Chlorphenamine
Encyclopedia
Chlorphenamine or chlorpheniramine (USAN
, former BAN
), commonly marketed in the form of chlorpheniramine maleate (Chlorphen-12), is a first-generation alkylamine antihistamine
used in the prevention of the symptom
s 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 as well. Although not generally approved as an antidepressant
or anti-anxiety
medication, chlorphenamine appears to have these properties as well (see below).
Chlorphenamine is part of a series of antihistamines including pheniramine
(Naphcon) and its halogenated derivatives and others including fluorpheniramine, dexchlorpheniramine
(Polaramine), brompheniramine
(Dimetapp), dexbrompheniramine
(Drixoral), deschlorpheniramine, dipheniramine (also known as triprolidine
with the trade name 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 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). However, extensive clinical trials of its psychiatric properties in humans have not been conducted. It inhibits serotonin reuptake less than norepinephrine reuptake, however the literature is not consistent in this respect.
to form an allergy
medication with both antihistamine
and decongestant
properties. Brand names include Demazin, Allerest 12 Hour, Codral
Nighttime, Chlornade, Contac 12 Hour, 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. 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
.
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.
The second way is from pyridine
, which undergoes alkylation by 4-chlorobenzylchloride,
giving 2-(4-chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride
in the presence of sodium amide gives chlorphenamine.
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
, former BAN
British Approved Name
A British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia...
), commonly marketed in the form of chlorpheniramine maleate (Chlorphen-12), is a first-generation alkylamine antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
used in the prevention of the symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s of allergic
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
conditions such as rhinitis
Rhinitis
Rhinitis , commonly known as a stuffy nose, is the medical term describing irritation and inflammation of some internal areas of the nose. The primary symptom of rhinitis is nasal dripping. It is caused by chronic or acute inflammation of the mucous membrane of the nose due to viruses, bacteria or...
and urticaria
Urticaria
Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
. 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 as well. Although not generally approved as an antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
or anti-anxiety
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
medication, chlorphenamine appears to have these properties as well (see below).
Chlorphenamine is part of a series of antihistamines including pheniramine
Pheniramine
Pheniramine is an antihistamine with anticholinergic properties used to treat allergic conditions such as hay fever or urticaria. It has relatively strong sedative effects, and may sometimes be used off-label as an over-the-counter sleeping pill in a similar manner to other sedating antihistamines...
(Naphcon) and its halogenated derivatives and others including fluorpheniramine, dexchlorpheniramine
Dexchlorpheniramine
Dexchlorpheniramine is an antihistamine with anticholinergic properties used to treat allergic conditions such as hay fever or urticaria...
(Polaramine), brompheniramine
Brompheniramine
Brompheniramine , commonly marketed as its salt brompheniramine maleate is an antihistamine drug of the propylamine class...
(Dimetapp), dexbrompheniramine
Dexbrompheniramine
Dexbrompheniramine is an antihistamine with anticholinergic properties used to treat allergic conditions such as hay fever or urticaria. It is the pharmacologically active dextrorotatory isomer of brompheniramine...
(Drixoral), deschlorpheniramine, dipheniramine (also known as triprolidine
Triprolidine
Triprolidine is an over-the-counter antihistamine with anticholinergic properties. It is used to combat the symptoms associated with allergies and is sometimes combined with other cold medications designed to provide general relief for flu-like symptoms. Like many over-the-counter antihistamines,...
with the trade name 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.
Serotonergic and norepinephrinergic effects
In addition to being an histamine H1 receptor antagonistReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
, chlorphenamine has been shown to work as a serotonin-norepinephrine reuptake inhibitor
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
or SNRI. A similar antihistamine, brompheniramine
Brompheniramine
Brompheniramine , commonly marketed as its salt brompheniramine maleate is an antihistamine drug of the propylamine class...
, led to the discovery of the SSRI zimelidine
Zimelidine
Zimelidine was the first selective serotonin reuptake inhibitor antidepressant to be marketed. It is a pyridylallylamine, and is structurally different from other antidepressants....
. Limited clinical evidence shows that it is comparable to several antidepressant medications in its ability to inhibit the reuptake of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
and also norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(noradrenaline). However, extensive clinical trials of its psychiatric properties in humans have not been conducted. It inhibits serotonin reuptake less than norepinephrine reuptake, however the literature is not consistent in this respect.
Combination medications
Chlorphenamine is often combined with phenylpropanolaminePhenylpropanolamine
Phenylpropanolamine , also known as the stereoisomers norephedrine and norpseudoephedrine, is a psychoactive drug of the phenethylamine and amphetamine chemical classes which is used as a stimulant, decongestant, and anorectic agent. It is commonly used in prescription and over-the-counter cough...
to form an allergy
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
medication with both antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
and decongestant
Decongestant
A decongestant or nasal decongestant is a type of drug that is used to relieve nasal congestion.-Pharmacology:The vast majority of decongestants act via enhancing norepinephrine and epinephrine or adrenergic activity by stimulating the α-adrenergic receptors...
properties. Brand names include Demazin, Allerest 12 Hour, Codral
Codral
Codral is a brand name of cold and flu medication manufactured by Johnson & Johnson and sold primarily in Australia & New Zealand. Codral is the highest-selling cold and flu medication in Australia....
Nighttime, Chlornade, Contac 12 Hour, A. R. M. Allergy Relief, Ordrine, Ornade Spansules, Teldrin, Triaminic, and Tylenol
Tylenol
Tylenol is a North American brand of drugs advertised for reducing pain, reducing fever, and relieving the symptoms of allergies, cold, cough, and flu. The active ingredient of its original, flagship product, paracetamol , is marketed as an analgesic and antipyretic...
Cold/Allergy.
Chlorphenamine is combined with a narcotic (hydrocodone
Hydrocodone
Hydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from either of two naturally occurring opiates: codeine and thebaine. It is an orally active narcotic analgesic and antitussive...
) 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. 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
Dihydrocodeine
Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...
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
Coricidin
Coricidin, Coricidin 'D , or CoricidinHBP , is the name of a drug marketed by Schering-Plough that contains dextromethorphan and chlorpheniramine maleate...
, chlorphenamine is combined with the cough suppressant dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
.
Chemistry
Chlorphenamine, 3-(p-chlorophenyl)-3-(2-pyridyl)propyldimethylamine, is synthesized in two ways. The first is from 4-chlorbenzylcyanide, which is reacted with 2-chloropyridine in the presence of sodium amideSodium amide
Sodium amide, commonly called sodamide, is the chemical compound with the formula NaNH2. This solid, which is dangerously reactive toward water, is white when pure, but commercial samples are typically gray due to the presence of small quantities of metallic iron from the manufacturing process...
to form 4-chlorophenyl(2-pyridyl)acetonitrile. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide
Sodium amide
Sodium amide, commonly called sodamide, is the chemical compound with the formula NaNH2. This solid, which is dangerously reactive toward water, is white when pure, but commercial samples are typically gray due to the presence of small quantities of metallic iron from the manufacturing process...
gives γ-(4-chlorphenyl)-γ-cyano-N,N-dimethyl-2-pyridinepropanamine, the hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
and decarboxylation
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...
of which lead to chlorphenamine.
- D. Papa, E. Schwenk, N. Sperber, (1951).
The second way is from pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
, which undergoes alkylation by 4-chlorobenzylchloride,
giving 2-(4-chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride
in the presence of sodium amide gives chlorphenamine.
- D. Papa, E. Schwenk, N. Sperber, (1954).