Phenylpropanolamine

Phenylpropanolamine

Systematic (IUPAC) name
2-amino-1-phenylpropan-1-ol
Clinical data
AHFS/Drugs.com	Multum Consumer Information
Pregnancy cat.	?
Legal status	? (UK) ℞-only
Routes	Oral
Pharmacokinetic data
Half-life	2.1 to 3.4 hours.
Identifiers
CAS number	14838-15-4 Y
ATC code	R01BA01
PubChem	CID 10297
DrugBank	APRD00457
ChemSpider	9875 Y
UNII	33RU150WUN N
KEGG	D08368 Y
ChEMBL	CHEMBL136560 Y
Chemical data
Formula	C9H13NO
Mol. mass	151.206 g/mol
SMILES	eMolecules & PubChem
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
N(what is this?)  (verify)

Phenylpropanolamine (PPA; Accutrim), 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.^[1] 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 without a prescription due to a proposed increased risk of stroke in younger women. In Europe, however, it is still available by both prescription and over-the-counter. In Canada, it was withdrawn from the market on May 31, 2001.^[2] In India human use of PPA and its formulations were banned on 10th February 2011.^[3]

Pharmacology

Phenylpropanolamine acts as a potent and selective releasing agent of norepinephrine and epinephrine, or as a norepinephrine releasing agent (NRA). It also acts as a dopamine releasing agent (DRA) to a lesser extent. It works by mimicking the effects of endogenous catecholamines such as epinephrine and norepinephrine, and to a lesser degree dopamine.

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.

The use of it has been shown to potentiate the effects of caffeine.

Side Effects

A scientific study^[4] found an increased risk of hemorrhagic stroke in women who used PPA, although it is not clear which isomer is to blame. A study at the Yale University School of Medicine in 1999 had produced similar results.[2] Reports of cases of hemorrhagic strokes in PPA users had been circulating since the 1970s.

A report from the Dept. of Psychiatry, F. Edward Hebert School of Medicine, Bethesda, Maryland in Pharmacopsychiatry^[5] states:

We have reviewed 37 cases (published in North America and Europe since 1960) that received diagnoses of acute mania, paranoid schizophrenia, and organic psychosis and that were attributed to PPA product ingestion. Of the 27 North American case reports, more reactions followed the ingestion of combination products than preparations containing PPA alone; more occurred after ingestion of over-the-counter products than those obtained by prescription or on-the-street; and more of the cases followed ingestion of recommended doses than overdoses.
Failure to recognize PPA as an etiological agent in the onset of symptoms usually led to a diagnosis of schizophrenia or mania, lengthy hospitalization, and treatment with substantial doses of neuroleptics or lithium.

Detection of use

Phenylpropanolamine may be quantitated in blood, plasma or urine to confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with phenylpropanolamine, but chromatographic techniques can easily distinguish phenylpropanolamine from other phenethylamine derivatives. Blood or plasma phenylpropanolamine concentrations are typically in the 50-300 µg/L range in persons taking the drug therapeutically, 300-3000 µg/L in abusers or poisoned patients and 2–50 mg/L in cases of acute fatal overdosage.^[6][7] Phenylpropanolamine use may also trigger false positives for amphetamine in drug screening.^[8]

Legal Status

In Europe, PPA is still available in prescription decongestants such as Rinexin ,^[9] as well as over-the-counter medications such as Wick DayMed.

In the United Kingdom, PPA is available in many 'all in one' cough and cold medications which usually also feature paracetamol or another analgesic and caffeine. It can also be purchased on its own. It is classed as GSL (general sale license) and is completely derestricted, therefore saleable by any shop. As of August 11, 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^[10] 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.^[11] 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 PPA in Table I of United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances^[12]

Drugs containing PPA were banned in India on 27 January 2011.^[13]

Chemistry

Space filling model of phenylpropanolamine

There are four optical isomers of PPA: dextro- and levo- norephedrine, and dextro- and levo- norpseudoephedrine. d-Norpseudoephedrine is also known as cathine, and occurs naturally in Catha edulis ("Khat").^[14]

Phenylpropanolamine, structurally, is in the phenethylamine family, consisting of a cyclic benzene or phenyl group, a two carbon ethyl moity, 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.

Exogenous compounds in this family are degraded too rapidly to be active at a reasonable dose, however, the addition of the alpha methyl group allows the compound to avoid metabolism and confer an effect. Ephedrine is the N-methyl analogue of Phenylpropanolamine. In general N-methylation of phenethylamines confers greater stability by avoiding MAO degradation.

The beta hydroxyl group in general seems to convey more selectivity for nor-epinephrine and adrenergic receptors, however, the structure activity relationship is much more complex than this.

Phenylpropanolamine, D,L-erythro-1-phenyl-2-methylaminopropan-1-ol, is synthesized from propiophenone by nitrosation (with methyl nitrite) into an isonitroso derivative. Reduction of this by hydrogen in hydrochloric acid while simultaneously using two catalysts, palladium on carbon and platinum on carbon, gives norephedrine.

• W. N. Nagai, S. Kanao, Ann. Chem., 470, 157 (1929).
• G. Wilbert, P. Sosis, U.S. Patent 3,028,429 (1962).
• Hartung, W. H.; Munch, J. C. (1929). Journal of the American Chemical Society 51 (7): 2262. doi:10.1021/ja01382a044.  edit
• Hartung, W. H.; Chang, Y. T. (1952). Journal of the American Chemical Society 74 (23): 5927. doi:10.1021/ja01143a031.  edit

See also

• Phenethylamine
• Cathine
• Cathinone
• Methcathinone
• Ephedrine
• Pseudoephedrine
• Amphetamine
• Methamphetamine
• Phenmetrazine
• 4-Methylaminorex

External links

• Phenylpropanolamine Information Page at www.FDA.gov
• A Dose of Denial: How drug makers sought to keep popular cold and diet remedies on store shelves after their own study linked them to strokes. By Kevin Sack and Alicia Mundy.Los Angeles Times, March 28, 2004.
• Doubt Is Their Product by David Michaels, Scientific American, June 2005
• Phenylpropanolamine by Richard Clapp, a case study at DefendingScience.org
• Widely Circulated Email About Phenylpropanolamine Description of widely circulated email using out-of-date information about Phenylpropanolamine.
• Treatment of urethral sphincter mechanism incompetence in 11 bitches with a sustained-release formulation of phenylpropanolamine hydrochloride Use of Phenylpropanolamine in dogs.
• U.S. National Library of Medicine: Drug Information Portal - Phenylpropanolamine

References

1. ^ Flavahan NA (April 2005). "Phenylpropanolamine constricts mouse and human blood vessels by preferentially activating alpha2-adrenoceptors". J. Pharmacol. Exp. Ther. 313 (1): 432–9. doi:10.1124/jpet.104.076653. PMID 15608085. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15608085. 
2. ^ "Advisories, Warnings and Recalls - 2001". Health Canada. 2009-01-07. http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2001-eng.php. Retrieved 2011-01-10. 
3. ^ http://www.cdsco.nic.in/html/Drugsbanned.html
4. ^ Kernan WN, Viscoli CM, Brass LM et al. (December 2000). "Phenylpropanolamine and the risk of hemorrhagic stroke". N. Engl. J. Med. 343 (25): 1826–32. doi:10.1056/NEJM200012213432501. PMID 11117973. http://content.nejm.org/cgi/content/abstract/343/25/1826. 
5. ^ Lake CR, Masson EB, Quirk RS (July 1988). "Psychiatric side effects attributed to PPA". Pharmacopsychiatry 21 (4): 171–81. doi:10.1055/s-2007-1014671. PMID 3060884. 
6. ^ C. Lewis-Younger, Z. Horowitz and r. Mak. Elimination of phenylpropanolamine in peritoneal dialysis. Clin. Toxicol. 39: 509-510, 2001.
7. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1344-1346.
8. ^ Amphetamine Drug Testing, by Erowid. Modified 3 Nov. 2009 Accessed 5 Jan. 2011.
9. ^ Rinexin in Farmaceutiska Specialiteter i Sverige - the Swedish official drug catalog.(in Swedish)
10. ^ Food and Drug Administration Public Health Advisory, "Safety of Phenylpropanolamine"
11. ^ FDA moves PPA from OTC
12. ^ Implementation of the international drug control treaties: changes in the scope of control of substances, Commission on Narcotic Drugs, Forty-third session, Vienna, 6–15 March 2000.
13. ^ [1] Unsafe Drugs- nimesulide, Cisapride, Phenylpropanolamine Banned
14. ^ Sulzer D, Sonders MS, Poulsen NW, Galli A (April 2005). "Mechanisms of neurotransmitter release by amphetamines: a review" (PDF). Prog. Neurobiol. 75 (6): 406–33. doi:10.1016/j.pneurobio.2005.04.003. PMID 15955613. http://www.sulzerlab.org/pdf_articles/Sulzer05AMPHreview.pdf.