Chlorpromazine

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Chlorpromazine
Systematic (IUPAC) name
3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-1-amine
Identifiers
CAS number	50-53-3 (free base) 69-09-0 (hydrochloride)
ATC code	N05AA01
PubChem	2726
DrugBank	APRD00482
ChemSpider	2625
Chemical data
Formula	C17H19ClN2S
Mol. mass	318.86 g/mol (free base) 355.33 g/mol (hydrochloride)
Pharmacokinetic data
Bioavailability	Oral, 30 to 50% (interindividual variations 10–70%)
Metabolism	Hepatic, mostly CYP2D6-mediated
Half life	16 to 30 hours. In long term treatment, CPZ induces its own metabolism
Excretion	Biliary and renal, as metabolites (only traces of unchanged drug)
Therapeutic considerations
Pregnancy cat.	C—only when benefit for the mother exceeds risk to unborn child
Legal status	℞ Prescription only
Routes	Oral, rectal (suppository), IM, IV infusion

Chlorpromazine (as chlorpromazine hydrochloride, abbreviated CPZ, marketed in the US as Thorazine, as [ Largactil in UK) is a phenothiazine antipsychotic, and the oldest in the antipsychotic family of drugs. It is a typical antipsychotic. It is principally used in the treatment of schizophrenia, though it has also been used to treat severe manic episodes in people with bipolar disorder. It has also been proven in stopping uncontrollable hiccups. Synthesized on December 11, 1950, chlorpromazine was the first drug developed with a specific antipsychotic action. Its use has been described as the single biggest advance in psychiatric treatment, with a dramatic effect on the prognosis of the inmates of asylums worldwide. It was the prototype for the phenothiazine class, which later grew to comprise several other agents. Its use today has been largely supplanted by the newer atypical antipsychotics such as olanzapine, quetiapine, and risperidone.

Chlorpromazine works on a variety of receptors in the central nervous system; these include anticholinergic, antidopaminergic and antihistamine effects as well as some antagonism of adrenergic receptors.^[1] Chlorpromazine, along with many of the older antipsychotics which have minimal effect on the serotonergic pathways, is considered a typical antipsychotic.

Its receptor affinities result in a side-effect profile that is predominantly anticholinergic in nature: constipation, sedation, hypotension and antiemetic properties. It also has anxiolytic (alleviation of anxiety) properties. Extrapyramidal side-effects that are common in many antipsychotics may occur, but are ameliorated by chlorpromazine's anticholinergic activity. They include akathisia and parkinsonian tremor, which can be very unpleasant though reversible. A more chronic side-effect is tardive dyskinesia, which may be irreversible in some patients.^[2] 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. It is often administered in acute settings as a syrup, which has a faster onset of action than tablets. Intravenous administration is not generally recommended.

[edit] History

In the 1930s, a drug called promethazine, a phenothiazine derivative, was discovered to possess sedative and antihistaminic effects, but it was not strong enough to be used as an anesthetic on its own. It was then thought it could be used as an anesthetic potentiator, but this use also was not economically successful. This instigated the hunt for a new phenothiazine derivative with better sedative potential. The French chemist Paul Charpentier produced a series of compounds and selected one with the least peripheral activity, known as RP4560 or chlorpromazine, on 11 December 1950. Simone Courvoisier ran initial behavioural tests in rats and noted the compound induced disinterest or detachment. Following this, chlorpromazine was distributed for testing to physicians in France and abroad between April and August 1951.

Its effects on mental state were first reported by the French doctor Henri Laborit 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. Laborit initially felt its benefit would be in anesthesia and medical stress.

The first published clinical trial was that of Jean Delay and Pierre Deniker at the Hôpital Ste. Anne in Paris in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents.^[3] The response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour.

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. By 1954, chlorpromazine was being used in the United States to treat schizophrenia, mania, psychomotor excitement, and other psychotic disorders.^{[4] [5] [6]}

The drug had been developed by Laboratoires Rhône-Poulenc in 1950 but they sold the North American rights in 1952 to Smith-Kline & French (today's GlaxoSmithKline). GlaxoSmithKline has since discontinued the drug and it is now only available as a generic drug. 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.^[3] 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 such as triflupromazine and trifluoperazine.

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%.^{[citation needed]}

[edit] Pharmacology

[edit] Pharmacokinetics

Chlorpromazine, and many other phenothiazine derivatives, are very lipophilic molecules that readily bind with membranes and proteins. Approximately 95-98% of the drug is bound in the plasma; 85% of the drug is bound to the plasma protein albumin. Renal disease may cause this range to expand significantly. Highest concentrations of the drug can be found in the brain, lung, and other tissues that receive a high supply of blood. It can also enter fetal circulation and breast milk, so pregnant and nursing mothers must beware, especially since fetuses have a low rate of phenothiazine metabolism. The elderly also have a slower rate of metabolism, but it seems that children have the highest. The anticholinergic properties only slightly influence chlorpromazine's absorption from the gastrointestinal tract, compared to other neuropleptics such as Fluphenazine.

Bioavailability: Only about 32% of the administered dose is available to the systemic circulation in the active form. Over time and multiple administrations, bioavailability may drop to 20%. Peak concentrations are achieved in 1 to 4 hours. ^[7]

Three Common Metabolites of Chlorpromazine

Chlorpromazine is derived from phenothiazine, 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 metabolism in the liver. Its elimination half-life is 16–30 hours, due to high lipophilicity, high membrane-binding, and high protein-binding. It has many active metabolites (approximately 75 different ones) with greatly varying halflives and pharmacological profiles. The cytochrome P450 isoenzymes 1A2 and 2D6 are needed for metabolism of chlorpromazine.

Chlorpromazine is typically degraded by the liver by the action of cytochrome-P450 family enzymes, usually CYP2D6. Less than 1% of the unchanged drug is excreted via the urine. There are on the order of 10 or more major metabolites generated by the hepatic pathway in appreciable concentrations. The three most common appear in the following image. The first is the doubly N-demethylated species, followed by the 7-hydroxylated form, and finally chlorophenothiazine, in which the entire R1 side chain is missing. ^[8]

Often, due to their high lipophilic character, these and other metabolites may be detected in the urine several months after discontinuation of use. Most metabolites lack any sort of neuroleptic activity, but a few are biologically active. These include 7-hydroxychlorpromazine, mesoridazine, 9-hydroxyresperidone, and a few N-demethylated metabolites. ^[9]

[edit] 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. ^[10]

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;
• serotonin receptors (5-HT₁ and 5-HT₂), with anxiolytic, 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),
• 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).

[edit] 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) 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 antipsychotic 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.

[edit] Adverse effects

The main side effects of chlorpromazine are due to its anticholinergic properties; these effects overshadow and counteract, to some extent, the extrapyramidal side effects typical of many early generation neuroleptics. These include sedation, slurred speech, dry mouth, constipation, urinary retention and possible lowering of seizure threshold. Appetite may be increased with resultant weight gain, Glucose tolerance may be impaired.^[11] Photosensitivity may occur, resulting in increased risk of sunburn.

Tardive dyskinesia and akathisia are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as haloperidol or trifluoperazine, and some evidence suggests that, in conservative dosing, the incidence of such effects with chlorpromazine may be comparable with that of newer agents such as risperidone or olanzapine.^[12]

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.^[13][14]

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. However, heavy sedation is usually due to excessive doses of Chlorpromazine aimed at pacifying difficult patients in institutional settings. The dose required to treat psychotic symptoms is smaller and therefore less sedative than is commonly depicted.

In some rare cases psychosis or death can result as a result of the paradoxical lowering of blood pressure, or death due to cardiac arrest.^[15]

[edit] 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 drugs 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 such as SSRIs, St. John's Wort and barbiturates can inhibit various CYP isoenzymes, such as CYP2D6, which are needed for the metabolization of chlorpromazine and/or its metabolites. Theoretically, this should increase the half-lives of chlorpromazine and possibly its metabolites, making 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.

[edit] 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. However, its use in food-producing animals has been banned EU-wide according to the Council's regulation 2377/90.

[edit] Dosage and administration

Use is determined by an attending physician. 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). Intravenous injection of undiluted solution is contraindicated due to risk of 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 (liver function tests, kidney-values, blood cell counts, ECG and EEG. 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).

[edit] 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)^{[citation needed]} . The dose should rather be slowly reduced at a rate of approximately 20–25% per week.

[edit] 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.^[16]

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 risperidone is more commonly used in such situations. ^[17]

[edit] 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.^[18]

It has also been used to stimulate the appetite of patients with eating disorders, as most anti-psychotics make patients feel hungrier and thus eat more.

[edit] 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 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 had additional indications for insomnia and itching skin disease.

Some jurisdictions in the United States use Chloropromazine as a sedative/tranquilizer prior to carrying out a death sentence by lethal injection.^[19]

[edit] References

[edit] 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. 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. http://www.clarkprosecutor.org/html/death/methods.htm. Retrieved on 2008-08-03. 

[edit] External links

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