Phentermine

Phentermine
Clinical data
Trade names Adipex-p, Duromine, Metermine, Suprenza
AHFS/Drugs.com Monograph
MedlinePlus a682187
License data
Pregnancy
category
  • AU: B3
  • US: X (Contraindicated)
Dependence
liability		 Low
Addiction
liability		 Very low
Routes of
administration		 by mouth
ATC code A08AA01 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability High (almost complete)[1]
Protein binding Approximately 96.3%
Metabolism Hepatic[1]
Biological half-life 25 hours, urinary pH-dependent[1]
Excretion Urinary (62–85% unchanged)[1]
Identifiers
Synonyms α-methyl-amphetamine
α,α-dimethylphenethylamine
CAS Number 122-09-8 YesY
PubChem (CID) 4771
IUPHAR/BPS 7269
DrugBank DB00191 YesY
ChemSpider 4607 YesY
UNII C045TQL4WP YesY
KEGG D05458 YesY
ChEBI CHEBI:8080 YesY
ChEMBL CHEMBL1574 YesY
ECHA InfoCard 100.004.112
Chemical and physical data
Formula C10H15N
Molar mass 149.233 g/mol
3D model (Jmol) Interactive image
  (verify)

Phentermine (α,α-Dimethylphenethylamine), a contraction of "phenyl-tertiary-butylamine", is a psychostimulant drug of the substituted amphetamine chemical class, with pharmacology similar to amphetamine. It is used medically as an appetite suppressant for short term use, as an adjunct to exercise and reducing calorie intake.

It has cardiovascular, gastrointestinal, and CNS side effects; rare cases of pulmonary hypertension and cardiac valvular disease have been reported. It should not be used by people who have a history of drug abuse, have any cardiovascular disease, hyperthyroidism, glaucoma, peptic ulcers, prostatic hypertrophy, or epilepsy, or are pregnant, planning to become pregnant, or breast-feeding. It should not be taken by anyone taking a monoamine oxidase inhibitor, and people should not drink alcohol while they are taking it.

It was first introduced in 1959, and became part of the drug combination Fen-phen that was withdrawn from the market in 1997 due to the fenfluramine component damaging people's heart valves. In 2012 a different combination drug, phentermine/topiramate was approved in the US.

There are various formulations phentermine as a single agent available under many brand names, in many countries.[2]

Medical uses

Phentermine is used for a short period time to promote weight loss, if exercise and calorie reduction are not sufficient, and in addition to exercise and calorie reduction.[1][3]

There is no evidence that phentermine is safe for women who are pregnant.[1][3]

Contraindications

Phentermine use is contraindicated in those who:[3]

People taking phentermine should not drink alcohol as it can increase the CNS side effects.[3]

Phentermine may prevent drugs like clonidine, methyldopa, and guanethidine from having any effect. Drugs to treat hypothyroidism may increase the effect of phentermine.[3]

Adverse effects

Rare cases of pulmonary hypertension and cardiac valvular disease have been reported.[3] The appetite-suppressing effect usually wears out after a few weeks as the person taking it develops drug tolerance; there is also a risk of addiction. People taking phentermine may be impaired when driving or operating machinery.[3]

Other adverse effects include:[1][3]

Mechanism of action

Phentermine has some similarity in its pharmacodynamics with its parent compound, amphetamine, as they both are TAAR1 agonists,[4] where the activation of TAAR1 in monoamine neurons facilitates the efflux or, release into the synapse, of these neurochemicals; at clinically relevant doses, phentermine primarily acts as a releasing agent of norepinephrine in neurons, although, to a lesser extent, it releases dopamine and serotonin into synapses as well.[5] Phentermine may also trigger the release of monoamines from VMAT2, which is a common pharmacodynamic effect among substituted amphetamines. The primary mechanism of phentermine's action in treating obesity is the reduction of hunger perception, which is a cognitive process mediated primarily through several nuclei within the hypothalamus (in particular, the lateral hypothalamic nucleus, arcuate nucleus, and ventromedial nucleus). Outside the brain, phentermine releases norepinephrine and epinephrine – also known as noradrenaline and adrenaline respectively – causing fat cells to break down stored fat as well.

History

Amphetamine was used as a treatment for obesity when it was introduced in 1938, and from the 1940's to the 1960s was prescribed in combination with thyroid hormone, digitalis, and diuretics as “Rainbow Pills”; however this approach caused addiction, hypertension, severe heart toxicity, and death.[6]

In 1959, phentermine first received approval from the United States FDA as an appetite-suppressing drug.[7] Aminorex, a drug similar to amphetamine was introduced in Europe in 1965 but was withdrawn in 1968 because it caused chronic pulmonary hypertension; about 50% of the people in whom it caused pulmonary hypertension died of the adverse affect.[6]

Eventually a hydrocholide salt and a resin form became available.[7]

Phentermine was marketed with fenfluramine or dexfenfluramine 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.[8] Studies later showed nearly 30% of people taking fenfluramine or dexfenfluramine for up to 24 months had abnormal valve findings.[6]

Phentermine is still available by itself in most countries, including the US.[7] However, because it is similar to amphetamine, it is classified as a controlled substance in many countries. Internationally, phentermine is a schedule IV drug under the Convention on Psychotropic Substances.[9] 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.[10]

A company called Vivus developed a combination drug, phentermine/topiramate that it originally called Qnexa and then called Qsymia, which was invented and used off-label by Thomas Najarian, who opened a weight-clinic in Los Osos, California in 2001; Najarian had previously worked at Interneuron Pharmaceuticals, which had developed one of the fen-phen drugs previously withdrawn from the market.[11] The FDA rejected the combination drug in 2010 due to concerns over its safety.[11] In 2012 the FDA approved it after Vivus re-applied with further safety data.[12] At the time, one obesity specialist estimated that around 70% of his colleagues were already prescribing the combination off-label.[11]

Chemistry

Synthesis

Phentermine can be produced from benzaldehyde and 2-nitropropane as follows:[13][14]

  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

Society and culture

Brands

Phentermine is marketed under many brand names and formulations worldwide, including Acxion, Adipex, Duromine, Elvenir, Fentermina , Fentermina (Spanish), Osymia (Phentermine and Topiramate), Panbesy, Phentermin (German), Phentermine (French), Qsymia (Phentermine and Topiramate), Razin, Redusa, Sentis, Suprenza, and Terfamex.[2]

See also

References

  1. 1 2 3 4 5 6 7 "METERMINE (Phentermine)" (PDF). TGA eBusiness Services. iNova Pharmaceuticals (Australia) Pty Limited. 22 July 2013. Retrieved 16 November 2013.
  2. 1 2 "International brands for phentermine". Drugs.com. Retrieved 13 October 2016.
  3. 1 2 3 4 5 6 7 8 "Phentermine label at FDA" (Last updated: January 2012). FDA. Retrieved 13 October 2016.
  4. ↑ 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 3766527Freely accessible. 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).
  5. ↑ 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.
  6. 1 2 3 Weigle, DS (June 2003). "Pharmacological therapy of obesity: past, present, and future.". The Journal of clinical endocrinology and metabolism. 88 (6): 2462–9. PMID 12788841.
  7. 1 2 3 Ryan, Donna A.; Bray, George A. (2014). "Sibutramine, Phentermine, and Diethylproprion: Sympathomimetic Drugs in the Management of Obesity". In Bray, George A.; Bouchard, Claude. Handbook of Obesity - Volume 2 Clinical Applications, Fourth Edition. (4th ed. ed.). Hoboken: Taylor and Francis. p. 234. ISBN 9781841849829.
  8. ↑ "FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)". Fda.gov. Retrieved 12 July 2013.
  9. ↑ Convention on Psychotropic Substances (PDF file)
  10. ↑ Rueda-Clausen, CF; Padwal, RS; Sharma, AM (August 2013). "New pharmacological approaches for obesity management.". Nature reviews. Endocrinology. 9 (8): 467–78. PMID 23752772.
  11. 1 2 3 Pollack, Andrew (16 February 2012). "Diet Treatment, Already in Use, to Get F.D.A. Review". The New York Times.
  12. ↑ "FDA approves weight-management drug Qsymia". FDA. 17 July 2012.
  13. ↑ U.S. Patent 2,408,345
  14. ↑ U.S. Patent 2,590,079
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