Phentermine

Phentermine

Systematic (IUPAC) name
2-methyl-1-phenylpropan-2-amine
Clinical data
Trade names	Adipex-p, Duromine, Metermine, Suprenza
AHFS/Drugs.com	monograph
MedlinePlus	a682187
Licence data	US FDA:link
Pregnancy category	AU: B3 US: X (Contraindicated)
Legal status	AU: S4 (Prescription only) CA: Schedule IV DE: Anlage III (Prescription only) US: Schedule IV
Dependence liability	Low
Addiction liability	Very low
Routes of administration	Medical: oral, Recreational: oral, insufflation, intravenous
Pharmacokinetic data
Bioavailability	High (almost complete)
Protein binding	Approximately 96.3%
Metabolism	Hepatic
Biological half-life	25 hours, urinary pH-dependent
Excretion	Urinary (62–85% unchanged)
Identifiers
CAS Number	122-09-8 Y
ATC code	A08AA01 (WHO)
PubChem	CID: 4771
IUPHAR/BPS	7269
DrugBank	DB00191 Y
ChemSpider	4607 Y
UNII	C045TQL4WP Y
KEGG	D05458 Y
ChEBI	CHEBI:8080 Y
ChEMBL	CHEMBL1574 Y
Synonyms	α-methyl-amphetamine α,α-dimethylphenethylamine
Chemical data
Formula	C10H15N
Molecular mass	149.233 g/mol
SMILES NC(Cc1ccccc1)(C)C
InChI InChI=1S/C10H15N/c1-10(2,11)8-9-6-4-3-5-7-9/h3-7H,8,11H2,1-2H3 Y Key:DHHVAGZRUROJKS-UHFFFAOYSA-N Y
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Phentermine, a contraction of "phenyl-tertiary-butylamine", is a psychostimulant and anorectic drug of the substituted phenethylamine and substituted amphetamine chemical classes, with pharmacology similar to amphetamine. It is used medically as an appetite suppressant.

Phentermine is approved in Australia as an appetite suppressant and is medically prescribed as a diet pill; intended for obese patients and patients that are considered a medical risk due to weight. Phentermine is a prescription that helps aid weight-loss and is designed for short-term use with a combination of exercise and a healthy diet.

Phentermine is FDA approved, and is currently 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.

There are various phentermine brands and supplements available through tablets, capsules, and drinks such as: Vites, Adipex and Qsymia (previously known as Qnexa) available in various dosages. Manufacturers of phentermine diet pills have their own 37.5 mg dosages, Phentermine 37.5 mg tablets or capsules are generally manufactured by generic pharmaceutical groups.

Medical uses

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

Adverse effects

Generally, phentermine appears to be relatively well tolerated.

Adverse effects by incidence

Common (>1% incidence) adverse effects include:

• Xerostomia (dry mouth)
• Restlessness
• Nervousness
• Euphoria
• Agitation
• Arrhythmia
• Tachycardia
• Hypertension
• Diarrhea
• Vomiting
• Headache
• Rash
• Urinary frequency
• Facial oedema
• Unpleasant taste
• Urticaria
• Impotence
• Changes in libido

Contraindications

Phentermine use is contraindicated in those who are:

• Known hypersensitivity or idiosyncratic reaction to sympathomimetic amines
• Taking another amphetamine pharmaceutical (i.e., racemic amphetamine, Adderall, dextroamphetamine, or lisdexamfetamine), methamphetamine, dexfenfluramine, fenfluramine, furazolidone, guanadrel, guanethidine, or have taken a monoamine oxidase inhibitor (MAOI) (e.g., phenelzine) in the last 14 days
• Hyperthyroidism
• Glaucoma
• Peptic ulcer
• Prostatic hypertrophy
• Epilepsy
• Cotreatment with drugs that increase blood pressure
• Contraindicated in cardiac disease (e.g. advanced arteriosclerosis, pulmonary hypertension, uncontrolled hypertension, arrhythmias) and cerebrovascular disease (stroke)
• Pregnant, planning to become pregnant, or are breast-feeding
• Those receiving serotonergic medications such as the selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitor, tricyclic antidepressant, due to the potential for serotonin syndrome to be precipitated by the cotreatment.

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. Carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide, methazolamide) may decrease the excretion of phentermine.

Mechanism of action

Phentermine has some similarity in its pharmacodynamics with its parent compound, amphetamine, as they both are TAAR1 agonists, 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. 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. 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. 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 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.

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.

Trade names

• Acxion (MX)
• 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
• PhenObestin 37.5
• 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)

Physical and chemical properties

Synthesis

Phentermine can be produced from benzaldehyde and 2-nitropropane as follows:

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

External links

• MedLine Plus - Phentermine
• International Programme on Chemical Safety - Phentermine
• TOXNET
• U.S. National Library of Medicine: Drug Information Portal - Phentermine