Phentermine mechanism of action (MOA)

1. Central Nervous System Stimulation

Phentermine is structurally similar to amphetamine. Its primary mechanism occurs in the hypothalamus (the part of the brain that regulates hunger).

• Neurotransmitter Release: It enters the presynaptic neurons and triggers the release of norepinephrine (and to a lesser extent, dopamine and serotonin) into the synaptic cleft.
• Reuptake Inhibition: It also inhibits the reuptake of these neurotransmitters, leaving higher concentrations available in the brain.

2. The "Fight or Flight" Response

The increased levels of norepinephrine stimulate the sympathetic nervous system (the "fight or flight" response).

• In the hypothalamus, this stimulation activates the POMC (proopiomelanocortin) neurons.
• This activation signals to the body that it is under stress or threat.
• In response, the body suppresses unnecessary functions—like hunger—to focus on survival.

3. Resulting Physiological Effects

• Appetite Suppression: The primary goal; the patient simply does not feel hungry.
• Increased Metabolic Rate: It can cause a slight increase in resting energy expenditure (thermogenesis).
• Increased Blood Pressure and Heart Rate: As a stimulant, it raises cardiovascular output (which is why it must be monitored by a doctor).

Important Clinical Context

• Tolerance: The anorexigenic (appetite suppressing) effect tends to diminish after a few weeks because the body downregulates receptors to compensate for the constant stimulation.
• Short-term use: Due to the risk of tolerance and dependence, it is typically prescribed for only 12 weeks or less.
• Contraindications: It should not be used with MAO inhibitors (risk of hypertensive crisis) or in patients with a history of heart disease, stroke, or uncontrolled high blood pressure.