Chemistry:Chlorphenamine

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Chlorphenamine (CP, CPM), also known as chlorpheniramine, is an antihistamine used to treat the symptoms of allergic conditions such as allergic rhinitis (hay fever).[1] It is taken orally (by mouth).[1] The medication takes effect within two hours and lasts for about 4–6 hours.[1] It is a first-generation antihistamine and works by blocking the histamine H1 receptor.[1]

Common side effects include sleepiness, restlessness, and weakness. Other side effects may include dry mouth and wheeziness.[1]

Chlorpheniramine was patented in 1948 and came into medical use in 1949.[2] It is available as a generic medication and over the counter.[1][3]

In 2023, it was the 318th most commonly prescribed medication in the United States, with more than 200,000 prescriptions.[4]

Medical uses

Combination products

Chlorphenamine is often combined with phenylpropanolamine to form an allergy medication with both antihistamine and decongestant properties, although phenylpropanolamine was removed from the U.S. market per studies concluding that it increased the risk of stroke in young women.[5] 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.[6]

In the drug Coricidin, chlorphenamine is combined with the cough suppressant dextromethorphan. In the drug Cêgripe, chlorphenamine is combined with the analgesic paracetamol (also known as acetaminophen, sold as Tylenol).[7]

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.[1]

Chlorphenamine produces less sedation than other first-generation antihistamines.[8]

A large study on people 65 years old or older linked the development of Alzheimer's disease and other forms of dementia to the "higher cumulative" use of chlorphenamine and other first-generation antihistamines, due to their anticholinergic properties.[9] Chlorphenamine is rated as a "high burden" anticholinergic by experts on a semi-subjective scale.[10] This is inconsistent with the in vitro experiments showing low affinity to muscarinic acetylcholine receptors (see below).

Pharmacology

Pharmacodynamics

Site Ki (nM) Species Ref
NET 1,440 Human [11]
DAT 1,060 Human [11]
5-HT2A 3,130 Rat [12]
5-HT2C 3,120 Rat [13]
H1 2.5–3.0 Human [14][15]
H2 ND ND ND
H3 >10,000 Rat [16]
H4 2,910 Human [17]
M1 25,700 Human [18]
M2 17,000 Human [18]
M3 52,500 Human [18]
M4 77,600 Human [18]
M5 28,200 Human [18]
Values are Ki, unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. Values at the mAChRs and hERG are IC50 (nM).

Chlorphenamine acts primarily as a potent H1 antihistamine. It is specifically a potent inverse agonist of the histamine H1 receptor.[19][20] The drug is also commonly described as possessing weak anticholinergic activity by acting as an antagonist of the muscarinic acetylcholine receptors. The dextrorotatory stereoisomer, 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.[21][22] The smaller the Kd value, the greater the binding affinity of the ligand for its target.

In addition to acting as an inverse agonist at the H1 receptor, chlorphenamine has been found to act as a serotonin reuptake inhibitor (Kd = 15.2 nM for the serotonin transporter).[11][23] It has only weak affinity for the norepinephrine and dopamine transporters (Kd = 1,440 nM and 1,060 nM, respectively).[11]

A study found that dexchlorphenamine had Ki values for the human cloned H1 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.[24] Another study found that dexchlorphenamine had a Ki value of 20 to 30 μM for the 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.[25]

Pharmacokinetics

The elimination half-life of chlorphenamine has variously ranged between 13.9 and 43.4 hours in adults following a single dose in clinical studies.[26]

Chemistry

Chlorphenamine is an alkylamine and is a part of a series of antihistamines including pheniramine (Naphcon) and its halogenated derivatives including fluorpheniramine, dexchlorphenamine (Polaramine), brompheniramine (Dimetapp), dexbrompheniramine (Drixoral), deschlorpheniramine, and iodopheniramine. The halogenated alkylamine antihistamines all exhibit optical isomerism, and chlorphenamine in the indicated products is racemic chlorphenamine maleate, whereas dexchlorphenamine is the dextrorotary stereoisomer.

Synthesis

There are several patented methods for the synthesis of chlorphenamine. In one example, 4-chlorophenylacetonitrile is reacted with 2-chloropyridine in the presence of sodium amide to form 4-chlorophenyl(2-pyridyl)acetonitrile. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives γ-(4-chlorphenyl)-γ-cyano-N,N-dimethyl-2-pyridinepropanamine, the hydrolysis and decarboxylation of which lead to chlorphenamine.

Chlorpheniramine synthesis[27]

A second method boom starts from pyridine, which undergoes alkylation by 4-chlorophenylacetonitrile,[28] giving 2-(4-chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives chlorphenamine.

Chlorpheniramine synthesis[29]

Society and culture

Names

Chlorphenamine is the INN while chlorpheniramine is the USAN and former BAN.

Brand names include Chlor-Trimeton, Demazin, Allerest 12 Hour, Piriton, Chlorphen-12, Tylenol Cold/Allergy, and numerous others according to country.[1]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Chlorpheniramine" (in en). American Society of Health-System Pharmacists. 26 July 2023. https://www.drugs.com/mtm/chlorpheniramine.html. Retrieved 20 August 2023. 
  2. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 546. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA546. 
  3. ↑ "Over-the-Counter Medicines for Allergies" (in en). https://www.healthlinkbc.ca/health-topics/hw121413. 
  4. ↑ "Chlorpheniramine Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Chlorpheniramine. 
  5. ↑ "Phenylpropanolamine (PPA) Information Page – FDA moves PPA from OTC" (Press release). US Food and Drug Administration. 23 December 2005. Archived from the original on 12 January 2009.
  6. ↑ https://www.jodrugs.com/tradenames/167408-vernate.aspx Information on defunct drug Vernate
  7. ↑ "Cêgripe". https://www.cegripe.pt/medicamentos-para-a-gripe/cegripe. 
  8. ↑ Pharmaceutical Innovation: Revolutionizing Human Health. Chemical Heritage Foundation. 1999. pp. 230–231. ISBN 978-0-941901-21-5. https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA230. 
  9. ↑ "Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study". JAMA Internal Medicine 175 (3): 401–407. March 2015. doi:10.1001/jamainternmed.2014.7663. PMID 25621434. 
  10. ↑ "Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review". BMC Geriatrics 15 (31). March 2015. doi:10.1186/s12877-015-0029-9. PMID 25879993. 
  11. ↑ 11.0 11.1 11.2 11.3 Cite error: Invalid <ref> tag; no text was provided for refs named pmid9537821
  12. ↑ "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. January 1987. doi:10.1111/j.1471-4159.1987.tb13135.x. PMID 3794694. 
  13. ↑ "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. October 1988. doi:10.1016/S0022-3565(25)19989-8. PMID 3139864. 
  14. ↑ "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". European Journal of Biochemistry 224 (2): 489–495. September 1994. doi:10.1111/j.1432-1033.1994.00489.x. PMID 7925364. 
  15. ↑ "Characteristics of histamine H1 receptors on HeLa cells". European Journal of Pharmacology 245 (3): 291–295. May 1993. doi:10.1016/0922-4106(93)90110-u. PMID 8335064. 
  16. ↑ "Biexponential kinetics of (R)-alpha-[3H]methylhistamine binding to the rat brain H3 histamine receptor". Journal of Neurochemistry 55 (5): 1612–1616. November 1990. doi:10.1111/j.1471-4159.1990.tb04946.x. PMID 2213013. 
  17. ↑ "Discovery of a novel member of the histamine receptor family". Molecular Pharmacology 59 (3): 427–433. March 2001. doi:10.1124/mol.59.3.427. PMID 11179435. https://cdr.lib.unc.edu/downloads/8336h388z. Retrieved 21 January 2023. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 "Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes". Pharmacotherapy 19 (4): 447–451. April 1999. doi:10.1592/phco.19.6.447.31041. PMID 10212017. 
  19. ↑ "Advances in H1-antihistamines". The New England Journal of Medicine 351 (21): 2203–2217. November 2004. doi:10.1056/NEJMra033121. PMID 15548781. 
  20. ↑ "H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects". Clinical and Experimental Allergy 32 (4): 489–498. April 2002. doi:10.1046/j.0954-7894.2002.01314.x. PMID 11972592. 
  21. ↑ "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". The Journal of Pharmacology and Experimental Therapeutics 230 (1): 94–102. July 1984. doi:10.1016/S0022-3565(25)21446-X. PMID 6086881. 
  22. ↑ "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology 114 (4): 559–565. May 1994. doi:10.1007/bf02244985. PMID 7855217. 
  23. ↑ "Central and peripheral monoaminergic membrane-pump blockade by some addictive analgesics and antihistamines". The Journal of Pharmacy and Pharmacology 21 (7): 460–464. July 1969. doi:10.1111/j.2042-7158.1969.tb08287.x. PMID 4390069. 
  24. ↑ "A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors". The Journal of Pharmacology and Experimental Therapeutics 302 (1): 328–336. July 2002. doi:10.1124/jpet.302.1.328. PMID 12065734. 
  25. ↑ "Muscarinic cholinergic binding in rat brain". Proceedings of the National Academy of Sciences of the United States of America 71 (5): 1725–1729. May 1974. doi:10.1073/pnas.71.5.1725. PMID 4151898. Bibcode: 1974PNAS...71.1725Y. 
  26. ↑ "Chlorpheniramine plasma concentration and histamine H1-receptor occupancy". Clinical Pharmacology and Therapeutics 58 (2): 210–220. August 1995. doi:10.1016/0009-9236(95)90199-X. PMID 7648771. 
  27. ↑ D. Papa, E. Schwenk, N. Sperber, U.S. Patent 2,567,245 (1951)
  28. ↑ "Brominations with pyridine hydrobromide perbromide". Journal of the American Chemical Society 70 (1): 417–418. January 1948. doi:10.1021/ja01181a508. PMID 18918843. Bibcode: 1948JAChS..70..417D. 
  29. ↑ D. Papa, E. Schwenk, N. Sperber, U.S. Patent 2,676,964 (1954)



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