Phentermine

Effects

Overview

Psychostimulant of the substituted amphetamine class. The drug is used medically as an appetite suppressant. PW

Psychostimulant of the substituted amphetamine class. Used in medicine as an appetite suppressant. TS

Phentermine, sold under the brand name Adipex-P among others, is a medication used together with diet and exercise to treat obesity. It is available by itself or as the combination phentermine/topiramate. Phentermine is taken by mouth.[1][2] WP

Common side effects include a fast heart beat, high blood pressure, trouble sleeping, dizziness, and restlessness. Serious side effects may include abuse, but do not include pulmonary hypertension or valvular heart disease, as the latter complications were caused by the fenfluramine component of the "fen-phen" combination. Phentermine is a norepinephrine and dopamine releasing agent (NDRA) and produces stimulant, rewarding, and appetite suppressant effects. Chemically, it is a substituted amphetamine.[1][3–6] WP

Phentermine was approved for medical use in the United States in 1959. It is available as a generic medication. In 2023, it was the 168th most commonly prescribed medication in the United States, with more than 3 million prescriptions. Phentermine was withdrawn from the market in the United Kingdom in 2000, while the combination medication fen-phen, of which it was a part, was withdrawn from the market in 1997, due to side effects of fenfluramine.[1][7][8][9] WP

History

History

In 1959, phentermine first received approval from the US Food and Drug Administration (FDA) as an appetite suppressant. Eventually a hydrochloride salt and a resin form became available.[10] WP

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. Studies later showed nearly 30% of people taking fenfluramine or dexfenfluramine for up to 24 months had abnormal valve findings.[11][12][13] WP

Phentermine is still available by itself in most countries, including the US. 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. 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][14][15] WP

The company 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. The FDA rejected the combination drug in 2010 due to concerns over its safety. In 2012, the FDA approved Qsymia after Vivus re-applied with further safety data. At the time, one obesity specialist estimated that around 70% of his colleagues were already prescribing the combination off-label.[16][17][18] WP

Legal status

• History and legal status PW
• Phentermine was first approved by the FDA in 1959 as an appetite suppressant. It gained widespread popularity in the 1990s as part of the combination known as "Fen-Phen" (along with fenfluramine), which was withdrawn from the market in 1997 due to fenfluramine causing heart valve problems. Phentermine by itself was not associated with those serious effects and continues to be available in countries like the United States. PW
• Internationally, phentermine is classified as a Schedule IV substance under the Convention on Psychotropic Substances. In the United States, it is a Schedule IV controlled substance under the Controlled Substances Act, indicating a potential for abuse lower than substances in Schedules I, II, and III, but still significant. It is not marketed in many European countries, including the United Kingdom, where it was withdrawn in 2000. PW
• United States: Schedule IV prescription medication PW
• Most countries: Prescription-only, regulated stimulant PW
• Legal status varies by country. PW

Etymology

The term phentermine is contracted from phenyl-tertiary-butyl amine. WP

Brand names

Phentermine is sold 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.[19] WP

Pharmacology

Monoamine releasing agent

Phentermine is a substrate of the monoamine transporters (MATs) and acts as a monoamine releasing agent (MRA), specifically as a norepinephrine–dopamine releasing agent (NDRA). It also acts as a norepinephrine–dopamine reuptake inhibitor (NDRI) to a lesser extent. The drug robustly and dose-dependently elevates brain norepinephrine and dopamine levels in animals. Phentermine is more potent in its effects on norepinephrine than on dopamine and the drug shows only weak effects on serotonin. Unlike many other amphetamines and MRAs, phentermine is completely inactive at the vesicular monoamine transporter 2 (VMAT2). Due to its actions on the catecholamines, phentermine produces effects including stimulation, rewarding effects, appetite suppression, and sympathomimetic effects in animals and humans.[3][4][5][20][21] WP

In terms of monoamine release in vitro using rat brain synaptosomes, phentermine is about 6-fold less potent than dextroamphetamine in the case of norepinephrine release, 11-fold less potent than dextroamphetamine in the case of dopamine release, and has a ratio of norepinephrine release versus dopamine release of about 6.6:1 compared to dextroamphetamine's ratio of about 3.5:1. It is more than 3-fold less potent than amphetamine in elevating brain dopamine and serotonin levels in rodents in vivo, is about 10-fold less potent than amphetamine in terms of self-administration in monkeys, and is a relatively weak reinforcer in rodents. Although phentermine induces the release of dopamine at sufficiently high concentrations in vitro and at sufficiently high doses in rodents and monkeys in vivo, it may result in only weak or negligible brain dopamine release in humans at typical clinical doses. This may be due to its selectivity for induction of norepinephrine over dopamine release and may be analogous to the case of ephedrine (which is at least 10-fold selective for induction of norepinephrine over dopamine release). The effects of phentermine may be more related to noradrenergic activation rather than dopaminergic activity. However, more research is needed to assess the preceding notions.[3][4][5][22] WP

As with other MRAs, phentermine produces dopaminergic neurotoxicity in rodents at high doses. It can also produce serotonergic neurotoxicity at very high doses in rodents. The clinical significance of these findings for humans, in which employed doses may be much lower, are unclear.[5] WP

The combination of phentermine with a serotonin releasing agent (SRA) like fenfluramine results in suppression of brain dopamine release by phentermine and marked attenuation or abolition of phentermine's stimulant and rewarding effects in animals and humans. Conversely, combined phentermine and fenfluramine administration synergistically enhances the appetite suppression of these drugs in animals and results in greater weight loss than either drug alone in humans. Fenfluramine produces serotonergic neurotoxicity in animals and addition of phentermine results in either no change or augmentation of this neurotoxicity.[3][5][22–26] WP

Other actions

Phentermine has been found to be completely inactive as a ligand or agonist of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. This is in contrast to the serotonin releasing agents (SRAs) fenfluramine, norfenfluramine, and to a lesser extent chlorphentermine. However, another study found that phentermine was a weak human serotonin 5-HT2C receptor partial agonist (EC₅₀ (half-maximal effective concentration) = 1,394 nM, Vₘₐₓ = 66%). In accordance with its lack of serotonin release and serotonin 5-HT2B receptor agonism, phentermine appears to show no risk of primary pulmonary hypertension (PPH) or valvular heart disease (VHD) in humans.[4][5][22][27] WP

Phentermine has been found to be active as an agonist of the rat and human trace amine-associated receptor 1 (TAAR1). It appears to be a weak human TAAR1 partial agonist (EC₅₀ (half-maximal effective concentration) = 5,470 nM and Eₘₐₓ (maximal efficacy) = 68% in one study). The drug shows reduced activity as a TAAR1 agonist compared to amphetamine. TAAR1 agonism by amphetamines that possess this action may serve to auto-inhibit and constrain their effects.[28–35] WP

Phentermine is a very weak monoamine oxidase inhibitor (MAOI) in vitro. It specifically inhibits monoamine oxidase A (MAO-A) (IC₅₀ (half-maximal inhibitory concentration) = 85,000–143,000 nM) and monoamine oxidase B (MAO-B) (IC₅₀ (half-maximal inhibitory concentration) = 285,000 nM). However, its potency as a MAOI is far below its potency as a monoamine releasing agent. Relatedly, phentermine does not show neurochemical signs of MAOI activity in rodents in vivo. As such, the significance of phentermine as an MAOI in humans is questionable.[5][36][37] WP

Absorption

The pharmacokinetics of phentermine are dose-dependent. Peak concentrations of phentermine are reached 6 hours following oral administration of a dose of 15 mg. The steady-state levels of phentermine with continuous administration have been found to be around 200 ng/mL in clinical studies. The oral bioavailability of phentermine is not affected by intake of a high-fat meal.[38] WP⚠ Wikipedia itself has flagged this text: unreliable medical source?.

Phentermine is a lipophilic amine that is rapidly absorbed through the gastrointestinal tract following oral ingestion. Its weakly basic nature facilitates absorption in the small intestine, where it exists primarily in a non-ionized form at physiological pH. Peak plasma concentrations can vary slightly based on formulation (immediate vs. extended-release) and gastric motility.[38] WP⚠ Wikipedia itself has flagged this text: unreliable medical source?.

Distribution

The volume of distribution of phentermine is 5 L/kg. Its plasma protein binding is approximately 17.5%.[38] WP⚠ Wikipedia itself has flagged this text: unreliable medical source?.

Metabolism

Phentermine undergoes minimal metabolism. Only about 6% of an administered dose of phentermine is metabolized. It is metabolized to a minor extent by para-hydroxylation, N-oxidation, and N-hydroxylation, followed by conjugation.[38] WP⚠ Wikipedia itself has flagged this text: unreliable medical source?.

Elimination

The drug is eliminated mainly in urine. It is excreted 62 to 85% unchanged in urine. The elimination half-life of phentermine is 20 to 25 hours. The elimination of phentermine is modified by urine acidicity or pH. In the case of acidic urine (pH < 5), the elimination half-life of phentermine has been found to be 7 to 8 hours. The clearance of phentermine is 8.79 L/h.[38][39] WP⚠ Wikipedia itself has flagged this text: unreliable medical source?.

Chemistry

Formula

C10H15N PC

CAS number

122-09-8 PC

Molar mass (g/mol)

149.23 PC

IUPAC name (computed by PubChem)

2-methyl-1-phenylpropan-2-amine PC

SMILES

CC(C)(CC1=CC=CC=C1)N PC

InChIKey

DHHVAGZRUROJKS-UHFFFAOYSA-N PC

PubChem CID

4771

Pop culture

No references added yet.

References

1. Other Phentermine Monograph for Professionals
2. Other Phentermine and topiramate Uses, Side Effects & Warnings
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7. Other Top 300 of 2023
8. Other Phentermine Drug Usage Statistics, United States, 2014 - 2023
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19. Other International brands for phentermine
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