Chlorphenamine

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Chlorphenamine
Chlorphenamine.svg
Clinical data
Trade names Chlor-Trimeton; Piriton
AHFS/Drugs.com Monograph
MedlinePlus a682543
Pregnancy
category
  • AU: A
  • US: B (No risk in non-human studies)
Routes of
administration
Oral, IV, IM, SC
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 25 to 50%
Protein binding 72%
Metabolism Hepatic (CYP2D6)
Biological half-life 21–27 hours
Excretion Renal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.004.596
Chemical and physical data
Formula C16H19ClN2
Molar mass 274.788 g/mol
3D model (JSmol)
Solubility in water 0.55 g/100 mL, liquid mg/mL (20 °C)
 NYesY (what is this?)  (verify)

Chlorphenamine (INN), also called chlorpheniramine (USAN and former BAN), aka CP commonly marketed in the form of chlorphenamine maleate, is a first-generation alkylamine antihistamine used in the prevention of the symptoms of allergic conditions such as rhinitis and urticaria. Its sedative effects are relatively weak compared to other first-generation antihistamines. Chlorphenamine is one of the most commonly used antihistamines in small-animal veterinary practice. Although not generally approved as an antidepressant or anti-anxiety medication, chlorphenamine appears to have these properties as well.[1][2]

Medical uses[edit]

Combination products[edit]

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. Chlorphenamine remains available with no such risk. Brand names had included Demazin, Allerest 12 Hour, Codral Nighttime, Chlornade, Contac 12 Hour, Exchange Select Allergy Multi-Symptom, A. R. M. Allergy Relief, Ordrine, Ornade Spansules, Teldrin, Triaminic, and Tylenol Cold/Allergy.

Chlorphenamine is combined with a narcotic (hydrocodone) in the product Tussionex, which is indicated for treatment of cough and upper respiratory symptoms associated with allergy or cold in adults and children 6 years of age and older.[3] This combination is manufactured as a time-released formula, which allows for administration every 12 hours, versus the more common 4-to-6-hour regimen for other narcotic cough suppressants.

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 & cold preparations containing codeine and chlorphenamine are available.

In the drug Coricidin, chlorphenamine is combined with the cough suppressant dextromethorphan.

Side effects[edit]

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.

A large study linked the development of Alzheimer's disease and other forms of dementia to the use of chlorphenamine and other first-generation antihistamines, due to their anticholinergic properties.[4]

Pharmacology[edit]

In addition to being a histamine H1 receptor antagonist, chlorphenamine has been found to act as a potent serotonin reuptake inhibitor (KD = 15.2 nM for the serotonin transporter).[5][6] It has only weak affinity for the norepinephrine and dopamine transporters (KD = 1,440 nM and 1,060 nM, respectively).[5] A similar antihistamine, brompheniramine, led to the discovery of the selective serotonin reuptake inhibitor (SSRI) zimelidine. Limited clinical evidence shows that chlorphenamine is comparable to several antidepressant medications in its ability to inhibit the reuptake of serotonin, and may be useful in the treatment of depression and anxiety disorders.[7]

Chemistry[edit]

Chlorphenamine is part of a series of antihistamines including pheniramine (Naphcon) and its halogenated derivatives and others including fluorpheniramine, dexchlorphenamine (Polaramine), brompheniramine (Dimetapp), dexbrompheniramine (Drixoral), deschlorpheniramine, triprolidine (Actifed), 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[edit]

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 1: D. Papa, E. Schwenk, N. Sperber, U.S. Patent 2,567,245 (1951).

A second method starts from pyridine, which undergoes alkylation by 4-chlorophenylacetonitrile,[8] giving 2-(4-chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives chlorphenamine.

Chlorpheniramine synthesis 2: D. Papa, E. Schwenk, N. Sperber, U.S. Patent 2,676,964 (1954).

References[edit]

  1. ^ Carlsson, Arvid; Lindqvist, Margit. "Central and peripheral monoaminergic membrane-pump blockade by some addictive analgesics and antihistamines". Journal of Pharmacy and Pharmacology. Journal of Pharmacy and Pharmacology. Retrieved 1 December 2013. 
  2. ^ Gruetter CA, Lemke SM, Anestis DK, Szarek JL, Valentovic MA (Jul 1992). "Potentiation of 5-hydroxytryptamine-induced contraction in rat aorta by chlorpheniramine, citalopram and fluoxetine". Eur J Pharmacol. Department of Pharmacology, Marshall University School of Medicine, Huntington, WV. 217: 109–18. PMID 1358631. doi:10.1016/0014-2999(92)90827-q. 
  3. ^ "Tussionex® Pennkinetic® (hydrocodone polistirex and chlorpheniramine polistirex) Extended-Release Suspension" (PDF). UCB. 2011. 
  4. ^ Gray, Shelly L.; Anderson, Melissa L.; Dublin, Sascha; Hanlon, Joseph T.; Hubbard, Rebecca; Walker, Rod; Yu, Onchee; Crane, Paul K.; Larson, Eric B. (January 26, 2015). "Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study". JAMA Intern. Med. 175 (3): 401–7. PMC 4358759Freely accessible. PMID 25621434. doi:10.1001/jamainternmed.2014.7663. Retrieved January 27, 2015. 
  5. ^ a b Tatsumi M, Groshan K, Blakely RD, Richelson E (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". Eur. J. Pharmacol. 340 (2-3): 249–58. PMID 9537821. 
  6. ^ Carlsson A, Lindqvist M (1969). "Central and peripheral monoaminergic membrane-pump blockade by some addictive analgesics and antihistamines". J. Pharm. Pharmacol. 21 (7): 460–4. PMID 4390069. 
  7. ^ Hellbom, E. (2006). "Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment". Medical Hypotheses. 66 (4): 689–690. PMID 16413139. doi:10.1016/j.mehy.2005.12.006. 
  8. ^ Djerassi, Carl (1948). "Brominations with Pyridine Hydrobromide Perbromide". Journal of the American Chemical Society. 70 (1): 417–418. doi:10.1021/ja01181a508.