# Chlorphenamine
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> Source: https://en.wikipedia.org/wiki/Chlorphenamine
> Source revision: 1356473788
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{{Short description|Antihistamine used to treat allergies}}
{{distinguish | Chloropyramine}}
{{Use dmy dates|date=October 2020}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 443519064
| image = Chlorphenamine.svg
| image_class = skin-invert-image
| width = 200
| alt =
| image2 = Chlorpheniramine for veterinary use.jpg
| alt2 =
| tradename = Chlor-Trimeton; Piriton; Chlor-Tripolon; Allergex
| Drugs.com = {{drugs.com|monograph|chlorpheniramine-maleate-tannate-dexchlorpheniramine-maleate}}
| MedlinePlus = a682543
| pregnancy_AU = A
| routes_of_administration = [Oral](/source/Oral_administration), [intravenous](/source/Intravenous_therapy), [intramuscular](/source/Intramuscular_injection), [subcutaneous](/source/Subcutaneous_injection)
| ATC_prefix = R06
| ATC_suffix = AB04
| legal_AU = S3
| legal_UK = P
| legal_US = OTC
| legal_status = [CN](/source/China): [OTC](/source/Over-the-counter_drug)
| bioavailability = 25 to 50%
| protein_bound = 72%
| metabolism = [Liver](/source/Liver) ([CYP2D6](/source/CYP2D6))
| elimination_half-life = 13.9–43.4 hours[ It is taken [orally](/source/oral_administration) (by mouth).][{{cite web |title=Chlorpheniramine |url=https://www.drugs.com/mtm/chlorpheniramine.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |date=26 July 2023 |accessdate=20 August 2023 |language=en |archive-date=20 August 2023 |archive-url=https://web.archive.org/web/20230820022645/https://www.drugs.com/mtm/chlorpheniramine.html |url-status=live }}] The medication takes effect within two hours and lasts for about 4–6 hours.[ It is a [first-generation antihistamine](/source/first-generation_antihistamine) and works by blocking the [histamine H1 receptor](/source/Histamine_H1_receptor).][
Chlorpheniramine was patented in 1948 and came into medical use in 1949.][{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=546 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA546 |language=en}}] It is available as a [generic medication](/source/generic_medication) and [over the counter](/source/over_the_counter).[{{cite web |title=Over-the-Counter Medicines for Allergies |url=https://www.healthlinkbc.ca/health-topics/hw121413 |website=HealthLink BC |access-date=15 July 2019 |language=en |archive-date=15 July 2019 |archive-url=https://web.archive.org/web/20190715162600/https://www.healthlinkbc.ca/health-topics/hw121413 |url-status=dead }}]
In 2023, it was the 318th most commonly prescribed medication in the United States, with more than 200,000 prescriptions.[{{cite web | title = Chlorpheniramine Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Chlorpheniramine | access-date = 21 August 2025 }}]
==Medical uses==
===Combination products===
Chlorphenamine is often combined with [phenylpropanolamine](/source/phenylpropanolamine) to form an [allergy](/source/allergy) medication with both [antihistamine](/source/antihistamine) and [decongestant](/source/decongestant) properties, although phenylpropanolamine was removed from the U.S. market per studies concluding that it increased the risk of stroke in young women.[{{cite press release|url=https://www.fda.gov/cder/drug/infopage/ppa/ |archive-url=https://web.archive.org/web/20090112142816/https://www.fda.gov/cder/drug/infopage/ppa/ |archive-date=12 January 2009 |title=Phenylpropanolamine (PPA) Information Page – FDA moves PPA from OTC |publisher=US Food and Drug Administration |date=23 December 2005}}] '''Vernate''' was a trade name of one such product available in the U.S. prior to the FDA ban; it was manufactured by Tutag and was among the medications prescribed to [Elvis Presley](/source/Elvis_Presley).[https://www.jodrugs.com/tradenames/167408-vernate.aspx Information on defunct drug '''Vernate''']
In the drug [Coricidin](/source/Coricidin), chlorphenamine is combined with the cough suppressant [dextromethorphan](/source/dextromethorphan). In the drug Cêgripe, chlorphenamine is combined with the analgesic [paracetamol](/source/paracetamol) (also known as acetaminophen, sold as ''Tylenol'').[{{Cite web|url=https://www.cegripe.pt/medicamentos-para-a-gripe/cegripe|title=Cêgripe|website=Cegripe.pt|access-date=10 June 2022|archive-date=25 June 2022|archive-url=https://web.archive.org/web/20220625035651/https://www.cegripe.pt/medicamentos-para-a-gripe/cegripe|url-status=live}}]
==Side effects==
The adverse effects include drowsiness, dizziness, confusion, constipation, anxiety, nausea, blurred vision, restlessness, decreased coordination, dry mouth, shallow breathing, hallucinations, irritability, problems with memory or concentration, tinnitus and trouble urinating.[{{cite book | vauthors = Landau R, Achilladelis B, Scriabine A | date = 1999 | title = Pharmaceutical Innovation: Revolutionizing Human Health | publisher = Chemical Heritage Foundation | pages = 230–231 | isbn = 978-0-941901-21-5 | url = https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA230}}]
A large study on people 65 years old or older linked the development of [Alzheimer's disease](/source/Alzheimer's_disease) and other forms of dementia to the "higher cumulative" use of chlorphenamine and other first-generation antihistamines, due to their [anticholinergic](/source/anticholinergic) properties.[{{cite journal | vauthors = Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB | display-authors = 6 | title = Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study | journal = JAMA Internal Medicine | volume = 175 | issue = 3 | pages = 401–407 | date = March 2015 | pmid = 25621434 | pmc = 4358759 | doi = 10.1001/jamainternmed.2014.7663 | author5-link = Rebecca Hubbard }}] Chlorphenamine is rated as a "high burden" anticholinergic by experts on a semi-subjective scale.[{{cite journal | vauthors = Salahudeen MS, Duffull SB, Nishtala PS | title = Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review | journal = BMC Geriatrics | volume = 15 | issue = 31 | article-number = 31 | date = March 2015 | pmid = 25879993 | pmc = 4377853 | doi = 10.1186/s12877-015-0029-9 | df = dmy-all | doi-access = free }}] This is inconsistent with the ''in vitro'' experiments showing low affinity to muscarinic acetylcholine receptors (see below).
==Pharmacology==
===Pharmacodynamics===
{| class="wikitable floatright" style="font-size:small;"
|+ Chlorphenamine[{{cite web | title = PDSP Ki Database | work = Psychoactive Drug Screening Program (PDSP) | author1-link = Bryan Roth | vauthors = Roth BL, Driscol J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://kidbdev.med.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=chlorpheniramine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | archive-date = 2 October 2020 | archive-url = https://web.archive.org/web/20201002023803/https://kidbdev.med.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=chlorpheniramine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | url-status = live }}]
|-
! Site !! Ki (nM) !! Species !! Ref
|-
| {{abbrlink|SERT|Serotonin transporter}} || 15.2 || Human || [{{cite journal | vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = European Journal of Pharmacology | volume = 340 | issue = 2–3 | pages = 249–258 | date = December 1997 | pmid = 9537821 | doi = 10.1016/s0014-2999(97)01393-9 }}]
|-
| {{abbrlink|NET|Norepinephrine transporter}} || 1,440 || Human || [{{cite journal | vauthors = Hoffman BJ, Scheffel U, Lever JR, Karpa MD, Hartig PR | title = N1-methyl-2-125I-lysergic acid diethylamide, a preferred ligand for in vitro and in vivo characterization of serotonin receptors | journal = Journal of Neurochemistry | volume = 48 | issue = 1 | pages = 115–124 | date = January 1987 | pmid = 3794694 | doi = 10.1111/j.1471-4159.1987.tb13135.x | s2cid = 23311638 }}]
|-
| [5-HT2C](/source/5-HT2C_receptor) || 3,120 || Rat || [{{cite journal | vauthors = Sanders-Bush E, Breeding M | title = Putative selective 5-HT-2 antagonists block serotonin 5-HT-1c receptors in the choroid plexus | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 247 | issue = 1 | pages = 169–173 | date = October 1988 | doi = 10.1016/S0022-3565(25)19989-8 | pmid = 3139864 }}]
|-
| [H1](/source/Histamine_H1_receptor) || 2.5–3.0 || Human || [{{cite journal | vauthors = Moguilevsky N, Varsalona F, Noyer M, Gillard M, Guillaume JP, Garcia L, Szpirer C, Szpirer J, Bollen A | display-authors = 6 | title = Stable expression of human H1-histamine-receptor cDNA in Chinese hamster ovary cells. Pharmacological characterisation of the protein, tissue distribution of messenger RNA and chromosomal localisation of the gene | journal = European Journal of Biochemistry | volume = 224 | issue = 2 | pages = 489–495 | date = September 1994 | pmid = 7925364 | doi = 10.1111/j.1432-1033.1994.00489.x | doi-access = free }}][{{cite journal | vauthors = Arias-Montaño JA, Young JM | title = Characteristics of histamine H1 receptors on HeLa cells | journal = European Journal of Pharmacology | volume = 245 | issue = 3 | pages = 291–295 | date = May 1993 | pmid = 8335064 | doi = 10.1016/0922-4106(93)90110-u }}]
|-
| [H2](/source/Histamine_H2_receptor) || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [H3](/source/Histamine_H3_receptor) || >10,000 || Rat || [{{cite journal | vauthors = West RE, Zweig A, Granzow RT, Siegel MI, Egan RW | title = Biexponential kinetics of (R)-alpha-[3H]methylhistamine binding to the rat brain H3 histamine receptor | journal = Journal of Neurochemistry | volume = 55 | issue = 5 | pages = 1612–1616 | date = November 1990 | pmid = 2213013 | doi = 10.1111/j.1471-4159.1990.tb04946.x | s2cid = 83953993 }}]
|-
| [H4](/source/Histamine_H4_receptor) || 2,910 || Human || [{{cite journal | vauthors = Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee SP, Lynch KR, Roth BL, O'Dowd BF | display-authors = 6 | title = Discovery of a novel member of the histamine receptor family | journal = Molecular Pharmacology | volume = 59 | issue = 3 | pages = 427–433 | date = March 2001 | pmid = 11179435 | doi = 10.1124/mol.59.3.427 | url = https://cdr.lib.unc.edu/downloads/8336h388z | access-date = 21 January 2023 | archive-date = 10 January 2023 | archive-url = https://web.archive.org/web/20230110194010/https://cdr.lib.unc.edu/downloads/8336h388z | url-status = live }}]
|-
| [M1](/source/Muscarinic_acetylcholine_receptor_M1) || 25,700 || Human || [{{cite journal | vauthors = Yasuda SU, Yasuda RP | title = Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes | journal = Pharmacotherapy | volume = 19 | issue = 4 | pages = 447–451 | date = April 1999 | pmid = 10212017 | doi = 10.1592/phco.19.6.447.31041 | s2cid = 39502992 }}]
|-
| [M2](/source/Muscarinic_acetylcholine_receptor_M2) || 17,000 || Human || [{{cite journal | vauthors = Suessbrich H, Waldegger S, Lang F, Busch AE | title = Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole | journal = FEBS Letters | volume = 385 | issue = 1–2 | pages = 77–80 | date = April 1996 | pmid = 8641472 | doi = 10.1016/0014-5793(96)00355-9 | s2cid = 40355762 | doi-access = free | bibcode = 1996FEBSL.385...77S }}]
|- class="sortbottom"
| colspan="4" style="width: 1px;" | Values are Ki, unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. Values at the {{abbrlink|mAChRs|muscarinic acetylcholine receptors}} and {{abbrlink|hERG|Human Ether-à-go-go-Related Gene}} are [IC50](/source/IC50) (nM).
|}
Chlorphenamine acts primarily as a potent H1 [antihistamine](/source/antihistamine). It is specifically a potent [inverse agonist](/source/inverse_agonist) of the [histamine](/source/histamine) [H1 receptor](/source/H1_receptor).[{{cite journal | vauthors = Simons FE | title = Advances in H1-antihistamines | journal = The New England Journal of Medicine | volume = 351 | issue = 21 | pages = 2203–2217 | date = November 2004 | pmid = 15548781 | doi = 10.1056/NEJMra033121 }}][{{cite journal | vauthors = Leurs R, Church MK, Taglialatela M | title = H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects | journal = Clinical and Experimental Allergy | volume = 32 | issue = 4 | pages = 489–498 | date = April 2002 | pmid = 11972592 | doi = 10.1046/j.0954-7894.2002.01314.x | s2cid = 11849647 }}] The drug is also commonly described as possessing weak [anticholinergic](/source/anticholinergic) activity by acting as an [antagonist](/source/receptor_antagonist) of the [muscarinic acetylcholine receptor](/source/muscarinic_acetylcholine_receptor)s. The [dextrorotatory](/source/dextrorotatory) [stereoisomer](/source/stereoisomer), [dexchlorpheniramine](/source/dexchlorpheniramine), has been reported to possess Kd values of 15 nM for the H1 receptor and 1,300 nM for the muscarinic acetylcholine receptors in human brain tissue.[{{cite journal | vauthors = Richelson E, Nelson A | title = Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 230 | issue = 1 | pages = 94–102 | date = July 1984 | doi = 10.1016/S0022-3565(25)21446-X | pmid = 6086881 }}][{{cite journal | vauthors = Cusack B, Nelson A, Richelson E | title = Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal = Psychopharmacology | volume = 114 | issue = 4 | pages = 559–565 | date = May 1994 | pmid = 7855217 | doi = 10.1007/bf02244985 | s2cid = 21236268 }}] The smaller the Kd value, the greater the binding affinity of the ligand for its target.
In addition to acting as an [inverse agonist](/source/inverse_agonist) at the H1 receptor, chlorphenamine has been found to act as a [serotonin reuptake inhibitor](/source/serotonin_reuptake_inhibitor) (Kd = 15.2 nM for the [serotonin transporter](/source/serotonin_transporter)).[{{cite journal | vauthors = Carlsson A, Lindqvist M | title = Central and peripheral monoaminergic membrane-pump blockade by some addictive analgesics and antihistamines | journal = The Journal of Pharmacy and Pharmacology | volume = 21 | issue = 7 | pages = 460–464 | date = July 1969 | pmid = 4390069 | doi = 10.1111/j.2042-7158.1969.tb08287.x | s2cid = 39627573 }}] It has only weak affinity for the [norepinephrine](/source/norepinephrine_transporter) and [dopamine transporter](/source/dopamine_transporter)s (Kd = 1,440 nM and 1,060 nM, respectively).[{{cite journal | vauthors = Booth RG, Moniri NH, Bakker RA, Choksi NY, Nix WB, Timmerman H, Leurs R | title = A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 302 | issue = 1 | pages = 328–336 | date = July 2002 | pmid = 12065734 | doi = 10.1124/jpet.302.1.328 | s2cid = 2600032 }}] Another study found that dexchlorphenamine had a Ki value of 20 to 30 μM for the [muscarinic acetylcholine receptor](/source/muscarinic_acetylcholine_receptor) using rat brain tissue while levchlorphenamine had a Ki value of 40 to 50 μM for this receptor, indicating that both enantiomers have very low affinity for it.[{{cite journal | vauthors = Yamamura HI, Snyder SH | title = Muscarinic cholinergic binding in rat brain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 71 | issue = 5 | pages = 1725–1729 | date = May 1974 | pmid = 4151898 | pmc = 388311 | doi = 10.1073/pnas.71.5.1725 | doi-access = free | bibcode = 1974PNAS...71.1725Y }}]
===Pharmacokinetics===
The [elimination half-life](/source/elimination_half-life) of chlorphenamine has variously ranged between 13.9 and 43.4 hours in adults following a single dose in clinical studies.[{{cite journal | vauthors = Yasuda SU, Wellstein A, Likhari P, Barbey JT, Woosley RL | title = Chlorpheniramine plasma concentration and histamine H1-receptor occupancy | journal = Clinical Pharmacology and Therapeutics | volume = 58 | issue = 2 | pages = 210–220 | date = August 1995 | pmid = 7648771 | doi = 10.1016/0009-9236(95)90199-X | s2cid = 35759573 }}]
==Chemistry==
Chlorphenamine is an [alkylamine](/source/aliphatic_amine) and is a part of a series of antihistamines including [pheniramine](/source/pheniramine) (Naphcon) and its [halogen](/source/halogen)ated derivatives including [fluorpheniramine](/source/fluorpheniramine), [dexchlorphenamine](/source/dexchlorphenamine) (Polaramine), [brompheniramine](/source/brompheniramine) (Dimetapp), [dexbrompheniramine](/source/dexbrompheniramine) (Drixoral), [deschlorpheniramine](/source/deschlorpheniramine), and [iodopheniramine](/source/iodopheniramine). The halogenated alkylamine antihistamines all exhibit [optical isomerism](/source/optical_isomerism), and chlorphenamine in the indicated products is racemic chlorphenamine [maleate](/source/maleate), whereas dexchlorphenamine is the [dextrorotary](/source/dextrorotary) stereoisomer.
===Synthesis===
There are several patented methods for the [synthesis](/source/organic_synthesis) of chlorphenamine. In one example, [4-chlorophenylacetonitrile](/source/4-chlorophenylacetonitrile) is reacted with [2-chloropyridine](/source/2-chloropyridine) in the presence of [sodium amide](/source/sodium_amide) to form 4-chlorophenyl(2-pyridyl)acetonitrile. Alkylating this with 2-dimethylaminoethylchloride in the presence of [sodium amide](/source/sodium_amide) gives γ-(4-chlorphenyl)-γ-cyano-''N'',''N''-dimethyl-2-pyridinepropanamine, the [hydrolysis](/source/hydrolysis) and [decarboxylation](/source/decarboxylation) of which lead to chlorphenamine.
center|thumb|600px|class=skin-invert-image|Chlorpheniramine synthesis[D. Papa, E. Schwenk, N. Sperber, {{US Patent|2567245}} (1951)]
A second method boom starts from [pyridine](/source/pyridine), which undergoes alkylation by 4-chlorophenylacetonitrile,[{{cite journal | vauthors = Djerassi C, Scholz CR | title = Brominations with pyridine hydrobromide perbromide | journal = Journal of the American Chemical Society | volume = 70 | issue = 1 | pages = 417–418 | date = January 1948 | pmid = 18918843 | doi = 10.1021/ja01181a508 | bibcode = 1948JAChS..70..417D }}] giving 2-(4-chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives chlorphenamine.
600px|thumb|center|class=skin-invert-image|Chlorpheniramine synthesis[D. Papa, E. Schwenk, N. Sperber, {{US Patent|2676964}} (1954)]
== Society and culture ==
=== Names ===
''Chlorphenamine'' is the {{abbrlink|INN|International Nonproprietary Name}} while ''chlorpheniramine'' is the {{abbrlink|USAN|United States Adopted Name}} and former {{abbrlink|BAN|British Approved Name}}.
Brand names include Chlor-Trimeton, Demazin, Allerest 12 Hour, Piriton, Chlorphen-12, Tylenol Cold/Allergy, and numerous others according to country.