Phentermine

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Phentermine
Phentermine2DACS.svg
Phentermine3Dan.gif
Systematic (IUPAC) name
2-methyl-1-phenylpropan-2-amine
Clinical data
Trade namesAdipex-p, Duromine, Metermine, Suprenza
AHFS/Drugs.commonograph
MedlinePlusa682187
Pregnancy cat.B3 (AU) X (US)
Legal statusPrescription Only (S4) (AU) Schedule IV (US)
RoutesOral, Insufflation, Intravenous
Pharmacokinetic data
BioavailabilityHigh (almost complete)[1]
Protein bindingApproximately 96.3%
MetabolismHepatic[1]
Half-life25 hours, urinary pH-dependent[1]
ExcretionUrinary (62-85% unchanged)[1]
Identifiers
CAS number122-09-8 YesY
ATC codeA08AA01
PubChemCID 4771
DrugBankDB00191
ChemSpider4607 YesY
UNIIC045TQL4WP YesY
KEGGD05458 YesY
ChEBICHEBI:8080 YesY
ChEMBLCHEMBL1574 YesY
Synonymsα-methyl-amphetamine
α,α-dimethylphenethylamine
Chemical data
FormulaC10H15N 
Mol. mass149.233 g/mol
 YesY (what is this?)  (verify)
 
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Phentermine
Phentermine2DACS.svg
Phentermine3Dan.gif
Systematic (IUPAC) name
2-methyl-1-phenylpropan-2-amine
Clinical data
Trade namesAdipex-p, Duromine, Metermine, Suprenza
AHFS/Drugs.commonograph
MedlinePlusa682187
Pregnancy cat.B3 (AU) X (US)
Legal statusPrescription Only (S4) (AU) Schedule IV (US)
RoutesOral, Insufflation, Intravenous
Pharmacokinetic data
BioavailabilityHigh (almost complete)[1]
Protein bindingApproximately 96.3%
MetabolismHepatic[1]
Half-life25 hours, urinary pH-dependent[1]
ExcretionUrinary (62-85% unchanged)[1]
Identifiers
CAS number122-09-8 YesY
ATC codeA08AA01
PubChemCID 4771
DrugBankDB00191
ChemSpider4607 YesY
UNIIC045TQL4WP YesY
KEGGD05458 YesY
ChEBICHEBI:8080 YesY
ChEMBLCHEMBL1574 YesY
Synonymsα-methyl-amphetamine
α,α-dimethylphenethylamine
Chemical data
FormulaC10H15N 
Mol. mass149.233 g/mol
 YesY (what is this?)  (verify)

Phentermine, a contraction of "phenyl-tertiary-butylamine", is a psychostimulant drug of the phenethylamine class, with pharmacology similar to amphetamine. It is used medically as an appetite suppressant.

It is approved as an appetite suppressant to help reduce weight in obese patients when used short-term and combined with exercise, diet, and behavioral modification. It is typically prescribed for individuals who are at increased medical risk due to their weight.

Medical uses[edit]

Phentermine is used for the short-term treatment of obesity.[2]

Adverse effects[edit]

Generally, phentermine appears to be relatively well tolerated.[3]

Adverse effects by incidence[1][4][5][6]

Common (>1% incidence) adverse effects include:

Rare (<1% incidence) adverse effects include:


Cautions[edit]

Phentermine use is contraindicated in those who are:[5][6]

Medicines which may interact with phentermine, such as dexfenfluramine, fenfluramine, furazolidone, or MAOIs (e.g., phenelzine) are contraindicated because of the risk of serious side effects, such as increasing headache, high blood pressure, slow heart rate, elevated temperature, or possibly fatal lung problems, may be increased. Guanadrel (Hylorel) or guanethidine (Ismelin) effectiveness may be decreased by phentermine. Antacids may decrease the excretion of phentermine.[7] Carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide, methazolamide) may decrease the excretion of phentermine.[7]

Mechanism of action[edit]

Phentermine.jpg

Phentermine has some similarity in its pharmacodynamics with its parent compound, amphetamine, as they both are TAAR1 agonists.[8] Phentermine works on the hypothalamus portion of the brain to stimulate the adrenal glands to release norepinephrine, a neurotransmitter or chemical messenger that signals a fight-or-flight response, reducing hunger. Phentermine works outside the brain, as well, to release epinephrine or adrenaline, causing fat cells to break down stored fat, but the principal basis of efficacy is hunger-reduction. At clinically relevant doses, phentermine also releases serotonin and dopamine, but to a much lesser extent than that of norepinephrine.[9]

Dosing and administration[edit]

Generally, it is recommended by the U.S. Food and Drug Administration (FDA) that phentermine should be used only for short-term (usually interpreted as 'up to 12 weeks'), while following nonpharmacological approaches to weight loss such as healthy dieting and exercise.[10]

History[edit]

In 1959, phentermine first received approval from the FDA as an appetite-suppressing drug. Phentermine hydrochloride then became available in the early 1970s. It was previously sold as Fastin from King Pharmaceuticals for SmithKline Beecham, but in 1998, it was removed from the market. Medeva Pharmaceuticals sells the name brand of phentermine called Ionamin and Gate Pharmaceuticals sells it as Adipex-P. Phentermine is also currently sold as a generic. Since the drug was approved, almost no clinical studies have been performed.

Phentermine was marketed with fenfluramine as a combination appetite suppressant and fat burning agent under the popular name Fen-Phen. In 1997, after 24 cases of heart valve disease in Fen-Phen users, fenfluramine and dexfenfluramine were voluntarily taken off the market at the request of the FDA.[11] Studies later proved nearly 30% of people taking fenfluramine or dexfenfluramine had abnormal valve findings.

Phentermine is still available by itself in most countries, including the US. However, because it is similar to amphetamines, it is classified as a controlled substance in many countries. Internationally, phentermine is a schedule IV drug under the Convention on Psychotropic Substances.[12] In the United States, it is classified as a Schedule IV controlled substance under the Controlled Substances Act. In contrast, amphetamine preparations are classified as Schedule II controlled substances.

Phentermine is being studied in combination with other medications for obesity. The first such combination is the appetite suppressant phentermine/topiramate (Qsymia formerly Qnexa). In 2012, the FDA approved its sale in the United States.[13]

Trade names[edit]

  • Adipex P (immediate release)
  • Adiphene (India)
  • Anoxine-AM
  • Ionamin (slow-release resin, Australia, discontinued in the US)
  • Duromine (slow-release resin, New Zealand, Australia and South Africa)
  • Metermine (slow-release resin, Australia)
  • Mirapront
  • Obephen
  • Obermine
  • Obestin-30
  • Phentermaxx
  • Phentrol
  • Phenterex
  • Phentromin
  • Pro-Fast SA
  • Qsymia (with topiramate)
  • Razin (Israel)
  • Redusa
  • Panbesy
  • Phentermine Trenker
  • Obenix
  • Oby-Trim
  • Teramine
  • Zantryl
  • Sinpet (MX)
  • Supremin (PH)
  • Suprenza (orally disintegrating tablet)
  • Umine (NZ)
  • Weltmine (KP)

Chemistry[edit]

  1. Benzaldehyde and 2-nitropropane are cross-reacted in a variant of the Henry reaction
  2. The nitro group is reduced with hydrogen gas over Raney nickel catalyst.
  3. The hydroxyl group is chlorinated with thionyl chloride to yield 2-amino-1-chloro-2-methyl-1-phenylpropane.
  4. This is reduced with hydrogen gas over a palladium on magnesium glycinate catalyst to yield the product, phentermine.[14][15]

References[edit]

  1. ^ a b c d e "METERMINE (Phentermine)" (PDF). TGA eBusiness Services. iNova Pharmaceuticals (Australia) Pty Limited. 22 July 2013. Retrieved 16 November 2013. 
  2. ^ "phentermine". The American Society of Health-System Pharmacists. Retrieved 3 April 2011. 
  3. ^ Nelson DL, Gehlert DR (February 2006). "Central nervous system biogenic amine targets for control of appetite and energy expenditure". Endocrine 29 (1): 49–60. doi:10.1385/ENDO:29:1:149. PMID 16622292. 
  4. ^ "ADIPEX-P (phentermine hydrochloride) tablet ADIPEX-P (phentermine hydrochloride) capsule [Teva Select Brands]". DailyMed. Teva Select Brands. April 2013. Retrieved 16 November 2013. 
  5. ^ a b Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  6. ^ a b "phentermine (Rx) - Adipex P, Suprenza". Medscape Reference. WebMD. Retrieved 17 November 2013. 
  7. ^ a b "Phentermine". Merck & Co., Inc. 2008. Retrieved 2008-05-15.  Unknown parameter |unused_data= ignored (help)
  8. ^ Barak LS, Salahpour A, Zhang X, Masri B, Sotnikova TD, Ramsey AJ, Violin JD, Lefkowitz RJ, Caron MG, Gainetdinov RR (September 2008). "Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor". Mol. Pharmacol. 74 (3): 585–94. doi:10.1124/mol.108.048884. PMC 3766527. PMID 18524885. "we confirmed agonistic activity at human TAAR1 of several other compounds, including the trace amines octopamine and tryptamine, the amphetamine derivatives l-amphetamine, d-methamphetamine, (�)-MDMA, and phentermine, and the catecholamine metabolites 3-MT and 4-MT (Bunzow et al., 2001; Lindemann and Hoener, 2005; Reese et al., 2007; Wainscott et al., 2007; Wolinsky et al., 2007; Xie and Miller, 2007; Xie et al., 2007)." 
  9. ^ Rothman RB, Baumann MH, Dersch CM, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they dopamine and serotonin". Synapse 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  10. ^ "HEALTH ADVISORY ON FENFLURAMINE/PHENTERMINE FOR OBESITY". Archived from the original on 30 May 2009. Retrieved 30 May 2009. 
  11. ^ "FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)". Fda.gov. Retrieved 2013-07-12. 
  12. ^ Convention on Psychotropic Substances (PDF file)
  13. ^ "FDA approves weight-management drug Qsymia". FDA. July 17, 2012. 
  14. ^ U.S. Patent 2,408,345
  15. ^ U.S. Patent 2,590,079

External links[edit]