Chlorphenamine

Chlorpheniramine
Systematic (IUPAC) name
3-(4-chlorophenyl)-N,N-dimethyl-
3-pyridin-2-yl-propan-1-amine
Clinical data
Trade names Chlor-trimeton
AHFS/Drugs.com monograph
MedlinePlus a682543
Pregnancy cat. A(AU) B(US)
Legal status Pharmacist Only (S3) (AU) GSL (UK) OTC (US)
(for oral forms)
Routes Oral, IV, IM, SC
Pharmacokinetic data
Bioavailability 25 to 50%
Protein binding 72%
Metabolism Hepatic (CYP2D6)
Half-life 21–27 hours
Excretion Renal
Identifiers
CAS number 132-22-9 Y
ATC code R06AB04
PubChem CID 2725
IUPHAR ligand 1210
DrugBank DB01114
ChemSpider 2624 Y
UNII 3U6IO1965U Y
KEGG D07398 Y
ChEBI CHEBI:52010 Y
ChEMBL CHEMBL505 Y
Chemical data
Formula C16H19ClN2 
Mol. mass 274.788 g/mol
SMILES eMolecules & PubChem
Physical data
Solubility in water 0.55 g/100 mL, liquid mg/mL (20 °C)
 Y(what is this?)  (verify)

Chlorphenamine (INN) or chlorpheniramine (USAN, former BAN), commonly marketed in the form of chlorpheniramine maleate (Chlorphen-12[1]), 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 as well. Although not generally approved as an antidepressant or anti-anxiety medication, chlorphenamine appears to have these properties as well[2] (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.

Contents

Serotonergic and norepinephrinergic effects

In addition to being an histamine H1 receptor antagonist, chlorphenamine has been shown to work as a serotonin-norepinephrine reuptake inhibitor or SNRI.[3] 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).[4] However, extensive clinical trials of its psychiatric properties in humans have not been conducted. It inhibits serotonin reuptake less than norepinephrine reuptake,[5] however the literature is not consistent in this respect.[6]

Combination medications

Chlorphenamine is often combined with phenylpropanolamine 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.[7] 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.

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 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.

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.

See also

References

  1. ^ "Chlorphen-12". http://www.chlorphen12.com. 
  2. ^ http://www.healyprozac.com/Book/Introduction.pdf
  3. ^ Carlsson A., Linqvist M. (1969). "Central and peripheral monoaminergic membrane-pump blockade by some addictive analgesics and antihistamines". J Pharm Pharmacol 21 (7): 460–464. PMID 4390069. 
  4. ^ 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. http://linkinghub.elsevier.com/retrieve/pii/S030698770500647X. 
  5. ^ Domino Edward F. (1999). "History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants". Psychosomatic Medicine 61 (5): 591–598. PMID 10511010. http://www.psychosomaticmedicine.org/cgi/content/full/61/5/591. 
  6. ^ Compare, for example, Hellbom (2005) with Domino (1999)
  7. ^ UCB : Tussionex (Respiratory Disease). 2007. UCB, Inc.. 11 Jul 2008 <http://www.ucb-group.com/products/860.asp>.