Phenylpropanolamine (PPA) is a
sympathomimetic agent which is used as a
decongestant
A decongestant, or nasal decongestant, is a type of pharmaceutical drug that is used to relieve nasal congestion in the upper respiratory tract. The active ingredient in most decongestants is either pseudoephedrine or phenylephrine (the latter of ...
and
appetite suppressant
An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic.
The term is (from the Greek ''ἀν-'' (an-) = "without" and ...
.
It was commonly used in
prescription and
over-the-counter
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
cough and cold preparation
R05C Expectorants, excluding combinations with cough suppressants R05CA Expectorants
:R05CA01 Tyloxapol
:R05CA02 Potassium iodide
:R05CA03 Guaifenesin
:R05CA04 Carapichea ipecacuanha, Ipecacuanha
:R05CA05 Althaea (plant), Altheae radix
:R05CA06 Se ...
s. In
veterinary medicine
Veterinary medicine is the branch of medicine that deals with the prevention, management, diagnosis, and treatment of disease, disorder, and injury in animals. Along with this, it deals with animal rearing, husbandry, breeding, research on nutri ...
, it is used to control
urinary incontinence
Urinary incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a large impact on quality of life. It has been identified as an important issue in geria ...
in dogs.
Chemistry
PPA is also known as β-hydroxyamphetamine, and is a member of the
phenethylamine
Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...
and
amphetamine
Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
chemical class Chemical classification systems attempt to classify elements or compounds according to certain chemical functional or structural properties. Whereas the structural properties are largely intrinsic, functional properties and the derived classificat ...
es.
It is closely related to the
cathinone
Cathinone (also known as benzoylethanamine, or β-keto-amphetamine) is a monoamine alkaloid found in the shrub '' Catha edulis'' (khat) and is chemically similar to ephedrine, cathine, methcathinone and other amphetamines. It is probably the m ...
s (β-ketoamphetamines).
The compound exists as four
stereoisomer
In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...
s, which include
''d''- and
''l''-norephedrine and
''d''- and
''l''-norpseudoephedrine.
''d''-Norpseudoephedrine is also known as
cathine
-norpseudoephedrine, also known as cathine and (+)-norpseudoephedrine, is a psychoactive drug of the phenethylamine and amphetamine chemical classes which acts as a stimulant. Along with cathinone, it is found naturally in '' Catha edulis'' (kha ...
,
and is found
naturally in ''
Catha edulis
Khat or qat ( ''ch’at''; Oromo: ''Jimaa'', so, qaad, khaad, khat or chat, ar, القات ''al-qāt'') is a flowering plant native to eastern and southern Africa. Khat contains the alkaloid cathinone, a stimulant, which is said to cause e ...
'' (
khat
Khat or qat ( ''ch’at''; Oromo: ''Jimaa'', so, qaad, khaad, khat or chat, ar, القات ''al-qāt'') is a flowering plant native to eastern and southern Africa. Khat contains the alkaloid cathinone, a stimulant, which is said to cause e ...
).
Pharmaceutical drug
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
preparations of PPA have varied in their stereoisomer composition in different countries, which may explain differences in
misuse
Abuse is the improper usage or treatment of a thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, crimes, or other t ...
and
side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
profiles.
Analogues of PPA include
ephedrine
Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in ...
,
pseudoephedrine
Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses.
It was first characteri ...
,
amphetamine
Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
,
methamphetamine
Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamph ...
, and
cathinone
Cathinone (also known as benzoylethanamine, or β-keto-amphetamine) is a monoamine alkaloid found in the shrub '' Catha edulis'' (khat) and is chemically similar to ephedrine, cathine, methcathinone and other amphetamines. It is probably the m ...
.
PPA, structurally, is in the
substituted phenethylamine
Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative compounds of phenethylamine which can be formed by ...
class, 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
In the nomenclature of organic chemistry, a locant is a term to indicate the position of a functional group or substituent within a molecule.
Numeric locants
The International Union of Pure and Applied Chemistry (IUPAC) recommends the use of ...
(the first carbon before the nitrogen group) also makes this compound a member of the
substituted amphetamine
Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with sub ...
class.
Ephedrine
Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in ...
is the ''N''-methyl analogue of PPA.
Exogenous compounds in this family are degraded too rapidly by
monoamine oxidase
Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first ...
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
Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine in ...
receptors.
History
Phenylpropanolamine was patented in 1938.
In the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
, PPA is no longer sold due to an increased risk of
haemorrhagic stroke
Intracerebral hemorrhage (ICH), also known as cerebral bleed, intraparenchymal bleed, and hemorrhagic stroke, or haemorrhagic stroke, is a sudden bleeding into the tissues of the brain, into its ventricles, or into both. It is one kind of bleed ...
. In a few countries in
Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
, however, it is still available either by prescription or sometimes over-the-counter. In
Canada
Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...
, it was withdrawn from the market on 31 May 2001. It was voluntarily withdrawn from the Australian market by July 2001. In
India
India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the so ...
, human use of PPA and its formulations was banned on 10 February 2011, but the ban was overturned by the judiciary in September 2011.
Pharmacology
Mechanism of action
Although originally thought to act as a direct
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of
adrenergic receptor
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...
s, PPA was subsequently found to show only weak or negligible
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Partn ...
for these
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
s, and has been instead characterized as an indirect
sympathomimetic
Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in hea ...
which acts by
inducing norepinephrine release and thereby activating adrenergic receptors.
Pharmacodynamics
PPA acts primarily as a
selective norepinephrine releasing agent
A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into ...
.
It also acts as a
dopamine releasing agent
A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective DRAs are currently known. Many releasing agents of both dopamine and norepinephrine (norepinephrine–dopamine releasi ...
with around 10-fold lower
potency
Potency may refer to:
* Potency (pharmacology), a measure of the activity of a drug in a biological system
* Virility
* Cell potency, a measure of the differentiation potential of stem cells
* In homeopathic dilutions, potency is a measure of how ...
.
The stereoisomers of the drug have only weak or negligible
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Partn ...
for
α- and
β-adrenergic receptor
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...
s.
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.
Activity profiles of isomers
Pharmacokinetics
Norephedrine is a
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
of
amphetamine
Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
, as shown below.
Drug interactions
Certain drugs increase the chances of ''
déjà vu
''Déjà vu'' ( , ; "already seen") is a French loanword for the phenomenon of feeling as though one has lived through the present situation before.Schnider, Armin. (2008). ''The Confabulating Mind: How the Brain Creates Reality''. Oxford Univer ...
'' occurring in the user, resulting in a strong sensation that an event or experience currently being experienced has already been experienced in the past. Some pharmaceutical drugs, when taken together, have also been implicated in the cause of ''déjà vu''. Taiminen and Jääskeläinen (2001) reported the case of an otherwise healthy male who started experiencing intense and recurrent sensations of ''déjà vu'' upon taking the drugs
amantadine
Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to wid ...
and phenylpropanolamine together to relieve flu symptoms. He found the experience so interesting that he completed the full course of his treatment and reported it to the psychologists to write up as a case study. Because of the
dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...
action of the drugs and previous findings from electrode stimulation of the brain (e.g. Bancaud, Brunet-Bourgin, Chauvel, & Halgren, 1994), Taiminen and Jääskeläinen speculate that ''déjà vu'' occurs as a result of
hyperdopaminergic action in the
mesial
This is a list of definitions of commonly used terms of location and direction in dentistry. This set of terms provides orientation within the oral cavity, much as anatomical terms of location provide orientation throughout the body.
Terms
...
temporal areas of the brain.
Society and culture
Legal status
In Sweden, PPA is still available in prescription decongestants, PPA is also still available in Germany. It is used in some
polypill
A polypill is a type of combination drug, drug combination consisting of a single drug product in pill form (i.e., tablet (pharmacy), tablet or capsule (pharmacy), capsule) and thus ''combines'' multiple medications (that is, more than one active ...
medications like Wick DayMed capsules.
In the
United Kingdom
The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the continental mainland. It comprises England, Scotland, Wales and North ...
, PPA was available in many 'all in one' cough and cold medications which usually also feature
paracetamol
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
or another
analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
and
caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
and could also be purchased on its own; however, it is no longer approved for human use. A European Category 1 Licence is required to purchase PPA for academic use.
In the United States, the
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) issued a public health advisory against the use of the drug in November 2000. In this advisory, the FDA requested but did not require 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 but it’s still possible for it to be sold as a prescription only product. Because of its potential use in
amphetamine
Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
manufacture, it is controlled by the
Combat Methamphetamine Epidemic Act of 2005
The Combat Methamphetamine Epidemic Act of 2005 (CMEA) is federal legislation enacted in the United States on March 9, 2006, to regulate, among other things, retail over-the-counter sales of following products because of their use in the manufactu ...
. It is still available for veterinary use in dogs, however, as a treatment for
urinary incontinence
Urinary incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a large impact on quality of life. It has been identified as an important issue in geria ...
.
Internationally, an item on the agenda of the 2000
Commission on Narcotic Drugs
The Commission on Narcotic Drugs (CND) is one of the functional commissions of the United Nations' Economic and Social Council (ECOSOC), and is the central drug policy-making body within the United Nations System. The CND also has important man ...
session called for including the stereoisomer norephedrine in Table I of
.
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 pediatric drugs PPA and
nimesulide
Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) with pain medication and fever reducing properties. Its approved indications are the treatment of acute pain, the symptomatic treatment of osteoarthritis, and primary dysmenorrhoea in ...
.
Notes
Reference notes
References
External links
Phenylpropanolamine Information Pageat FDA.gov (update, includes earlier reports)
U.S. National Library of Medicine: Drug Information Portal – Phenylpropanolamine
{{Phenethylamines
Phenylethanolamines
Alpha-1 adrenergic receptor agonists
Alpha-2 adrenergic receptor agonists
Amphetamine alkaloids
Anorectics
Beta-adrenergic agonists
Decongestants
Norepinephrine releasing agents
Veterinary drugs
Withdrawn drugs