Phentermine Mechanism of Action
Phentermine is a sympathomimetic amine that functions primarily as a norepinephrine-releasing agent, reducing appetite through enhancement of norepinephrine release and blockade of norepinephrine reuptake in the central nervous system. 1
Primary Mechanism
Phentermine acts as a potent substrate at the norepinephrine transporter, simultaneously promoting norepinephrine release while blocking its reuptake. 1, 2
The drug has weaker activity at the dopamine transporter and negligible activity toward the serotonin transporter. 2
In vivo microdialysis studies in conscious rats demonstrate that phentermine increases striatal dopamine release to 147-320% of baseline (dose-dependent), without significantly affecting serotonin concentrations. 3
Pharmacologic Classification
Phentermine is classified as a sympathomimetic amine anorectic with pharmacologic activity similar to amphetamine (d- and dl-amphetamine), though it is less potent than amphetamine. 4, 2
The FDA label describes phentermine as an "anorectic" or "anorexigenic" drug, though it has not been definitively established whether the primary action is purely appetite suppression versus other central nervous system actions or metabolic effects. 4
Physiologic Effects
Typical actions include central nervous system stimulation and elevation of blood pressure through sympathetic nervous system activation. 4
The drug reduces appetite and affects food intake via enhanced norepinephrine signaling in hypothalamic satiety centers. 1
Phentermine may also increase resting energy expenditure, though appetite suppression appears to be the dominant mechanism. 5
Clinical Implications of Mechanism
Tachyphylaxis and tolerance have been demonstrated with phentermine, as with all drugs in this pharmacologic class. 4
The declining effect over time and addiction potential necessitate short-term use recommendations (typically ≤12 weeks). 2
Patients with greater baseline hunger and less cognitive restraint are more likely to achieve significant weight loss with phentermine, consistent with its appetite-suppressing mechanism. 6
Important Mechanistic Caveats
The noradrenergic mechanism explains phentermine's cardiovascular effects (increased heart rate and blood pressure), which require monitoring during therapy. 1
Unlike fenfluramine (withdrawn from market), phentermine does not significantly affect serotonin systems, which distinguishes its safety profile from serotonergic appetite suppressants. 2, 3
The drug's amphetamine-like structure and mechanism confer Schedule IV controlled substance status due to potential for abuse and dependence. 1, 7