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] It is a first-generation antihistamine and works by blocking the histamine H₁ receptor.^[2]

Chlorphenamine

Clinical data
Trade names	Chlor-Trimeton; Piriton; Chlor-Tripolon
AHFS/Drugs.com	Monograph
MedlinePlus	a682543
Pregnancy category	AU: A
Routes of administration	Oral, Intravenous, Intramuscular, Subcutaneous
ATC code	R06AB04 (WHO)
Legal status
Legal status	AU: S3 (Pharmacist only) UK: P (Pharmacy medicines) US: OTC CN: OTC
Pharmacokinetic data
Bioavailability	25 to 50%
Protein binding	72%
Metabolism	Liver (CYP2D6)
Elimination half-life	13.9–43.4 hours[1]
Excretion	Kidney
Identifiers
IUPAC name 3-(4-Chlorophenyl)-N,N-dimethyl-3-(pyridin-2-yl)-propan-1-amine
CAS Number	132-22-9 Y
PubChem CID	2725
IUPHAR/BPS	1210
DrugBank	DB01114 Y
ChemSpider	2624 Y
UNII	3U6IO1965U
KEGG	D07398 Y
ChEBI	CHEBI:52010 Y
ChEMBL	ChEMBL505 Y
CompTox Dashboard (EPA)	DTXSID0022804
ECHA InfoCard	100.004.596
Chemical and physical data
Formula	C16H19ClN2
Molar mass	274.79 g·mol−1
3D model (JSmol)	Interactive image
Solubility in water	0.55 g/100 mL, liquid mg/mL (20 °C)
SMILES Clc1ccc(cc1)C(c2ncccc2)CCN(C)C
InChI 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 Y Key:SOYKEARSMXGVTM-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

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

Name

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]

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.

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.^[2]

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]

Site	Ki (nM)	Species	Ref
SERTTooltip Serotonin transporter	15.2	Human	[11]
NETTooltip Norepinephrine transporter	1,440	Human	[11]
DATTooltip Dopamine transporter	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]
hERGTooltip Human Ether-à-go-go-Related Gene	20,900	Human	[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 K_d 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 K_d 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 (K_d = 15.2 nM for the serotonin transporter).^[11][24] It has only weak affinity for the norepinephrine and dopamine transporters (K_d = 1,440 nM and 1,060 nM, respectively).^[11]

A study found that dexchlorphenamine had K_i values for the human cloned H₁ receptor of 2.67 to 4.81 nM while levchlorphenamine had K_i values of 211 to 361 nM for this receptor, indicating that dexchlorphenamine is the active enantiomer.^[25] Another study found that dexchlorphenamine had a K_i value of 20 to 30 μM for the muscarinic acetylcholine receptor using rat brain tissue while levchlorphenamine had a K_i 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]

References

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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.
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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.
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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)