Phentermine

Last updated

Phentermine
Fentermina.svg
Phentermine-3d-CPK.png
Clinical data
Trade names Adipex-p, Duromine, Metermine, Suprenza, others
Other namesα-methyl-amphetamine
α,α-dimethylphenethylamine
AHFS/Drugs.com Monograph
MedlinePlus a682187
License data
Pregnancy
category
  • AU:B3
Dependence
liability 		Limited [1]
Addiction
liability 		Low [2]
Routes of
administration 		By mouth
Drug class Appetite suppressant [3]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability High (almost complete) [5]
Protein binding Approximately 96.3%
Metabolism Liver [5]
Elimination half-life 25 hours, urinary pH-dependent [5]
Excretion Urinary (62–85% unchanged) [5]
Identifiers
  • 2-methyl-1-phenylpropan-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.004.112 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H15N
Molar mass 149.237 g·mol−1
3D model (JSmol)
  • NC(Cc1ccccc1)(C)C
  • InChI=1S/C10H15N/c1-10(2,11)8-9-6-4-3-5-7-9/h3-7H,8,11H2,1-2H3 Yes check.svgY
  • Key:DHHVAGZRUROJKS-UHFFFAOYSA-N Yes check.svgY
   (verify)

Phentermine (phenyl-tertiary-butyl amine), with several brand names including Ionamin and Sentis, is a medication used together with diet and exercise to treat obesity. [3] It is taken by mouth for up to a few weeks at a time, after which the benefits subside. [3] It is also available as the combination phentermine/topiramate. [6]

Contents

Common side effects include a fast heart beat, high blood pressure, trouble sleeping, dizziness, and restlessness. [3] Serious side effects may include abuse, but do not include pulmonary hypertension or valvular heart disease, as the latter were caused by the fenfluramine component of the fen-phen drug combination. [3] Use is not recommended during pregnancy or breastfeeding, [7] or with SSRIs or MAO inhibitors. [3] It works mainly as an appetite suppressant, likely as a result of being a CNS stimulant. [3] Chemically, phentermine is a substituted amphetamine. [8]

Phentermine was approved for medical use in the United States in 1959. [3] It is available as a generic medication. [3] In 2020, it was the 181st most commonly prescribed medication in the United States, with more than 3 million prescriptions. [9] [10] Phentermine was withdrawn from the market in the United Kingdom in 2000, while the combination medication fen-phen, of which it was a part, was withdrawn from the market in 1997 due to side effects [11] of fenfluramine which caused increased levels of circulating serotonin which stimulated serotonin receptors on heart valves and thus causing valve insufficiency and leading to primary pulmonary hypertension (PPH). According to the NIH (National Institutes of Health) there is no evidence that phentermine causes PPH.[ citation needed ]

Medical uses

Phentermine is used for a short period of time to promote weight loss, if exercise and calorie reduction are not sufficient, and in addition to exercise and calorie reduction. [5] [12]

Phentermine is approved for up to 12 weeks of use and most weight loss occurs in the first weeks. [12] However, significant loss continues through the sixth month and has been shown to continue at a slower rate through the ninth month. [13]

Contraindications

Phentermine is contraindicated for users who: [5] [12]

Adverse effects

Tolerance usually occurs; however, risks of dependence and addiction are considered negligible. [13] [14] People taking phentermine may be impaired when driving or operating machinery. [12] Consumption of alcohol with phentermine may produce adverse effects. [12]

There is currently no evidence regarding whether or not phentermine is safe for pregnant women. [5] [12]

Other adverse effects include: [5] [12]

Interactions

Phentermine may decrease the effect of drugs like clonidine, methyldopa, and guanethidine. Drugs to treat hypothyroidism may increase the effect of phentermine. [12]

Mechanism of action

Phentermine.jpg

Phentermine has some similarity in its pharmacodynamics with its parent compound, amphetamine, as they both are TAAR1 agonists, [15] 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. [14] [16] 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

In 1959, phentermine first received approval from the United States FDA as an appetite-suppressing drug. [17] Eventually a hydrochloride salt and a resin form became available. [17]

Phentermine was marketed with fenfluramine or dexfenfluramine as a combination appetite suppressant and fat burning agent under the popular name fen-phen. [18] 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. [19] Studies later showed nearly 30% of people taking fenfluramine or dexfenfluramine for up to 24 months had abnormal valve findings. [20]

Phentermine is still available by itself in most countries, including the US. [17] 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. [21] 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. [22]

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. [23] The FDA rejected the combination drug in 2010 due to concerns over its safety. [23] In 2012 the FDA approved it after Vivus re-applied with further safety data. [24] At the time, one obesity specialist estimated that around 70% of his colleagues were already prescribing the combination off-label. [23]

Chemistry

Phentermine is a substituted amphetamine which has a methyl group on amphetamine's alpha carbon. [8] It is a positional isomer of methamphetamine and other methylamphetamines. The molecular formula of phentermine is C 10 H 15 N .

Names

Phentermine is contracted from phenyl-tertiary-butyl amine.

It is marketed under many brand names and formulations worldwide, including Acxion, Adipex, Adipex-P, Duromine, Elvenir, Fastin, Ionamin, Lomaira (phentermine hydrochloride), Panbesy, Qsymia (phentermine and topiramate), Razin, Redusa, Sentis, Suprenza, and Terfamex. [25]

Related Research Articles

<span class="mw-page-title-main">Amphetamine</span> Central nervous system stimulant

Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.

<span class="mw-page-title-main">Tranylcypromine</span> Irreversible non-selective MAO inhibitor Antidepressant drug

Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.

<span class="mw-page-title-main">Fenfluramine/phentermine</span> Drug combination prescribed for weight loss; later withdrawn from market

The drug combination fenfluramine/phentermine, usually called fen-phen, was an anti-obesity treatment in the early 1990s that utilized two anorectics. Fenfluramine was marketed by American Home Products as Pondimin, but was shown to cause potentially fatal pulmonary hypertension and heart valve problems, which eventually led to its withdrawal in 1997 and legal damages of over $13 billion. Phentermine was not shown to have harmful effects.

An anorectic or anorexic is a drug which 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 desire to eat. The understanding of anorexiant effects is crucial in the development of interventions for weight management, eating disorders, and related health concerns. The anorexiant effect can be induced through diverse mechanisms, ranging from hormonal regulation to neural signaling. Ghrelin, leptin, and peptide YY are among the hormones involved in appetite control. Additionally, neurotransmitters such as serotonin and dopamine in the central nervous system contribute significantly to the regulation of food intake.

<span class="mw-page-title-main">Adderall</span> Drug mixture used mainly to treat ADHD and narcolepsy

Adderall and Mydayis are trade names for a combination drug called mixed amphetamine salts containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.

<span class="mw-page-title-main">Fenfluramine</span> Medication used to treat seizures

Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications. Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

<span class="mw-page-title-main">Sibutramine</span> Appetite suppressant

Sibutramine, formerly sold under the brand name Meridia among others, is an appetite suppressant which has been discontinued in many countries. It works as a serotonin–norepinephrine reuptake inhibitor similar to a tricyclic antidepressant. Until 2010, it was widely marketed and prescribed as an adjunct in the treatment of obesity along with diet and exercise. It has been associated with increased cardiovascular diseases and strokes and has been withdrawn from the market in 2010 in several countries and regions including Australia, Canada, China, the European Union, Hong Kong, India, Mexico, New Zealand, the Philippines, Thailand, the United Kingdom, and the United States. However, the drug remains available in some countries.

<span class="mw-page-title-main">Levomethamphetamine</span> Nasal decongestant and optical isomer of methamphetamine

Levomethamphetamine is the levorotatory (L-enantiomer) form of methamphetamine. Levomethamphetamine is a sympathomimetic vasoconstrictor that is the active ingredient in some over-the-counter (OTC) nasal decongestant inhalers in the United States.

<span class="mw-page-title-main">Dexfenfluramine</span> Serotonergic anorectic medication

Dexfenfluramine, marketed as dexfenfluramine hydrochloride under the name Redux, is a serotonergic anorectic drug: it reduces appetite by increasing the amount of extracellular serotonin in the brain. It is the d-enantiomer of fenfluramine and is structurally similar to amphetamine, but lacks any psychologically stimulating effects.

<span class="mw-page-title-main">Chlorphentermine</span> Weight loss medication

Chlorphentermine is a serotonergic appetite suppressant of the amphetamine family. Developed in 1962, it is the 4-chloro derivative of the better known appetite suppressant phentermine, which is still in current use.

<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane (PAL-287) is an experimental drug under investigation as of 2007 for the treatment of alcohol and stimulant addiction.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons.

<span class="mw-page-title-main">Norepinephrine releasing agent</span> Catecholaminergic type of drug

A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into the synapse. This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine therefore an increase in adrenergic neurotransmission.

<span class="mw-page-title-main">Serotonin–norepinephrine releasing agent</span> Drug class

A serotonin–norepinephrine releasing agent (SNRA) is a type of drug which induces the release of serotonin and norepinephrine in the body and/or brain.

<span class="mw-page-title-main">Norepinephrine–dopamine reuptake inhibitor</span> Drug that inhibits the reuptake of norepinephrine and dopamine

A norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson's disease. The drug acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.

<span class="mw-page-title-main">Phentermine/topiramate</span> Obesity medication

Phentermine/topiramate, sold under the brand name Qsymia, is a combination drug of phentermine and topiramate used to treat obesity. It is used together with dietary changes and exercise. If less than 3% weight loss is seen after 3 months it is recommended the medication be stopped. The weight loss is modest. Effects on heart related health problems or death is unclear.

<span class="mw-page-title-main">Levofenfluramine</span> Non-marketed drug of the amphetamine class

Levofenfluramine (INN), or (−)-3-trifluoromethyl-N-ethylamphetamine, also known as (−)-fenfluramine or (R)-fenfluramine, is a drug of the amphetamine family that, itself (i.e., in enantiopure form), was never marketed. It is the levorotatory enantiomer of fenfluramine, the racemic form of the compound, whereas the dextrorotatory enantiomer is dexfenfluramine. Both fenfluramine and dexfenfluramine are anorectic agents that have been used clinically in the treatment of obesity (and hence, levofenfluramine has been as well since it is a component of fenfluramine). However, they have since been discontinued due to reports of causing cardiovascular conditions such as valvular heart disease and pulmonary hypertension, adverse effects that are likely to be caused by excessive stimulation of 5-HT2B receptors expressed on heart valves.

5-HT2C receptor agonists are a class of drugs that activate 5-HT2C receptors. They have been investigated for the treatment of a number of conditions including obesity, psychiatric disorders, sexual dysfunction and urinary incontinence.

References

  1. ↑ Tarascon Pocket Pharmacopoeia 2017 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2016. p. 7. ISBN   9781284118971.
  2. ↑ Sadock BJ, Sadock VA (2010). Kaplan and Sadock's Pocket Handbook of Clinical Psychiatry. Lippincott Williams & Wilkins. p. 435. ISBN   9781605472645.
  3. 1 2 3 4 5 6 7 8 9 "Phentermine Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 13 April 2019.
  4. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  5. 1 2 3 4 5 6 7 8 "METERMINE (Phentermine)" (PDF). TGA eBusiness Services. iNova Pharmaceuticals (Australia) Pty Limited. 22 July 2013. Retrieved 16 November 2013.
  6. ↑ "Phentermine and topiramate Uses, Side Effects & Warnings". Drugs.com. Retrieved 13 April 2019.
  7. ↑ "Phentermine Use During Pregnancy". Drugs.com. Retrieved 13 April 2019.
  8. 1 2 Hagel JM, Krizevski R, Marsolais F, Lewinsohn E, Facchini PJ (July 2012). "Biosynthesis of amphetamine analogs in plants". Trends in Plant Science. 17 (7): 404–412. doi:10.1016/j.tplants.2012.03.004. PMID   22502775.
  9. ↑ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  10. ↑ "Phentermine - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  11. ↑ Bagchi D, Preuss HG (2012). Obesity: Epidemiology, Pathophysiology, and Prevention (Second ed.). CRC Press. p. 314. ISBN   9781439854259.
  12. 1 2 3 4 5 6 7 8 "Phentermine label at FDA" (Last updated: January 2012). FDA. Retrieved 13 October 2016.
  13. 1 2 Glazer G (August 2001). "Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety". Archives of Internal Medicine. 161 (15): 1814–1824. doi: 10.1001/archinte.161.15.1814 . PMID   11493122.
  14. 1 2 Haslam D (March 2016). "Weight management in obesity - past and present". International Journal of Clinical Practice. 70 (3): 206–217. doi:10.1111/ijcp.12771. PMC   4832440 . PMID   26811245.
  15. ↑ Barak LS, Salahpour A, Zhang X, Masri B, Sotnikova TD, Ramsey AJ, et al. (September 2008). "Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor". Molecular Pharmacology. 74 (3): 585–594. 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).
  16. ↑ Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release 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. S2CID   15573624.
  17. 1 2 3 Ryan DA, Bray GA (2014). "Sibutramine, Phentermine, and Diethylproprion: Sympathomimetic Drugs in the Management of Obesity". In Bray GA, Bouchard C (eds.). Handbook of Obesity - Volume 2 Clinical Applications (Fourth ed.). Hoboken: Taylor and Francis. p. 234. ISBN   9781841849829.
  18. ↑ Kolata, Gina (23 September 1997). "How Fen-Phen, A Diet 'Miracle,' Rose and Fell". New York Times. NY, NY, USA.
  19. ↑ "FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)". Fda.gov. Retrieved 12 July 2013.
  20. ↑ Weigle DS (June 2003). "Pharmacological therapy of obesity: past, present, and future". The Journal of Clinical Endocrinology and Metabolism. 88 (6): 2462–2469. doi: 10.1210/jc.2003-030151 . PMID   12788841.
  21. ↑ Convention on Psychotropic Substances Archived 14 March 2014 at the Wayback Machine
  22. ↑ Rueda-Clausen CF, Padwal RS, Sharma AM (August 2013). "New pharmacological approaches for obesity management". Nature Reviews. Endocrinology. 9 (8): 467–478. doi:10.1038/nrendo.2013.113. PMID   23752772. S2CID   20072687.
  23. 1 2 3 Pollack A (16 February 2012). "Diet Treatment, Already in Use, to Get F.D.A. Review". The New York Times.
  24. ↑ "FDA approves weight-management drug Qsymia". FDA. 17 July 2012.
  25. ↑ "International brands for phentermine". Drugs.com. Retrieved 13 October 2016.
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