indication

Used as an anorectic in the treatment of obesity.

pharmacology

Phenmetrazine is a sympathomimetic drug used primarily as an appetite depressant. Its actions and mechanisms are similar to dextroamphetamine. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. Phenmetrazine was originally sold under the tradename Preludin as an anorectic. It has since been removed from the market. It is by some considered to have a greater potential for addiction than the amphetamines, and has been abused in many countries, for example Sweden.

mechanism of action

Phenmetrazine is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron leading to an increase in the release of these monoamines into the extraneuronal space. Dopamine integrates incoming sensory stimuli, initiates and controls fine movement (nigro-neostriatal pathway), controls emotional behavior (midbrain mesolimbic-forebrain system) and controls hypothalamic-pituitary endocrine system (tubero-infundibular system). It is this latter effect on the tubero-infundibular systm that seems to lead to reduced food intake. Phenmetrazine also acts as a monoamine oxidase inhibitor.

toxicity

Adult monkeys have an LD₅₀ of 15 to 20 mg/kg, whereas for young monkeys the LD₅₀ is only 5 mg/kg. Symptoms of overdose include acute central nervous system stimulation, cardiotoxicity causing tachycardia, arrhythmias, hypertension, and cardiovascular collapse. Whilst some patients show signs of toxicity at blood concentrations of 20 µg/L, chronic abusers of amphetamine have been known to have blood concentration of up to 3000 µg/L.

biotransformation

Primarily hepatic (via CYP3A and CYP2D6). Resistant to metabolism by monoamine oxidase. Metabolism involves deamination to para-hydroxyamphetamine and phenylacetone; this latter compound is subsequently oxidize to benzoic acid and excreted as glucuronide or glycine (hippuric acid) conjugate. Smaller amounts of amphetamine are converted to norephedrine by oxidation.

absorption

Readily absorbed from the gastro-intestinal tract and buccal mucosa.

half life

16 to 31 hours

drug interactions

Chlorpromazine: Decreased anorexic effect, may increase psychotic symptoms

Fluphenazine: Decreased anorexic effect, may increase psychotic symptoms

Guanethidine: Phenmetrazine may decrease the effect of guanethidine.

Isocarboxazid: Possible hypertensive crisis

Mesoridazine: Decreased anorexic effect, may increase psychotic symptoms

Methotrimeprazine: Decreased anorexic effect, may increase psychotic symptoms

Perphenazine: Decreased anorexic effect, may increase psychotic symptoms

Prochlorperazine: Decreased anorexic effect, may increase pyschotic symptoms

Promethazine: Decreased anorexic effect, may increase pyschotic symptoms

Propericiazine: Decreased anorexic effect, may increase pyschotic symptoms

Rasagiline: Possible hypertensive crisis

Thioridazine: Decreased anorexic effect, may increase psychotic symptoms

Trifluoperazine: Decreased anorexic effect, may increase psychotic symptoms