Pharmacodynamics and mechanism of action
Bupropion is a norepinephrine and dopamine reuptake inhibitor that exerts its pharmacological effects by binding and inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, thereby prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters.
When used as a smoking cessation agent, bupropion, by inhibiting dopamine reuptake, affects the reward system in the brain. In addition, it appears to have a mild antagonistic effect at the nicotinic acetylcholinergic receptor (AChR). This attenuates the overall effect of nicotine and decreases the craving to smoke.
From a chemical point of view, bupropion is not related to tricyclic, tetracyclic, selective serotonin reuptake inhibitors or other known antidepressants. Therefore, it is classified from the group of "atypical antidepressants". It has no clinically relevant serotonergic effects and no effects on histamine or epinephrine receptors. The lack of activity at these receptors results in a more tolerable side effect profile; for example, compared with SSRIs or TCAs, bupropion causes fewer sexual side effects, sedation, or weight gain.
Following oral administration, bupropion is rapidly and completely absorbed, reaching maximum blood plasma concentration after 1.5 hours. Sustained release formulations, delay the time to maximum drug concentration to 3 -5 hours. The absolute bioavailability of bupropion is not precisely known, but is estimated to be relatively low at 5-20% due to the very strong first-pass effect.
Bupropion is metabolized in the body via several pathways. The oxidative pathway leads via the cytochrome P450 isozymes CYP2B6 and CYP2C19. The reductive pathway leads to the respective breakdown products via the enzyme 11β-hydroxysteroid dehydrogenase type 1 in the liver and the enzyme AKR7A2/AKR7A3 in the intestine. Some of the metabolites of bupropion are also pharmacologically active and contribute to the effects of the substance. Bupropion is almost completely metabolized and excreted in the urine and stool.
Drug interactions are possible with CYP2B6 inhibitors: these include drugs such as paroxetine, sertraline, norfluoxetine, diazepam, clopidogrel, and orphenadrine. Concomitant use results in an increase in bupropion blood concentration. Concomitant use with CYP2B6 inducers such as carbamazepine, clotrimazole, rifampicin, ritonavir, St. John's wort, and phenobarbital is expected to result in lower bupropion levels and reduced efficacy. Bupropion and its metabolites are inhibitors of CYP2D6. This may result in interactions with substances that are degraded by this enzyme.