Chlorphenamine

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Chlorphenamine
Clinical data
Trade namesChlor-Trimeton; Piriton; Chlor-Tripolon
AHFS/Drugs.comMonograph
MedlinePlusa682543
Pregnancy
category
  • AU: A
Subcutaneous
ATC code
Legal status
Legal status
  • AU: S3 (Pharmacist only)
  • UK: P (
    Pharmacy medicines
    )
  • US: OTC
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
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)

Chlorphenamine (CP, CPM), also known as chlorpheniramine, is an

H1 receptor.[2]

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.

Name

Chlorphenamine is the

INNTooltip International Nonproprietary Name while chlorpheniramine is the USANTooltip United States Adopted Name and former BAN
Tooltip 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

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]
hERG
Tooltip 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
hERGTooltip Human Ether-à-go-go-Related Gene are IC50
(nM).

Chlorphenamine acts primarily as a potent H1

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 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

dextrorotary
stereoisomer.

Synthesis

There are several patented methods for the

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

  1. ^
    S2CID 35759573
    .
  2. ^ a b c d e f g h "Chlorpheniramine". Drugs.com. American Society of Health-System Pharmacists. 26 July 2023. Archived from the original on 20 August 2023. Retrieved 20 August 2023.
  3. .
  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. Archived from the original on 25 June 2022. Retrieved 10 June 2022.
  7. .
  8. .
  9. .
  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. Archived from the original on 2 October 2020. Retrieved 14 August 2017.
  11. ^
    PMID 9537821
    .
  12. .
  13. .
  14. .
  15. .
  16. .
  17. from the original on 10 January 2023. Retrieved 21 January 2023.
  18. ^ .
  19. .
  20. .
  21. .
  22. .
  23. .
  24. .
  25. .
  26. .
  27. ^ D. Papa, E. Schwenk, N. Sperber, U.S. patent 2,567,245 (1951)
  28. PMID 18918843
    .
  29. ^ D. Papa, E. Schwenk, N. Sperber, U.S. patent 2,676,964 (1954)