|Ball-and-stick model of the phenylpropanolamine molecule|
|Systematic (IUPAC) name|
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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 by either 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 In Canada, it was withdrawn from the market on 31 May 2001.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 were banned on 10 February 2011, but the ban was overturned by the court in September 2011.
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[when?], 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).
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.
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CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP OF SYMPATHOMIMETIC AMINES
β-Phenylethylamine (Table 12–1) can be viewed as the parent compound of the sympathomimetic amines, consisting of a benzene ring and an ethylamine side chain. The structure permits substitutions to be made on the aromatic ring, the α- and β-carbon atoms, and the terminal amino group to yield a variety of compounds with sympathomimetic activity. ...N-methylation increases the potency of primary amines ...
Substitution on the α-Carbon Atom
This substitution blocks oxidation by MAO, greatly prolonging the duration of action of non-catecholamines because their degradation depends largely on the action of this enzyme. The duration of action of drugs such as ephedrine or amphetamine is thus measured in hours rather than in minutes. Similarly, compounds with an α-methyl substituent persist in the nerve terminals and are more likely to release NE from storage sites. Agents such as metaraminol exhibit a greater degree of indirect sympathomimetic activity.
Substitution on the β-Carbon Atom
Substitution of a hydroxyl group on the β carbon generally decreases actions within the CNS, largely because it lowers lipid solubility. However, such substitution greatly enhances agonist activity at both α- and β- adrenergic receptors. Although ephedrine is less potent than methamphetamine as a central stimulant, it is more powerful in dilating bronchioles and increasing blood pressure and heart rate.
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- W. N. Nagai, S. Kanao, Ann. Chem., 470, 157 (1929).
- G. Wilbert, P. Sosis, U.S. Patent 3,028,429 (1962).
- Phenylpropanolamine Information Page at FDA.gov (update, includes earlier reports)
- U.S. National Library of Medicine: Drug Information Portal – Phenylpropanolamine