Phenylpropanolamine

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Phenylpropanolamine
RS-Norephedrin
Ball-and-stick model of the phenylpropanolamine molecule
Clinical data
Trade namesMany[1][2]
AHFS/Drugs.comMultum Consumer Information
Pregnancy
category
  • AU: B2
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic (CYP2D6)
Elimination half-life2.1–3.4 hours
Identifiers
  • (1R,2S)-2-amino-1-phenylpropan-1-ol
JSmol)
  • O[C@H](c1ccccc1)[C@@H](N)C
  • InChI=1S/C9H13NO/c1-7(10)9(11)8-5-3-2-4-6-8/h2-7,9,11H,10H2,1H3/t7-,9-/m0/s1 checkY
  • Key:DLNKOYKMWOXYQA-CBAPKCEASA-N checkY
  (verify)

Phenylpropanolamine (PPA) is a

cough and cold preparations. In veterinary medicine, it is used to control urinary incontinence in dogs.[6][7]

Chemistry

Space filling model of phenylpropanolamine

PPA is also known as β-hydroxyamphetamine, and is a member of the

misuse and side effect profiles.[5] Analogues of PPA include ephedrine, pseudoephedrine, amphetamine, methamphetamine, and cathinone.[8]

PPA, structurally, is in the

alpha carbon (the first carbon before the nitrogen group) also makes this compound a member of the substituted amphetamine class.[11] 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.[11] However, the addition of the α-methyl group allows the compound to avoid metabolism and confer an effect.[11] In general, N-methylation of primary amines increases their potency, whereas β-hydroxylation decreases CNS activity, but conveys more selectivity for adrenergic receptors.[11]

History

Phenylpropanolamine was patented in 1938.

haemorrhagic stroke.[13] 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 In Canada, it was withdrawn from the market on 31 May 2001.[14] It was voluntarily withdrawn from the Australian market by July 2001.[15] In India, human use of PPA and its formulations was banned on 10 February 2011,[16] but the ban was overturned by the judiciary in September 2011.[17]

Pharmacology

Mechanism of action

Although originally thought to act as a direct

affinity for these receptors, and has been instead characterized as an indirect sympathomimetic[5] which acts by inducing norepinephrine release and thereby activating adrenergic receptors.[18]

Pharmacodynamics

PPA acts primarily as a

β-adrenergic receptors.[18]

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.[citation needed]

Activity profiles of isomers

PPA isomers, monoamine release (EC50, nM)[18][19]
Compound NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin
Norephedrine
  D-Norephedrine 42.1 302 >10000
  L-Norephedrine (phenylpropanolamine) 137 1371 >10000
Norpseudoephedrine
  D-Norpseudoephedrine (cathine) 15.0 68.3 >10000
  L-Norpseudoephedrine 30.1 294 >10000

Pharmacokinetics

Norephedrine is a metabolite of amphetamine, as shown below.

Metabolic pathways of amphetamine in humans[sources 1]
Graphic of several routes of amphetamine metabolism
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
The image above contains clickable links
In humans, norephedrine occurs as a metabolite of
dopamine β-hydroxylase
.

Drug interactions

Certain drugs increase the chances of

mesial temporal
areas of the brain.

Legal status

In Sweden, PPA is still available in prescription decongestants;[33] 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[34] 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.[35] Under the 2020 CARES Act, it requires FDA approval before it can be marketed again effectively banning the drug even as a prescription drug.[36]

Because of its potential use in amphetamine manufacture, phenylpropanolamine 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.[37]

Drugs containing PPA were banned in India on 27 January 2011.[38] On 13 September 2011, Madras High Court revoked a ban on manufacture and sale of pediatric drugs PPA and nimesulide.[39]

Notes

  1. ^ 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[21][26] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;[26][28] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[29][30]

Reference notes

  1. ^ [20][21][22][23][24][25][26][27]

References

  1. ^
    ISBN 978-3-88763-075-1
    .
  2. ^ "Phenylpropanolamine Uses, Side Effects & Warnings".
  3. ^ Anvisa (24 July 2023). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 25 July 2023). Archived from the original on 27 August 2023. Retrieved 27 August 2023.
  4. ^
    ISBN 978-1-4757-2085-3
    .
  5. ^
    ISBN 978-94-011-4439-1
    .
  6. ISBN 978-0-12-385927-3
    .
  7. ISBN 978-0-8138-2061-3
    .
  8. ^
    ISBN 978-0-7817-6879-5
    .
  9. ^
    ISBN 978-0-85404-178-7
    .
  10. S2CID 22816940
    .
  11. ^
    ISBN 9780071624428
    . CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP OF SYMPATHOMIMETIC AMINES
    β-Phenylethylamine (Table 12–1) can be viewed as the parent compound of the sympathomimetic amines, consisting of a benzene ring and an ethylamine side chain. The structure permits substitutions to be made on the aromatic ring, the α- and β-carbon atoms, and the terminal amino group to yield a variety of compounds with sympathomimetic activity. ...N-methylation increases the potency of primary amines ...
    Substitution on the α-Carbon Atom
    This substitution blocks oxidation by MAO, greatly prolonging the duration of action of non-catecholamines because their degradation depends largely on the action of this enzyme. The duration of action of drugs such as ephedrine or amphetamine is thus measured in hours rather than in minutes. Similarly, compounds with an α-methyl substituent persist in the nerve terminals and are more likely to release NE from storage sites. Agents such as metaraminol exhibit a greater degree of indirect sympathomimetic activity.
    Substitution on the β-Carbon Atom
    Substitution of a hydroxyl group on the β carbon generally decreases actions within the CNS, largely because it lowers lipid solubility. However, such substitution greatly enhances agonist activity at both α- and β- adrenergic receptors. Although ephedrine is less potent than methamphetamine as a central stimulant, it is more powerful in dilating bronchioles and increasing blood pressure and heart rate.
  12. ISBN 9783527607495
    .
  13. S2CID 211233331
    .
  14. ^ "Advisories, Warnings and Recalls – 2001". Health Canada. 7 January 2009. Archived from the original on 3 May 2010.
  15. ^ "Alert Phenylpropanolamine". Therapeutic Goods Administration. 7 March 2006. Retrieved 31 December 2018.
  16. ^ "Drugs Banned In India". Dte.GHS, Ministry of Health and Family Welfare, Government of India. Central Drugs Standard Control Organization. Archived from the original on 13 October 2013. Retrieved 7 January 2014.
  17. ^ "Madras High Court revokes ban on manufacture and sale of paediatric drugs nimesulide and PPA – India Medical Times".
  18. ^
    S2CID 19015584
    .
  19. PMID 17017961
    .
  20. ^ "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013.
  21. ^
    ISBN 9781609133450
    . The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
  22. PMID 4809526
    . Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
  23. PMID 15922018.
    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
  24. PMID 10027866
    .
  25. PMID 12191709
    .
  26. ^
    PMID 13977820
    . Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
  27. S2CID 23738007
    . Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
  28. S2CID 28641000
    . The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
  29. PMID 4457764
    . In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
    The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
  30. PMID 2600821
    . The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
  31. S2CID 6733989
    .
  32. PMID 8149215
    .
  33. ^ "Rinexin in Farmaceutiska Specialiteter i Sverige" ["Rinexin" from the Pharmaceutical Specialties of Sweden] (drug catalog) (in Swedish). Retrieved 7 January 2014.
  34. ^ "Phenylpopanolamine Advisory" (Press release). US Food and Drug Administration. 6 November 2000. Archived from the original on 26 January 2010.
  35. ^ "Phenylpropanolamine (PPA) Information Page – FDA moves PPA from OTC" (Press release). US Food and Drug Administration. 23 December 2005. Archived from the original on 12 January 2009.
  36. ^ Over-the-Counter (OTC) Drug Review | OTC Monograph Reform in the CARES Act
  37. ^ Implementation of the international drug control treaties: changes in the scope of control of substances. Vienna: Commission on Narcotic Drugs, Forty-third session. 6–15 March 2000. Archived from the original on 14 August 2003.
  38. ^ "Unsafe Drugs- nimesulide, Cisapride, Phenylpropanolamine Banned". 27 January 2011.
  39. ^ "Madras High Court Revokes Ban on Manufacture and Sale PPA". Scribd.com. 13 September 2011. Retrieved 7 January 2014.

External links

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