Chlorpromazine
Systematic (IUPAC) name
3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-1-amine
Identifiers
CAS number	50-53-3
ATC code	N05AA01
PubChem	2726
DrugBank	APRD00482
Chemical data
Formula	C17H19ClN2S1 •HCl
Mol. mass	355.3 (as hydrochloride)
Pharmacokinetic data
Bioavailability	30-50% (interindividual variations 10–70%)
Metabolism	hepatic
Half life	16–30 hours, in longterm treatment CPZ induces its own metabolism
Excretion	biliar and urine as metabolites (only traces of unchanged drug)
Therapeutic considerations
Pregnancy cat.	C : Only when benefit for the mother exeeds risk to unborn child
Legal status	RX-Medication-only
Routes	oral, rectal, i.m., i.v.-infusion

Chlorpromazine was the first antipsychotic drug, used during the 1950s and 1960s. Used as chlorpromazine hydrochloride and sold under the tradenames Largactil® and Thorazine®, it has sedative, hypotensive and antiemetic properties as well as anticholinergic and antidopaminergic effects. It also has anxiolytic (alleviation of anxiety) properties. Today, chlorpromazine is considered a typical antipsychotic.

Contents 1 Chemistry 2 Mechanism of action 2.1 Central 2.2 Peripheral 3 History 4 Side effects 5 Interactions 6 Uses 6.1 Common uses 6.1.1 As an antipsychotic 6.1.2 Other uses 6.2 Off-label and controversial uses 6.3 Veterinary uses 7 Dosage 8 Necessary examinations and laboratory checks during treatment 9 Discontinuation of treatment 10 Sources 11 External links

Chemistry

Chlorpromazine is derived from phenothiazine, and has an aliphatic side chain, typical for low to middle potency neuroleptics. The oral bioavailability is estimated to be 30–50% due to extensive first pass metabolization in the liver. Its elimination-halflife is 16–30 hours. It has many active metabolites (approx. 75 different ones) with greatly varying halflives and own pharmacological profiles. The CYP-450 isoenzymes 1A2 and 2D6 are needed for metabolization of chlorpromazine and the subtype 2D6 is inhibited by chlorpromazine (NB: possible interactions with other drugs).

Mechanism of action

Central

Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic 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),
• on 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
• on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, constipation, 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 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

Antagonist to H1 receptors (antiallergic effects), H2 receptors (reduction of forming of gastric juice), M1/M2-receptors (dry mouth, reduction in forming of gastric juice) and some 5-HT receptors (different anti-allergic/gastrointestinal actions).

Because it acts on so many receptors, chlorpromazine is often referred to as a "dirty drug", whereas the atypical neuroleptic amisulpride for example acts only on central D2/D3-receptors and is therefore a "clean drug". A lot more research needs to be done to understand the implications of this 'fact'. Here, it suffices to simply describe the relative pharmacology.

History

The drug had been developed by Laboratoires Rhône-Poulenc in 1950 but they sold the rights in 1952 to Smith-Kline & French (today's GlaxoSmithKline). The drug was being sold as an antiemetic when its other use was noted. Smith-Kline was quick to encourage clinical trials and in 1954 the drug was approved in the US for psychiatric treatment. The effect of this drug in emptying psychiatric hospitals has been compared to that of penicillin and infectious diseases.^[1] Over 100 million people were treated but the popularity of the drug fell from the late 1960s as the severe extrapyramidal side effects and tardive dyskinesia became more of a concern. From chlorpromazine a number of other similar neuroleptics were developed (e.g. triflupromazine, trifluoperazine).

Previously used as an antihistamine and 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.^[1] 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%.

Side effects

Side effects of chlorpromazine are typical of early generation neuroleptics. They include extrapyramidal side effects such as tardive dyskinesia and akathisia. A particularly severe side effect is the neuroleptic malignant syndrome which occurs in approximately 0.05% and can be fatal. Also, chlorpromazine may lower seizure threshold. The agent is also known to accumulate 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.

Additional side effects include dry mouth, increased appetite with weight gain, constipation and urinary retention. Glucose tolerance may be impaired. An allergic skin rash and photosensitivity may occur. Other important and severe side effects are a strong reduction in the number of white blood cells, referred to as leukopenia, or, in extreme cases, even agranulocytosis may result, which may lead to death via uncontrollable infections and/or sepsis. 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, barbiturates, narcotics, antihistamines, OTC-antiemetics etc.). A dose reduction of chlorpromazine or the other drug may be necessary. Chlorpromazine also intensifies the actions and undesired side effects of antihypertensive medications and anticholinergic drugs. The combination of chlorpromazine with other antipsychotics may result in increased central depression, hypotension and extrapyramidal side effects, but may sometimes enhance the clinical results of therapy. The anti-worm drug (antihelminthic) piperazine may intensify extrapyramidal side effects. In general, all neuroleptics may lead to seizures in combination with tramadol (Ultram). Chlorpromazine may increase the insulin needs of diabetic patients.

Drugs like SSRIs, St. John's Wort and barbiturates can inhibit various CYP-isoenzymes such as CYP2D6, needed for metabolization of chlorpromazine and/or its metabolites. Theoretically, this should increase the half-lives of chlorpromazine and possibly its metabolites, dosing changes necessary. The exact clinical significance of this enzyme induction and its therapeutic consequences are unknown at present time and remain to be evaluated.

Uses

Common uses

Great care needs to be exercised when evaluating the use of drugs such as chlorpromazine developed in an era of 'fashionable' substance use and medicine. Modern clinical practice is followed up by a vastly superior patient monitoring system .It is increasingly clear that there was substantive 'abuse' of chlorpromazine often seen as a panacea for a whole range of anti-social behaviours whose interplay with economic and political conditions is often more important than 'generic' behavioural 'defects'. Just as 50-100 years ago , 'mad' houses were often substitute 'prisons', chlorpromazine and other drugs touted by their makers as the miracle in a 'pill' have been used to the same 'effect'. Todays computers with their ability to collate vast amounts of information and a much more 'open' medical practice with a wider array of drugs available mean that there is that ever more greater chance of preventing abuse.

As an antipsychotic

The use of chlorpromazine has been primarily replaced by newer generation of atypical antipsychotics which have an improved side effect profile. Chlorpromazine is classified as a low- to moderate-potency antipsychotic and in the past was used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of manic depression as well as amphetamine-induced psychoses.

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 haloperidol is more commonly used in such situations.

Other uses

It has also been used in porphyria, as part of tetanus treatment and for behavioral problems in children.

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. [1]

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 opioid-treated cancer patients encounter and to intensify and prolong the analgesic action of the opioids given. Interestingly, it remains controversial whether or not chlorpromazine has its own 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.

Chlorpromazine, as well as other neuroleptics, may also be used to alleviate the symptoms of alcohol withdrawal (chlorpromazine may lower the seizure-threshold in alcoholics).

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 where capital punishment is used. The condemned may be offered the sedative and some states require that it be administered, even against the wishes of the condemned.[2]

Veterinary uses

Chlorpromazine is primarily used as an antiemetic in dogs and cats. It is also sometimes used as a preanesthetic and 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

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 Thorazine (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.

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.

Necessary examinations and laboratory checks during treatment

All patients treated with chlorpromazine on a long-term-basis should have the following checked regularly: blood-pressure, pulse rate, laboratory-tests (liver function tests, kidney-values, blood cell counts including differenciated white blood counts, counts of red blood cells and thrombocytes), ECG and EEG. The frequency of all checks should be determined for the individual patient and may be done in shorter intervals during the first 3 months of treatment and less often afterwards. Some side effects seem to appear more frequently during the first months of therapy (sedation, hypotension, liver damage) while others do not (e.g. tardive dyskinesia).

Discontinuation of treatment

At regular intervals the treating physician should evaluate whether continued treatment is needed. The drug should never be discontinued suddenly, due to very 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, or even slower, to avoid the aforementioned bothersome symptoms.

Sources

• Goodman & Gilman, The Pharmacological Basis of Therapeutics
• 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.

External links

• Medlineplus.org article on chlorpromazine
• National Institute of Neurological Disorders and Stroke (NINDS) Tardive Dyskinesia information page
• Links to external chemical sources

v • d • e Antipsychotics (N05A)
Phenothiazine typical antipsychotics	Chlorpromazine, Fluphenazine, Mesoridazine, Perphenazine, Prochlorperazine, Promazine, Thioridazine, Trifluoperazine
Other typical antipsychotics	Chlorprothixene, Droperidol, Flupentixol, Benperidol,Haloperidol, Loxapine, Molindone, Pimozide, Sulforidazine, Thiothixene
Atypical antipsychotics	Amisulpride, Aripiprazole, Clozapine, Melperone,Olanzapine, Quetiapine, Risperidone, Paliperidone, Sertindole, Sulpiride, Ziprasidone, Zotepine