Chlorphenamine

Chlorphenamine (INN), also called chlorpheniramine (USAN and

former BAN), 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]

Chlorphenamine is part of a series of antihistamines including pheniramine (Naphcon)

and its halogenated derivatives and others
including fluorpheniramine, dexchlorpheniramine (Polaramine), brompheniramine (Dim
etapp), 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
dexchlorpheniramine is the dextrorotary stereoisomer.

Chlorphenamine Structure :

Serotonergic and norepinephrinergic effects

 In addition to being a histamine H1 receptor (HRH1) antagonist, chlorphenamine
has been shown to work as a serotonin-norepinephrine reuptake inhibitor or SNRI. A
similar antihistamine, brompheniramine, led to the discovery of the SSRI zimelidine.
Limited clinical evidence shows that it is comparable to several antidepressant
medications in its ability to inhibit the reuptake of serotonin and
also norepinephrine (noradrenaline). A study performed on Fischer 344/Brown Norway
F1 hybrid rats showed that intraventricular administration of chlorphenamine reduced
fear-related behaviors and improved maze performance. It was also noted that long-term
administration of chlorphenamine reduced age-related deficits in motor function.

Combination medications

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. Chlorpheniramine
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.[6] 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.

Adverse 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. A large study

linked the development of Alzheimer's disease and other forms of dementia to

the use of chlorpheniramine and other first-generation antihistamines, due to

their anticholinergic properties.

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 -(4-chlorphenyl)--cyano-N,N-dimethyl-2-pyridinepropanamine,
the hydrolysis and decarboxylation of which lead to chlorphenamine.
 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.
References

1. Jump up^ 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. Jump up^ 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: 10918. doi:10.1016/0014-2999(92)90827-
q. PMID 1358631.

3. Jump up^ Carlsson, A.; Linqvist M. (1969). "Central and peripheral

monoaminergic membrane-pump blockade by some addictive analgesics and
antihistamines". Journal of Pharmacy and Pharmacology. 21 (7): 460
464. doi:10.1111/j.2042-7158.1969.tb08287.x. PMID 4390069.

4. Jump up^ Hellbom, E. (2006). "Chlorpheniramine, selective serotonin-

reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment". Medical
Hypotheses. 66 (4): 689
690. doi:10.1016/j.mehy.2005.12.006. PMID 16413139.

5. Jump up^ Hasenhrl, R. U.; Weth, K.; Huston, J. P. (1999).

"Intraventricular infusion of the histamine H1 receptor antagonist
chlorpheniramine improves maze performance and has anxiolytic-like effects in
aged hybrid Fischer 344Brown Norway rats". Experimental Brain
Research. 128 (4): 435440. doi:10.1007/s002210050866. PMID 10541737.

6. Jump up^ "Tussionex Pennkinetic (hydrocodone polistirex and

chlorpheniramine polistirex) Extended-Release Suspension" (PDF). UCB. 2011.

7. Jump up^ 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. doi:10.1001/jamainternmed.2014.7663. PMC 4358759 . PMID 25621434.
Retrieved January 27, 2015.

8. Jump up^ Djerassi, Carl (1948). "Brominations with Pyridine

Hydrobromide Perbromide". Journal of the American Chemical Society. 70 (1):
417418. doi:10.1021/ja01181a508.