Editing Chlorpromazine (section)

==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 symptoms|extrapyramidal]] side effects, while high-potency antipsychotics (such as [[haloperidol]]) have the reverse profile.<ref name =GG/>

===Pharmacodynamics===
{| class="wikitable sortable" style = "float: right; margin-left:15px; text-align:center"
|+Chlorpromazine
!Site
!Ki
!Species
!Ref
|-
|[[5-HT1A receptor|5-HT<sub>1A</sub>]]
|3115
|Human
|<ref>{{cite journal | vauthors = Maheux J, Ethier I, Rouillard C, Lévesque D | title = Induction patterns of transcription factors of the nur family (nurr1, nur77, and nor-1) by typical and atypical antipsychotics in the mouse brain: implication for their mechanism of action | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 313 | issue = 1 | pages = 460–473 | date = April 2005 | pmid = 15615863 | doi = 10.1124/jpet.104.080184 | hdl-access = free | s2cid = 1436507 | hdl = 20.500.11794/17025 }}</ref>
|-
|[[5-HT1B receptor|5-HT<sub>1B</sub>]]
|1489
|Human
|<ref name=":0">{{Cite web|title=Chlorpromazine|url=https://pdsp.unc.edu/databases/pdspImg.php|website=PDSP Database}}</ref>
|-
|[[5-HT1D receptor|5-HT<sub>1D</sub>]]
|452
|Human
|<ref name=":0" />
|-
|[[5-HT1E receptor|5-HT<sub>1E</sub>]]
|344
|Human
|<ref name=":0" />
|-
|[[5-HT2A receptor|5-HT<sub>2A</sub>]]
|2.75
|Human
|<ref>{{cite journal | vauthors = Gillman PK | title = Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity | journal = British Journal of Anaesthesia | volume = 95 | issue = 4 | pages = 434–441 | date = October 2005 | pmid = 16051647 | doi = 10.1093/bja/aei210 | doi-access = free }}</ref>
|-
| [[5-HT2B receptor|5-HT<sub>2B</sub>]]
| 6.0
| Bovine
| <ref name="BenderParrLivingston2023">{{cite journal | vauthors = Bender AM, Parr LC, Livingston WB, Lindsley CW, Merryman WD | title = 2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery | journal = J Med Chem | volume = 66 | issue = 16 | pages = 11027–11039 | date = August 2023 | pmid = 37584406 | pmc = 11073569 | doi = 10.1021/acs.jmedchem.3c01178 | url = }}</ref>
|-
|[[5-HT2C receptor|5-HT<sub>2C</sub>]]
|25
|Human
|<ref>{{cite journal | vauthors = Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL | title = H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs | journal = Neuropsychopharmacology | volume = 28 | issue = 3 | pages = 519–526 | date = March 2003 | pmid = 12629531 | doi = 10.1038/sj.npp.1300027 | author8-link = Herbert Y. Meltzer | doi-access = free | author9-link = Bryan Roth }}</ref>
|-
|[[5-HT3 receptor|5-HT<sub>3</sub>]]
|776
|Human
|<ref name=":1">{{cite journal | vauthors = Silvestre JS, Prous J | title = Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes | journal = Methods and Findings in Experimental and Clinical Pharmacology | volume = 27 | issue = 5 | pages = 289–304 | date = June 2005 | pmid = 16082416 | doi = 10.1358/mf.2005.27.5.908643 }}</ref>
|-
|[[5-HT5A receptor|5-HT<sub>5A</sub>]]
|118
|Human
|<ref name=":0" />
|-
|[[5-HT6 receptor|5-HT<sub>6</sub>]]
|19.5
|Human
|<ref name=":1" />
|-
|[[5-HT7 receptor|5-HT<sub>7</sub>]]
|21
|Human
|<ref name=":0" />
|-
|[[Alpha-1A adrenergic receptor|α<sub>1A</sub>]]
|0.28
|Human
|<ref name=":0" />
|-
|[[Alpha-1B adrenergic receptor|α<sub>1B</sub>]]
|0.81
|Human
|<ref name=":0" />
|-
|[[Alpha-2A adrenergic receptor|α<sub>2A</sub>]]
|184
|Human
|<ref name=":0" />
|-
|[[Alpha-2B adrenergic receptor|α<sub>2B</sub>]]
|28
|Human
|<ref name=":0" />
|-
|[[Alpha-2C adrenergic receptor|α<sub>2C</sub>]]
|46
|Human
|<ref name=":0" />
|-
|[[Beta-1 adrenergic receptor|β<sub>1</sub>]]
|10000+
|Human
|<ref name=":0" />
|-
|[[Beta-2 adrenergic receptor|β<sub>2</sub>]]
|10000+
|Human
|<ref name=":0" />
|-
|[[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]]
|47
|Human
|<ref name=":0" />
|-
|[[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]]
|433
|Human
|<ref name=":0" />
|-
|[[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]]
|47
|Human
|<ref name=":0" />
|-
|[[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]]
|151
|Human
|<ref name=":0" />
|-
|[[Dopamine receptor D1|D<sub>1</sub>]]
|114.8
|Human
|<ref name=":1" />
|-
|[[Dopamine receptor D2|D<sub>2</sub>]]
|7.244
|Human
|<ref name=":1" />
|-
|[[Dopamine receptor D3|D<sub>3</sub>]]
|6.9
|Human
|<ref name=":2">{{cite journal | vauthors = von Coburg Y, Kottke T, Weizel L, Ligneau X, Stark H | title = Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics | journal = Bioorganic & Medicinal Chemistry Letters | volume = 19 | issue = 2 | pages = 538–542 | date = January 2009 | pmid = 19091563 | doi = 10.1016/j.bmcl.2008.09.012 }}</ref>
|-
|[[Dopamine receptor D4|D<sub>4</sub>]]
|32.36
|Human
|<ref name=":1" />
|-
|[[Histamine H1 receptor|H<sub>1</sub>]]
|4.25
|Human
|<ref name=":2" />
|-
|[[Histamine H2 receptor|H<sub>2</sub>]]
|174
|Human
|<ref name=":0" />
|-
|[[Histamine H3 receptor|H<sub>3</sub>]]
|1000
|Human
|<ref name=":2" />
|-
|[[Histamine H4 receptor|H<sub>4</sub>]]
|5048
|Human
|<ref name=":0" />
|-
|[[Norepinephrine transporter|NET]]
|2,443
|Human
|<ref name=":0" />
|-
|[[Dopamine transporter|DAT]]
|10000+
|Human
|<ref name=":0" />
|}

Chlorpromazine is a very effective antagonist of [[Dopamine receptor D2|D2]] [[dopamine]] receptors and similar receptors, such as [[Dopamine receptor D3|D3]] and [[Dopamine receptor D5|D5]]. Unlike most other drugs of this genre, it also has a high affinity for [[Dopamine receptor D1|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 in 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.<ref name="GG"/>

Chlorpromazine acts as an [[receptor antagonist|antagonist]] (blocking agent) on different postsynaptic and presynaptic receptors:

*[[Dopamine receptor]]s (subtypes D<sub>1</sub>, D<sub>2</sub>, D<sub>3</sub> and D<sub>4</sub>), 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 receptor]]s (5-HT<sub>2</sub>, 5-HT<sub>6</sub> and 5-HT<sub>7</sub>), with anxiolytic, antidepressant and antiaggressive properties as well as an attenuation of [[extrapyramidal side effect]]s, but also leading to weight gain and ejaculation difficulties.
*[[Histamine receptor]]s ([[histamine H1 receptor|H<sub>1</sub> receptor]]s, accounting for sedation, antiemetic effect, vertigo, and weight gain)
*[[Adrenergic receptor|α<sub>1</sub>- and α<sub>2</sub>-adrenergic receptor]]s (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism – controversial. Also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor as well as with [[intraoperative floppy iris syndrome]] due to its effect on the iris dilator muscle.<ref>{{cite book | vauthors = Tsai LM |title=Lens and cataract |date=2021 |publisher= American Academy of Ophthalmology |location=San Francisco |isbn=978-1681044491 |pages=162}}</ref>
*[[Muscarinic acetylcholine receptor|M<sub>1</sub> and M<sub>2</sub> muscarinic acetylcholine receptor]]s (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, [[sinus tachycardia]], [[electrocardiogram|electrocardiographic]] changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).{{medcn|date=March 2023}}

The presumed effectiveness 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.<ref name="Girault, 2004">{{cite journal | vauthors = Girault JA, Greengard P | title = The neurobiology of dopamine signaling | journal = Archives of Neurology | volume = 61 | issue = 5 | pages = 641–644 | date = May 2004 | pmid = 15148138 | doi = 10.1001/archneur.61.5.641 | doi-access = free }}</ref>

Chlorpromazine and other typical [[antipsychotics]] are primarily blockers of [[D2 receptors]]. 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.<ref name="Kin">{{Cite book| vauthors = McKim WA | title=Drugs and behavior: an introduction to behavioral pharmacology| edition=6th| publisher=Prentice Hall| location=Upper Saddle River, New Jersey| year=2007| page=416| isbn=978-0-13-219788-5}}</ref>
Chlorpromazine tends to have a greater effect at [[serotonin]] receptors than at [[Dopamine receptor D2|D2]] receptors, which is notably the opposite effect of the other typical antipsychotics. Therefore, chlorpromazine's effects on dopamine and serotonin receptors are more similar to the atypical antipsychotics than to the typical antipsychotics.<ref name="Kin"/>

Chlorpromazine and other antipsychotics with [[sedative]] properties such as [[promazine]] and [[thioridazine]] are among the most potent agents at [[α-adrenergic receptor]]s. Furthermore, they are also among the most potent antipsychotics at [[histamine]] [[Histamine H1 receptor|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]].<ref name="Per">{{cite journal | vauthors = Peroutka SJ, Synder SH | title = Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency | journal = The American Journal of Psychiatry | volume = 137 | issue = 12 | pages = 1518–1522 | date = December 1980 | pmid = 6108081 | doi = 10.1176/ajp.137.12.1518 }}</ref>

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 the direct effects of 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 [[glycine]] activity from the effects of chlorpromazine was reported. Further work will be necessary to determine if the influence in NMDA receptors by antipsychotic drugs contributes to their effectiveness.<ref name="Lid">{{cite journal | vauthors = Lidsky TI, Yablonsky-Alter E, Zuck LG, Banerjee SP | title = Antipsychotic drug effects on glutamatergic activity | journal = Brain Research | volume = 764 | issue = 1–2 | pages = 46–52 | date = August 1997 | pmid = 9295192 | doi = 10.1016/S0006-8993(97)00423-X | s2cid = 37454572 }}</ref>

Chlorpromazine does also act as a [[FIASMA]] (functional inhibitor of [[Sphingomyelin phosphodiesterase|acid sphingomyelinase]]).<ref name="pmid18504571">{{cite journal | vauthors = Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer TW, Spitzer GM, Liedl KR, Gulbins E, Tripal P | title = Identification of novel functional inhibitors of acid sphingomyelinase | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e23852 | year = 2011 | pmid = 21909365 | pmc = 3166082 | doi = 10.1371/journal.pone.0023852 | veditors = Riezman H | doi-access = free | bibcode = 2011PLoSO...623852K }}</ref>

Chlorpromazine is an antagonist to [[histamine H1 receptor|H<sub>1</sub> receptor]]s (provoking antiallergic effects), [[histamine H2 receptor|H<sub>2</sub> receptor]]s (reduction of forming of gastric juice), [[muscarinic acetylcholine receptor|M<sub>1</sub> and M<sub>2</sub> receptor]]s (dry mouth, reduction in forming of gastric juice) and some [[5-HT receptor]]s (different anti-allergic/gastrointestinal actions).{{medcn|date=March 2023}}

Because it acts on so many receptors, chlorpromazine is often referred to as a "[[Dirty Drug|dirty drug]]".<ref name="Falkai">{{cite journal | vauthors = Falkai P, Vogeley K | title = [The chances of new atypical substances] | journal = Fortschritte der Neurologie-Psychiatrie | volume = 68 | issue = Suppl 1 | pages = S32–S37 | date = April 2000 | pmid = 10907611 | url = http://www.biopsychiatry.com/antipsychotics.htm | access-date = 6 July 2010 | publisher = biopsychiatry.com | url-status = live | archive-url = https://web.archive.org/web/20100724041027/http://www.biopsychiatry.com/antipsychotics.htm | archive-date = 24 July 2010 }}</ref>

===Pharmacokinetics===
{| class = wikitable
|+ <big>Pharmacokinetic parameters of chlorpromazine</big><ref name = TGA/><ref name = GG/><ref name=EMCS>{{cite web|title=Chlorpromazine Hydrochloride 100mg/5ml Oral Syrup – Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Rosemont Pharmaceuticals Limited|date=6 August 2013|access-date=8 December 2013|url=http://www.medicines.org.uk/emc/medicine/10751/SPC/Chlorpromazine+Hydrochloride+100mg+5ml+Oral+Syrup/|url-status=live|archive-url=https://web.archive.org/web/20131211235858/http://www.medicines.org.uk/emc/medicine/10751/SPC/Chlorpromazine+Hydrochloride+100mg+5ml+Oral+Syrup/|archive-date=11 December 2013}}</ref>
! Bioavailability !! t<sub>max</sub> !! C<sub>SS</sub> !!  Protein bound !! V<sub>d</sub> !! t<sub>1/2</sub> !! Details of metabolism !! Excretion !! Notes
|-
| 10–80% || 1–4 hours (Oral); 6–24 hours (IM) || 100–300&nbsp;ng/mL || 90–99% || 10–35 L/kg (mean: 22 L/kg) || 30±7 hours || [[CYP2D6]], [[CYP1A2]]—mediated into over 10 major metabolites.<ref name = GG/> 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.<ref name="Dahl">{{cite journal | vauthors = Dahl SG, Strandjord RE | title = Pharmacokinetics of chlorpromazine after single and chronic dosage | journal = Clinical Pharmacology and Therapeutics | volume = 21 | issue = 4 | pages = 437–448 | date = April 1977 | pmid = 849674 | doi = 10.1002/cpt1977214437 | s2cid = 6645825 }}</ref> || 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.<ref name =TGA/><ref name = "Yeu"/> 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.<ref name="Yeu">{{cite journal | vauthors = Yeung PK, Hubbard JW, Korchinski ED, Midha KK | title = Pharmacokinetics of chlorpromazine and key metabolites | journal = European Journal of Clinical Pharmacology | volume = 45 | issue = 6 | pages = 563–569 | year = 1993 | pmid = 8157044 | doi = 10.1007/BF00315316 | s2cid = 6410850 }}</ref>
|}

[[Image:MetabsofChlorpromazine.svg|class=skin-invert-image|thumb|left|600px|Three common metabolites of chlorpromazine]]
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