INTERFERE WITH NOREPINEPHRINE STORAGE
Reserpine (Serpasil) is the prototypical drug
interfering with norepinephrine storage. Reserpine lowers blood pressure by
reducing norepinephrine concentrations in the noradrenergic nerves in such a
way that less norep-inephrine is released during neuron activation. Reserpine
does not interfere with the release process per se as does guanethidine.
Under normal circumstances,
when an action poten-tial invades the sympathetic nerve terminal, a portion
ofthe released norepinephrine is recycled. This event re-quires two successive
steps: (1) transfer of norepineph-rine across the neuronal membrane into the
cytosol by an energy-dependent carrier-mediated active process, and (2)
transfer of the recaptured amine from the cy-tosol into the noradrenergic
storage vesicles, where it is stored until needed. Reserpine inhibits only the second uptake process. As a consequence of this inhibition of vesicular uptake, norepinephrine cannot
be stored in-traneuronally, and much of the cytosolic amine is me-tabolized by
In addition to impairing
norepinephrine storage and thereby enhancing its catabolism, reserpine impairs
the vesicular uptake of dopamine, the immediate precursor of norepinephrine.
Since dopamine must be taken up into the adrenergic vesicles to undergo hydroxylation
and form norepinephrine, reserpine administration im-pairs norepinephrine
synthesis. The combined effects of the blockade of dopamine and norepinephrine
vesicular uptake lead to transmitter depletion.
Reserpine also interferes
with the neuronal storage of a variety of central transmitter amines such that
sig-nificant depletion of norepinephrine, dopamine, and 5-hydroxytryptamine
(serotonin) occurs. This central transmitter depletion is responsible for the
sedation and other CNS side effects associated with reserpine ther-apy. The
depletion of brain amines also may contribute to the antihypertensive effects
The chief use of reserpine is
in the treatment of mild to moderate hypertension. As with other sympathetic
depressant drugs, tolerance to the antihypertensive ef-fects of reserpine can
occur, owing to a compensatory increase in blood volume that frequently
accompanies decreased peripheral vascular resistance. Reserpine, therefore,
should be used in conjunction with a diuretic.
Because of its sedative
properties, reserpine offers special benefit to hypertensive patients who
exhibit symp-toms of agitated psychotic states and who may be unable to
tolerate therapy with phenothiazine derivatives.
The most troublesome untoward
effects of treat-ment with reserpine involve the CNS. Sedation and de-pression
are the most common, although nightmares and thoughts of suicide also occur.
Reserpine treat-ment, therefore, is contraindicated in patients with a his-tory
of severe depression. The occasional report of re-serpine-induced
extrapyramidal symptoms, which are similar to those seen in patients with
Parkinson’ s dis-ease, is believed to be a result of dopamine depletion from
neurons in the CNS.
Peripheral nervous system
side effects are the result of a reserpine-induced reduction of sympathetic
func-tion and unopposed parasympathetic activity; symp-toms include nasal
congestion, postural hypotension, di-arrhea, bradycardia, increased gastric
secretion, and occasionally impotence. Because of the increased gas-tric
secretion, reserpine is contraindicated for patients with peptic ulcer. In
patients with little cardiac reserve, reserpine must be administered with
caution because of its ability to interfere with sympathetic stimulation of the