Phenylpropanolamine (PPA), sold under many brand names, is a sympathomimetic agent 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 o ...

and

appetite suppressant An anorectic is a drug that reduces appetite, resulting in lower food consumption, leading to weight loss. These substances work by affecting the central nervous system or certain neurotransmitters to create a feeling of fullness or reduce the desi ...

. It was once common 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 pres ...

cough and cold preparations. The medication is taken orally.

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of phenylpropanolamine include increased

heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...

and

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

. Rarely, PPA has been associated with

hemorrhagic stroke Stroke is a medical condition in which poor blood flow to a part of the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop ...

. PPA acts as a norepinephrine releasing agent, indirectly activating

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 b ...

s. As such, it is an indirectly acting sympathomimetic. It was once thought to act as a sympathomimetic with additional direct

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

action on adrenergic receptors, but this proved wrong. Chemically, phenylpropanolamine is a

substituted amphetamine Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...

and is closely related to

ephedrine Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent hypotension, low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred ...

pseudoephedrine Pseudoephedrine, sold under the brand name Sudafed among others, is a sympathomimetic medication which is used as a decongestant to treat nasal congestion. It has also been used off-label for certain other indications, like treatment of lo ...

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

, and

cathinone Cathinone (; also known as β-ketoamphetamine) 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 main contributor to t ...

. It is usually a

racemic mixture In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

of the (1''R'',2''S'')- and (1''S'',2''R'')-

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

s of β-hydroxyamphetamine and is also known as ''dl''-norephedrine. Phenylpropanolamine was first synthesized around 1910 and its effects on blood pressure were characterized around 1930. It was introduced as medicine by the 1930s. It was withdrawn from many markets starting in 2000 after learning that it was associated with increased risk of hemorrhagic stroke. It was previously available both

and by prescription. Phenylpropanolamine is available for both human and/or veterinary use in some countries.

Medical uses

Phenylpropanolamine is used as a

to treat

nasal congestion Nasal congestion is the partial or complete blockage of nasal passages, leading to impaired nasal breathing, usually due to membranes lining the nose becoming swollen from inflammation of blood vessels. Background In about 85% of cases, nasal ...

. It has also been used to suppress appetite and promote

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...

in the treatment of

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

and has shown effectiveness for this indication.

Available forms

Phenylpropanolamine was previously available in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

and in certain

combination drug A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...

forms by prescription. One such example of the latter was a combination of phenylpropanolamine and

chlorpheniramine Chlorphenamine (CP, CPM), also known as chlorpheniramine, is an antihistamine used to treat the symptoms of allergic conditions such as allergic rhinitis (hay fever). It is taken orally (by mouth). The medication takes effect within two hour ...

, which dually contained decongestant and antihistamine effects, marketed by Tutag as 'Vernate'. These forms have all been discontinued in the U.S., although. phenylpropanolamine remains available in some countries.

Side effects

Phenylpropanolamine produces sympathomimetic effects and can cause

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s such as increased

and

. It has been associated rarely with incidence of

. Certain drugs increase the chances of ''

déjà vu ''Déjà vu'' ( , ; "already seen") is the phenomenon of feeling like one has lived through the present situation in the past.Schnider, Armin. (2008). ''The Confabulating Mind: How the Brain Creates Reality''. Oxford University Press. pp. 167–1 ...

'' 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''. The 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 because ...

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"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

action of the drugs and previous findings from electrode stimulation of the brain, it was speculated 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.

Interactions

There has been very little research on

drug interaction In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect ...

s with phenylpropanolamine. In one study, phenylpropanolamine taken with

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...

was found to quadruple caffeine levels. In another study, phenylpropanolamine reduced

theophylline Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other met ...

clearance by 50%.

Pharmacology

Pharmacodynamics

Phenylpropanolamine acts primarily as a selective norepinephrine releasing agent. It also acts as a dopamine releasing agent with around 10-fold lower potency. 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 Pa ...

for α- and β-adrenergic receptors. Phenylpropanolamine was originally thought to act as a direct

s and hence to act as a mixed acting sympathomimetic, However, phenylpropanolamine was subsequently found to show only weak or negligible

for these

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

s and has been instead characterized as exclusively an indirectly acting sympathomimetic. It acts by inducing norepinephrine release and thereby indirectly activating adrenergic receptors. 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. Phenylpropanolamine has relatively low potency as a sympathomimetic. It is about 100 to 200times less potent than

epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...

(adrenaline) or

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

(noradrenaline) in its sympathomimetic effects, although responses are variable depending on tissue.

Pharmacokinetics

Absorption

Phenylpropanolamine is readily- and well-absorbed with

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Immediate-release forms of the drug reached

peak Peak or The Peak may refer to: Basic meanings Geology * Mountain peak ** Pyramidal peak, a mountaintop that has been sculpted by erosion to form a point Mathematics * Peak hour or rush hour, in traffic congestion * Peak (geometry), an (''n''-3)-d ...

levels about 1.5hours (range 1.0 to 2.3hours) following administration. Conversely, extended-release forms of phenylpropanolamine reach peak levels after 3.0 to 4.5hours. The

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...

of phenylpropanolamine are linear across an oral dose range of 25 to 100mg.

Steady-state In systems theory, a system or a process is in a steady state if the variables (called state variables) which define the behavior of the system or the process are unchanging in time. In continuous time, this means that for those properties ''p'' ...

levels of phenylpropanolamine are achieved within 12hours when the drug is taken once every 4hours. There is 62% accumulation of phenylpropanolamine at steady state in terms of peak levels, whereas area-under-the-curve levels are not increased with steady state.

Distribution

The

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of phenylpropanolamine is 3.0 to 4.5L/kg. Levels of phenylpropanolamine in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

are about 40% of those in the

heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...

and 20% of those in the

lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...

s. The

hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

of phenylpropanolamine at the β carbon increases its hydrophilicity, reduces its permeation through the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

, and limits its

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

(CNS) effects. Hence, phenylpropanolamine crosses into the brain only to some extent, has only weak CNS effects, and most of its effects are peripheral. In any case, phenylpropanolamine can produce

-like

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

effects at very high doses. Phenylpropanolamine is more lipophilic than structurally related sympathomimetics with hydroxyl groups on the phenyl ring like

(adrenaline) and

phenylephrine Phenylephrine, sold under the brand names Neosynephrine and Sudafed PE among others, is a medication used as a decongestant for uncomplicated nasal congestion in the form of a nasal spray or oral tablet, to dilate the pupil, to increase bloo ...

and has greater brain permeability than these agents. The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

of phenylpropanolamine is approximately 20%. However, it has been said that no recent studies have substantiated this value.

Metabolism

Phenylpropanolamine is not substantially

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. It also does not undergo significant

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

. Only about 3 to 4% of an oral dose of phenylpropanolamine is metabolized.

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 ...

s include

hippuric acid Hippuric acid (Greek language, Gr. ''hippos'', horse, ''ouron'', urine) is a carboxylic acid and organic compound. It is found in urine and is formed from the combination of benzoic acid and glycine. Levels of hippuric acid rise with the consumpt ...

(via

oxidative Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

deamination Deamination is the removal of an amino group from a molecule. Enzymes that catalysis, catalyse this reaction are called deaminases. In the human body, deamination takes place primarily in the liver; however, it can also occur in the kidney. In s ...

of the

side chain In organic chemistry and biochemistry, a side chain is a substituent, chemical group that is attached to a core part of the molecule called the "main chain" or backbone chain, backbone. The side chain is a hydrocarbon branching element of a mo ...

) and

4-hydroxynorephedrine ''p''-Hydroxynorephedrine (PHN or 4-hydroxynorephedrine) is the ''para''-hydroxy analog of norephedrine and an active sympathomimetic metabolite of amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylam ...

(via ''para''-

hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

). The

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...

at the α carbon of phenylpropanolamine blocks metabolism 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 fi ...

s (MAOs). Phenylpropanolamine is also not a

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

of catechol ''O''-methyltransferase. The

at the β carbon of phenylpropanolamine also helps to increase metabolic stability.

Elimination

Approximately 90% of a dose of phenylpropanolamine is excreted in the

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

unchanged within 24hours. About 4% of excreted material is in the form of

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 ...

s. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of immediate-release phenylpropanolamine is about 4hours, with a range in different studies of 3.7 to 4.9hours. The half-life of extended-release phenylpropanolamine has ranged from 4.3 to 5.8hours. The elimination of phenylpropanolamine is dependent on urinary pH. At a more

acid An acid is a molecule or ion capable of either donating a proton (i.e. Hydron, hydrogen cation, H+), known as a Brønsted–Lowry acid–base theory, Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis ...

ic urinary pH, the elimination of phenylpropanolamine is accelerated and its half-life and duration are shortened, whereas at more

basic Basic or BASIC may refer to: Science and technology * BASIC, a computer programming language * Basic (chemistry), having the properties of a base * Basic access authentication, in HTTP Entertainment * Basic (film), ''Basic'' (film), a 2003 film ...

urinary pH, the elimination of phenylpropanolamine is reduced and its half-life and duration are extended. Urinary acidifying agents like

ascorbic acid Ascorbic acid is an organic compound with formula , originally called hexuronic acid. It is a white solid, but impure samples can appear yellowish. It dissolves freely in water to give mildly acidic solutions. It is a mild reducing agent. Asco ...

and

ammonium chloride Ammonium chloride is an inorganic chemical compound with the chemical formula , also written as . It is an ammonium salt of hydrogen chloride. It consists of ammonium cations and chloride anions . It is a white crystalline salt (chemistry), sal ...

can increase the excretion of and thereby reduce exposure to

s including phenylpropanolamine, whereas urinary alkalinizing agents including

antacid An antacid is a substance which neutralization (chemistry), neutralizes gastric acid, stomach acidity and is used to relieve heartburn, indigestion, or an upset stomach. Some antacids have been used in the treatment of constipation and diarrhe ...

s like

sodium bicarbonate Sodium bicarbonate ( IUPAC name: sodium hydrogencarbonate), commonly known as baking soda or bicarbonate of soda (or simply “bicarb” especially in the UK) is a chemical compound with the formula NaHCO3. It is a salt composed of a sodium cat ...

as well as

acetazolamide Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, acute mountain sickness, periodic paralysis, idiopathic intracranial hypertension (raised brain pressure of unclear cause), heart f ...

can reduce the excretion of these agents and thereby increase exposure to them. Total body clearance of phenylpropanolamine has been reported to be 0.546L/h/kg, while renal clearance was 0.432L/h/kg.

Miscellaneous

As phenylpropanolamine is not extensively metabolized, it would probably not be affected by hepatic impairment. Conversely, there is likely to be accumulation of phenylpropanolamine with renal impairment due to its dependence on urinary excretion. Norephedrine is a minor

and

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

, as shown below. It is also a minor metabolite of

and a major metabolite of

Chemistry

Phenylpropanolamine, also known as (1''RS'',2''SR'')-α-methyl-β-hydroxyphenethylamine or as (1''RS'',2''SR'')-β-hydroxyamphetamine, is a

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 (chemistry), derivative compounds of phenethylamine ...

and

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

. It is closely related to the

s (β-ketoamphetamines). β-Hydroxyamphetamine 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''- ( dextrorotatory) and ''l''-norephedrine (

levorotatory Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circul ...

), and ''d''- and ''l''-norpseudoephedrine. ''d''-Norpseudoephedrine is also known as

cathine Cathine, also known as -norpseudoephedrine or as (+)-norpseudoephedrine, is a psychoactive drug of the phenethylamine and amphetamine groups which acts as a stimulant. Along with cathinone, it is found naturally in ''Catha edulis'' (khat), and ...

, and is found naturally in ''

Catha edulis Khat (''Catha edulis''), also known as Bushman's tea, especially in South Africa, is a flowering plant native to eastern and southeastern Africa. It has a history of cultivation originating in the Harari Region, Harar area (present day easter ...

'' (

khat Khat (''Catha edulis''), also known as Bushman's tea, especially in South Africa, is a flowering plant native to eastern and southeastern Africa. It has a history of cultivation originating in the Harar area (present day eastern Ethiopia) and ...

Pharmaceutical drug Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, 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 ...

preparations of phenylpropanolamine have varied in their stereoisomer composition in different countries, which may explain differences in misuse and

profiles. In any case,

racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

''dl''-norephedrine, or (1''RS'',2''SR'')-phenylpropanolamine, appears to be the most commonly used formulation of phenylpropanolamine pharmaceutically. Analogues of phenylpropanolamine include

, and

. Phenylpropanolamine, structurally, is in the substituted phenethylamine 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 n ...

(the first carbon before the nitrogen group) also makes this compound a member of the

class.

Ephedrine Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent hypotension, low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred ...

is the ''N''-methyl analogue of phenylpropanolamine. Exogenous compounds in this family are degraded too rapidly by

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 ...

receptors. Phenylpropanolamine is a small-molecule compound with the

molecular formula A chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, such as paren ...

C₉H₁₃NO and a

molecular weight A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

of 151.21g/mol. It has an experimental log P of 0.67, while its predicted log P values range from 0.57 to 0.89. The compound is relatively

lipophilic Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...

, but is also more

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...

than other amphetamines. The lipophilicity of amphetamines is closely related to their brain permeability. For comparison to phenylpropanolamine, the experimental log P of

is 2.1, of

is 1.8, of

is 1.1, of

is 0.7, of

is -0.3, and of

is -1.2. Methamphetamine has high brain permeability, whereas phenylephrine and norepinephrine are

peripherally selective drug Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest o ...

s. The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7). Phenylpropanolamine has been used pharmaceutically exclusively as the hydrochloride

salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

History

Phenylpropanolamine was first synthesized in the early 20th century, in or around 1910. It was

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...

ed as a mydriatic in 1913. The pressor effects of phenylpropanolamine were characterized in the late 1920s and the 1930s. Phenylpropanolamine was first introduced for medical use by the 1930s. In the United States, phenylpropanolamine is no longer sold due to an increased risk of haemorrhagic stroke. In a few countries in

Europe Europe is a continent located entirely in the Northern Hemisphere and mostly in the Eastern Hemisphere. It is bordered by the Arctic Ocean to the north, the Atlantic Ocean to the west, the Mediterranean Sea to the south, and Asia to the east ...

, however, it is still available either by prescription or sometimes over-the-counter. In

Canada Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...

, 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, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...

, human use of phenylpropanolamine and its formulations was banned on 10 February 2011, but the ban was overturned by the judiciary in September 2011.

Society and culture

Names

''Phenylpropanolamine'' is the generic name of the drug and its , , and , while ''phenylpropanolamine hydrochloride'' is its and in the case of the hydrochloride

. It is also known by the synonym ''norephedrine''. Brand names of phenylpropanolamine include Acutrim, Appedrine, Capton Diet, Control, Dexatrim, Emagrin Plus A.P., Glifentol, Kontexin, Merex, Monydrin, Mydriatine, Prolamine, Propadrine, Propagest, Recatol, Rinexin, Tinaroc, and Westrim, among many others. It has also been used in

combination In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are ...

s under brand names including Allerest, Demazin, Dimetapp, and Sinarest, among others.

Availability

Phenylpropanolamine is available for medical and veterinary use in some countries.

Exercise and sports

There has been interest in phenylpropanolamine as a

performance-enhancing drug Performance-enhancing substances (PESs), also known as performance-enhancing drugs (PEDs), are substances that are used to improve any form of activity performance in humans. Many substances, such as anabolic steroids, can be used to improve at ...

exercise Exercise or workout is physical activity that enhances or maintains fitness and overall health. It is performed for various reasons, including weight loss or maintenance, to aid growth and improve strength, develop muscles and the cardio ...

and

sports Sport is a physical activity or game, often competitive and organized, that maintains or improves physical ability and skills. Sport may provide enjoyment to participants and entertainment to spectators. The number of participants in ...

. However, clinical studies suggest that phenylpropanolamine is not effective in this regard. Phenylpropanolamine is not on the

World Anti-Doping Agency The World Anti-Doping Agency (WADA; , AMA) is an international organization co-founded by the governments of over 140 nations along with the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against d ...

(WADA) list of prohibited substances as of 2024.

Legal status

In Sweden, phenylpropanolamine is still available in prescription decongestants; Phenylpropanolamine is also still available in Germany. It is used in some polypill medications like Wick DayMed capsules. In the United Kingdom, phenylpropanolamine was available in many "all in one" cough and cold medications which usually also feature paracetamol (also known as acetaminophen) or another

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

and

and could also be purchased on its own. It is no longer approved for human use, however, and a European Category 1 Licence is required to purchase or acquire phenylpropanolamine for academic or research 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 respo ...

(FDA) issued a public health advisory recommending 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 phenylpropanolamine. The agency estimates that phenylpropanolamine caused between 200 and 500 strokes per year among 18-to-49-year-old users. In 2005, the FDA removed phenylpropanolamine from over-the-counter sale and removed its "

generally recognized as safe and effective Generally recognized as safe and effective (abbreviated as GRASE, GRAS/E, or GRAS/GRAE) is designation for certain old drugs that do not require prior approval from the U.S. Food and Drug Administration in order to enter the United States marketpl ...

" (GRASE) status. Under the 2020 CARES Act, it requires FDA approval before it can be marketed again effectively banning the drug, even as a prescription. Because of its potential use in

manufacture, phenylpropanolamine is controlled by the Combat Methamphetamine Epidemic Act of 2005. However, It is still available for veterinary use in dogs 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 significant effect on quality of life. Urinary incontinence is common in older women ...

. 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

norephedrine in Table I of

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 C ...

. Drugs containing phenylpropanolamine were banned in India on 27 January 2011. On 13 September 2011, Madras High Court revoked a ban on the manufacture and sale of pediatric drugs phenylpropanolamine and nimesulide.

Veterinary use

Phenylpropanolamine is available for use in

veterinary medicine Veterinary medicine is the branch of medicine that deals with the prevention, management, medical diagnosis, diagnosis, and treatment of disease, disorder, and injury in non-human animals. The scope of veterinary medicine is wide, covering all a ...

. It is used to control

in dogs. In June 2024, the US

(FDA) approved Phenylpropanolamine hydrochloride chewable tablets for the control of urinary incontinence due to a weakening of the muscles that control urination (urethral sphincter hypotonus) in dogs. fda.gov
/ref> This is the first generic phenylpropanolamine hydrochloride chewable tablets for dogs. Urinary incontinence happens when a dog loses its ability to control when it urinates. Urinary incontinence due to urethral sphincter hypotonus can happen as dogs age and as the dog’s muscle in its urethra (the tube that leads from the dog’s bladder to outside its body) weakens and loses control over its ability to hold urine. Phenylpropanolamine hydrochloride chewable tablets contain the same active ingredient (phenylpropanolamine hydrochloride) in the same concentration and dosage form as the approved brand name drug product, Proin chewable tablets, which were first approved in August 2011. In addition, the FDA determined that Phenylpropanolamine hydrochloride chewable tablets contain no inactive ingredients that may significantly affect the bioavailability of the active ingredient.

Notes

Reference notes

References

{{Authority control Amphetamine alkaloids Anorectics Anti-obesity drugs Antihypotensive agents Beta-Hydroxyamphetamines Decongestants Drugs acting on the cardiovascular system Drugs acting on the nervous system Drugs in sport Enantiopure drugs Ergogenic aids Human drug metabolites Norepinephrine releasing agents Peripherally selective drugs Recreational drug metabolites Stimulants Sympathomimetics Veterinary drugs Withdrawn anti-obesity drugs World Anti-Doping Agency prohibited substances