Chlorpromazine

Chlorpromazine (as chlorpromazine hydrochloride, abbreviated CPZ) is a phenothiazine antipsychotic.

Its principal use is in the treatment of schizophrenia, though it has also been used to treat hiccups and nausea. Its use today has been largely supplanted by the newer quetiapine.

Chlorpromazine works on a variety of receptors in the central nervous system; these include typical antipsychotic.

Its receptor affinities result in a side-effect profile that is predominantly anticholinergic in nature: constipation, sedation, hypotension, and Neuroleptic malignant syndrome is a rare though potentially fatal outcome of any antipsychotic use — about one in two thousand (0.05%) patients taking chlorpromazine may develop it.

Originally sold in the 1950s and 1960s, under the trade names Largactil and Thorazine, chlorpromazine was the first drug to come into use as an antipsychotic, and was the prototype for the phenothiazine class, which later grew to comprise several other agents. It is often administered in acute settings as a syrup, which has a faster onset of action than tablets. Parenteral administration is not generally recommended.

History

The drug had been developed by trifluoperazine).

Previously used as an antiemetic its effects on mental state were first reported by the French doctor Henri Laborit in 1951 or 1952 (different sources) as sedation without narcosis. It became possible to cause 'artificial hibernation' in patients, if used as a cocktail together with pethidine and hydergine. Patients with shock, severe trauma or burns, become, if treated so, sedated, without anxiety and unresponsive/indifferent to painful external stimuli like minor surgical interventions. The first published clinical trial was that of Jean Delay and Pierre Deniker at Ste. Anne Hôspital in Paris in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine.^[2] Drug treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour. Ironically, the antipsychotic properties of chlorpromazine appear to be unrelated to its sedative properties. During long term therapy some tolerance to the sedative effect develops.

Chlorpromazine substituted and eclipsed the old therapies of electro and insulin shocks and other methods such as psychosurgical means (lobotomy) causing permanent brain injury. Before the era of neuroleptics, starting with chlorpromazine, positive long-term results for psychotic patients were only 20%.

Pharmacology

Pharmacokinetics

Chlorpromazine is derived from 2D6 are needed for metabolism of chlorpromazine, and the 2D6 subtype is inhibited by chlorpromazine (NB: possible interactions with other drugs).

Central effects

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;
• extrapypramidal side effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties),
• histamine receptors (H₁ receptors, accounting for sedation, antiemetic effect, vertigo, fall in blood pressure and weight gain),
• α₁- and α₂-adrenergic 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
• 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).

Additionally, chlorpromazine is a 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).

Peripheral effects

Chlorpromazine is an antagonist to H₁ receptors (provoking antiallergic effects), H₂ receptors (reduction of forming of gastric juice), 5-HT receptors (different anti-allergic/gastrointestinal actions).

Because it acts on so many receptors, chlorpromazine is often referred to as a "amisulpride, for example, acts only on central D₂ and D₃ receptors and is therefore a "clean drug". Research still needs to be done to understand the implications of this fact.

Adverse effects

The main Photosensitivity may occur, resulting in increased risk of sunburn.

olanzapine.^[3]

A particularly severe side effect is neuroleptic malignant syndrome which occurs in approximately 0.05% of those taking chlorpromazine and can be fatal.

Other reported side effects are rare, though severe; these include a reduction in the number of white blood cells—referred to as leukopenia—or, in extreme cases, even agranulocytosis, which may occur in 0.01% of patients and lead to death via uncontrollable infections and/or sepsis. Chlorpromazine is also known to accumulate in the eye—in the posterior corneal stroma, lens, and uveal tract. Because it is a phototoxic compound, the potential exists for it to cause cellular damage after light exposure. Research confirms a significant risk of blindness from continued use of chlorpromazine, as well as other optological defects such as color blindness and benign pigementation of the cornea.[2][3]

Chlorpromazine is the neuroleptic drug with the highest rates (0.5% to 1%) of liver toxicity of the cholestatic type.

The sedation effect combined with indifference to physical stimuli, anecdotally known as the "thorazine shuffle," has long been associated with the drug. The image of psychiatric patients staggering mute around a padded cell has earned those particular side effects a place in mainstream pop culture.

Interactions

Chlorpromazine intensifies the central depressive action of drugs with such activity (tranquilizers, diabetic patients.

Drugs such as enzyme induction and its therapeutic consequences are unknown at present time and remain to be evaluated.

Veterinary uses

Chlorpromazine is primarily used as an muscle relaxant in cattle, swine, sheep, and goats. It is generally contraindicated for use with horses, due to a high incidence of ataxia and altered mentation.

Dosage and administration

In any case, use is determined by an attending physician. The following information is intended to serve as a guideline: A wide range is covered from 25 mg oral or intramuscular for mild sedation, every 8 hours, up to 100 mg every 6 hours for severely ill patients. Different qualified sources give 800 mg/day to 1,200 mg/day as highest dose. There has been at least one small clinical trial in treatment-resistant patients with a daily dose of 1,200 mg chlorpromazine (and 4 mg Benztropine to counteract early extrapyramidal side effects, which were anticipated with this unusual high chlorpromazine dose). Initial doses should be low and be increased gradually. It is recommended that most of the daily dose (e.g. 2/3) is given at bedtime for maximum hypnotic activity and minimal daytime sedation and hypotension. In the USA there are controlled release forms of chlorpromazine (e.g. 300 mg). After the individual dose is well established, such a CR capsule can be given with the evening meal as a single dose, covering the next 24 hours. It is often administered in acute settings as a syrup, which has a faster onset of action than tablets.

The lowest dosage compatible with good therapeutic effect should be given. Dosage in ambulatory patients should be particularly low (minimizing sedation and hypotension). The direct i.v.-injection of undiluted solution is contraindicated (massive fall in blood pressure, cardiovascular collapse), for i.v.-infusion of dilutions the (hospitalized) patient should be lying and the infusion rate should be as slow as possible. Afterwards the patient should rest in the lying position for at least 30 minutes.

Intramuscular administration is generally not recommended due to the unpredictable absorption and hence widely varying effect. The injection has been reported to be uncomfortable or painful and cause sterile abscesses.^{[citation needed]}

All patients treated with chlorpromazine on a long-term-basis should have the following checked regularly: blood-pressure, pulse rate, laboratory-tests (tardive dyskinesia).

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, etc. (which should not be construed as stemming from psychological or physical dependence). The dose should rather be slowly reduced at a rate of approximately 20–25% per week.

Indications

Chlorpromazine is classified as a low-potency 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. The use of chlorpromazine has been largely replaced by newer generation of atypical antipsychotics which are generally better tolerated. Recent global review of data supports its effectiveness as an antipsychotic.^[4]

Chlorpromazine formerly was the drug of choice to treat psychedelic/hallucinogen) intoxication in a hospital setting, resulting in it gaining an erroneous reputation as the LSD antidote. Now risperidone is more commonly used in such situations. ^[5]

Other uses

It has also been used in porphyria and as part of tetanus treatment.

It still is well recommended for short term management of severe anxiety and aggressive episodes.

Resistant and severe hiccups, severe nausea/emesis and preanesthetic conditioning have been other indications in the past.

It can be used to treat amphetamine overdose.^[6]

Off-label and controversial uses

Chlorpromazine is occasionally used off-label for treatment of severe migraine. Sometimes it is used in small doses to improve nausea/emesis analgesic properties. Analgesic properties may result from a central action on the hypothalamus; the patient may feel the pain much less than before. Other mechanisms may be an interaction with opioid receptors centrally and/or in the spinal cord. Some experts on the contrary say that chlorpromazine, like other phenothiazines, may even have antianalgesic properties. Chlorpromazine has been proposed as useful in newborns for the treatment of opioid withdrawal, if the mother was opioid-dependent. The latter indication remains highly controversial.

It has a unique action in cholera, reducing the loss of water by approximately 30%.

In Germany, the brand of chlorpromazine drug Propaphenin® has additional indications for insomnia and itching skin disease.

Some jurisdictions in the United States use Thorazine as a sedative/tranquilizer prior to carrying out a death sentence by lethal injection.[4] The condemned may be offered the sedative and some states require that it be administered, even against the wishes of the condemned.^{[citation needed]}

Was used in the 1970's as a treatment for Hyperactive children as a means of calming them down.

References

Sources

• Baldessarini, Ross J.; Frank I. Tarazi (2006). "Pharmacotherapy of Psychosis and Mania", in Laurence Brunton, John Lazo, Keith Parker (eds.): Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11^th ed., New York: McGraw-Hill. ISBN 978-0071422802. 
• Bezchlibnyk-Butler, K. Z. Clinical Handbook of Psychotropic Drugs (German Edition)
• Rote Liste (German Drug Compendium)
• Benkert, O. and H. Hippius. Psychiatrische Pharmakotherapie (German. 6th Edition, 1996)
• Physician's Desktop Reference (2004)
• Heinrich, K. Psychopharmaka in Klinik und Praxis (German, 2nd Edition, 1983)
• Römpp, Chemielexikon (German, 9th Edition)
• NINDS Information Homepage (see External links section)
• Plumb, Dondal C. Plumb's Veterinary Drug Handbook (Blackwell, 5th Edition, 2005)
• Methods of Execution. Clark County, IN Prosecuting Attorney web page. Retrieved on 2007-03-13.