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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. Although not generally approved as an antidepressant or anti-anxiety medication, chlorphenamine appears to have these properties as well.^[2] ^[3]

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.

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.^[4] 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).^[5] However, extensive clinical trials of its psychiatric properties in humans have not been conducted. It inhibits serotonin reuptake less than norepinephrine reuptake,^[6] however the literature is not consistent in this respect.^[7]

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.^[8]

Combination medications

Chlorphenamine is often combined with phenylpropanolamine to form an allergy medication with both antihistamine and decongestant properties, though phenylpropenolamine 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.^[9] 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.

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.

D. Papa, E. Schwenk, N. Sperber, U.S. Patent 2,567,245 (1951).

The second way is from pyridine, which undergoes alkylation by 4-chlorobenzylchloride,^[10] giving 2-(4-chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives chlorphenamine.

D. Papa, E. Schwenk, N. Sperber, U.S. Patent 2,676,964 (1954).

References

^ "Chlorphen-12".
^ 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.
^ Gruetter CA, Lemke SM, Anestis DK, Szarek JL, Valentovic MA. "Potentiation of 5-hydroxytryptamine-induced contraction in rat aorta by chlorpheniramine, citalopram and fluoxetine.". Department of Pharmacology, Marshall University School of Medicine, Huntington, WV. Retrieved 1 December 2013.
^ 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.
^ 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.
^ Domino, E. F. (1999). "History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants" (pdf). Psychosomatic Medicine 61 (5): 591–598. PMID 10511010.
^ Compare, for example, Hellbom (2005) with Domino (1999)
^ Hasenöhrl, 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 344×Brown Norway rats". Experimental Brain Research 128 (4): 435–440. doi:10.1007/s002210050866. PMID 10541737.
^ "Tussionex® Pennkinetic® (hydrocodone polistirex and chlorpheniramine polistirex) Extended-Release Suspension" (pdf). UCB. 2011.
^ http://pubs.acs.org/doi/abs/10.1021/ja01181a508

UpToDate Contents

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1. デキストロメトルファン乱用および中毒：臨床的特徴および診断 dextromethorphan abuse and poisoning clinical features and diagnosis
2. デキストロメトルファン中毒：治療 dextromethorphan poisoning treatment
3. 妊娠中のアレルギー疾患の認識およびマネージメント recognition and management of allergic disease during pregnancy
4. OTC咳止め・かぜ薬：小児の中毒へのアプローチ over the counter cough and cold preparations approach to pediatric poisoning
5. 成人における感冒：治療および予防 the common cold in adults treatment and prevention

English Journal

Pharmaceuticals and personal care products (PPCPs) in Australia's largest inland sewage treatment plant, and its contribution to a major Australian river during high and low flow.

Roberts J1, Kumar A2, Du J2, Hepplewhite C3, Ellis DJ4, Christy AG4, Beavis SG5.
The Science of the total environment.Sci Total Environ.2016 Jan 15;541:1625-37. doi: 10.1016/j.scitotenv.2015.03.145. Epub 2015 Oct 9.
Reports of pharmaceuticals in STPs and aquatic systems in the northern hemisphere have surged over the last decade. However, the Australian evidence base is relatively limited, and information on the role of seasonal dilution in attenuation of micropollutants is also scarce. We investigated the remo
PMID 26456435

Contribution of the central histaminergic transmission in the cataleptic and neuroleptic effects of haloperidol.

Jain NS1, Tandi L2, Verma L2.
Pharmacology, biochemistry, and behavior.Pharmacol Biochem Behav.2015 Dec;139(Pt A):59-66. doi: 10.1016/j.pbb.2015.10.004. Epub 2015 Oct 9.
The antipsychotic properties of haloperidol are primarily attributed to its ability to block dopamine D2 receptors. Histaminergic transmission modulates some of the behavioral effects of haloperidol. Hence, the present study investigated the contribution of central histaminergic transmission in the
PMID 26455279

The rest of the story of the letter to the editors: "Hypersensitivity to amoxicillin after… (DRESS) to carbamazepine…: a possible co-sensitization".

Chadli Z1, Ben Fredj N1, Youssef M2, Chaabane A1, Boughattas NA1, Zili JE2, Aouam K1.
British journal of clinical pharmacology.Br J Clin Pharmacol.2015 Nov 23. doi: 10.1111/bcp.12823. [Epub ahead of print]
We would like to report the rest of the story of the patient (case 1) who has been reported in a publication of Ben Fredj et al, entitled "Hypersensitivity to amoxicillin after drug rash with eosinophilia and systemic symptoms (DRESS) to carbamazepine and allopurinol: a possible co-sensitization", p
PMID 26594014

Japanese Journal

Peroxyoxalate chemiluminescence detection for the highly sensitive determination of fluorescence-labeled chlorpheniramine with Suzuki coupling reaction.

Adutwum Lawrence Asamoah,Kishikawa Naoya,Ohyama Kaname,Harada Shiro,Nakashima Kenichiro,Kuroda Naotaka
Analytical and bioanalytical chemistry 398(2), 823-829, 2010-09
… A sensitive and selective high performance liquid chromatography-peroxyoxalate chemiluminescence (PO-CL) method has been developed for the simultaneous determination of chlorpheniramine (CPA) and monodesmethyl chlorpheniramine (MDCPA) in human serum. …
NAID 120002614892

Multivariate Optimization and Validation of a Capillary Electrophoresis Method for the Simultaneous Determination of Dextromethorphan Hydrobromur, Phenylephrine Hydrochloride, Paracetamol and Chlorpheniramine Maleate in a Pharmaceutical Preparation Using Response Surface Methodology

PALABIYIK I. Murat,ONUR Feyyaz
Analytical sciences : the international journal of the Japan Society for Analytical Chemistry 26(8), 853-859, 2010-08-10
NAID 10026784731

Related Pictures

★リンクテーブル★

リンク元	「ヒスタミン受容体」「クロルフェニラミン」「Chlor-Trimeton」「chlorphenamine」
拡張検索	「chlorpheniramine maleate」「d-chlorpheniramine maleate」「chlorpheniramine polistirex」「dexchlorpheniramine」

「ヒスタミン受容体」

Chlorphenamine
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) OTC (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
ATC code	R06AB04
PubChem	CID 2725
IUPHAR ligand	1210
DrugBank	DB01114
ChemSpider	2624
UNII	3U6IO1965U
KEGG	D07398
ChEBI	CHEBI:52010
ChEMBL	CHEMBL505
Chemical data
Formula	C16H19ClN2
Mol. mass	274.788 g/mol
	SMILES Clc1ccc(cc1)C(c2ncccc2)CCN(C)C;
	InChI InChI=1S/C16H19ClN2/c1-19(2)12-10-15(16-5-3-4-11-18-16)13-6-8-14(17)9-7-13/h3-9,11,15H,10,12H2,1-2H3 ; Key:SOYKEARSMXGVTM-UHFFFAOYSA-N ;
Physical data
Solubility in water	0.55 g/100 mL, liquid mg/mL (20 °C)
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　　[★]

英: histamine receptor
関: ヒスタミン、抗ヒスタミン薬、受容体

7回膜貫通型受容体。Gタンパク質共役型受容体。

H1R：平滑筋、血管内皮、神経→血管拡張、血管透過性↑、気管収縮、知覚神経刺激によるかゆみ・痛み
H2R：胃、心臓、中枢、リンパ→胃酸分泌促進
H3R：中枢、気道、消化管。ヒスタミン合成やNeuro transmitterの遊離抑制
H4R：リンパ球をはじめとする免疫炭層細胞、骨髄、脾臓。機能は不明

H1Rはα1受容体と似ている。Gαqと共役している
H2Rはβ1受容体と似ている。Gαsと共役している