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Chlorpromazine was the first antipsychotic drug, used during the 1950s and 1960s. Used as chlorpromazine hydrochloride and sold under the tradenames Largactil® (the "liquid cosh") 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.
Introduction:
Chlorpromazine is classified as a low-potency antipsychotic and is used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of manic depression. It is also used in porphyria, as part of tetanus treatment and for behavioral problems in children. Resistant and severe Hiccups, severe nausea/emesis and preanesthetic conditioning may be other valueable (short-time) indications.
In the USA it is still one of the most commonly used antipsychotics.
It 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!) 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).
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 'artifical 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 made obsolete the old 'therapies' of electro- and insulin-shocks and other inhumane methods such as psycho-surgical 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%.
Mechanism of Action
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-recptors (reduction of forming of gastric juice), M1/M2-receptors (dry mouth, reduction in forming of gastric juice) and some 5-HT-receptors (different antiallergic/gastrointestinal actions).
Because it acts on so many receptors, Chlorpromazine is often referred to as 'dirty drug', whereas the atypical neuroleptic Amisulprid e.g. acts only on central D2/D3-receptors and is therefore a 'clean drug'. This distinction expresses no valuation of the drugs!
General Information:
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).
Central Nervous Side Effects:
Cases of early extrapyramidal side-effects (pseudoparkinsonism, early dyskinesia and other less frequent forms) can in most cases be treated by reducing the dose regime of Chlorpromazine and/or by co-administration of an antiparkinsonic drug such as Akineton® (Biperiden) or Benadryl®(Diphenhydramine) for some days or weeks. Levodopa should not be given, because it is likely to worsen the psychotic condition. Clonazepam (Klonopin®) treatment can help for akathisia, a state in which the affected person has a permanent und vexing unrest in his/her legs, but Klonopin® is habit forming in long-term regard. Akathisia is more often seen in patients taking Fluoxetin (Prozac®) at the same time.
There is no known sure alleviation or cure for tardive dyskinesia. Tardive dyskinesia is characterized by repetitive, involuntary, purposeless movements (NINDS-Definition). Features of the disorder may include grimacing, tongue protrusion, lip smacking, puckering and pursing, and rapid eye blinking. Rapid movements of the arms, legs, and trunk may also occur. Involuntary movements of the fingers may appear as though the patient is playing an invisible guitar or piano (quotation from NINDS-homepage). Tardive Dyskinesia is a state which can persist for months or years after withdrawal of Chlorpromazine or may even be permanent for the rest of life. Studies suggest that most patients find it harder to accept perioral and facial dyskinesia than the limb movements.
There is no sure alleviation or cure for tardive dyskinesia, but experimental medicine has early results that interestingly the atypical neuroleptic Clozaril® (Clozapine) may improve the state of the patient. Improvements are also seen, if Lorazepam (Ativan®), Diazepam (Valium®) or the aforementioned Clonazepam are used. Other Benzodiazepines, called 'low potency Benzodiazepines' seem to be of no or very little use. Positive results for Vitame E (Alpha-Tocopherol) or Melatonin are highly preliminary. Treatment with adrenergic blocking agents and dopamine agonists like bromocriptin remains also somewhat controversial.
The elderly and female patients are more prone to develop tardive dyskinesia. It is also important to know that the concurrent prophylactical use of a neuroleptic and an antiparkinsonian drug is useless to avoid early extrapyramidal side-effects and renders the patient more sensitive to tardive dyskinesia as most studies suggest. The incidence of tardive dyskinesia varies with the type of neuroleptic (typicals more often than atypicals), daily dose and duration of treatment (the higher the daily dose and the duration of treatment, the higher is the risk). Tardive dyskinesia is also the foremost reason that the patients (if their condition allows), their families, guardians and/or caregivers/nurses should receive full information about Chlorpromazine before starting treatment (informed consent). This is also true for all other antipsychotics. Tardive dyskinesia can become a serious handicap for people in social and personal regards!
NB: Children and aldolescents are much more sensitive to the early and late extrapyramidal side-effects of Chlorpromazine than adults! Treatment should be initiated only with a clear indication, the lowest dose regime possible and the shortest duration of treatment in accordance with good patient management!
During the first few weeks the patient might be grossly sedated and difficult to arise during the day, particulary when high doses are given. In order to avoid thromboembolic events, passive physical exercise/mobilization and/or the daily injection of Heparin-Sodium Injection USP (ca. 5,000 IU s.c.) may be necessary and useful, particularly in patients which have other predisposing factors (adipositas, hypercoagulability or thrombophlebitis of deep veins). As soon as possible, patients should start own physical activities.
Additional to simple sedation, Chlorpromazine causes cognitive and/or intellectual deficits in a high number of patients, which may be reversible or permanent, dependent from dosage and duration of Chlorpromazine treatment. The cases of permanent brain damage have led some to refer to as 'chemical lobotomy' "chemical lobotomy"*.
A dysphoric mood may be a subjective reason for some patients to stop treatment on their own initiative.
A particulary severe CNS side effect is the so-called 'Malignant Neuroleptic Syndrom' (MNS) which occurs in approximately 0.05% of all patients and leads to death in 10-30% of all those affected. The MNS is characterized by high fever (hyperpyrexia, 39 - 41 deg. Celsius), profound sweating, delirant sympomts and sometimes katatonia (inability to speak or react to external stimuli). The patient is transferred to intensive-care-treatment. MNS is treated with withdrawal of the neuroleptic, cooling blankets and the drug Dantrolene-Sodium via i.v. Infusion. The dopaminergic drug Bromocriptin has experimentally been used with mixed results. Exchange-transfusions are a last choice method. MNS may be caused by all known neuroleptics. Due to its relatively short halflife Chlorpromazine-induced MNS may possibly be better and faster controlled than MNS caused by drugs with long halflives or even by depot-neuroleptics ('apparent halflife' = some weeks!).
Also, Chlorpromazine may lead to seizures of the Grand-Mal-type with or without previous changes in EEG-monitoring. Valproic-Sodium (Depakene® in the USA and Canada), (Orfiril® or Ergenyl® in Europe) may then be given to counteract further seizures. Patients with epilepsia should receive optimal anticonvulsive therapy before Chlorpromazine is started!
Side Effects concerning Peripheral Nerve System and Whole Body:
The drug has also strong effects on the peripheral nerve system and the body itself including low blood pressure, high pulse (tachycardia), dry mouth (prophylaxis of tooth damage necessary, careful mouth hygiene), increased appetite with weight gain, obstipation, even life-threatening ileus (paralysis of the bowels) and difficulty/inability to urininate (men > 50 yrs. are affected).
As Chlorpromazine blocks the normal thermal regulation of the body, the patient should not be exposed to heat (reversible hyperthermia or even 'heat stroke').
Night sweats may also become troublesome. Often patients have to change their night garments twice during the night. The drug Agaricin may temporarily help for 4 to 6 weeks.
The glucose-tolerance my be impared and a latent Diabetes mellitus can become manifest, likewise in patients with known Diabetes the Insulin-dose may have to be adjusted. The increase in appetite is in most cases serious enough to avoid massive weight gain (5 kgs. and more) by dietary counseling and the avoidance of carbon hydrates wherever possible (no limonades, sugar cakes etc.)!
Also, allergic skin rash (3%-4%) and photosensitivity (sensitivity to light exposure) are quite common side effects on the skin.
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 damage of the cholostatic type which may also (infrequently) cause death. There is some evidence that the purity of Chlorpromazine determines the frquency of liver damage.
NB: Children and aldolescents with fever should not be treated with Chlorpromazine. Chlorpromazine as hepatotoxic drug may cause the life-threatening REYE-Syndrom with severe liver-damage. Thirty percent of all those affected die!
Chlorpromazine may depending on a critical dose and treatment time be deposed in the cornea and retina of the eyes leading sometimes to permanently disturbed vison and in the heart muscle. It can also precipate closed-angle-glaucoma (elevated pressure in the inner parts of the eye(s), particular in patients >40 yrs. Patients should undergo ophtalmic examinations regularly (at least 2 times a year).
Rarely sudden death due to silent pneumonia or sudden cardiac arrest (from ventricular fibrillation) occurs (obviously, less than 1 in 1,000 patients). A respiratory depression, encountered very rarely in healthy young individuals, might endanger patients with serious prexisting illness, like severe asthma or lung emphysema, as these patients require full Oxygen-tension in the blood. Also, problems of the patients to communicate their problems to physicians or nurses may contribute.
In both genders the sexual drive (libido) may be decreased due to sedation and indifference to external stimuli. Men frequently experience impotence and ejaculation difficulties. Women may have disturbances in their regular menstrual cycle, even to the point of amenorrhoe (no menstrual bleeding at all). These disturbances seem to be mediated centrally (action of Chlorpromazine on hypothalamus and increased Prolactin secretion) and/or peripherically (blockage of alpha-receptors in the testes). Particulary men sometimes stop treatment due to sexual side-effects!
Loss of libido can be treated with Neostigmin or Cyproheptadin (Nuran®)) 30 minutes before starting sexual activity. Impotence can sometimes be alleviated with the experimental drugs Bethanechol or Yohimbine or even with the cautious use of a 5-Phosphodiesterase-inhibitor such as Viagra®, Cialis® or Levitra/Vivanza® (additional hypotension may be possible, so the lowest possible dose of the Phosphodiesterase-inhibitor should be chosen).
Given the the high frequency and severity of side effects and the development of new typical (e.g. Haloperidol) and atypical neuroleptics (Olanzapin, Risperidone, Aripiprazole etc.) with a (probably) more favorable side effect profile, Chlorpromazine is nowadays seldom used in Continental Europe. In any case, the usefulness of continued therapy and the risks should be carefully judged, particularly if treating children and aldolescents < 18yrs.
Angloamerican authorities justify the widespread use of Chlorpromazine, particulary in the USA, stating that it is the best explored neuroleptic worldwide, which is true.
Cancer risk (Cancerogenity):
On Chlorpromazine treatment the body produces more Prolactin than normal in both sexes. As Prolactin stimulates the proliferation of breast cells, it was proposed that Chlorpromazine may cause an increased rate of breast-cancer. There has also been some evidence in animal experience supporting this suggestion. However, large studies have shown that for humans there is no increased risk in both genders!
Also, there is no epidemological evidence supporting any influence of Chlorpromazine on leucemia and liver-cell-carcinoma in men.
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 opioide-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 strong as 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, both indications are surely difficult to justify regarding the high frequency and severity of side-effects!
Veterinary Uses:
Chlorpromazine is also widely used as a tranquilizer in veterinary medicine (e. g. to calm down animals on the their transport to slaughterhouse), this practise has led to some fears about chlorpromazine residues in the resulting meals people consume. It is also used for sedation or anesthesia of cats and dogs.
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 25mg oral or i.m. for mild sedation, every 8 hours, up to 100mg every 6 hours for severely disturbed patients. Different qualified sources give 800mg/day to 1,200mg/day as highest dose. At least there is one small clinical trial in treatment-resistant patients with a daily dose of 1,200mg Chlorpromazine (and 4mg Benzatropine 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. 300mg). 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!
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 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, if 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. These symptoms do definetely 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.
General Remarks:
Generally, it is not appropriate to refuse a psychotic patient neuroleptic treatment for fears of side-effects!
Despite its psychotropic actions, the drug is not habit forming and is not a controlled substance (narcotic). Chlorpromazine is RX-only medication.
Schizophrenic patients should additionally receive ergotherapy and psychotherapy as soon as their mental state allow in order to increase social capabilities and to foster rehabilitation.
Sources:
Goodman & Gilman's : The Pharmacological Basis of Therapeutics, K. Z. Bezchlibnyk-Butler : Clinical Handbook of Psychotropic Drugs (German Edition), Rote Liste (German Drug Compendium), O. Benkert/H. Hippius Psychiatrische Pharmakotherapie (German. 6th. Edition, 1996), Physician's Desk Reference (Edition 2004), K. Heinrich : Psychopharmaka in Klinik und Praxis (German, 2nd. Edition, 1983), Römpp: Chemielexikon (German, 9th. Edition), NINDS Information Homepage (see external links)
External Links
- [1] for Tardive Dyskinesia
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