Adrenergic Neuron Βeta-Blocking Drugs

ADRENERGIC NEURON β-blocking DRUGS

The adrenergic neuron β-blocking drugs are antihyper-tensive because they prevent the release of transmitters from peripheral postganglionic sympathetic nerves. The contraction of vascular smooth muscle due to sympa-thetic nerve stimulation is thereby reduced, and blood pressure decreases. Guanethidine is the prototypical member of this class.

Guanethidine

Guanethidine (Ismelin) is a powerful antihypertensive agent that is quite effective in the treatment of moder-ate to severe hypertension. It is most frequently used in the treatment of severe hypertension that is resistant to other agents.

Guanethidine exerts its effects at peripheral sympa-thetic nerve endings following its active transport into the nerve varicosities by the neuronal amine transport sys-tem. This is the same uptake system that transports nor-epinephrine into the varicosity . The ac-cumulation of guanethidine in adrenergic neurons, through an as yet unexplained mechanism, disrupts the process by which action potentials trigger the release of stored norepinephrine and other cotransmitters from nerve terminals. It is this action of guanethidine that is primarily responsible for its antihypertensive proper-ties. Parasympathetic function is not altered, a fact that distinguishes guanethidine from the ganglionic blocking agents .

Guanethidine is suitable for oral use, and this is its usual route of administration. However, absorption from the gastrointestinal tract is variable. The half-life of guanethidine is 5 days, with about one-seventh of the total administered dose eliminated per day. The slow elimination contributes to the cumulative and pro-longed effects of the drug.

Guanethidine reduces blood pressure by its ability to diminish vascular tone; both the arterial and venous sides of the circulatory system are involved. The result-ing venous pooling contributes to orthostatic hypoten-sion, a prominent feature of guanethidine treatment. The reduction in blood pressure is more prominent when the patient is standing than recumbent.

A reduction in cardiac output attributable to a de-creased venous return and the inability of sympathetic nerve impulses to release enough transmitters to stimu-late the heart occur during the early stages of guanethi-dine therapy.

With the possible exception of minoxidil, guanethi-dine is the most potent orally effective antihypertensive drug. Because guanethidine produces a number of side effects that are due primarily to the imbalance between sympathetic and parasympathetic function it produces, it is generally reserved for the treatment of severe hy-pertension.

A common and troublesome side effect is postural hypotension. Sexual impotence does occur, and male patients may have difficulty ejaculating. Symptoms of unopposed parasympathetic activity include such gas-trointestinal disturbances as diarrhea and increased gas-tric secretion.

Guanethidine may aggravate congestive heart fail-ure or actually precipitate failure in patients with mar-ginal cardiac reserve, owing to its ability to produce vas-cular volume expansion, edema, and a reduced effectiveness of sympathetic cardiac stimulation.

Guanethidine is contraindicated in patients with pheochromocytoma because the drug may release cate-cholamines from the tumor. The concomitant use of monoamine oxidase (MAO) inhibitors and guanethi-dine is also to be avoided, since this combined drug treatment eliminates two of the principal mechanisms for terminating the actions of the catecholamines and certain other adrenomimetic drugs, that is, biotransfor-mation and neuronal uptake. Dangerously high concen-trations of catecholamines at receptor sites are possible.

The tricyclic antidepressants (e.g., desipramine and amitriptyline) and some phenothiazines block the sym-pathetic neuronal amine uptake system; they thereby would also block the uptake of guanethidine and thus reduce its hypotensive effectiveness. Conversely, guanethidine competitively inhibits the uptake of drugs that are substrates for neuronal uptake, such as the in-directly acting adrenomimetics, or sympathomimetics .