Chlorphenamine is often combined withphenylpropanolamine to form anallergy medication with bothantihistamine anddecongestant properties, although phenylpropanolamine was removed from the U.S. market per studies concluding that it increased the risk of stroke in young women.[6]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 toElvis Presley.[7]
In the drugCoricidin, chlorphenamine is combined with the cough suppressantdextromethorphan. In the drug Cêgripe, chlorphenamine is combined with the analgesicparacetamol (also known as acetaminophen, sold asTylenol).[8]
A large study on people 65 years old or older linked the development ofAlzheimer's disease and other forms of dementia to the "higher cumulative" use of chlorphenamine and other first-generation antihistamines, due to theiranticholinergic properties.[10] Chlorphenamine is rated as a "high burden" anticholinergic by experts on a semi-subjective scale.[11] This is inconsistent with thein vitro experiments showing low affinity to muscarinic acetylcholine receptors (see below).
Values are Ki, unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. Values at themAChRsTooltip muscarinic acetylcholine receptors andhERGTooltip Human Ether-à-go-go-Related Gene areIC50 (nM).
A study found that dexchlorphenamine had Ki values for the human clonedH1 receptor of 2.67 to 4.81 nM while levchlorphenamine had Ki values of 211 to 361 nM for this receptor, indicating that dexchlorphenamine is the active enantiomer.[27] Another study found that dexchlorphenamine had a Ki value of 20 to 30 μM for themuscarinic 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.[28]
There are several patented methods for thesynthesis of chlorphenamine. In one example,4-chlorophenylacetonitrile is reacted with2-chloropyridine in the presence ofsodium amide to form 4-chlorophenyl(2-pyridyl)acetonitrile. Alkylating this with 2-dimethylaminoethylchloride in the presence ofsodium amide gives γ-(4-chlorphenyl)-γ-cyano-N,N-dimethyl-2-pyridinepropanamine, thehydrolysis anddecarboxylation of which lead to chlorphenamine.
A second method boom starts frompyridine, which undergoes alkylation by 4-chlorophenylacetonitrile,[30] giving 2-(4-chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives chlorphenamine.
Chlorphenamine is theINNTooltip International Nonproprietary Name whilechlorpheniramine is theUSANTooltip United States Adopted Name and formerBANTooltip British Approved Name.
Brand names include Chlor-Trimeton, Demazin, Allerest 12 Hour, Piriton, Chlorphen-12, Tylenol Cold/Allergy, and numerous others according to country.[2]
^abYasuda SU, Wellstein A, Likhari P, Barbey JT, Woosley RL (August 1995). "Chlorpheniramine plasma concentration and histamine H1-receptor occupancy".Clinical Pharmacology and Therapeutics.58 (2):210–220.doi:10.1016/0009-9236(95)90199-X.PMID7648771.S2CID35759573.
^abcdefgh"Chlorpheniramine".Drugs.com. American Society of Health-System Pharmacists. 26 July 2023.Archived from the original on 20 August 2023. Retrieved20 August 2023.
^Roth BL, Driscol J."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health.Archived from the original on 2 October 2020. Retrieved14 August 2017.
^abcdeTatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters".European Journal of Pharmacology.340 (2–3):249–258.doi:10.1016/s0014-2999(97)01393-9.PMID9537821.
^Hoffman BJ, Scheffel U, Lever JR, Karpa MD, Hartig PR (January 1987). "N1-methyl-2-125I-lysergic acid diethylamide, a preferred ligand for in vitro and in vivo characterization of serotonin receptors".Journal of Neurochemistry.48 (1):115–124.doi:10.1111/j.1471-4159.1987.tb13135.x.PMID3794694.S2CID23311638.
^Sanders-Bush E, Breeding M (October 1988). "Putative selective 5-HT-2 antagonists block serotonin 5-HT-1c receptors in the choroid plexus".The Journal of Pharmacology and Experimental Therapeutics.247 (1):169–173.doi:10.1016/S0022-3565(25)19989-8.PMID3139864.
^Arias-Montaño JA, Young JM (May 1993). "Characteristics of histamine H1 receptors on HeLa cells".European Journal of Pharmacology.245 (3):291–295.doi:10.1016/0922-4106(93)90110-u.PMID8335064.
^West RE, Zweig A, Granzow RT, Siegel MI, Egan RW (November 1990). "Biexponential kinetics of (R)-alpha-[3H]methylhistamine binding to the rat brain H3 histamine receptor".Journal of Neurochemistry.55 (5):1612–1616.doi:10.1111/j.1471-4159.1990.tb04946.x.PMID2213013.S2CID83953993.
^abcdeYasuda SU, Yasuda RP (April 1999). "Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes".Pharmacotherapy.19 (4):447–451.doi:10.1592/phco.19.6.447.31041.PMID10212017.S2CID39502992.
^Simons FE (November 2004). "Advances in H1-antihistamines".The New England Journal of Medicine.351 (21):2203–2217.doi:10.1056/NEJMra033121.PMID15548781.
^Leurs R, Church MK, Taglialatela M (April 2002). "H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects".Clinical and Experimental Allergy.32 (4):489–498.doi:10.1046/j.0954-7894.2002.01314.x.PMID11972592.S2CID11849647.
^Richelson E, Nelson A (July 1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro".The Journal of Pharmacology and Experimental Therapeutics.230 (1):94–102.doi:10.1016/S0022-3565(25)21446-X.PMID6086881.
^Cusack B, Nelson A, Richelson E (May 1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds".Psychopharmacology.114 (4):559–565.doi:10.1007/bf02244985.PMID7855217.S2CID21236268.
^Carlsson A, Lindqvist M (July 1969). "Central and peripheral monoaminergic membrane-pump blockade by some addictive analgesics and antihistamines".The Journal of Pharmacy and Pharmacology.21 (7):460–464.doi:10.1111/j.2042-7158.1969.tb08287.x.PMID4390069.S2CID39627573.
^Booth RG, Moniri NH, Bakker RA, Choksi NY, Nix WB, Timmerman H, Leurs R (July 2002). "A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors".The Journal of Pharmacology and Experimental Therapeutics.302 (1):328–336.doi:10.1124/jpet.302.1.328.PMID12065734.S2CID2600032.
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