Phenylpropanolamine
Encyclopedia
Phenylpropanolamine 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 name
s 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, it was withdrawn from the market on May 31, 2001. In India
human use of PPA and its formulations were banned on 10th February 2011.
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.
A report from the Dept. of Psychiatry, F. Edward Hebert School of Medicine, Bethesda, Maryland in Pharmacopsychiatry states:
Phenylpropanolamine use may also trigger false positives for amphetamine in drug screening.
, 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 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 PPA 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.
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 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.
Psychoactive drug
A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that crosses the blood–brain barrier and acts primarily upon the central nervous system where it affects brain function, resulting in changes in perception, mood, consciousness, cognition, and behavior...
of the phenethylamine
Phenethylamine
Phenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
and amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
chemical classes which is used as a stimulant
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
, decongestant
Decongestant
A decongestant or nasal decongestant is a type of drug that is used to relieve nasal congestion.-Pharmacology:The vast majority of decongestants act via enhancing norepinephrine and epinephrine or adrenergic activity by stimulating the α-adrenergic receptors...
, and anorectic
Anorectic
An anorectic or anorexic , also known as anorexigenic or appetite suppressant, is a dietary supplement and/or drug which reduces appetite, food consumption, and as a result, causes weight loss to occur.-List of anorectics:Numerous pharmaceutical compounds are marketed as appetite suppressants.The...
agent. It is commonly used in prescription
Prescription drug
A prescription medication is a licensed medicine that is regulated by legislation to require a medical prescription before it can be obtained. The term is used to distinguish it from over-the-counter drugs which can be obtained without a prescription...
and over-the-counter
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
cough and cold preparations. In veterinary medicine
Veterinary medicine
Veterinary Medicine is the branch of science that deals with the prevention, diagnosis and treatment of disease, disorder and injury in non-human animals...
, it is used to control urinary incontinence
Urinary incontinence
Urinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
in dogs under trade name
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....
s Propalin and Proin.
In the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, PPA is no longer sold without a prescription due to a proposed increased risk of stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
in younger women. In Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
, however, it is still available by both prescription and over-the-counter. In Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
, it was withdrawn from the market on May 31, 2001. In India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
human use of PPA and its formulations were banned on 10th February 2011.
Pharmacology
Phenylpropanolamine acts as a potentPotency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...
and selective
Functional Selectivity
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...
releasing agent
Releasing agent
A releasing agent , or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and...
of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, or as a norepinephrine releasing agent
Norepinephrine releasing agent
A norepinephrine releasing agent is a type of drug which induces the release of norepinephrine and epinephrine from the pre-synaptic neuron into the synapse...
(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
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, and to a lesser degree dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
.
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 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.http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3647b1_tab19.doc 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 states:
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.Phenylpropanolamine use may also trigger false positives for amphetamine in drug screening.
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
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, PPA is available in many 'all in one' cough and cold medications which usually also feature paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
or another analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
and caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
. 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(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
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
manufacture, it is controlled by the Combat Methamphetamine Epidemic Act of 2005
Combat Methamphetamine Epidemic Act of 2005
The Combat Methamphetamine Epidemic Act of 2005 is federal legislation enacted in the United States on March 9, 2006, to regulate, among other things, retail over-the-counter sales of ephedrine, pseudoephedrine, and phenylpropanolamine products because of their use in the manufacture of illegal...
. It is still available for veterinary use in dogs, however, as a treatment for urinary incontinence
Urinary incontinence
Urinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
.
Internationally, an item on the agenda of the 2000 Commission on Narcotic Drugs
Commission on Narcotic Drugs
The Commission on Narcotic Drugs is the central drug policy-making body within the United Nations system. Its predecessor, the Advisory Committee on the Traffic in Opium and Other Dangerous Drugs, was established by the first Assembly of the League of Nations on December 15, 1920...
session called for including PPA in Table I of United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances
United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances
The United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988 is one of three major drug control treaties currently in force. It provides additional legal mechanisms for enforcing the 1961 Single Convention on Narcotic Drugs and the 1971 Convention on...
Drugs containing PPA were banned in India on 27 January 2011.
Chemistry
There are four optical isomers of PPA: dextro- and levo- norNor-
In chemical nomenclature, nor is a prefix to name a structural analog that can be derived from a parent compound by the removal of one carbon atom along with the accompanying hydrogen. The nor-compound can be derived by demethylation or by removal of a methylenegroup, a CH group or a C atom...
ephedrine
Ephedrine
Ephedrine is a sympathomimetic amine commonly used as a stimulant, appetite suppressant, concentration aid, decongestant, and to treat hypotension associated with anaesthesia....
, and dextro- and levo- nor
Nor-
In chemical nomenclature, nor is a prefix to name a structural analog that can be derived from a parent compound by the removal of one carbon atom along with the accompanying hydrogen. The nor-compound can be derived by demethylation or by removal of a methylenegroup, a CH group or a C atom...
pseudoephedrine
Pseudoephedrine
Pseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
. d-Norpseudoephedrine is also known as cathine
Cathine
Cathine, also known as d-norpseudoephedrine, is a psychoactive drug of the phenethylamine and amphetamine chemical classes which acts as a stimulant...
, and occurs naturally in Catha edulis ("Khat").
Phenylpropanolamine, structurally, is in the phenethylamine
Phenethylamine
Phenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
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
Alpha carbon
The alpha carbon in organic chemistry refers to the first carbon that attaches to a functional group . By extension, the second carbon is the beta carbon, and so on....
(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
Adrenergic
An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine . Thus, it is a kind of sympathomimetic agent...
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
Methyl nitrite
In organic chemistry, methyl nitrite is the simplest alkyl nitrite.-Structure:At room temperature, methyl nitrite exists as a mixture of cis and trans conformers...
) 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, (1962).
See also
- PhenethylaminePhenethylaminePhenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
- CathineCathineCathine, also known as d-norpseudoephedrine, is a psychoactive drug of the phenethylamine and amphetamine chemical classes which acts as a stimulant...
- CathinoneCathinoneCathinone, or Benzoylethanamine, is a monoamine alkaloid found in the shrub Catha edulis and is chemically similar to ephedrine, cathine and other amphetamines. Cathinone induces the release of dopamine from striatal preparations that are prelabelled either with dopamine or its precursors. It is...
- MethcathinoneMethcathinoneMethcathinone , is a psychoactive stimulant, sometimes used as a recreational drug and considered addictive. It is usually snorted, but can be smoked, injected, or taken orally...
- EphedrineEphedrineEphedrine is a sympathomimetic amine commonly used as a stimulant, appetite suppressant, concentration aid, decongestant, and to treat hypotension associated with anaesthesia....
- PseudoephedrinePseudoephedrinePseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
- AmphetamineAmphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
- MethamphetamineMethamphetamineMethamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
- PhenmetrazinePhenmetrazinePhenmetrazine is a stimulant drug of the morpholine chemical class that was previously used as an appetite suppressant, but has since been withdrawn from the market...
- 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