Phenylpropanolamine

Phenylpropanolamine

RS-Norephedrin
Ball-and-stick model of the phenylpropanolamine molecule
Systematic (IUPAC) name
(1S,2R)-2-amino-1-phenylpropan-1-ol
Clinical data
Trade names	Acutrim
AHFS/Drugs.com	Multum Consumer Information
Legal status	AU: S4 (Prescription only) UK: Unknown US: Prohibited
Routes of administration	Oral
Pharmacokinetic data
Metabolism	Hepatic: CYP2D6
Biological half-life	2.1–3.4 hours
Identifiers
CAS Number	14838-15-4 Y
ATC code	R01BA01 (WHO) QG04BX91 (WHO)
PubChem	CID: 10297
DrugBank	DB00397 Y
ChemSpider	9875 Y
UNII	33RU150WUN Y
KEGG	D08368 Y
ChEMBL	CHEMBL136560 Y
Chemical data
Formula	C9H13NO
Molecular mass	151.206 g/mol
SMILES O[C@H](c1ccccc1)[C@@H](N)C
InChI InChI=1S/C9H13NO/c1-7(10)9(11)8-5-3-2-4-6-8/h2-7,9,11H,10H2,1H3/t7-,9-/m0/s1 Y Key:DLNKOYKMWOXYQA-CBAPKCEASA-N Y
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Phenylpropanolamine (BAN and INN; PPA, β-hydroxyamphetamine), 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 and cold preparations. In veterinary medicine, it is used to control urinary incontinence in dogs under trade names Propalin and Proin.

In the United States, PPA is no longer sold due to a proposed increased risk of stroke in younger women. In a few countries in Europe, however, it is still available either by prescription or sometimes over-the-counter. In Canada, it was withdrawn from the market on 31 May 2001. In India human use of PPA and its formulations was banned on 10 February 2011, but the ban was overturned by the court in September 2011.

Pharmacology

Phenylpropanolamine acts as an alpha-adrenergic receptor and beta-adrenergic receptor agonist as well as a dopamine receptor D1 partial agonist.

Many sympathetic hormones and neurotransmitters are based on the phenethylamine skeleton, and function generally in "fight or flight" type responses, such as increasing heart rate, blood pressure, dilating the pupils, increased energy, drying of mucous membranes, increased sweating, and a significant number of additional effects.

Metabolic pathways of amphetamine in humans

4-Hydroxyphenylacetone

Phenylacetone

Benzoic acid

Hippuric acid

Amphetamine

Norephedrine

4-Hydroxyamphetamine

4-Hydroxynorephedrine

Para-
Hydroxylation

Para-
Hydroxylation

Para-
Hydroxylation

Beta-
Hydroxylation

Beta-
Hydroxylation

Oxidative
Deamination

Oxidation

Glycine
Conjugation

In humans, norephedrine occurs as a metabolite of amphetamine. The beta-hydroxylation of amphetamine is mediated by dopamine β-hydroxylase.

Legal status

In Europe, PPA is still available in prescription decongestants such as Rinexin, as well as over-the-counter medications such as Wick DayMed.

In the United Kingdom, PPA was available in many 'all in one' cough and cold medications which usually also feature paracetamol or another analgesic and caffeine and could also be purchased on its own; however, it is no longer approved for human use. As of 11 August, a European Category 1 Licence is required to purchase PPA for academic use.

In the United States, the Food and Drug Administration (FDA) issued a public health advisory against the use of the drug in November 2000. In this advisory, the FDA requested that all drug companies discontinue marketing products containing PPA. The agency estimates that PPA caused between 200 and 500 strokes per year among 18-to-49-year-old users. In 2005, the FDA removed PPA from over-the-counter sale. Because of its potential use in amphetamine manufacture, it is controlled by the Combat Methamphetamine Epidemic Act of 2005. It is still available for veterinary use in dogs, however, as a treatment for urinary incontinence.

Internationally, an item on the agenda of the 2000 Commission on Narcotic Drugs session called for including the stereoisomer norephedrine in Table I of United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.

Drugs containing PPA were banned in India on 27 January 2011. On 13 September 2011 Madras High Court revoked a ban on manufacture and sale of paediatric drugs nimesulide and phenylpropanolamine (PPA).

Chemistry

File:Phenylpropanolamine spacefill.png

Space filling model of phenylpropanolamine

There are four optical isomers of PPA: dextro- and levo- nor ephedrine, and dextro- and levo- nor pseudoephedrine. d-Norpseudoephedrine is also known as cathine, and occurs naturally in Catha edulis ("Khat").

Phenylpropanolamine, structurally, is in the phenethylamine family, consisting of a cyclic benzene or phenyl group, a two carbon ethyl moiety, and a terminal nitrogen, hence the name phen-ethyl-amine. The methyl group on the alpha carbon (the first carbon before the nitrogen group) also makes this compound a member of the amphetamine family. Ephedrine is the N-methyl analogue of phenylpropanolamine.

Exogenous compounds in this family are degraded too rapidly by monoamine oxidase to be active at all but the highest doses. However, the addition of the α-methyl group allows the compound to avoid metabolism and confer an effect. In general, N-methylation of primary amines increases their potency; whereas β-hydroxylation decreases CNS activity, but conveys more selectivity for adrenergic receptors.

See also

• Amphetamine
• Ephedrine
• Methamphetamine
• Pseudoephedrine
• Substituted amphetamine

References

• W. N. Nagai, S. Kanao, Ann. Chem., 470, 157 (1929).
• G. Wilbert, P. Sosis, U.S. Patent 3,028,429 (1962).

External links

• Phenylpropanolamine Information Page at FDA.gov (update, includes earlier reports)
• U.S. National Library of Medicine: Drug Information Portal – Phenylpropanolamine