Adrenergic mechanisms complexity

Neubig, R. R., Gantzos, R. D., and Thomsen, W. J. (1988). Mechanism of agonist and antagonist binding to alpha-2 adrenergic-receptors—evidence for a precoupled receptor guanine-nucleotide protein complex. Biochemistry 27, 2374-2384. 

Interactions of sympathomimetics with other vasoactive drugs are complex. Some drugs block the reuptake mechanism for noradrenaline in adrenergic nerve terminals and potentiate the pressor effects of noradrenaline e.g. cocaine, tricyclic antidepressants or highly noradrenaline-selective reuptake inhibitors such as roboxetine. Others deplete or destroy the intracellular stores within adrenergic nerve terminals (e.g. reserpine and guanethidine) and thus block the action of indirect S5unpathomimetics. 

The precise mechanisms by which phencyclidine causes its clinical effects have not been fully delineated. Phencyclidine blocks the N-methyl-D-aspartate (NMDA) receptors and thereby calcium influx into cells. Phencyclidine inhibits the biogenic amine reuptake complex and thereby inhibits norepinephrine and dopamine reuptake. Phencyclidine also increases adrenergic activity by indirectly releasing norepinephrine from presynaptic neurons. Phencyclidine in high doses stimulates sigma receptors. 

Fig. 5. The physiologic and pharmacologic pathway of P2 agonist on [It. XR. This pathway is complex and many signal cascade proteins shown may have relevant genetic variations that may modify sensitivity to pharmacotherapy. (From Johnson M. Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 2006 117 18-24 with permission.)...

The overall mechanism is actually considerably more complex since the adrenergic system interrelates with other pressor mechanisms involving, for example, angiotensin and serum sodium levels. 

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