Chlorpromazine (as chlorpromazine
hydrochlorideIn chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base...
, abbreviated
CPZ, marketed in the US as
Thorazine, as Largactil in Europe) is the oldest
typical antipsychoticTypical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis...
. The molecular structure is 2-chloro-10-(3-dimethylaminopropyl)-phenothiazine. It effectively treats
schizophreniaSchizophrenia , from the Greek roots skhizein and phrēn, phren- is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality...
, severe
maniaMania is a severe medical condition characterized by extremely elevated mood, energy, unusual thought patterns and sometimes psychosis...
in people with
bipolar disorderBipolar disorder, also known as manic depressive disorder, manic depression or bipolar affective disorder, is a serious mental disorder that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated mood clinically referred to as mania or, if...
, and uncontrollable hiccups. Synthesized on December 11, 1950, chlorpromazine was the first drug developed with specific
antipsychoticAntipsychotics are a group of psychoactive drugs commonly but not exclusively used to treat psychosis, which is typified by schizophrenia, but can also be present in severe bipolar disorder, as well as many other conditions. Over time a wide range of antipsychotics have been developed...
action. Its use has been described as the single biggest advance in psychiatric treatment, dramatically improving the prognosis of patients in psychiatric hospitals worldwide. It was the prototype for the
phenothiazinePhenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
class, which later grew to comprise several other agents. It is now used less commonly than the newer
atypical antipsychoticThe atypical antipsychotics are a group of antipsychotic drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
s such as
olanzapineOlanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
,
quetiapineQuetiapine fumarate , marketed by AstraZeneca as Seroquel or SeroquelXR and by Orion Pharma as Ketipinor, is an atypical antipsychotic used in the management of schizophrenia, bipolar I mania, bipolar II depression, bipolar I depression, and used off-label for a variety of other purposes,...
, and
risperidoneRisperidone is an atypical antipsychotic used to treat schizophrenia , the mixed and manic states associated with bipolar disorder, and irritability in children with autism...
.
Chlorpromazine works on a variety of receptors in the
central nervous systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
, producing
anticholinergicAn anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicyclomine....
, antidopaminergic, antihistaminic, and antiadrenergic effects. Its anticholinergic properties cause
constipationConstipation, costiveness, or irregularity is a condition of the digestive system in which a person experiences hard feces that are difficult to expel. This usually happens because the colon absorbs too much water from the food...
,
sedationSedation is a medical procedure involving the administration of sedative drugs, generally to facilitate a medical procedure with local anaesthesia.- Uses :...
,
hypotensionIn physiology and medicine, hypotension refers to an abnormally low blood pressure. This is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the opposite of hypertension, which is high blood...
and relieve nausea. It also has
anxiolyticAn anxiolytic is a drug used for the treatment of symptoms of anxiety. Anxiolytics have been shown to be useful in the treatment of anxiety disorders, as have antidepressants such as the selective serotonin reuptake inhibitors .Though not anxiolytics, beta-receptor blockers such as propranolol and...
(anxiety-relieving) properties. Its antidopaminergic properties can cause extrapyramidal symptoms such as
akathisiaAkathisia, or acathisia, is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless...
(restlessness),
dystoniaDystonia is a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be inherited or caused by other factors such as birth-related or other physical trauma, infection, poisoning Dystonia is a neurological...
, and
ParkinsonismParkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
. Chlorpromazine can cause
tardive dyskinesiaTardive dyskinesia is a variety of dyskinesia manifesting as a side effect of long-term or high-dose use of dopamine antagonists, usually antipsychotics. Other dopamine antagonists that can cause tardive dyskinesia are drugs for gastrointestinal disorders and neurological disorders...
, which is sometimes irreversible. About one in two thousand patients develop
neuroleptic malignant syndromeNeuroleptic malignant syndrome is a neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs. It generally presents with muscle rigidity, fever, autonomic instability and cognitive changes such as delirium, and is associated with elevated creatine...
. It is often administered in acute settings as a syrup, which has a faster onset of action than tablets.
IntravenousAn injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
administration is generally not recommended.
History
In 1933, the French pharmaceutical company Laboratoires Rhône-Poulenc began to search for new antihistamines. In 1947, it synthesized
promethazinePromethazine is a first-generation H
1 receptor antagonist, antihistamine and antiemetic medication. It can also have strong sedative effects and in some countries is prescribed for insomnia when benzodiazepines are contraindicated...
, a
phenothiazinePhenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs. A year later, the French surgeon Pierre Huguenard used promethazine together with
pethidinePethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Romania); Petidin Dolargan (in Poland);...
as part of a lytic cocktail to induce relaxation and indifference in surgical patients. Another surgeon,
Henri LaboritHenri Laborit was a French physician, writer and philosopher.Laborit was born in Hanoi, Vietnam and started his career as a neurosurgeon in the Marines and then moved on to fundamental research. He won the prestigious Albert Lasker Award for Clinical Medical Research in 1957...
, believed the compound stabilized the central nervous system by causing 'artificial hibernation', and described this state as 'sedation without
narcosisNarcosis may refer to:* Narcosis, the unconsciousness induced by a narcotic drug* Nitrogen narcosis, an effect of diving deep with nitrogenIn music:* Narcosis , an English metal band...
'. He suggested to Rhône-Poulenc that they develop a compound with better stabilizing properties. The chemist Paul Charpentier produced a series of compounds and selected the one with the least peripheral activity, known as RP4560 or chlorpromazine, on 11 December 1950. Simone Courvoisier conducted behavioural tests and found chlorpromazine produced indifference to
aversive stimuliIn psychology, aversives are unpleasant stimuli that induce changes in behavior through punishment; by applying an aversive immediately following a behavior, the likelihood of the behavior occurring in the future is reduced. Aversives can vary from being slightly unpleasant or irritating to...
in rats. Chlorpromazine was distributed for testing to physicians between April and August 1951.
The first published clinical trial was that of
Jean DelayJean Delay was a French psychiatrist, neurologist and writer. He discovered, jointly with J. M...
and
Pierre DenikerPierre Deniker was involved, jointly with Jean Delay and J. M. Harl, in the introduction of chlorpromazine , the first antipsychotic used in the treatment of schizophrenia, in the 1950's. Thorazine had been used in surgical procedures peri-operatively as an anti-nausea medication in France....
at the Hôpital Sainte-Anne in Paris in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents. 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
schizophreniaSchizophrenia , from the Greek roots skhizein and phrēn, phren- is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality...
,
maniaMania is a severe medical condition characterized by extremely elevated mood, energy, unusual thought patterns and sometimes psychosis...
, psychomotor excitement, and other
psychoticPsychosis literally means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
disorders.
Rhône-Poulenc licensed chlorpromazine to Smith Kline & French (today's
GlaxoSmithKline GlaxoSmithKline plc is a United Kingdom-based pharmaceutical, biological, and healthcare company. GSK is the world's second largest pharmaceutical company and a research-based company with a wide portfolio of pharmaceutical products covering anti-infectives, central nervous system, respiratory,...
) in 1953. In 1955 it was approved in the United States for the treatment of emesis (vomiting). The effect of this drug in emptying psychiatric hospitals has been compared to that of
penicillinPenicillin is a group of antibiotics derived from Penicillium fungi. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases such as syphilis and Staphylococcus infections...
and infectious diseases. 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 dyskinesiaTardive dyskinesia is a variety of dyskinesia manifesting as a side effect of long-term or high-dose use of dopamine antagonists, usually antipsychotics. Other dopamine antagonists that can cause tardive dyskinesia are drugs for gastrointestinal disorders and neurological disorders...
became more of a concern. From chlorpromazine a number of other similar
antipsychoticAntipsychotics are a group of psychoactive drugs commonly but not exclusively used to treat psychosis, which is typified by schizophrenia, but can also be present in severe bipolar disorder, as well as many other conditions. Over time a wide range of antipsychotics have been developed...
s were developed such as
triflupromazineTriflupromazine is an antipsychotic medication of the phenothiazine class . Among different effects of triflupromazine indication for use of this drug is severe emesis...
and
trifluoperazineTrifluoperazine is a typical antipsychotic drug of the phenothiazine group.- Pharmacodynamics :...
.
Chlorpromazine largely replaced
electroconvulsive therapyElectroconvulsive therapy , also known as electroshock, is a well-established, albeit controversial, psychiatric treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect...
,
psychosurgeryPsychosurgery is a subset of neurosurgery intended to modulate the performance of the brain, and thus effect changes in cognition, with the intent to treat or alleviate severe mental illness...
, and
insulin shock therapyInsulin shock therapy or insulin coma therapy was a form of psychiatric treatment in which patients were repeatedly injected with large doses of insulin in order to produce daily comas over several weeks...
. The development and marketing of antipsychotic drugs was one of the forces that propelled deinstitutionalization, which is the systematic removal of people with severe mental illness from institutions like psychiatric hospitals. In 1955 there were 558,922 resident patients in American state and county psychiatric hospitals. By 1970 the number dropped to 337,619; by 1980 to 150,000; and by 1990 between 110,000 to 120,000 patients.
Pharmacokinetics
Chlorpromazine, and many other
phenothiazinePhenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
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
albuminAlbumin refers generally to any protein with water solubility, which is moderately soluble in concentrated salt solutions, and experiences heat coagulation...
. 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.
The drug can also enter fetal circulation and breast milk, so pregnant and nursing mothers must beware, especially since fetuses have a low rate of
phenothiazinePhenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
metabolism. With gas chromatography, levels of chlorpromazine and some of its metabolites can be measured in the milk and plasma of nursing mothers. In one case study of nursing mothers on chlorpromazine therapy, the drug itself was detected in milk samples and ranged from 7 ng/ml to 98 ng/ml. The metabolite chlorpromazine sulphoxide was present in all samples. Plasma levels of CPZ ranged from 16 ng/ml to 52 ng/ml. However, there was no clear or consistent relationship between plasma and milk levels of CPZ. In one mother who did in fact feed her baby her breast milk, the milk CPZ level was 92 ng/ml and the baby was reported to be drowsy and lethargic. Therefore, there should be some caution in allowing nursing mothers currently on CPZ therapy and presumably related antipsychotics to breast feed their children.
Chlorpromazine is able to cross the placental barrier and it has been shown that drug doses higher than 500 mg daily in late pregnancy are associated with an increased incidence of respiratory distress in newborns. One case study reported that a newborn who was not breast fed but was exposed to CPZ in utero had detectably large amounts of the drug in its urine. This indicated the drug can in fact cross the placental barrier and is slowly cleared out of the body due to the infant's immature liver. Pregnant women and nursing mothers should thus be advised of the effects of CPZ on their newborn's health.
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
antipsychoticAntipsychotics are a group of psychoactive drugs commonly but not exclusively used to treat psychosis, which is typified by schizophrenia, but can also be present in severe bipolar disorder, as well as many other conditions. Over time a wide range of antipsychotics have been developed...
s such as
fluphenazineFluphenazine is a typical antipsychotic drug used for the treatment of psychoses such as schizophrenia and acute manic phases of bipolar disorder...
.
BioavailabilityIn pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%...
: 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 (range 1.5–8 hours),after an oral dose
Chlorpromazine is derived from
phenothiazinePhenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
, has an aliphatic side chain, typical for low to middle potency antipsychotics. Chlorpromazine is slowly absorbed from the intramuscular injection site with the peak plasma concentration occurring 6–24 hours after administration of the drug. The oral
bioavailabilityIn pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%...
is estimated to be 30–50% that of intramuscular doses and about 10% that of intravenous doses due to extensive
first pass metabolismThe first-pass effect is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation...
in the liver. Its elimination half-life is 16–30 hours (8–35 hours, although it is as short as 2 hours or as long as 60 hours in some individuals)
, due to high lipophilicity, high membrane-binding, and high protein-binding. It has many active metabolites (more than 100 metabolites being theoretically possible) with greatly varying halflives and pharmacological profiles.A number of the metabolites may contribute to the pharmacological effects of chlorpromazine including 7-hydroxychlorpromazine, chlorpromazine-N-oxide, 3-hydroxychlorpromazine and desmethylchlorpromazine.) Although the metabolite chlorpromazine-N-oxide does not possess activity in vitro, it can exert an indirect pharmacological effect in vivo by reverting back to chlorpromazine. The major routes of metabolism include hydroxylation, N-oxidation, sulphoxidation, demethylation, deamination and conjugation. There is little evidence supporting the development of metabolic tolerance or an increase in the metabolism of chlorpromazine due to microsomal liver enzymes following multiple doses of the drug. The mechanism of action of chlorpromazine is that the drug can act as an uncoupling agent of oxidative phosphorylation and also as an inhibitor of ATP-ase and cytochrome oxidase. However, the relationship that may exist between these mechanisms are not entirely understood.
The cytochrome P450 isoenzymes
1A2Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body.Expression of CYP1A2 appears to be induced by various dietary constituents....
and
2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Whilst CYP2D6 is involved in the oxidation of a wide range of substrates of all the CYPs, there is considerable...
are needed for metabolism of chlorpromazine. CYP 2D6 is the main enzyme catalyzing 7-hydroxylation of chlorpromazine, the reaction being partially catalyzed by CYP 1A2.
Chlorpromazine is typically degraded by the liver by the action of cytochrome-P450 family enzymes, usually
CYP2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Whilst CYP2D6 is involved in the oxidation of a wide range of substrates of all the CYPs, there is considerable...
. Less than 1% of the unchanged drug is excreted via the kidneys in the urine. In which 20-70% is excreted as conjugated or unconjugated metabolites, whereas 5-6% is excreted in feces. 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.
Often, due to their high lipophilic character, these and other metabolites may be detected in the urine up to 18 months. after discontinuation of use. Most metabolites lack any sort of antipsychotic activity, but a few are biologically active. These include 7-hydroxychlorpromazine,
mesoridazineMesoridazine is a piperidine neuroleptic drug belonging to the class of drugs called phenothiazines, used in the treatment of schizophrenia. It is a metabolite of thioridazine...
, 9-hydroxyresperidone, and a few N-demethylated metabolites.
Pharmacodynamics and Central effects
Chlorpromazine is a very effective antagonist of D
2 dopamine receptors and similar receptors, such as D
3 and D
5. Unlike most other drugs of this genre, it also has a high affinity for D
1 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.
Chlorpromazine acts as an
antagonistA receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
(blocking agent) on different postsynaptic receptors:
- dopamine receptor
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....
s (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms;in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects
- serotonin receptors (5-HT1 and 5-HT2), with anxiolytic, and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties),
- histamine receptor
The histamine receptors are a class of G-protein coupled receptors with histamine as their endogenous ligand.There are four known histamine receptors:*H1 receptor*H2 receptor*H3 receptor*H4 receptor-Comparison:...
s (H1 receptors, accounting for sedation, antiemetic effect, vertigo, fall in blood pressure and weight gain),
- α1- and α2-adrenergic receptor
The adrenergic receptors are a class of G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
s (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 receptor
Muscarinic receptors, or mAChRs, are G protein-coupled acetylcholine receptors found in the plasma membranes of certain neurons and other cells...
s (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographicElectrocardiography is a transthoracic interpretation of the electrical activity of the heart over time captured and externally recorded by skin electrodes. It is a noninvasive recording produced by an electrocardiographic device...
changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).
The presumed efficacy of the antipsychotic drugs relied on their ability to block dopamine receptors. This assumption arose from the dopamine hypothesis that maintains that both schizophrenia and bipolar disorder are a result of excessive dopamine activity. Furthermore, psychomotor stimulants like cocaine that increase dopamine levels can cause psychotic symptoms if taken in excess.
Chlorpromazine and other typical antipsychotics are primarily blockers of D2 receptors. In fact an almost perfect correlation exists between the therapeutic dose of a typical antipsychotic and the drug's affinity for the D2 receptor. Therefore, a larger dose is required if the drug’s affinity for the D2 receptor is relatively weak. A correlation exists between average clinical potency and affinity of the antipsychotics for dopamine receptors.
Chlorpromazine tends to have greater effect at serotonin receptors than at D2 receptors, which is notably the opposite effect of the other typical antipsychotics. Therefore, chlorpromazine with respect to its effects on dopamine and serotonin receptors is similar to the atypical antipsychotics than the typical antipsychotics.
Chlorpromazine and other antipsychotics with sedative properties such as promazine and thioridazine are among the most potent agents at α-adrenergic receptors. Furthermore, they are also among the most potent antipsychotics at histamine H1 receptors. This finding is in agreement with the pharmaceutical development of chlorpromazine and other antipsychotics as anti-histamine agents. Furthermore, the brain has a higher density of histamine H1 receptors than any body organ examined which may account for why chlorpromazine and other phenothiazine antipsychotics are as potent at these sites as the most potent classical antihistamines.
Additionally, chlorpromazine is a presynaptic inhibitor of
dopamineDopamine is a neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors — D
1, D
2, D
3, D
4, and...
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).
In addition to influencing the neurotransmitters dopamine, serotonin, epinephrine, norepinephrine, and acetylcholine it has been reported that antipsychotic drugs could achieve glutamatergic effects. This mechanism involves direct effects on antipsychotic drugs on glutamate receptors. By using the technique of functional neurochemical assay chlorpromazine and phenothiazine derivatives have been shown to have inhibitory effects on NMDA receptors that appeared to be mediated by action at the Zn site. It was found that there is an increase of NMDA activity at low concentrations and suppression at high concentrations of the drug. No significant difference in glutamate and glycine activity from the effects of chlorpromazine were reported. Further work will be necessary to determine if the influence in NMDA receptors by antipsychotic drugs contributes to their effectiveness.
Peripheral effects
Chlorpromazine is an antagonist to H
1 receptors (provoking antiallergic effects), H
2 receptors (reduction of forming of gastric juice),
M1 and M2 receptorMuscarinic receptors, or mAChRs, are G protein-coupled acetylcholine receptors found in the plasma membranes of certain neurons and other cells...
s (dry mouth, reduction in forming of gastric juice) and some
5-HT receptorThe serotonin receptors are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous system. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts...
s (different anti-allergic/gastrointestinal actions).
Because it acts on so many receptors, chlorpromazine is often referred to as a "
dirty drugA dirty drug is an informal term used in pharmacology to describe drugs that may bind to many different molecular targets or receptors in the body, and so tend to have a wide range of effects and possibly negative side effects...
", whereas the atypical antipsychotic
amisulprideAmisulpride , is a psychoactive drug that is used as an atypical antipsychotic and antidepressant. It was introduced by Sanofi-Aventis in the 1990s.- Pharmacology :...
, for example, acts only on central D
2 and D
3 receptors and is therefore a "clean drug". Research still needs to be done to understand the implications of this fact.
Adverse effects
The main
side effectAn adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dose. The meaning of this expression differs from the meaning of "side effect", as this last expression might also imply that the effects can be beneficial...
s 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 antipsychotics. These include sedation, slurred speech, dry mouth,
constipationConstipation, costiveness, or irregularity is a condition of the digestive system in which a person experiences hard feces that are difficult to expel. This usually happens because the colon absorbs too much water from the food...
, urinary retention and possible lowering of seizure threshold. Appetite may be increased with resultant weight gain,
Glucose toleranceA glucose tolerance test in medical practice is the administration of glucose to determine how quickly it is cleared from the blood. The test is usually used to test for diabetes, insulin resistance, and sometimes reactive hypoglycemia. The glucose is most often given orally so the common test is...
may be impaired. Dermatological reactions are frequently observed. In fact three types of skin disorders are observed: hypersensitivity reaction, contact dermatitis, and
photosensitivityPhotosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.-Interpretation in medicine:Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
. During long-term therapy in schizophrenic patients chlorpromazine can induce abnormal pigmentation of the skin. This can be manifested as gray-blue pigementation in regions exposed to sunlight.
Chlorpromazine, which has sedating effects, will increase sleep time when given at high doses or when first administered. Sleep cycles or REM sleep is not altered by antipsychotics.
There are striking adverse effects on the reproductive system. Phenothiazines are known to cause
hyperprolactinaemiaHyperprolactinaemia , or hyperprolactinemia in the United States , is the presence of abnormally-high levels of prolactin in the blood...
leading to amenorrhea, cessation of normal cyclic ovarian function, loss of libido, occasional
hirsutismHirsutism is excessive and increased hair growth on female humans in locations where the occurrence of terminal hair normally is minimal or absent. For example, a beard, or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
, false positive pregnancy tests, and long-term risk of osteoporosis in women. The effects of hyperprolactinemia in men are impotence, loss of libido, and hypospermatogenesis. These antipsychotics have significant effects on gonadal hormones including significantly lower levels of estradiol and progesterone in women whereas men display significantly lower levels of testosterone and DHEA when undergoing antipsychotic drug treatment compared to controls.
According to one study of the effects on the reproductive system in rats treated with chlorpromazine there were significant decreases in the weight of the testis, epididymis, seminal vesicles, and prostate gland. This was accompanied by a decline in sperm motility, sperm counts, viability, and serum levels of testosterone in chlorpromazine rats compared to control rats. It has been reported that a change in either the absolute or relative weight of an organ after a chemical is administered is an indication of the toxic effect of the chemical. Therefore, the observed change in the relative weight of the testis and other accessory reproductive organs in rats treated with chlorpromazine indicates that the drug might be toxic to these organs at least during the period of treatments. Furthermore, the weights of the kidney, heart, liver, and adrenal glands of these treated rats were not affected both during administration of the drug and recovery periods, suggesting that the drug is not toxic to these organs.
antipsychotic drugs may cause
priapismPriapism is a potentially harmful and painful medical condition in which the erect clitoris or penis does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours...
, a pathologically prolonged and painful penile erection, which is usually unassociated with sexual desire or intercourse. Although this effect is rare it is a potentially serious complication that can lead to permanent impotence and other serious complications.
Doses of antipsychotics that are considered therapeutically low are sufficient to trigger an epileptic seizure in particularly vulnerable patients for example those with an abnormally low genetically determined seizure threshold. The drug dose ability to provoke seizures is presumably due to a reduced seizure threshold. The incidence of the first unprovoked seizure in the general population is 0.07 to 0.09%, whereas the incidence rates have been reported to range from 0.1 to 1.5% in patients treated with therapeutic doses of the most commonly used antipsychotic drugs. Furthermore, the seizure risk rises markedly to a range of 4 to 30% in patients who have taken an overdose. This most notable variability among studies may possibly be due to methodological differences which makes the research data that much harder to interpret. The risk of a seizure being provoked during antipsychotic drug medication is greatly influenced by the individuals inherited seizure threshold and particularly by the presence of a history of epilepsy, brain damage or other conditions. There is an agreement however that seizures triggered by drugs are a dose-dependent adverse effect.
Tardive dyskinesiaTardive dyskinesia is a variety of dyskinesia manifesting as a side effect of long-term or high-dose use of dopamine antagonists, usually antipsychotics. Other dopamine antagonists that can cause tardive dyskinesia are drugs for gastrointestinal disorders and neurological disorders...
and
akathisiaAkathisia, or acathisia, is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless...
are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as
haloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
or
trifluoperazineTrifluoperazine is a typical antipsychotic drug of the phenothiazine group.- Pharmacodynamics :...
, 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
risperidoneRisperidone is an atypical antipsychotic used to treat schizophrenia , the mixed and manic states associated with bipolar disorder, and irritability in children with autism...
or
olanzapineOlanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
.
A particularly severe side effect is
neuroleptic malignant syndromeNeuroleptic malignant syndrome is a neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs. It generally presents with muscle rigidity, fever, autonomic instability and cognitive changes such as delirium, and is associated with elevated creatine...
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
leukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
—or, in extreme cases, even
agranulocytosisAgranulocytosis, also known as agranulosis, is an acute condition involving a severe and dangerous leukopenia, most commonly of neutrophils, causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
, which may occur in 0.01% of patients and lead to death via uncontrollable infections and/or
sepsisSepsis is a serious medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection.
. Chlorpromazine is also known to accumulate in the eyeEyes are organs that detect light, and send electrical impulses along the optic nerve to the visual and other areas of the brain. Complex optical systems with resolving power have come in ten fundamentally different forms, and 96% of animal species possess a complex optical system...
—in the posterior corneal stroma, lensThe lens is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. The lens, by changing shape, functions to change the focal distance of the eye so that it can focus on objects at various distances, thus allowing a sharp real...
, and uveal tractThe uvea , also called the uveal layer, uveal coat, uveal tract, or vascular tunic, is the pigmented middle of the three concentric layers that make up an eye. The name is possibly a reference to its reddish-blue or almost black colour, wrinkled appearance and grape-like size and shape when...
. 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 pigmentation of the cornea.
Chlorpromazine is the antipsychotic 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 psychosisPsychosis literally means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
or deathDeath is the termination of the biological functions that define a living organism. It refers to both a particular event and to the condition that results thereby. The true nature of the latter has for millennia been a central concern of the world's religious traditions and of philosophical...
can result from the paradoxical lowering of blood pressure, or death due to cardiac arrest attributed to dysrhythmia.
Cardiotoxic effects of phenothiazines in overdose are similar to that of the tricyclic antidepressants. Cardiac arrhythmia and apparent sudden death have been associated with therapeutic doses of chlorpromazine, however they are rare cases. The sudden cardiovascular collapse being attributable to ventricular dysrhythmia. Supraventricular tachycardia may also develop. Patients on chlorpromazine therapy exhibit abnormalities on the electrocardiographic T and U waves. These major cardiac arrhythmias that are lethal are a potential hazard even in patients without heart disease who are receiving therapeutic doses of antipsychotic drugs. In order to quantify the risk of cardiac complications to patients receiving therapeutic doses of phenothiazines a prospective clinical trial is suggested.
Interactions
Chlorpromazine intensifies the central depressive action of drugs with such activity (tranquilizerA tranquilizer, or tranquiliser , is a drug that induces tranquillity in an individual.The term "tranquilizer" is imprecise, and is usually qualified, or replaced with more precise terms:...
s, barbiturateBarbiturates are drugs that act as central nervous system depressants, and, by virtue of this, they produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, hypnotics and as anticonvulsants. They have addiction potential, both physical and...
s, 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 antihypertensiveThe antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5–6 mmHg can decrease the risk of stroke by 40%, of coronary heart disease by 15–20%, and reduce the likelihood of dementia, heart failure, and mortality from...
drugs and anticholinergicAn anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicyclomine....
drugs. The combination of chlorpromazine with other antipsychotics may result in increased central depressionDepression in physiology and medicine refers to a lowering, in particular a reduction in a particular biological variable or the function of an organ...
, hypotensionIn physiology and medicine, hypotension refers to an abnormally low blood pressure. This is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the opposite of hypertension, which is high blood...
and extrapyramidal side effects, but may sometimes enhance the clinical results of therapy. The anti-worm drug (antihelminthic) piperazinePiperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen atoms. Piperazine exists as small alkaline deliquescent crystals with a saline taste....
may intensify extrapyramidal side effects. In general, all antipsychotics may lead to seizures in combination with tramadolTramadol is a centrally acting analgesic, used for treating moderate to severe pain.Tramadol was developed by the German pharmaceutical company Grünenthal GmbH in the late 1970s.Tramadol possesses...
(Ultram). Chlorpromazine may increase the insulin needs of diabetic patients.
Chlorpromazine is able to inhibit dextromethorphan 0-demethylation a selective marker for CYP2D6 in a concentration dependent manner. Chlorpromazine is able to inhibit the catalytic activity of cytochrome P450 isoforms. CYP2D6 enzyme is not only important in the metabolism of chlorpromazine and associated antipsychotics but is also important in the metabolism of tricyclic antidepressants and selective serotonin reuptake inhibitors that are commonly prescribed to patients with psychiatric disorders. This may result in significant drug interactions which may put these people at a heightened risk for side effects that may be masked by the positive effects or side effects of antipsychotic drugs themselves. Therefore, drugs that inhibit the enzymes that metabolize chlorpromazine would be expected to cause increases in the concentration of other antipsychotic drugs that are coadministered. These increases in concentration may in turn lead to the development of antipsychotic induced side effects. Therefore, chlorpromazine may develop pharmacokinetic interactions with other antipsychotics and antidepressant drugs that are coadministered.
Differential expression of various CYP isoforms in specific brain locations leads to the conclusion that antipsychotic drugs could be metabolized to different products in different regions of the brain. The varying levels of expression of the CYP isoforms between individuals and for each particular antipsychotic as well as the possibility of differential metabolism in the brain provides one possible reason why there is such a wide range of adverse effects and therapeutic effects of chlorpromazine and the other antipsychotic drugs in the population of patients currently using.
Pharmacokinetic variation in the interaction with other drugs and the variation in patient compliance may represent the variability in response to antipsychotic drug treatment between patients. Monitoring plasma levels by specific chemical assay methods may offer some guidance to the variability in the pharmokinetics and metabolism of antipsychotic drugs in order to individualize drug doses, consequently perhaps alleviating the risk of the adverse effects. Furthermore if plasma levels are monitored then any form of drug induced toxicity can be suspected as well as controlling for the lack of compliance by the patient.
Chlorpromazine impairs the metabolism of tricyclic antidepressants which can thus increase the risk of toxicity.
Combination with other antidopaminergic agents such as metoclopramide and prochlorperazine increases the risk of extrapyramidal symptom effects.
Chlorpromazine can enhance the central nervous system depression produced by other CNS depressent drugs. For example administration of chlorpromazine with ethanol results in potentiated sedative effects and impaired co-ordination.
An interaction between phenothiazine and caffeinated beverages has been reported. Addition of coffee or tea to phenothiazine or butyrphenone antipsychotics forms a precipitant in vitro. This finding was of initial concern as many psychiatric patients might drink coffee or tea immediately after receiving oral medication. However in humans caffeine use was only slightly related to antipsychotic levels. These negative findings between in vitro studies and human epidemiological studies can be attributable to the stomach acidity which reverses any preciptation. It still remains unclear whether the caffeine-antipsychotic precipitation phenomenon has any clinical significance. The neurophysiology of this relationship is derived from the fact that cytochrome P450 CYP1A2 isoenzyme is responsible for metabolism of caffeine as well as chlorpromazine, thus they may compete for the isoenzyme. Support of this possible competition of the isoenzyme comes from the observation that high doses of caffeine can cause tremors and restless legs both of which could be mistaken for or could aggravate neurolpetic induced extrapyramidal effects
Drugs such as SSRI Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders...
s, St. John's Wort and barbiturates can inhibit various CYP isoenzymes, such as CYP2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Whilst CYP2D6 is involved in the oxidation of a wide range of substrates of all the CYPs, there is considerable...
, 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 inductionEnzyme induction is a process in which a molecule induces the expression of an enzyme.Enzyme inhibition can refer to* the inhibition of the expression of the enzyme by another molecule...
and its therapeutic consequences are unknown at present time and remain to be evaluated.
Tolerance and Withdrawal
There is no evidence that tolerance develops to the drug's antipsychotic effects. A patient can be maintained for years on a therapeutically effective dose without any decrease in effectiveness being reported. Tolerance appears to develop to the sedating effects of chlorpromazine when it is first administered. Tolerance also appears to develop to the extrapyramidal, antipsychotic or parkinsonian effects, although this is debatable.
A failure to notice withdrawal symptoms may be due to the relatively long half life of the drug resulting in the extremely slow excretion from the body.However, there are reports of muscular discomfort, exaggeration of psychotic symptoms and movement diosorders, and difficulty sleeping when the antipsychotic drug is suddenly withdrawn, but after years of normal doses these effects are not normally seen. Physical dependence, if it occurs at all, is rare due to compliance problems and the subjective experience of antipsychotics being never described as pleasant.
Veterinary uses
Chlorpromazine is primarily used as an antiemeticAn antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics and chemotherapy directed against cancer.-Types of Antiemetics:...
in dogThe dog is a domesticated form of the Gray Wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties. The domestic dog has been one of the most widely kept working and companion animals in human history...
s and catThe cat , also known as the domestic cat or housecat to distinguish it from other felines and felids, is a small carnivorous mammal that is valued by humans for its companionship and its ability to hunt vermin and household pests...
s. It is also sometimes used as a preanesthetic and muscle relaxantA muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
in cattleCattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...
, swine, sheep, and goatThe domestic goat is a subspecies of goat domesticated from the wild goat of southwest Asia and Eastern Europe. The goat is a member of the Bovidae family and is closely related to the sheep: both are in the goat-antelope subfamily Caprinae. There are over three hundred distinct breeds of...
s. It is generally contraindicated for use with horseThe horse is a hoofed mammal, a subspecies of one of seven extant species of the family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...
s, due to a high incidence of ataxiaAtaxia is a neurological sign and symptom consisting of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of parts of the nervous system that coordinate movement, such as the cerebellum...
and altered mentation. Its use in food-producing animals has been banned in the EU according to the Council's regulation 2377/90.
Dosage and administration
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 BenztropineBenztropine mesilate , benztropine mesylate, or benztropine marketed as Cogentin, is an anticholinergic drug principally used for the treatment of:*Drug-induced parkinsonism, akathisia and acute dystonia;*Parkinson disease; and...
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 hypotensionIn physiology and medicine, hypotension refers to an abnormally low blood pressure. This is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the opposite of hypertension, which is high blood...
. 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.
Chlorpromazine and other antipsychotic drugs need to be taken continuously or chronically to prevent the symptoms of the disease from reappearing. While abuse of antipsychotics is unlikely due to their unpleasant effects, they are rather a class of drugs with considerable compliance problems because prescribed patients often stop taking them. For this reason various administration techniques have been developed that do not depend on a patient's compliance. Among them is administration of depot injectionsAn injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
which slowly relases the drug and maintains the appropriate blood levels. Depot injections usually only work with drugs that are highly lipid-soluble, otherwise they would be released too quickly. The technique involves the drug being dissolved in a high concentration in a viscous oil (often sesame oil), which is then injected into a muscle (usually the gluteus maximus) of the buttocks. The drug slowly diffuses from the oil into the body fluids. A single depot injection of a antipsychotic drug can be effective for as long as 4 weeks.
The lowest dosage compatible with good therapeutic effect should be given. Dosage in ambulatory patients should be particularly low (minimizing sedationSedation is a medical procedure involving the administration of sedative drugs, generally to facilitate a medical procedure with local anaesthesia.- Uses :...
and hypotensionIn physiology and medicine, hypotension refers to an abnormally low blood pressure. This is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the opposite of hypertension, which is high blood...
). 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.
All patients treated with chlorpromazine on a long-term-basis should have the following checked regularly: blood-pressure, pulse rate, laboratory-tests (liver function testsLiver function tests , which include liver enzymes, are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. Most liver diseases cause only mild symptoms initially, but it is vital that these diseases be detected early. Hepatic ...
, kidneyThe kidneys are paired organs, which have the production of urine as their primary function. Kidneys are seen in many types of animals, including vertebrates and some invertebrates. They are part of the urinary system, but have several secondary functions concerned with homeostatic functions. ...
-values, blood cell countsA complete blood count , also known as full blood count or full blood exam or blood panel, is a test requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
, ECG and EEGEEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
. Some side effects seem to appear more frequently during the first months of therapy (sedationSedation is a medical procedure involving the administration of sedative drugs, generally to facilitate a medical procedure with local anaesthesia.- Uses :...
, hypotensionIn physiology and medicine, hypotension refers to an abnormally low blood pressure. This is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the opposite of hypertension, which is high blood...
, liver damageHepatotoxicity implies chemical-driven liver damage. The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents when taken in overdoses and sometimes even when introduced within therapeutic ranges may injure...
) while others do not (e.g. tardive dyskinesiaTardive dyskinesia is a variety of dyskinesia manifesting as a side effect of long-term or high-dose use of dopamine antagonists, usually antipsychotics. Other dopamine antagonists that can cause tardive dyskinesia are drugs for gastrointestinal disorders and neurological disorders...
).
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. Rather, the dose should be slowly reduced at a rate of approximately 20 percent to 25 percent 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 psychosesPsychosis literally means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, including schizophreniaSchizophrenia , from the Greek roots skhizein and phrēn, phren- is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality...
and the manic phase of bipolar disorderBipolar disorder, also known as manic depressive disorder, manic depression or bipolar affective disorder, is a serious mental disorder that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated mood clinically referred to as mania or, if...
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.
Chlorpromazine formerly was the drug of choice to treat LSDLysergic acid diethylamide, LSD-25, LSD, formerly lysergide, commonly known as acid, is a semisynthetic psychedelic drug of the ergoline family...
(and other psychedelicThe term psychedelic is derived from the Greek words ψυχή and δηλείν , translating to "mind-manifesting". A psychedelic experience is characterized by the perception of aspects of one's mind previously unknown, or by the creative exuberance of the mind liberated from its ostensibly ordinary fetters...
/hallucinogen) intoxication in a hospital setting, resulting in it gaining an erroneous reputation as the LSD antidote. Now risperidoneRisperidone is an atypical antipsychotic used to treat schizophrenia , the mixed and manic states associated with bipolar disorder, and irritability in children with autism...
is more commonly used in such situations.
Other uses
It has also been used in porphyriaPorphyrias are a group of inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...
and as part of tetanusTetanus, also called lockjaw, is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, obligate anaerobic bacterium Clostridium tetani. Infection generally occurs through...
treatment.
It still is well recommended for short term management of severe anxiety and aggressive episodes.
Resistant and severe hiccups, severe nauseaNausea is the sensation of unease and discomfort in the stomach with an urge to vomit.-Causes:...
/emesis and preanesthetic conditioning have been other indications in the past.
It can be used to treat amphetamineAmphetamine is a psychostimulant drug that is known to produce increased wakefulness and focus in association with decreased fatigue and appetite. Amphetamine is related to drugs such as methamphetamine and dextroamphetamine, which are a group of potent drugs that act by increasing levels of...
overdose.
It has also been used to stimulate the appetite of patients with eating disorders, as most anti-psychotics make patients feel hungrier.
Off-label and controversial uses
Chlorpromazine is occasionally used off-label for treatment of severe migraineMigraine is a neurological syndrome characterized by altered bodily perceptions, severe headaches, and nausea. Physiologically, the migraine headache is a neurological condition more common to women than to men. The word migraine was borrowed from Old French migraigne...
. Sometimes it is used in small doses to improve the nausea that opioidAn opioid is a chemical that works by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract...
-treated cancer patients encounter and to intensify and prolong the analgesic action of the opioids given. It remains controversial whether or not chlorpromazine has its own analgesicAn analgesic is any member of the diverse group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos...
properties. Analgesic properties may result from a central action on the hypothalamusThe hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland ....
; the patient may feel pain much less than before. Other mechanisms may be an interaction with opioid receptors centrally and/or in the spinal cordThe spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain. The brain and spinal cord together make up the central nervous system. It is around 45 cm long in men and around 43 cm long in women. The length of the spinal cord is much shorter than...
. Some experts even 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 choleraCholera, sometimes known as Asiatic or epidemic cholera, is an infectious gastroenteritis caused by enterotoxin-producing strains of the bacterium Vibrio cholerae. Transmission to humans occurs through eating food or drinking water contaminated with Vibrio cholerae from other cholera patients...
, reducing the loss of water by approximately 30 percent.
In Germany, the brand of chlorpromazine drug Propaphenin had additional indications for insomniaInsomnia is a symptom of any of several sleep disorders, characterized by persistent difficulty falling asleep or staying asleep despite the opportunity. Insomnia is a symptom, not a stand-alone diagnosis or a disease. By definition, insomnia is "difficulty initiating or maintaining sleep, or both"...
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 injectionLethal injection refers to the practice of injecting a criminal with a fatal dose of drugs for the express purpose of executing the subject...
.
Sources
- 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)
External links