Phentermine

Phentermine

Systematic (IUPAC) name
2-methyl-1-phenylpropan-2-amine
Clinical data
Trade names	Adipex-p
AHFS/Drugs.com	monograph
MedlinePlus	a682187
Pregnancy cat.	C(US)
Legal status	Schedule IV (US)
Routes	Oral, Insufflation, Intravenous
Pharmacokinetic data
Bioavailability	Peak plasma levels occur within 1 to 4.5 hours. Absorption is usually complete by 4 to 6 hours
Protein binding	Approximately 96.3%
Metabolism	hepatic
Half-life	16 to 31 hours
Excretion	Urinary elimination
Identifiers
CAS number	122-09-8 Y
ATC code	A08AA01 C01CA11
PubChem	CID 4771
DrugBank	APRD00093
ChemSpider	4607 Y
UNII	C045TQL4WP Y
KEGG	D05458 Y
ChEBI	CHEBI:8080 Y
ChEMBL	CHEMBL1574 Y
Chemical data
Formula	C10H15N
Mol. mass	149.233 g/mol
SMILES	eMolecules & PubChem
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
N(what is this?)  (verify)

Phentermine, a contraction of "phenyl-tertiary-butylamine", is a psychostimulant drug of the phenethylamine class, chemically related 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 because of their weight and works by helping to release certain chemicals in the brain that control appetite.

Medical uses

Phentermine is used for the short-term treatment of obesity.^[1]

Adverse effects

Generally, phentermine appears to be relatively well tolerated.^[2] It can produce side effects consistent with its catecholamine-releasing properties, e.g., tachycardia (increased heart rate) and elevated blood pressure, but the incidence and magnitude of these appear to be less than with the amphetamines. Because phentermine acts through sympathomimetic pathways, the drug may increase blood pressure and heart rate. It may also cause palpitations, restlessness, and insomnia. Additionally, phentermine has the potential to cause psychological dependence. After short term use, tolerance begins and can be followed by rebound weight gain.

More common

Cardiovascular

Primary pulmonary hypertension and/or regurgitant cardiac valvular disease, palpitation, tachycardia, elevation of blood pressure.

Central Nervous System

Overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache.

Gastrointestinal

Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances.

Allergic

Urticaria, endocrine Impotence, changes in libido.

Less common

Convulsions (seizures) Fever Hallucinations Hostility with urge to attack Irregular blood pressure Lightheadedness or fainting Periods of mania followed by period of depression Tremors, trembling or shaking

Overactive reflexes Panic Restlessness Severe nausea, vomiting or diarrhea Stomach cramps Weakness Constipation

Cautions

People with the following should not use phentermine:

• An allergy to any ingredient in Phentermine or other sympathomimetics (e.g., pseudoephedrine)
• Are also taking amphetamine (i.e. Adderall, Dexedrine, Vyvanse), bupropion (WellButrin), dexfenfluramine, fenfluramine, furazolidone, guanadrel, guanethidine, or have taken a monoamine oxidase inhibitor (MAOI) (e.g., phenelzine, in the last 14 days)
• Have severe high blood pressure, an overactive thyroid, glaucoma, heart or blood vessel disease, or severe narrowing of the blood vessels
• Are in an agitated state, or have a history of substance abuse

Medical conditions which may interact with phentermine

• Are pregnant, planning to become pregnant, or are breast-feeding
• Are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
• Have allergies to medicines, foods, or other substances
• Have a brain or spinal cord disorder, hardening of the arteries, high blood pressure, diabetes, or high cholesterol or lipid levels

Medicines which may interact

• Dexfenfluramine, fenfluramine, furazolidone, or MAOIs (e.g., phenelzine) because 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) because their effectiveness may be decreased by phentermine
• Antacids: Antacids may decrease the excretion of phentermine.^[3]
• Carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide, methazolamide): Carbonic anhydrase inhibitors may decrease the excretion of phentermine.^[3]

Mechanism of action

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.^[4]

Dosing and administration

Generally, it is recommended by the Food and Drug Administration (FDA) that phentermine should be used short-term (usually interpreted as 'up to 12 weeks'), while following nonpharmacological approaches to weight loss such as healthy dieting and exercise.^[5]

History

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, however 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 in 1959 there have been almost no clinical studies performed. The most recent study was in 1990 which combined phentermine with fenfluramine or dexfenfluramine and became known as Fen-Phen.^{[citation needed]}

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 that nearly 30% of people taking fenfluramine or dexfenfluramine had abnormal valve findings. The FDA did not ask manufacturers to remove phentermine from the market.

Phentermine is still available by itself in most countries, including the U.S. However, because it is similar to amphetamines, it is classified as a controlled substance in many countries (including Australia). Internationally, phentermine is a schedule IV drug under the Convention on Psychotropic Substances.^[6] 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 with other medication for obesity. The experimental appetite suppressant drug Qnexa is a mixture of Phentermine and Topiramate. The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed Qnexa on July 15, 2010. The committee voted narrowly against recommending approval.^[7]

Trade names

Adipex P (Immediate release) Adiphene (India) Anoxine-AM Ionamin (Slow Release Resin, Australia, discontinued in the US) Duromine (Slow Release Resin, New Zealand, Australia & South Africa) Metermine (Slow Release Resin, Australia) Mirapront Obephen Obermine Obestin-30 Phentremine Phentrol Phenterex

Phentromin Pro-Fast SA Qnexa (with Topiramate) Redusa Panbesy Phentermine Trenker Obenix Oby-Trim Teramine Zantryl Sinpet (MX) Supremin (PH) Umine (NZ) Weltmine (KP)

Chemistry

1. Benzaldehyde and 3-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-2-methyl-1-phenylpropylchloride.
4. This is reduced with hydrogen gas over a palladium on calcium carbonate catalyst to yield the product, phentermine.^[8][9]

References

1. ^ "phentermine". The American Society of Health-System Pharmacists. http://www.drugs.com/monograph/phentermine.html. Retrieved 3 April 2011. 
2. ^ 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. 
3. ^ ^{a b} "Phentermine". Merck & Co., Inc.. 2008. http://www.merck.com/mmpe/lexicomp/phentermine.html. Retrieved 2008-05-15. 
4. ^ 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. 
5. ^ http://www.fda.gov/bbs/topics/news/new00575.html
6. ^ Incb.org (PDF file)
7. ^ Pollack, Andrew (July 15, 2010). "F.D.A. Panel Votes Against Obesity Drug Qnexa From Vivus". The New York Times. http://www.nytimes.com/2010/07/16/health/16obese.html?_r=2&adxnnl=1&adxnnlx=1279288929-UQFYLLLDPECmGtc8vauuMw. 
8. ^ U.S. Patent 2,408,345
9. ^ U.S. Patent 2,590,079

External links

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