seizures since the drug tends to lower the seizure threshold.

The anticholinergic action of chlorpromazine may be a factor in some cases of intestinal pseudo-obstruction.

Chlorpromazine may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumor.

Neuroleptic drugs elevate prolactin levels, the elevation persists chronic administration.

Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been r ported, the clinical significance of elevated serum prolactin levels in unknown for most patients.

Chlorpromazine may impair sensitivity and adaptation to changes of environment temperature so that fatal hyperthermia and heat stroke are possible complications.Abrupt withdrawal

In general, phenothiazines do not produce psychic dependence; however gastritis, nausea and vomiting, dizziness, and tremulousness have been reported following abrupt cessation of high dose therapy.

Reports suggest that these symptoms can be reduced if concomitant antiparkinsonian agents are continued for several weeks after phenothiazone is withdrawn.

OCCUPATIONAL HAZARDS Where patients are participating in activities requiring complete mental

alertness such as driving an automobile or operating machinery, administer the phenothiazine cautiously, forewarn the patient and increase the dosage gradually.

Photensitivity may occur, patients should utilize sunscreens when exposed to sunlight for significant lengths of time.

Drug Interactions Anticonvulsants:

Chlorpromozine may lower the seizure threshold. Anticonvulsant therapy should be monitored closely and may require dosage adjustment.

Acohols:

Additive CNS depressant effects

Amphetamines:

Amphetamines may cause exacerbation of psychotic symptoms. Antihistamines, second generation

Chlorpromazine can prolong the QT interval. Although no case reports exist, patients on chlorpromazine should be administered antihistamine drugs such as astermizole and terfenadine with great caution. The concomitant administration of these agents may have the potential to cause additive effects on the QT interval and increase propensity to ventricular arrhythmia.

Antacids:

may impair the absorption of chlorpromazine. Monitor for decreased effect.

Anticholincrgics:

Routine use together is not advisable. If combined use in necessary, monitor carefully for decreased antipsychotic response, adynamic iluc (constipation, abdominal pain and distension). Predisposition to heat stroke may be increased with this combination.

Antidepressant, tricyclic:

May result in increased chlorpromazine concentration, monitor for adverse effects.

CNS Depressants:

Chropromazine and other CNS depressants (alcohol, antihistamines, general anesthetics, opiates or other narcotic analgesics, barbiturates, benzodiazepines and other sedative/hypnotic agents) may result in additive CNS depressant effects. Monitor to avoid excessive sedation or respiratory depression.

Epinephrine

Patients on chlorpromazine who are hypotensive should not be given epinephrine. Chlorpromazibe blocks peripheral alpha-adrenergic receptors, thereby inhibiting alpha-agonist effects of epinephrine such as vasoconstriction and increased blood pressure. The beta –agonist effects of epinephrine (vasodilation) may be left unopposed and a further fall in blood pressure may result. Agents such as phenylephrine methozamine or norepinephrine may be a suitable alternative to raise blood pressure.

Hypotensive Agents:

Chlorpromazine and antihypertensives may result in additive hypotensive effects and increased risk of orthostatis hypotension of syncope (fainting). Chlorpromazine may block the antihypertensice effects of guanethidine by preventing its uptake into sympathetic nerves.

LevodapaPhenothiazines may inhibit the antiparkinsonian effects of levodapa due to their dopamine blocking effects in the CNS. Generally phenothiazines should not be administered to patients who require levodopa.

LithiumPatients receiving lithium and chlorpromazine for treatment of acute mania should be monitored closely for signs of adverse neurologic effects, especially if serum concentrations of lithium are in the upper range. Rare cases of severe neurotoxicity have been reported.

PregnancySafe use of phenothiazines in pregnancy has not been established. Most studies indicate these agents are not teratogenic but there are reports of defects in infacts exposed to these during the first trimester. Toxic effects observed after high doses near term include:

Hypotania, lethargy, depressed reflexes, paralytic ilues, jaundice, and persistent extrapyramidal syndrome. Therefore, they should be administered cautiously, to women of childbearing potential particulary during the first trimester of pregnancy and near term.

Lactation

Phenothiazines are distrbibuted into milk. Use with caution during lactation because of possible sedative and anticholinergic side effects on the infant.

Geriatrics:

Use reduces dosages. Chlorpromazine may advrsely affect many of the conditions commonly occuring in the aged, including cardiovascular problems, parkinsonian extrapyramidal effect and anticholinergic effects (e.g constipation, blurred vision).

Adverse Effects

In general members of the aliphatic group of phenothiazines have strong sedative, hypotensive and anticholinergic properties and mild to moderate extrapyramidal effects.

Automatic Nervous System:

Anticholinergic efffects including dry mouth, blurred vision, constipation, ileus, nasal stuffiness, photophobia. Syncope and impaired temperature regulation have also occurred.

Cardiovascular:

Chlorpromazine has peripheral alpha-adrenergic blocking activity. Its effects on the heart include: direct negative inotropic and quinidine-like actions. Its effect on

the ECG include prolongation of the PR and QT intervals, blunting of the T wave and depression of the S-T segment. Vantricular arrythmia and sudden death has occurred rarely.

Orthostatic hypotension is common after parenteral administration and usually lasts one-half to 2 hours. Patients should be supine when parental chlorpromazine is administered. Tachycardia, fainting and dizziness have also occurred. Hypotension can also occur after oral administration. Tolerance to hypertensive effects generally develop over time, however hypotension can persist in some patients, especially the elderly.

CNS:Extrapyramidal reactions, including pseudoparkinsonism (with motor retardation, rigidity, mask like facies, pill rolling and other tremors, drooling, shuffling gait, etc);.

dystonic reactions (including peririral spasms, trismus, tics, torricollis, oculogyric crises, protusion of the tongue, difficulty swallowing, carpoedal spasm, opisthotonos of the back muscles); and akathisia. In addition, slowing of the EEG ryhythm, disturbed body temperature and lowering of the convulsion threshold have occurred. Dizziness had been reported.

Tardive dyskineia may appear in some patients on long term antipsychotic therapy or may appear after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear to be irreversible. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g protrusion of the tongue, puffing of the cheeks, puckering of the mouth and chewing movements). Sometimes these may be accompanied by involuntary movements of the extremities.

There is no known effective treatment for tardive dyskinesia; antiparkinonian agents usually do not alleviate the symptoms of this syndrome.

All antipsychotic agents should be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked.

The physician may be able to reduce the risk of this syndrome by minimizing the unnecessary use of neuroleptics and reducing the dose or discontinuing the drug, if possible, when manifestations of this syndrome are recognized, particularly in patients over the age of 50.

Fine vernicular movements of the tongue may be an early sign of the syndrome. If the medication is stopped at that, time, the syndrome may not develop.

Dermatologic:

Itching, rash, hypertrophic papillae of the tongue, angioneurotic edema, erythema, allergic purpura, exforliative dermatis, photosensitivity. Contact dermatitis has occurred in personnel handling solutions or injections of chlropromazine

Endrocrine:Increased prolactic secretion; gynecomastia, galactorrhea, mastalgia, altered libido, menstrual irregularities, eight gain, alterations in glucose tolerance and false positive pregnancy tests have occurred.

GastrointestinalNausca, vomiting, increase or decrease in appetite, gastric irritation, constipation, paralytic ileus, rarely diarrhea. Dry mouth.

GenitourinaryUrinary retention, priapism, inhibition of ejaculationAntipsychotic drugs may cause priapism, a pathologically prolonged and painfaul penile erection, which is usually unassociated with sexual desire or intercourse. Although this effect is rare it is a potential serious complication that can lead to permanent impotence and other serious complications.

HematologicAgrunulocytosus, leukopenia, granulocytopenia, eosinophilia, thrombocytopenia, anemia, aplastic anemia, pancytopenia. Agranulocytosis occurs in fewer than 1 in 10000 patients receiving chlorpromazine.

Hepatic: Cholestatic jaundice can occur infrequently (0.1-4%) and is usually part of a

hypersensitivity reaction. Jaundice usually occurs within 2 to 4 weeks of initiation of therapy and

chlorpromazine should be discontinued immediately. Rarely progression to chronic juandice has occurred Pre-existing liver dysfunction has not yet been proven to be a risk factor for this reaction.

Signs and symptoms of cholestatic juandice include; upper abdominal pain, nause, flu-like symptoms, yellow skin and conjuctiva, fewer, elevated liver enzymes, biluiria.

Hypersensitivity:

Cholestatic jaundice (see under Hepatic), various dermatoses (see under Dermatologic), blood dycrasias (see under Hematologic), photosensitivity, laryngeal edema, bronchospasm, ongioneurotoc edema and anahylactiod reaction.

Ophthalmologic:

A perculiar skin-eye syndrome has been recognized as an adverse effect following long-term treatment with phenothiazines.

This reaction is marked by progressive pigmentation of areas of skin or conjuctiva and/or discoloration of the exposed sclera and cornea.

Opacities of the anterior lens and cornea described as irregular or stellate in shape have also be reported.

Patients receiving higher doses of phenothiazines for prolonged periods should have periodic complete eye examinations.

General Systemic Events Sudden death has occasionally been reported in patients who have

received phenothiazines. In some cases, the death was apparently due to cardiac arrest; in

others, the cause appeated to be asphyxia due to failure of the cough reflex.

In some patients, the cause could not be determined not could it be established that the death was due to the phenothiazine.

Neuroleptic Malignant Syndrome As with other neuroleptic drugs, a symptoms complex sometimes referred to

as neuroleptic malignant syndrome (NMS) has been reported. Cardinal features of NMS are hyperpyrexia, muscle rigidity, altered mental

status (including catatonic sign) and evidence of autonomic instability (irregular pulse of unstable blood pressure).

Additional signs may include elevated CPK, myoglobinuria (rhaddomyolysis), and acute renal failure. NMS is rate but potentially fatal and therefore requires intensive symptomatic and supportive treatment. Immediate discontinuation of neuroleptic treatment is mandatory.

NMS has been successfully managed with various agents e.g dantrolene and bronocrptine or amantadine.

A toxically reference should be consulted for detailed information.

Overdose Symptoms

Parkinsonism, acute dystonias, somnolence, seizures, dry mouth, blurred vision, urinary retension, tachycardia, cardiac arrhythmias, hypotension, hypothermia or hyperthermia.

Treatment Empty stomach using gastric lavage. Administer activated charcoal and a

saline cathartic. Repeat activated charcoal and cathartic every 4 to 6 hours to speed climination. Support respiratory and cardiac functions as needed. Maintain fluid and electrolyte balance.

Treat hypotension with i.v fluids and by placing the patient in shock position. If unresponsive, dopamine may be required.

Seizures may be treated with i.v diazepam. Teat arrhythmias with phenytoin. Acute dystonic reactions may be treated with i.v. diphenydramine,

benztropine or trihexphenidyl. Hemodialysis is ineffective. Hemoperfusion may be effective in severe cases but is usually not necessary

Dosage Adults

Oral: In general medicine and psychiatry, average daily oral dose of 25 to 75mg

(mild cases) or 75 to 150 (more severe cases) in 2-4 divided doses. It is occasionally necessary to give a higher dosage which, when increased gradually, can reach 900mg or more per day in some psychiatric patients.

Optimum therapeutic response may not occur for weeks or months. Once the optimum dosage has been reached, it is maintained as long as

necessary for the control of symptoms during the critical phase of the illness. Eventually, however, it should be gradually reduced so that the patients can be maintained on the lowest effective dosage.

Elderly and debilitation patients should start with initial doses at the lowest end of the dosage range (e.g. 25mg daily). Such patients are more susceptible to hypotension and CNS effect and special caution should be exercised when using chlorpromazine in this age group.

During maintenance treatment, if it becomes desirable to reduce the number of daily drug administrations, the dosage may be administered once or twice, with the largest dose at bedtime.

Parental: The usual single parental dose ranges from 25 to 50mg and can be

repeated 3 or 4 times per day. Elderly or debilitated patients may require lower dosages. The i.m. route is

used primarily when rapid action is required to control acute severe symptomatology.

Administer by slow deep i.m. injection into upper quadrant of buttock. Oral administration should be substituted as soon as possible. To minimize the occurrence of hypotension keep patients lying down for at least 30 minutes after injection.

Chlorpromazine ampuls should be protected from light. Pink or discoloured solution should be discarded.

Rectal:

100 to 300 mg daily Children

Usually single dose is 0.5mg/kg. This dose may be repeated every 4 to 6 hours as necessary.

Parenteral:

Usualy single dose in 0.5mg/kg i.m. This dose may be repeated every 6 to 8 hours as necessary. Children 6 months to 5 years (up to 23 kg) should receive no more than 40 mg/day. Children 5 to 12 years (23 to 46kg) should receive no more than 75 mg/day, except in unmanageable cases where dosages can be carefully titrated upward.

Rectal

The usualy rectal dose is 1 mg/kg which can be repeated every 4 to 6 hours as necessary.