| Watchedfields: | verified |
| Verifiedrevid: | 464201364 |
| Iupac Name: | (1R,2S)-2-amino-1-phenylpropan-1-ol |
| Alt2: | Ball-and-stick model of the phenylpropanolamine molecule |
| Tradename: | Many |
| Pregnancy Au: | B2 |
| Legal Au: | S4 |
| Legal Br: | F3 |
| Legal Br Comment: | [1] |
| Legal Ca: | Schedule VI |
| Legal Us Comment: | Rx-Only |
| Routes Of Administration: | By mouth |
| Bioavailability: | High |
| Protein Bound: | 20% |
| Metabolism: | Minimal (3–4%) |
| Metabolites: | • Hippuric acid (~4%) • 4-Hydroxynorephedrine (≤1%) |
| Onset: | Oral 15–30minutes |
| Elimination Half-Life: | 4 (3.7–4.9)hours[2] |
| Duration Of Action: | Oral: 3hours |
| Excretion: | Urine 90% (unchanged) |
| Cas Number: | 14838-15-4 |
| Atc Prefix: | R01 |
| Atc Suffix: | BA01 |
| Pubchem: | 10297 |
| Drugbank: | DB00397 |
| Chemspiderid: | 9875 |
| Unii: | 33RU150WUN |
| Kegg: | D08368 |
| Chembl: | 136560 |
| Synonyms: | PPA; Norephedrine; α-Methyl-β-hydroxyphenethylamine; β-Hydroxyamphetamine |
| C: | 9 |
| H: | 13 |
| N: | 1 |
| O: | 1 |
| Smiles: | O[C@H](c1ccccc1)[C@@H](N)C |
| Stdinchi: | 1S/C9H13NO/c1-7(10)9(11)8-5-3-2-4-6-8/h2-7,9,11H,10H2,1H3/t7-,9-/m0/s1 |
| Stdinchikey: | DLNKOYKMWOXYQA-CBAPKCEASA-N |
Phenylpropanolamine (PPA), sold under many brand names, is a sympathomimetic agent which is used as a decongestant and appetite suppressant.[3] It was previously commonly used in prescription and over-the-counter cough and cold preparations. The medication is taken by mouth.
Side effects of PPA include increased heart rate and blood pressure, among others. Rarely, PPA has been associated with hemorrhagic stroke. PPA acts as a norepinephrine releasing agent, thereby indirectly activating adrenergic receptors.[4] [5] [6] As such, it is an indirectly acting sympathomimetic. It was previously thought to act as a mixed acting sympathomimetic with additional direct agonist actions on adrenergic receptors, but this proved not to be the case. Chemically, PPA is a substituted amphetamine and is closely related to ephedrine, pseudoephedrine, amphetamine, and cathinone.[7]
PPA was first synthesized around 1910 and its effects on blood pressure were first characterized around 1930. It was introduced for medical use by the 1930s. The medication was withdrawn from many markets starting in 2000 following findings that it was associated with increased risk of hemorrhagic stroke.[8] It was previously available both over-the-counter and by prescription. PPA remains available for medical and/or veterinary use in some countries.
PPA is used as a decongestant to treat nasal congestion.[9] [10] It has also been used to suppress appetite and promote weight loss in the treatment of obesity and has shown effectiveness for this indication.[11] [12] [13]
PPA was previously available over-the-counter and in certain combination forms by prescription in the United States.[14] [15] However, these forms have all been discontinued. PPA remains available in certain other countries.
PPA produces sympathomimetic effects and can cause side effects such as increased heart rate and blood pressure.[16] [17] It has been associated rarely with incidence of hemorrhagic stroke.
Certain drugs increase the chances of déjà vu 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.[18] reported the case of an otherwise healthy male who started experiencing intense and recurrent sensations of déjà vu upon taking the drugs amantadine and PPA 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 action of the drugs and previous findings from electrode stimulation of the brain,[19] it was speculated that déjà vu occurs as a result of hyperdopaminergic action in the mesial temporal areas of the brain.
There has been very little research on drug interactions with PPA. In one study, PPA taken with caffeine was found to quadruple caffeine levels. In another study, PPA reduced theophylline clearance by 50%.
PPA 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 for α- and β-adrenergic receptors.
| Compound | data-sort-type="number" | ! | data-sort-type="number" | ! | data-sort-type="number" | ! | Ref |
|---|---|---|---|---|---|---|---|
| Dextroamphetamine (S(+)-amphetamine) | 6.6–7.2 | 5.8–24.8 | 698–1765 | [21] [22] | |||
| 12.4 | 18.5 | 2366 | |||||
| 43.1–72.4 | 236–1350 | >10000 | |||||
| 218 | 2104 | >10000 | |||||
| Dextromethamphetamine (S(+)-methamphetamine) | 12.3–13.8 | 8.5–24.5 | 736–1291.7 | [23] | |||
| Levomethamphetamine (R(–)-methamphetamine) | 28.5 | 416 | 4640 | ||||
| (+)-Phenylpropanolamine ((+)-norephedrine) | 42.1 | 302 | >10000 | ||||
| (–)-Phenylpropanolamine ((–)-norephedrine) | 137 | 1371 | >10000 | ||||
| Cathine ((+)-norpseudoephedrine) | 15.0 | 68.3 | >10000 | ||||
| 30.1 | 294 | >10000 | |||||
| 4092 | 9125 | >10000 | |||||
| Pseudoephedrine ((+)-pseudoephedrine) | 224 | 1988 | >10000 | ||||
| The smaller the value, the more strongly the substance releases the neurotransmitter. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. | |||||||
PPA was originally thought to act as a direct agonist of adrenergic receptors and hence to act as a mixed acting sympathomimetic, However, PPA was subsequently found to show only weak or negligible affinity for these receptors 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.
PPA has relatively low potency as a sympathomimetic. It is about 100 to 200times less potent than epinephrine (adrenaline) or norepinephrine (noradrenaline) in its sympathomimetic effects, although responses are variable depending on tissue.
PPA is readily- and well-absorbed with oral administration.[24] Immediate-release forms of the drug reached peak levels about 1.5hours (range 1.0 to 2.3hours) following administration.[25] Conversely, extended-release forms of PPA reach peak levels after 3.0 to 4.5hours. The pharmacokinetics of PPA are linear across an oral dose range of 25 to 100mg. Steady-state levels of PPA are achieved within 12hours when the drug is taken once every 4hours. There is 62% accumulation of PPA at steady state in terms of peak levels, whereas area-under-the-curve levels are not increased with steady state.
The volume of distribution of PPA is 3.0 to 4.5L/kg. Levels of PPA in the brain are about 40% of those in the heart and 20% of those in the lungs. The hydroxyl group of PPA at the β carbon increases its hydrophilicity, reduces its permeation through the blood–brain barrier, and limits its central nervous system (CNS) effects. Hence, PPA crosses into the brain only to some extent, has only weak CNS effects, and most of its effects are peripheral. In any case, PPA can produce amphetamine-like psychostimulant effects at very high doses. PPA is more lipophilic than structurally related sympathomimetics with hydroxyl groups on the phenyl ring like epinephrine (adrenaline) and phenylephrine and has greater brain permeability than these agents.
The plasma protein binding of PPA is approximately 20%. However, it has been said that no recent studies have substantiated this value.
PPA is not substantially metabolized. It also does not undergo significant first-pass metabolism. Only about 3 to 4% of an oral dose of PPA is metabolized. Metabolites include hippuric acid (via oxidative deamination of the side chain) and 4-hydroxynorephedrine (via para-hydroxylation). The methyl group at the α carbon of PPA blocks metabolism by monoamine oxidases (MAOs).[26] PPA is also not a substrate of catechol O-methyltransferase. The hydroxyl group at the β carbon of PPA also helps to increase metabolic stability.
Approximately 90% of a dose of PPA is excreted in the urine unchanged within 24hours. About 4% of excreted material is in the form of metabolites.
The elimination half-life of immediate-release PPA is about 4hours, with a range in different studies of 3.7 to 4.9hours.[27] The half-life of extended-release PPA has ranged from 4.3 to 5.8hours.
The elimination of PPA is dependent on urinary pH. At a more acidic urinary pH, the elimination of PPA is accelerated and its half-life and duration are shortened, whereas at more basic urinary pH, the elimination of PPA is reduced and its half-life and duration are extended. Urinary acidifying agents like ascorbic acid and ammonium chloride can increase the excretion of and thereby reduce exposure to amphetamines including PPA, whereas urinary alkalinizing agents including antacids like sodium bicarbonate as well as acetazolamide can reduce the excretion of these agents and thereby increase exposure to them.[28] [29]
Total body clearance of PPA has been reported to be 0.546L/h/kg, while renal clearance was 0.432L/h/kg.
As PPA is not extensively metabolized, it would probably not be affected by hepatic impairment. Conversely, there is likely to be accumulation of PPA with renal impairment due to its dependence on urinary excretion.
Norephedrine is a minor metabolite of amphetamine and methamphetamine, as shown below. It is also a minor metabolite of ephedrine and a major metabolite of cathinone.
PPA, also known as α-methyl-β-hydroxyphenethylamine or as β-hydroxyamphetamine, is a substituted phenethylamine and amphetamine derivative.[30] [31] It is closely related to the cathinones (β-ketoamphetamines). The compound exists as four stereoisomers, which include d- (dextrorotatory) and l-norephedrine (levorotatory), and d- and l-norpseudoephedrine. d-Norpseudoephedrine is also known as cathine, and is found naturally in Catha edulis (khat).[32] Pharmaceutical drug preparations of PPA have varied in their stereoisomer composition in different countries, which may explain differences in misuse and side effect profiles. In any case, racemic dl-norephedrine appears to be the most commonly used formulation pharmaceutically. Analogues of PPA include ephedrine, pseudoephedrine, amphetamine, methamphetamine, and cathinone.
PPA, 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 (the first carbon before the nitrogen group) also makes this compound a member of the substituted amphetamine class. Ephedrine is the N-methyl analogue of PPA.
Exogenous compounds in this family are degraded too rapidly by monoamine oxidase to be active at all but the highest doses. However, the addition of the α-methyl group allows the compound to avoid metabolism and confer an effect. In general, N-methylation of primary amines increases their potency, whereas β-hydroxylation decreases CNS activity, but conveys more selectivity for adrenergic receptors.[33]
PPA is a small-molecule compound with the molecular formula C9H13NO and a molecular weight of 151.21g/mol.[34] [35] 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,[36] but is also more hydrophilic than other amphetamines. The lipophilicity of amphetamines is closely related to their brain permeability.[37] For comparison to PPA, the experimental log P of methamphetamine is 2.1,[38] of amphetamine is 1.8,[39] of ephedrine is 1.1,[40] of pseudoephedrine is 0.7,[41] of phenylephrine is -0.3,[42] and of norepinephrine is -1.2.[43] Methamphetamine has high brain permeability, whereas phenylephrine and norepinephrine are peripherally selective drugs.[44] [45] The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7).[46]
PPA has been used pharmaceutically exclusively as the hydrochloride salt.
PPA was first synthesized in the early 20th century, in or around 1910.[47] It was patented as a mydriatic in 1913. The pressor effects of PPA were characterized in the late 1920s and the 1930s. PPA was first introduced for medical use by the 1930s.
In the United States, PPA is no longer sold due to an increased risk of haemorrhagic stroke.[48] In a few countries in Europe, however, it is still available either by prescription or sometimes over-the-counter. In Canada, it was withdrawn from the market on 31 May 2001.[49] It was voluntarily withdrawn from the Australian market by July 2001.[50] In India, human use of PPA and its formulations was banned on 10 February 2011,[51] but the ban was overturned by the judiciary in September 2011.[52]
Phenylpropanolamine is the generic name of the drug and its,, and, while phenylpropanolamine hydrochloride is its and in the case of the hydrochloride salt.[53] [54] [55] It is also known by the synonym norephedrine.
Brand names of PPA have included 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.[56] It has also been used in combinations under brand names including Allerest, Demazin, Dimetapp, and Sinarest, among others.
PPA remains available for medical and veterinary use in certain countries.
There has been interest in PPA as a performance-enhancing drug in exercise and sports.[57] However, clinical studies suggest that PPA is not effective in this regard.[58] PPA is not on the World Anti-Doping Agency (WADA) list of prohibited substances as of 2024.[59]
In Sweden, PPA is still available in prescription decongestants;[60] PPA is also still available in Germany. It is used in some polypill medications like Wick DayMed capsules.
In the United Kingdom, PPA was available in many "all in one" cough and cold medications which usually also feature paracetamol or another analgesic and caffeine and could also be purchased on its own; however, it is no longer approved for human use. 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[61] 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 and removed its "generally recognized as safe and effective" (GRASE) status.[62] Under the 2020 CARES Act, it requires FDA approval before it can be marketed again effectively banning the drug even as a prescription drug.[63]
Because of its potential use in amphetamine manufacture, PPA is controlled by the Combat Methamphetamine Epidemic Act of 2005. It is still available for veterinary use in dogs, however, as a treatment for urinary incontinence.
Internationally, an item on the agenda of the 2000 Commission on Narcotic Drugs session called for including the stereoisomer norephedrine in Table I of United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.[64]
Drugs containing PPA were banned in India on 27 January 2011.[65] On 13 September 2011, Madras High Court revoked a ban on manufacture and sale of pediatric drugs PPA and nimesulide.[66]
PPA remains available for use in veterinary medicine. It is used to control urinary incontinence in dogs.[67] [68]