Chlorpromazine
Drugs

DESCRIPTION

Chemical features

Molecular Formula	C17-H19-Cl-N2-S
Molecular Weight	318.86
Melting Point	About 60 °C
pH	Alkaline
Solubilities	Very soluble in ethanol, ether, benzene and chloroform
Drug classes	Antiemetic, Antipsychotic, Gastrointestinal Agent
Reported Fatal Dose	Toxic dose: 100-200 ug/dL; Lethal dose: 0.3-1.2 mg/dL

Chlorpromazine (abbreviated CPZ; marketed in the United States as Thorazine and elsewhere as Largactil or Megaphen) is a dopamine antagonist of the typical antipsychotic class of medications possessing additional antiadrenergic, antiserotonergic, anticholinergic and antihistaminergic properties used to treat schizophrenia.
Both the clinical indications and side effect profile of CPZ are determined by this broad action. It helps relieve nausea but it also causes constipation and hypotension (anticholinergic properties). Its antidopaminergic properties causes “Parkinson’s-like symptoms” but help limit schizophrenic attacks.
In recent years, chlorpromazine has been largely superseded by the newer atypical antipsychotics, which are usually better tolerated, and its use is now restricted to fewer indications.

HISTORY

In 1933, the French pharmaceutical company Laboratoires Rhône-Poulenc began to search for new antihistamines, following the studies of Daniel Bovet . In 1947, Paul Charpentier, who worked at the Laboratoires Rhône-Poulenc, was studying a new drug for malaria and sleeping sickness.
Instead of these, he found out a remedy useful for Bovet, named promethazine, a phenothiazine derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs. A year later Henri Laborit, using this compound in a cocktail of 5 drugs to treat shock (such as surgery damages), noticed that the antihistaminic promethazine had a brilliant effect on the CNS: patients didin’t feel any pain nor remember anything of the operation. According to this, Laborit suggested the Rhône-Poulenc to improve their substance in order to use it also as an anaesthetic. The chemist Paul Charpentier produced a series of compounds and selected the one with the least peripheral activity, known as RP4560 or chlorpromazine, on 11 December 1950. Simone Courvoisier conducted behavioural tests and found chlorpromazine produced indifference to aversive stimuli in rats.
Chlorpromazine was distributed for testing to physicians between April and August 1951. Laborit also trialled the medicine on at the Val-de-Grâce military hospital in Paris, noticing its hypothermic effect and suggesting that it may induce artificial hibernation. (A new vegetative stabilizer, 1952.) Laborit thought this would allow the body to better tolerate major surgery by reducing shock, a novel idea at the time.
Known colloquially as Laborit's drug, chlorpromazine was released onto the market in 1953 by Rhône-Poulenc and given the trade name Largactil, derived from large broad and acti* activity.
Pierre Deniker had heard about Laborit's work from his brother in law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the Hôpital Sainte-Anne in Paris where he was Men's Service Chief. Together with the Director of the hospital, Professor Jean Delay, they published first clinical trial in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents. The response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour. They also found that doses higher than those used by Laborit were required, giving patients 75–100 mg daily. (Therapeutic use in psychiatry of phenothiazine of central elective action (4560 RP), 1952). Deniker then visited America, where the publication of their work alerted the American psychiatric community that the new treatment might represent a real breakthrough. Heinz Lehmann of the Verdun Protestant Hospital in Montreal trialled it in 70 patients and also noted its striking effects, with patients' symptoms resolving after many years of unrelenting psychosis.
(Chlorpromazine; new inhibiting agent for psychomotor excitement and manic states, 1954).
By 1954, chlorpromazine with the name of Thorazine was being used in the United States to treat schizophrenia, mania, psychomotor excitement, and other psychotic disorders.
In 1955 it was approved in the United States for the treatment of emesis (vomiting).
The effect of this drug in emptying psychiatric hospitals has been compared to that of penicillin and infectious diseases. Chlorpromazine largely replaced electroconvulsive therapy, psychosurgery, and insulin shock therapy. But the popularity of the drug fell from the late 1960s as newer drugs came on the scene.

MEDICAL USES

Chlorpromazine is classified as a typical antipsychotic and in the past was used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of bipolar disorder, as well as amphetamine-induced psychoses.
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 aggressive episodes.
Resistant and severe hiccups, and severe nausea/emesis are other uses. It is often, particularly in a palliative setting, used in small doses to improve the nausea that opioid-treated cancer patients encounter and to intensify and prolong the analgesic action of the opioids given.
Chlorpromazine is occasionally used off-label for treatment of severe migraine (Chlorpromazine in migraine, 2007).
Its action on the autonomic system produces vasodilation, hypotension, and tachycardia. Salivary and gastric secretions are reduced.

PHARMACOKINETICS

Pharmaceutical form

In acute settings, it is often administered as a syrup, which has a faster onset of action than tablets, and can also be given by intramuscular injection. IV administration is very irritating and is not advised; its use is limited to severe hiccups, surgery, and tetanus.

• Tablet, Long Acting Capsule, Liquid
  The dose may need to be changed several times to find what works best for the patient. The drug must be taken with food or milk to avoid stomach upset; in case of syrup, the patient may mix the liquid with fruit juice, milk, soda, coffee, tea, water, pudding, or apple sauce.
  The absorption of orally administered chlorpromazine is dependent on the dosage form. Peak plasma levels are reached at 2 to 3 hours. There is a wide inter-subject variability (ten times or more) in the plasma concentrations achieved. Plasma concentrations may be decreased significantly by food in the stomach and by the concomitant administration of anticholinergic antiparkinsonism drugs.

• Injectable
  This medicine is given through a needle placed in a vein or as a shot into muscles.

Distribution

Chlorpromazine is widely distributed in the body and crosses the blood-brain barrier to achieve higher concentrations in the brain than in the plasma. Chlorpromazine and its metabolites also cross the placental barrier and are excreted in milk. 90-99% of the chlorpromazine taken is bound by blood proteins, such as albumin. T _1/2 is about 30-36 hours.

Metabolism

Through CYP2D6 and CYP1A2, 160 metabolites are created, in the liver and in the kidneys. The major routes of metabolism include hydroxylation, N-oxidation, sulphoxidation, demethylation, deamination and conjugation. In man, after chronic use, the highest concentration of unconjugated chlorpromazine metabolites is found in the lung and liver.
Most metabolites of phenothiazines are pharmacologically inactive; however, certain metabolites (eg, 7-hydroxychlorpromazine, mesoridazine) show moderate pharmacologic activity and may contribute to the action of the drugs.
The onset of pharmacologic action following oral administration of chlorpromazine hydrochloride in an extended-release formulation is approximately 30-60 minutes; the duration of action is 10-12 hours.

Excretion

Urine (43-65% after 24 hours) and faeces

Notes

Its high degree of lipophilicity (fat solubility) allows it to be detected in the urine for up to 18 months. Less than 1% of the unchanged drug is excreted via the kidneys in the urine. In which 20-70% is excreted as conjugated or unconjugated metabolites, whereas 5-6% is excreted in faeces.

PHARMACODYNAMICS AND CENTRAL EFFECTS

Chlorpromazine is a very effective antagonist 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. Blocking these receptors causes diminished neurotransmitter binding in the forebrain, resulting in many different effects. Dopamine, unable to bind with a receptor, causes a feedback loop that causes 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 blockade of receptors only compounds this effect.
Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic receptors:

• Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms; in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects. The presumed effectiveness of the antipsychotic drugs relied on their ability to block dopamine receptors. This assumption arose from the dopamine hypothesis that maintains that both schizophrenia and bipolar disorder are a result of excessive dopamine activity.

• Serotonin receptors (5-HT1 and 5-HT2), with anxiolytic, and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain and ejaculation difficulties.

• Histamine receptors (H1 receptors, accounting for sedation, antiemetic effect, vertigo, and weight gain). Chlorpromazine and other antipsychotics with sedative properties such as promazine and thioridazine are among the most potent agents at histamine H1 receptors. This finding is in agreement with the pharmaceutical development of chlorpromazine and other antipsychotics as anti-histamine agents. Furthermore, the brain has a higher density of histamine H1 receptors than any body organ examined which may account for why chlorpromazine and other phenothiazine antipsychotics are as potent at these sites as the most potent classical antihistamines. It is not sure if the antiemetic effect is because of the interaction with H1 receptors or with receptors in the medullary chemoreceptor trigger zone (CTZ).

• α1- and α2-adrenergic receptors (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunctionc

• M1 and M2 muscarinic acetylcholine 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).

PERIPHERAL EFFECTS

Chlorpromazine is an antagonist 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)
• 5-HT receptors (different anti-allergic/gastrointestinal actions).

DISCONTINUATION

At regular intervals the treating physician should evaluate whether continued treatment is needed. The drug should never be discontinued suddenly, due to unpleasant withdrawal-symptoms, such as agitation, sleeplessness, states of anxiety, stomach pain, dizziness, nausea and vomiting. Preferably the dose should be gradually reduced.

MOST COMMON SIDE EFFECTS

• Very common
  • Sedation
  • Somnolence
  • Extrapyramidal symptoms
  • Weight gain
  • Orthostatic hypotension
  • Dry mouth
  • Constipation
  • If given in high doses over a long period during pregnancy, chlorpromazine may cause damage to the retina of the foetus.

• Common
  • Dermatitis, Urticaria
  • Photosensitivity
  • Impaired thermoregulation (poikilothermic effect) and other hypothalamic abnormalities
  • Mental confusion
  • Agitation: Chlorpromazine for psychosis induced aggression or agitation.
  • Excitement
  • Restlessness
  • Pain at the injection site
  • Injection site abscess
  • Drug induced liver injury, which has been associated with the induction of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha). Pro-inflammatory cytokines activate the mitogen activated protein kinase, c-Jun-N-terminal kinase (JNK) in the liver. However, the mechanism by which inflammation alters drug-induced hepatotoxicity is not known.
  • hematological disorders, including agranulocytosis, eosinophilia, leucopenia, hemolytic anemia, aplastic anemia, thrombocytopenic purpura and pancytopenia. Hyperglycemia, hypoglycemia and glycosuria have also been reported

In patients undergoing chlorpromazine for a long time

• Parkinson’s disease
• Inexpressive face
• Slow and difficult movements
• Tremor or muscular twitching, spasm, rigidity, convulsions
• Disabling unvoluntary movements

INTERACTIONS

Substances that limit absorption	Alcohol, Antacids, Lithium, Barbiturates
Substances that reduce clearance, therefore increase exposure to chlorpromazine	Ciprofloxacin
Chlorpromazine potentiates	Barbiturates, Benzodiazepines, Opioids, Lithium, Anaesthetics, Morphine, Respiratory depression
Chlorpromazine reduces	Antidiabetic agents’ activity, Levodopa activity, Amfetamines, Anticoagulants