Pharmacodynamic actions of the newer autonomic drugs used in the treatment of essential hypertension ∗

Abstract

The pharmacodynamic actions of the more recently available autonomie agents employed in the treatment of hypertension have been summarized. The agents discussed include guanethidine (Ismelin) and bretylium (Darenthin), both of which produce selective blockade of the sympathetic nervous system, and methyl-dopa (Aldornet), an inhibitor of aromatic amino acid decarboxylase. Available evidence indicates that guanethidine and bretylium inhibit transmission of nerve impulses over sympathetic pathways by an action located in postganglionic adrenergic neurons. This action, demonstrated directly in laboratory animals, probably occurs in man and forms the basis for their antihypertensive actions. The mode of action of guanethidine may involve a latent depletion of norepinephrine, the sympathetic transmitter, from adrenergic neurons. Bretylium, however, apparently blocks release of the transmitter in response to the nerve impulse without causing its depletion. Guanethidine may have a similar action early after its administration. Methyldopa has been demonstrated to inhibit the decarboxylation of several aromatic amino acids including dihydroxyphenylalanine and 5-hydroxytryptophan. In laboratory animals, it causes a short-lasting decrease in serotonin levels in the brain and a considerably longer-lasting decline in tissue levels of norepinephrine both in the brain and peripheral tissues. Although this action resembles effects of rcserpine and guanethidine, it is not associated with disruption in transmission over sympathetic pathways as is the case with the latter agents. The mechanism and site of the antihypertensive action of methyldopa in man or laboratory animals is unresolved at present. It is not yet clear whether its catecholamine-de-pleting or decarboxylase inhibitory activity is responsible for its antihypertensive action in some as yet undefined manner. Additional studies are required to assess the importance of these actions.