Chlorpromazine

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 has also anxiolytic (alleviation of anxiety) properties. Today, chlorpromazine is considered a typical antipsychotic.

Chemistry
Chlorpromazine is derived from phenothiazine, its chemical name is 2-chloro-10-[3(-dimethylamino) propyl] phenothiazine monohydrochloride and its molecular formula is C17H19ClN2S•HCl. Chlorpromazine has an aliphatic side chain, typical for low to middle potency neuroleptics. The oral bioavailability is estimated to be 30% to 50% due to extensive first pass metabolization in the liver. Its elemination-halflife is 16 to 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).

Central
Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic 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), 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 finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, 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 weak 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 'dirty drug', whereas the atypical neuroleptic amisulpride e.g. acts only on central D2/D3-receptors and is therefore a 'clean drug'. This distinction expresses no valuation of the drugs.

History
The drug had been developed by Laboratoires Rhône-Poulenc in 1950 but they had sold the rights in 1952 to Smith-Kline & French. 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. 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 Demerol and Hydergin. Patients with shock, severe trauma or burns, become, if treated so, sedated, without anxiety and unreponsive/indifferent to painful external stimuli like minor surgical interventions. It was first used for psychiatric patients by Pierre Deniker and Jean Delay in 1953. 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 sedation 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. Chlorpromazine has given approximately 70% of all schizophrenic patients a complete remission or near so and a normal, gainful human life. 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, 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.

Additional side effects include dry mouth, increased appetite with weight gain, constipation, 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.

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 the opioid tramadol (Ultram). Chlorpromazine may increase the insulin needs of diabetic patients.

Drugs like SSRI-s, St. John's Wort and barbiturates can induce various CYP-isoenzymes needed for metabolization of chlorpromazine and/or its metabolites. Theoretically, this should decrease the half-lives of chlorpromazine and its metabolites and making more frequent and/or higher dosing necessary. The exact clinical significance of this enzyme induction and its therapeutic consequences are unknown at present time and remain to be evaluated.

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.

Chlopromazine formerly was the drug of choice to treat LSD 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.

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. 

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, if 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 (NB: chlorpromazine may lower the seizure-threshold in alcoholics).

It has an 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.

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 in the horse, due to a high incidence of ataxia and altered mentation.

Dosage
Dosage : In any case, use as determined by 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 disturbed patients. Different qualified sources give 800 mg/day to 1,200 mg/day as highest dose. At least there is 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 hytotension. 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 regularly checked their blood-pressure, pulse-rate, laboratory-tests (liver-function-studies, 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
Also, in regular intervals the treating physician should evaluate whether continued treatment is needed. If not, the drug should never be stopped suddenly, due to very unpleasant 'withdrawal-symptoms', such as agitation, sleeplessness, states of anxiety, etc. However, these symptoms definitely do not indicate psychological or physical dependence. The dose should rather be slowly tapered down at a rate of approximately 20-25% per week or even slower to avoid the aforementioned bothersome symptoms.