Chlorphenamine

Chlorphenamine (CP, CPM), also known as chlorpheniramine, is an antihistamine used to treat the symptoms of allergic conditions such as allergic rhinitis (hay fever).[2] It is taken orally (by mouth).[2] The medication takes effect within two hours and lasts for about 4-6 hours.[2]

Not to be confused with Chlorphenacemide.

Chlorphenamine
Clinical data
Trade namesChlor-Trimeton; Piriton; Chlor-Tripolon
AHFS/Drugs.comMonograph
MedlinePlusa682543
Pregnancy
category
  • AU: A
Routes of
administration		Oral, Intravenous, Intramuscular, Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability25 to 50%
Protein binding72%
MetabolismLiver (CYP2D6)
Elimination half-life13.9–43.4 hours[1]
ExcretionKidney
Identifiers
  • 3-(4-Chlorophenyl)-N,N-dimethyl-3-(pyridin-2-yl)-propan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.004.596
Chemical and physical data
FormulaC16H19ClN2
Molar mass274.79 g·mol−1
3D model (JSmol)
Solubility in water0.55 g/100 mL, liquid mg/mL (20 °C)
  • Clc1ccc(cc1)C(c2ncccc2)CCN(C)C
  • InChI=1S/C16H19ClN2/c1-19(2)12-10-15(16-5-3-4-11-18-16)13-6-8-14(17)9-7-13/h3-9,11,15H,10,12H2,1-2H3 checkY
  • Key:SOYKEARSMXGVTM-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Common side effects include sleepiness, restlessness, and weakness.[2] Other side effects may include dry mouth and wheeziness.[2] It is a first-generation antihistamine and works by blocking the H1 receptor.[2]

Chlorpheniramine was patented in 1948 and came into medical use in 1949.[3] It is available as a generic medication and over the counter.[2][4]

Medical uses

Combination products

Chlorphenamine is often combined with phenylpropanolamine to form an allergy medication with both antihistamine and decongestant properties, though phenylpropanolamine is no longer available in the US after studies showed it increased the risk of stroke in young women.[5] Chlorphenamine remains available with no such risk.

Chlorphenamine may be combined with the opioid hydrocodone. Chlorphenamine/dihydrocodeine immediate-release syrups are also marketed. The antihistamine is helpful in cases where allergy or common cold is the reason for the cough; it is also a potentiator of opioids, allowing enhanced suppression of cough, analgesia, and other effects from a given quantity of the drug by itself. In various places in the world, cough and cold preparations containing codeine and chlorphenamine are available.

In the drug Coricidin, chlorphenamine is combined with the cough suppressant dextromethorphan. In the drug Cêgripe, chlorphenamine is combined with the analgesic paracetamol.[6]

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.

Chlorphenamine produces less sedation than other first-generation antihistamines.[7]

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.[8] Chlorphenamine is rated as a "high burden" anticholinergic by experts on a semi-subjective scale.[9]

Pharmacology

Pharmacodynamics
Chlorphenamine[10]
SiteKi (nM)SpeciesRef
SERTTooltip Serotonin transporter15.2Human[11]
NETTooltip Norepinephrine transporter1,440Human[11]
DATTooltip Dopamine transporter1,060Human[11]
5-HT2A3,130Rat[12]
5-HT2C3,120Rat[13]
H12.5–3.0Human[14][15]
H2NDNDND
H3>10,000Rat[16]
H42,910Human[17]
M125,700Human[18]
M217,000Human[18]
M352,500Human[18]
M477,600Human[18]
M528,200Human[18]
hERGTooltip Human Ether-à-go-go-Related Gene20,900Human[19]
Values are Ki, unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. Values at the mAChRsTooltip muscarinic acetylcholine receptors and hERGTooltip Human Ether-à-go-go-Related Gene are IC50 (nM).

Chlorphenamine acts primarily as a potent H1 antihistamine. It is specifically a potent inverse agonist of the histamine H1 receptor.[20][21] 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.[22][23] 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][24] It has only weak affinity for the norepinephrine and dopamine transporters (Kd = 1,440 nM and 1,060 nM, respectively).[11] A similar antihistamine, brompheniramine, led to the discovery of the selective serotonin reuptake inhibitor (SSRI) zimelidine.

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.[25] 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.[26]

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.[1]

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 INNTooltip International Nonproprietary Name while chlorpheniramine is the USANTooltip United States Adopted Name and former BANTooltip 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]

References
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  2. "Chlorpheniramine". Drugs.com. American Society of Health-System Pharmacists. 26 July 2023. Retrieved 20 August 2023.
  3. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 546. ISBN 9783527607495.
  4. "Over-the-Counter Medicines for Allergies". HealthLink BC. Archived from the original on 15 July 2019. Retrieved 15 July 2019.
  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. "Cêgripe". Cegripe.pt. Retrieved 10 June 2022.
  7. Ralph Landau; Basil Achilladelis; Alexander Scriabine (1999). Pharmaceutical Innovation: Revolutionizing Human Health. Chemical Heritage Foundation. pp. 230–231. ISBN 978-0-941901-21-5.
  8. Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, et al. (March 2015). "Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study". JAMA Internal Medicine. 175 (3): 401–407. doi:10.1001/jamainternmed.2014.7663. PMC 4358759. PMID 25621434.
  9. Salahudeen MS, Duffull SB, Nishtala PS (March 2015). "Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review". BMC Geriatrics. 15 (31): 31. doi:10.1186/s12877-015-0029-9. PMC 4377853. PMID 25879993.
  10. 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. Retrieved 14 August 2017.
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  12. 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. PMID 3794694. S2CID 23311638.
  13. 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. PMID 3139864.
  14. Moguilevsky N, Varsalona F, Noyer M, Gillard M, Guillaume JP, Garcia L, et al. (September 1994). "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. doi:10.1111/j.1432-1033.1994.00489.x. PMID 7925364.
  15. 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. PMID 8335064.
  16. 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. PMID 2213013. S2CID 83953993.
  17. Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, et al. (March 2001). "Discovery of a novel member of the histamine receptor family". Molecular Pharmacology. 59 (3): 427–433. doi:10.1124/mol.59.3.427. PMID 11179435.
  18. Yasuda 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. PMID 10212017. S2CID 39502992.
  19. Suessbrich H, Waldegger S, Lang F, Busch AE (April 1996). "Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole". FEBS Letters. 385 (1–2): 77–80. doi:10.1016/0014-5793(96)00355-9. PMID 8641472. S2CID 40355762.
  20. Simons FE (November 2004). "Advances in H1-antihistamines". The New England Journal of Medicine. 351 (21): 2203–2217. doi:10.1056/NEJMra033121. PMID 15548781.
  21. 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. PMID 11972592. S2CID 11849647.
  22. 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. PMID 6086881.
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  24. 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. PMID 4390069. S2CID 39627573.
  25. 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. PMID 12065734. S2CID 2600032.
  26. Yamamura HI, Snyder SH (May 1974). "Muscarinic cholinergic binding in rat brain". Proceedings of the National Academy of Sciences of the United States of America. 71 (5): 1725–1729. Bibcode:1974PNAS...71.1725Y. doi:10.1073/pnas.71.5.1725. PMC 388311. PMID 4151898.
  27. D. Papa, E. Schwenk, N. Sperber, U.S. Patent 2,567,245 (1951)
  28. Djerassi C, Scholz CR (January 1948). "Brominations with pyridine hydrobromide perbromide". Journal of the American Chemical Society. 70 (1): 417–418. doi:10.1021/ja01181a508. PMID 18918843.
  29. D. Papa, E. Schwenk, N. Sperber, U.S. Patent 2,676,964 (1954)
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