Adrenoceptor agonists direct-acting

Dobutamine is a directly acting synthetic catecholamine with predominant effects at pi receptors. It has weak 32 and a effects. It is a racemic mixture and both stereoisomers are p-adrenoceptor agonists. The (+) isomer is approximately ten times more potent as a p-receptor agonist than the (-) isomer, which is mainly responsible for the o-adrenoceptor activity. Unlike dopamine, dobutamine does not act by releasing noradrenaline or via dopaminergic receptors. 

Direct-acting agonists typically have a 3-hydroxyl group, although dopamine does not. In addition to facilitating activation of adrenoceptors, this hydroxyl group may be important for storage of sympathomimetic amines in neural vesicles. 

The major direct-acting adrenoceptor agonist drugs are described. The alpha agonist phenylephrine increases mean BP, has no effect on pulse pressure, and elicits a reflex bradycardia. Isoproterenol, a beta agonist, decreases mean BP, increases pulse pressure, and causes marked tachycardia. Cardiovascular effects of norepinephrine (NE) are similar to phenylephrine, but it is also a cardiac (3, adrenoceptor activator. The cardiovascular effects of epinephrine (E) are betalike at low doses and alphalike at high doses. 

The tricyclics and some related antidepressants block or inhibit the uptake of noradrenaline (norepinephrine) into adrenergic neurones. Thus the most important means by which noradrenaline is removed from the adrenoceptor area is inactivated and the concentration of noradrenaline outside the neurone can rise. If more noradrenaline (or one of the other directly acting alpha or alpha/beta agonists) is then given, the adrenoceptors of the cardiovascular system concerned with raising blood pressure become grossly stimulated by this superabundance of amines, and the normal response becomes exaggerated. 

As was noted on p. 68, some agonists, such as amphetamine and tyra-mine, do not act directly on the adrenoceptor. Instead, they exert their effects indirectly on the adrenergic neuron by causing the release of neurotransmitter from storage vesicles. Similarly, some agents act on the adrenergic neuron, to either interfere in neurotransmitter release or alter the uptake of the neurotransmitter into the adrenergic nerve. 

Neurotransmission across adrenergic junctions is mediated by norepinephrine (NE). Adrenergic effectors may act indirectly by influencing NE synthesis, monoamine oxidase (MAO) enzymes, the mobile NE pool, the NE transporter, prejunctional a-adrenoceptors, granule uptake, or release of NE, or they may ad directly on the postjunctional receptor as agonists or antagonists. 

Mode of action Sympathomimetic agonists may directly activate their adrenoceptors, or they may act indirectly to increase the concentration of catecholamine transmitter in the synapse. Amphetamine derivatives and tyramine cause the release of stored catecholamines these sympathomimetics are therefore mainly indirect in their mode of action. Another form of indirect action is seen with cocaine and the tricyclic antidepressants these drugs inhibit reupmke of catecholamines by nerve terminals and thus increase the synaptic activity of released transmitter. 

---