chlorpromazine chlorpromazine chlorpromazine (cpz), marketed under the brand names thorazine and largactil among others, is an antipsychotic medication. it is primarily used to treat psychotic disorders such as schizophrenia. other uses include the treatment of bipolar disorder, severe behavioral problems in children including those with attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. it can be given orally (by mouth), by intramuscular injection (injection into a muscle), or intravenously (injection into a vein). not to be confused with chlorpropamide. chlorpromazineclinical datatrade nameslargactil, thorazine, sonazine, othersahfs/drugs.commonographmedlineplusa682040license data us dailymed: chlorpromazine us fda: chlorpromazine pregnancycategory au: c routes ofadministrationby mouth, rectal, intramuscular, intravenousdrug classtypical antipsychoticatc coden05aa01 (who) legal statuslegal status au: s4 (prescription only) uk: pom (prescription only) us: ℞-only eu: rx-only in general: ℞ (prescription only) pharmacokinetic databioavailability10–80% (oral; large interindividual variation)protein binding90–99%metabolismliver, mostly cyp2d6-mediatedelimination half-life30 hoursexcretionurine (43–65% in 24 hrs)identifiers iupac name 3-(2-chloro-10h-phenothiazin-10-yl)-n,n-dimethylpropan-1-amine cas number50-53-3 y (free base)69-09-0 (hydrochloride)pubchem cid2726iuphar/bps83drugbankdb00477 ychemspider2625 yuniiu42b7vya4pkeggd00270 yas hcl: d00789 ychebichebi:3647 ychemblchembl71 ycomptox dashboard (epa)dtxsid0022808 echa infocard100.000.042 chemical and physical dataformulac17h19cln2smolar mass318.86 g·mol−13d model (jsmol)interactive image smiles cn(c)cccn1c2ccccc2sc2ccc(cl)cc21 inchi inchi=1s/c17h19cln2s/c1-19(2)10-5-11-20-14-6-3-4-7-16(14)21-17-9-8-13(18)12-15(17)20/h3-4,6-9,12h,5,10-11h2,1-2h3 ykey:zpeimtdsqakgnt-uhfffaoysa-n y (verify) chlorpromazine is in the typical antipsychotic class, and, chemically, is one of the phenothiazines. its mechanism of action is not entirely clear but believed to be related to its ability as a dopamine antagonist. it also has anti-serotonergic and antihistaminergic properties. common side effects include movement problems, sleepiness, dry mouth, low blood pressure upon standing, and increased weight. serious side effects may include the potentially permanent movement disorder tardive dyskinesia, neuroleptic malignant syndrome, severe lowering of the seizure threshold, and low white blood cell levels. in older people with psychosis as a result of dementia it may increase the risk of death. it is unclear if it is safe for use in pregnancy. chlorpromazine was developed in 1950 and was the first antipsychotic on the market. it is on the world health organization's list of essential medicines. its introduction has been labeled as one of the great advances in the history of psychiatry. it is available as a generic medication. medical uses chlorpromazine is used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of bipolar disorder, as well as amphetamine-induced psychosis. in a 2013 comparison of fifteen antipsychotics in schizophrenia, chlorpromazine demonstrated mild-standard effectiveness. it was 13% more effective than lurasidone and iloperidone, approximately as effective as ziprasidone and asenapine, and 12–16% less effective than haloperidol, quetiapine, and aripiprazole. a 2014 systematic review carried out by cochrane included 55 trials that compared the effectiveness of chlorpromazine versus placebo for the treatment of schizophrenia. compared to the placebo group, patients under chlorpromazine experienced less relapse during 6 months to 2 years follow-up. no difference was found between the two groups beyond two years of follow-up. patients under chlorpromazine showed a global improvement in symptoms and functioning. the systematic review also highlighted the fact that the side effects of the drug were 'severe and debilitating', including sedation, considerable weight gain, a lowering of blood pressure, and an increased risk of acute movement disorders. they also noted that the quality of evidence of the 55 included trials was very low and that 315 trials could not be included in the systematic review due to their poor quality. they called for further research on the subject, as chlorpromazine is a cheap benchmark drug and one of the most used treatments for schizophrenia worldwide. chlorpromazine has also been used in porphyria and as part of tetanus treatment. it still is recommended for short-term management of severe anxiety and psychotic aggression. resistant and severe hiccups, severe nausea/emesis, and preanesthetic conditioning are other uses. symptoms of delirium in hospitalized aids patients have been effectively treated with low doses of chlorpromazine. other chlorpromazine is occasionally used off-label for treatment of severe migraine. it is often, particularly as palliation, used in small doses to reduce nausea by opioid-treated cancer patients and to intensify and prolong the analgesia of the opioids as well. efficacy has been shown in treatment of symptomatic hypertensive emergency. in germany, chlorpromazine still carries label indications for insomnia, severe pruritus, and preanesthesia. chlorpromazine and other phenothiazines have been demonstrated to possess antimicrobial properties, but are not currently used for this purpose except for a very small number of cases. for example, miki et al. 1992 trialed daily doses of chlorpromazine, reversing chloroquine resistance in plasmodium chabaudi isolates in mice. weeks et al., 2018 find that it also possesses a wide spectrum anthelmintic effect. chlorpromazine is an antagonist of several insect monoamine receptors. it is the most active antagonist known of silk moth (bombyx mori) octopamine receptor α, intermediate for bm tyramine receptors 1 & 2, weak for drosophila octopamine receptor β, high for drosophila tyramine receptor 1, intermediate for migratory locust (locusta migratoria) tyramine receptor 1, and high for american cockroach (periplaneta americana) octopamine receptor α and tyramine receptor 1. comparison of chlorpromazine to placebo measured outcomefindings summaryfindings rangequality of evidence global effects no improvement (9 weeks – 6 months)30% less risk of having no improvement in mental state, behaviour and functioningrr 0.7 ci 0.6 to 0.9very low (estimate of effect uncertain) relapse (6 months – 2 years)35% less risk of relapserr 0.7 ci 0.5 to 0.9 adverse effects there appears to be a dose-dependent risk for seizures with chlorpromazine treatment. tardive dyskinesia (involuntary, repetitive body movements) and akathisia (a feeling of inner restlessness and inability to stay still) are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as haloperidol or trifluoperazine, and some evidence suggests that, with conservative dosing, the incidence of such effects for chlorpromazine may be comparable to that of newer agents such as risperidone or olanzapine. chlorpromazine may deposit in ocular tissues when taken in high dosages for long periods of time. comparison of chlorpromazine to placebo measured outcomefindings summaryfindings rangequality of evidence adverse effects weight gain5 times more likely to have considerable weight gain, around 40% with chlorpromazine gaining weightrr 4.9 ci 2.3 to 10.4very low (estimate of effect uncertain) sedation3 times more likely to cause sedation, around 30% with chlorpromazinerr 2.8 ci 2.3 to 3.5 acute movement disorder3.5 times more likely to cause easily reversible but unpleasant severe stiffening of muscles, around 6% with chlorpromazinerr 3.5 ci 1.5 to 8.0 parkinsonism2 times more likely to cause parkinsonism (symptoms such as tremor, hesitancy of movement, decreased facial expression), around 17% with chlorpromazinerr 2.1 ci 1.6 to 2.8 decreased blood pressure with dizziness3 times more likely to cause decreased blood pressure and dizziness, around 15% with chlorpromazinerr 2.4 ci 1.7 to 3.3 contraindications absolute contraindications include: circulatory depression cns depression coma drug intoxication bone marrow suppression phaeochromocytoma hepatic failure active liver disease previous hypersensitivity (including jaundice, agranulocytosis, etc.) to phenothiazines, especially chlorpromazine, or any of the excipients in the formulation being used. relative contraindications include: epilepsy parkinson's disease myasthenia gravis hypoparathyroidism prostatic hypertrophy very rarely, elongation of the qt interval may occur, increasing the risk of potentially fatal arrhythmias. interactions consuming food prior to taking chlorpromazine orally limits its absorption; likewise, cotreatment with benztropine can also reduce chlorpromazine absorption. alcohol can also reduce chlorpromazine absorption. antacids slow chlorpromazine absorption. lithium and chronic treatment with barbiturates can increase chlorpromazine clearance significantly. tricyclic antidepressants (tcas) can decrease chlorpromazine clearance and hence increase chlorpromazine exposure. cotreatment with cyp1a2 inhibitors like ciprofloxacin, fluvoxamine or vemurafenib can reduce chlorpromazine clearance and hence increase exposure and potentially also adverse effects. chlorpromazine can also potentiate the cns depressant effects of drugs like barbiturates, benzodiazepines, opioids, lithium and anesthetics and hence increase the potential for adverse effects such as respiratory depression and sedation. chlorprozamine is also a moderate inhibitor of cyp2d6 and a substrate for cyp2d6, and hence can inhibit its own metabolism. it can also inhibit the clearance of cyp2d6 substrates such as dextromethorphan, potentiating their effects. other drugs like codeine and tamoxifen, which require cyp2d6-mediated activation into their respective active metabolites, may have their therapeutic effects attenuated. likewise, cyp2d6 inhibitors such as paroxetine or fluoxetine can reduce chlorpromazine clearance, increasing serum levels of chlorpromazine and potentially its adverse effects. chlorpromazine also reduces phenytoin levels and increases valproic acid levels. it also reduces propranolol clearance and antagonizes the therapeutic effects of antidiabetic agents, levodopa (a parkinson's medication. this is likely due to the fact that chlorpromazine antagonizes the d2 receptor which is one of the receptors dopamine, a levodopa metabolite, activates), amphetamines and anticoagulants. it may also interact with anticholinergic drugs such as orphenadrine to produce hypoglycaemia (low blood sugar). chlorpromazine may also interact with epinephrine (adrenaline) to produce a paradoxical fall in blood pressure. monoamine oxidase inhibitors (maois) and thiazide diuretics may also accentuate the orthostatic hypotension experienced by those receiving chlorpromazine treatment. quinidine may interact with chlorpromazine to increase myocardial depression. likewise, it may also antagonize the effects of clonidine and guanethidine. it also may reduce the seizure threshold and hence a corresponding titration of anticonvulsant treatments should be considered. prochlorperazine and desferrioxamine may also interact with chlorpromazine to produce transient metabolic encephalopathy. other drugs that prolong the qt interval, such as quinidine, verapamil, amiodarone, sotalol and methadone, may also interact with chlorpromazine to produce additive qt interval prolongation. discontinuation the british national formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. other symptoms may include restlessness, increased sweating, and trouble sleeping. less commonly, there may be a feeling of the world spinning, numbness, or muscle pains. symptoms generally resolve after a short period of time. there is tentative evidence that discontinuation of antipsychotics can result in psychosis. it may also result in reoccurrence of the condition that is being treated. rarely, tardive dyskinesia can occur when the medication is stopped. pharmacology chlorpromazine is classified as a low-potency typical antipsychotic. low-potency antipsychotics have more anticholinergic side effects, such as dry mouth, sedation, and constipation, and lower rates of extrapyramidal side effects, while high-potency antipsychotics (such as haloperidol) have the reverse profile. pharmacokinetics pharmacokinetic parameters of chlorpromazine bioavailabilitytmaxcssprotein boundvdt1/2details of metabolismexcretionnotes 10–80%1–4 hours (oral); 6–24 hours (im)100–300 ng/ml90–99%10–35 l/kg (mean: 22 l/kg)30±7 hourscyp2d6, cyp1a2—mediated into over 10 major metabolites. the major routes of metabolism include hydroxylation, n-oxidation, sulfoxidation, 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.urine (43–65% after 24 hours)its high degree of lipophilicity (fat solubility) allows it to be detected in the urine for up to 18 months. 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. three common metabolites of chlorpromazine pharmacodynamics chlorpromazine site ki species ref 5-ht1a 3115 human 5-ht1b 1,489 human 5-ht1d 452 human 5-ht1e 344 human 5-ht2a 2.75 human 5-ht2c 25 human 5-ht3 776 human 5-ht5a 118 human 5-ht6 19.5 human 5-ht7 21 human α1a 0.28 human α1b 0.81 human α2a 184 human α2b 28 human α2c 46 human β1 >10,000 human β2 >10,000 human m1 47 human m2 433 human m3 47 human m4 151 human d1 114.8 human d2 7.244 human d3 6.9 human d4 32.36 human h1 4.25 human h2 174 human h3 1,000 human h4 5,048 human net 2,443 human dat >10,000 human 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 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 antagonist (blocking agent) on different postsynaptic and presynaptic receptors: dopamine receptors (subtypes d1, d2, d3 and d4), which account for its different antipsychotic properties on productive