Английская Википедия:Chlorphenamine

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Шаблон:Short description Шаблон:Distinguish Шаблон:Use dmy dates Шаблон:Drugbox Chlorphenamine (CP, CPM), also known as chlorpheniramine, is an antihistamine used to treat the symptoms of allergic conditions such as allergic rhinitis (hay fever). It is taken orally (by mouth). The medication takes effect within two hours and lasts for about 4-6 hours.

Common side effects include sleepiness, restlessness, and weakness. Other side effects may include dry mouth and wheeziness. It is a first-generation antihistamine and works by blocking the H1 receptor.

Chlorpheniramine was patented in 1948 and came into medical use in 1949. It is available as a generic medication and over the counter.

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. Chlorphenamine remains available with no such risk.

Chlorphenamine may be combined with the opioid hydrocodone. 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 and cold preparations containing codeine and chlorphenamine are available.Шаблон:Citation needed

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

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.

Chlorphenamine produces less sedation than other first-generation antihistamines.

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. Chlorphenamine is rated as a "high burden" anticholinergic by experts on a semi-subjective scale.

Pharmacology

Pharmacodynamics

Chlorphenamine

Site	Ki (nM)	Species	Ref
Шаблон:Abbrlink	15.2	Human
Шаблон:Abbrlink	1,440	Human
Шаблон:Abbrlink	1,060	Human
5-HT2A	3,130	Rat
5-HT2C	3,120	Rat
H1	2.5–3.0	Human
H2	Шаблон:Abbr	Шаблон:Abbr	Шаблон:Abbr
H3	>10,000	Rat
H4	2,910	Human
M1	25,700	Human
M2	17,000	Human
M3	52,500	Human
M4	77,600	Human
M5	28,200	Human
Шаблон:Abbrlink	20,900	Human
Values are Ki, unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. Values at the Шаблон:Abbrlink and Шаблон:Abbrlink are IC50 (nM).

Chlorphenamine acts primarily as a potent H₁ antihistamine. It is specifically a potent inverse agonist of the histamine H₁ receptor. 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. 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). It has only weak affinity for the norepinephrine and dopamine transporters (K_d = 1,440 nM and 1,060 nM, respectively). A similar antihistamine, brompheniramine, led to the discovery of the selective serotonin reuptake inhibitor (SSRI) zimelidine.Шаблон:Citation needed

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. 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.

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.

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.

Файл:Chlorpheniramine synthesis.png

Chlorpheniramine synthesis

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

Файл:Chlorpheniramine synthesis 2.png

Chlorpheniramine synthesis

Society and culture

Names

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

Brand names include Chlor-Trimeton, Demazin, Allerest 12 Hour, Piriton, Chlorphen-12, Tylenol Cold/Allergy, and numerous others according to country.