Mechanism of action
Phentermine is an indirect-acting sympathomimetic agent that acts by releasing noradrenaline from the presynaptic vesicles in the lateral hypothalamus. This increase in noradrenaline concentration in the synaptic cleft results in the stimulation of beta2-adrenergic receptors. Phentermine is classified as an indirect sympathomimetic due to the increase in the level of norepinephrine, dopamine and its indirect effect towards serotonin. Some reports have indicated that phentermine inhibits the neuropeptide Y which is a principal signaling pathway for the induction of hunger. This combined effect produces a continuous flight-or-fight response in the body which reduces the hunger signal as this state is on the immediate need for energy. Lastly, some reports have indicated that phentermine is a weak inhibitor of monoamine oxidase but this mechanism does not tend to produce a clinically significant response.
Although the mechanism of action of the sympathomimetic appetite suppressants in the treatment of obesity is not fully known, these medications have pharmacological effects similar to those of amphetamines. Amphetamine and related sympathomimetic medications ... are thought to stimulate the release of norepinephrine and/or dopamine from storage sites in nerve terminals in the lateral hypothalamic feeding center, thereby producing a decrease in appetite. ... It has not been established that the actions of these medications in treating obesity is primarily suppression of appetite; other CNS actions and/or metabolic effects, such as decreased gastric acid secretion or increased energy expenditure, may be involved.
Pharmacodynamics
It is reported that the main mechanism of action of phentermine is the generation of appetite suppression, maybe due to the increase in leptin, but it is considered that other mechanisms should be involved. Some reports have indicated that the weight loss effect is mainly due to the increase in resting energy expenditure. In clinical studies where phentermine was used as a monotherapy and as combination therapy, this drug has shown an average weight loss of 3.6 kg when compared with the placebo in 2-24 weeks. Patients treated with phentermine also showed increased maintenance of the weight after treatment discontinuation. As well, even though it is a derivative of the amphetamines, it has not been registered to produce any of the effects of amphetamine such as central nervous system stimulation, elevation of blood pressure, tachyphylaxis or QTc prolongation.
Pharmacokinetics
Half-life
The mean terminal half-life of phentermine is reported to be of approximately 20 hours. In conditions where there is acidic urine (pH <5), the elimination half-life is of 7-8 hours.
... Elimination half-life is approximately 7-8 hours in acid urine (pH5), compared with 19-24 hours under normal conditions.
S(+)-phentermine was eliminated much more rapidly in rat (k= 1.32/hr) after iv administration than in man (k= 0.029/hr) after oral dose. Half-lives were 25-35 min in rat & 12-24 hr in man.
Absorption
Phentermine shows a dose-dependent pharmacokinetic profile. After oral administration of a dose of 15 mg, the maximal concentration was achieved after 6 hours and its bioavailability was not affected by the consumption of high-fat meals. The reported plasma concentration at steady-state is of around 200 ng/ml as observed in clinical trials.
Phentermine is excreted mainly in the urine from which about 70-80% of the administered dose can be found as the unchanged drug.
The reported volume of distribution for phentermine is reported to be of 5 L/kg.
The reported clearance when administered orally is 8.79 L/h as observed in pharmacokinetic population studies.
Absorbed readily after oral administration. Distributed widely throughout body.
The volume of distribution is 3 to 4 L/kg ... A majority of the drug is excreted unchanged in the urine. An average of 48% of the dose is excreted in the urine in 24 hours, which increases to 84% in acidic urine.
Metabolism
Phentermine undergoes minimal p-hydroxylation, N-oxidation and N-hydroxylation followed by conjugation. The total proportion of the drug that goes under metabolism only represents about 6% of the administered dose where about 5% is represented by the N-oxidized and N-Hydroxylated metabolites.
Phentermine is not significantly biotransformed; 70 to 80 % of a given dose is excreted unchanged in the urine.
There are two primary pathways of oxidative metabolism: n-hydroxylation to n-hydroxyphentermine & p-hydroxylation to para-hydroxyphentermine. N-hydroxyphentermine is metabolized further to alpha-nitrophentermine. In rats the dominant pathway is p-hydroxylation to give para-hydroxyphentermine, accounting for more than 60% of administered dose. P-hydroxylation reactions in rat liver microsomes indicated that phentermine metabolism was inhibited by skf525a & iprindol, and was not inducible with phenobarbital or 3-methylcholanthrene, suggesting a system different from aromatic c-hydroxylation. The n-hydroxylation reaction for rabbit & guinea pig (two-enzyme system) & rat (single enzyme system) is the reduced form of nicotinamide-adenine dinucleotide phosphate-dependent, inhibited by carbon monoxide & induced by phenobarbital, suggesting involvement of cytochrome p450 system.
Although no quantitative data are available, urinary metabolites found in man are p-hydroxyphentermine and n-hydroxyphentermine. N-hydroxy metabolite can be reduced in vivo but conversion to this metabolite appears to be inefficient means of elimination.
The role of the cytochrome p450 system in the oxidation of phentermine to N-hydroxyphentermine by liver microsomal prepn was studied in a reconstituted system which consisted of cytochrome p450 and the reduced form of nicotinamide-adenine dinucleotide phosphate cytochrome p450 reductase purified from liver microsomes of phenobarbital-induced rabbits. In this system, phentermine was oxidized to N-hydroxyphentermine. The reaction was the reduced form of nicotinamide-adenine dinucleotide phosphate-dependent and required the presence of both the cytochrome p450 and reductase preparations.
Hepatic.
Half Life: 16 to 31 hours
Protein binding
The protein binding of phentermine is determined to be of 17.5%.
External links
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