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).<ref name=AHFS2019/> It is taken orally (by mouth).<ref name=AHFS2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The medication takes effect within two hours and lasts for about 4–6 hours.<ref name=AHFS2019/> It is a first-generation antihistamine and works by blocking the histamine H₁ receptor.<ref name="AHFS2019" />

Common side effects include sleepiness, restlessness, and weakness. Other side effects may include dry mouth and wheeziness.<ref name=AHFS2019/>

Chlorpheniramine was patented in 1948 and came into medical use in 1949.<ref name=Fis2006>Template:Cite book</ref> It is available as a generic medication and over the counter.<ref name=AHFS2019/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In 2022, it was the 291st most commonly prescribed medication in the United States, with more than 400,000 prescriptions.<ref name="Top 300 of 2022">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

Combination products

Chlorphenamine is often combined with phenylpropanolamine to form an allergy medication with both antihistamine and decongestant properties, although phenylpropanolamine was removed from the U.S. market per studies concluding that it increased the risk of stroke in young women.<ref>Template:Cite press release</ref> Vernate was a trade name of one such product available in the U.S. prior to the FDA ban; it was manufactured by Tutag and was among the medications prescribed to Elvis Presley.<ref>https://www.jodrugs.com/tradenames/167408-vernate.aspx Information on defunct drug Vernate</ref>

In the drug Coricidin, chlorphenamine is combined with the cough suppressant dextromethorphan. In the drug Cêgripe, chlorphenamine is combined with the analgesic paracetamol (also known as acetaminophen, sold as Tylenol).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="AHFS2019" />

Chlorphenamine produces less sedation than other first-generation antihistamines.<ref name="LandauAchilladelisScriabine1999">Template:Cite book</ref>

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.<ref>Template:Cite journal</ref> Chlorphenamine is rated as a "high burden" anticholinergic by experts on a semi-subjective scale.<ref>Template:Cite journal</ref> This is inconsistent with the in vitro experiments showing low affinity to muscarinic acetylcholine receptors (see below).

Pharmacology

Pharmacodynamics

citation

CitationClass=web }}</ref>
Site	Ki (nM)	Species	Ref
Template:Abbrlink	15.2	Human	<ref name="pmid9537821">Template:Cite journal</ref>
Template:Abbrlink	1,440	Human	<ref name="pmid9537821" />
Template:Abbrlink	1,060	Human	<ref name="pmid9537821" />
5-HT2A	3,130	Rat	<ref name="pmid3794694">Template:Cite journal</ref>
5-HT2C	3,120	Rat	<ref name="pmid3139864">Template:Cite journal</ref>
H1	2.5–3.0	Human	<ref name="pmid7925364">Template:Cite journal</ref><ref name="pmid8335064">Template:Cite journal</ref>
H2	Template:Abbr	Template:Abbr	Template:Abbr
H3	>10,000	Rat	<ref name="pmid2213013">Template:Cite journal</ref>
H4	2,910	Human	<ref name="pmid11179435">Template:Cite journal</ref>
M1	25,700	Human	<ref name="pmid10212017">Template:Cite journal</ref>
M2	17,000	Human	<ref name="pmid10212017" />
M3	52,500	Human	<ref name="pmid10212017" />
M4	77,600	Human	<ref name="pmid10212017" />
M5	28,200	Human	<ref name="pmid10212017" />
Template:Abbrlink	20,900	Human	<ref name="pmid8641472">Template:Cite journal</ref>
Values are Ki, unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. Values at the Template:Abbrlink and Template:Abbrlink are IC50 (nM).

Chlorphenamine acts primarily as a potent H₁ antihistamine. It is specifically a potent inverse agonist of the histamine H₁ receptor.<ref name="pmid15548781">Template:Cite journal</ref><ref name="DOI:0954-7894.2002.01314.x">Template:Cite journal</ref> 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.<ref name="pmid6086881">Template:Cite journal</ref><ref name="pmid7855217">Template:Cite journal</ref> 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).<ref name="pmid9537821"/><ref name="pmid4390069">Template:Cite journal</ref> It has only weak affinity for the norepinephrine and dopamine transporters (K_d = 1,440 nM and 1,060 nM, respectively).<ref name="pmid9537821" />

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.<ref name="pmid12065734">Template:Cite journal</ref> 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.<ref name="pmid4151898">Template:Cite journal</ref>

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.<ref name="pmid7648771">Template:Cite journal</ref>

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.

File:Chlorpheniramine synthesis.png

Chlorpheniramine synthesis<ref>D. Papa, E. Schwenk, N. Sperber, Template:US Patent (1951)</ref>

A second method boom starts from pyridine, which undergoes alkylation by 4-chlorophenylacetonitrile,<ref>Template:Cite journal</ref> giving 2-(4-chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives chlorphenamine.

File:Chlorpheniramine synthesis 2.png

Chlorpheniramine synthesis<ref>D. Papa, E. Schwenk, N. Sperber, Template:US Patent (1954)</ref>

Society and culture

Names

Chlorphenamine is the Template:Abbrlink while chlorpheniramine is the Template:Abbrlink and former Template:Abbrlink.

Brand names include Chlor-Trimeton, Demazin, Allerest 12 Hour, Piriton, Chlorphen-12, Tylenol Cold/Allergy, and numerous others according to country.<ref name="AHFS2019" />