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 (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
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
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
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
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 .