DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

776 result of the lack of sympathetic compensation for these stresses. A
general feeling of fatigue and lassitude is partially, but not entirely,
related to postural hypotension. Sexual dysfunction usually presents
as delayed or retrograde ejaculation. Diarrhea also may occur.
Because guanadrel is actively transported to its site of action,
drugs that block or compete for the catecholamine transporter on the
presynaptic membrane will inhibit the effect of guanadrel. Such
drugs include the tricyclic antidepressants cocaine, chlorpromazine,
ephedrine, phenylpropanolamine, and amphetamine (see Chapter 8).
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Therapeutic Uses. Because of the availability of a number of drugs
that lower blood pressure without producing similar adverse effects,
guanadrel is used very rarely; the drug is no longer marketed in the
U.S. The usual starting dose is 10 mg daily, and side effects can be
minimized by not exceeding 20 mg daily.
Reserpine
Reserpine was the first drug that was found to interfere
with the function of the sympathetic nervous system in
humans, and its use began the modern era of effective
pharmacotherapy of hypertension.
Reserpine is an alkaloid extracted from the root of Rauwolfia
serpentina, a climbing shrub indigenous to India. Ancient Hindu
Ayurvedic writings describe medicinal uses of the plant; Sen and
Bose described its use in the Indian biomedical literature. However,
rauwolfia alkaloids were not used in western medicine until the
mid-1950s.
Locus and Mechanism of Action. Reserpine binds tightly to adrenergic
storage vesicles in central and peripheral adrenergic neurons and
remains bound for prolonged periods of time. The interaction
inhibits the vesicular catecholamine transporter, VMAT2, so that
nerve endings lose their capacity to concentrate and store NE and
dopamine. Catecholamines leak into the cytoplasm, where they are
metabolized. Consequently, little or no active transmitter is released
from nerve endings, resulting in a pharmacological sympathectomy.
Recovery of sympathetic function requires synthesis of new storage
vesicles, which takes days to weeks after discontinuation of the drug.
Because reserpine depletes amines in the CNS as well as in the
peripheral adrenergic neuron, it is probable that its antihypertensive
effects are related to both central and peripheral actions.
Pharmacological Effects. Both cardiac output and peripheral vascular
resistance are reduced during long-term therapy with reserpine.
Absorption, Metabolism, and Excretion. Few data are available on
the pharmacokinetic properties of reserpine because of the lack of an
assay capable of detecting low concentrations of the drug or its
metabolites. Reserpine that is bound to isolated storage vesicles cannot
be removed by dialysis, indicating that the binding is not in equilibrium
with the surrounding medium. Because of the irreversible
nature of reserpine binding, the amount of drug in plasma is unlikely
to bear any consistent relationship to drug concentration at the site
of action. Free reserpine is entirely metabolized; none of the parent
drug is excreted unchanged.
Toxicity and Precautions. Most adverse effects of reserpine are due
to its effect on the CNS. Sedation and inability to concentrate or perform
complex tasks are the most common adverse effects. More serious
is the occasional psychotic depression that can lead to suicide.
Depression usually appears insidiously over many weeks or months
and may not be attributed to the drug because of the delayed and
gradual onset of symptoms. Reserpine must be discontinued at the
first sign of depression; reserpine-induced depression may last several
months after the drug is discontinued. The risk of depression is
likely dose related. Depression appears to be uncommon, but not
unknown, with doses of 0.25 mg/day or less. The drug should never
be given to patients with a history of depression. Other adverse
effects include nasal stuffiness and exacerbation of peptic ulcer disease,
which is uncommon with small oral doses.
Therapeutic Uses. With the availability of newer drugs that are both
effective and well tolerated, the use of reserpine has diminished
because of its CNS side effects. Nonetheless, there has been some
recent interest in using reserpine at low doses, in combination with
diuretics, in the treatment of hypertension, especially in the elderly.
Reserpine is used once daily with a diuretic, and several weeks are
necessary to achieve a maximum effect. The daily dose should be
limited to 0.25 mg or less, and as little as 0.05 mg/day may be efficacious
when a diuretic is also used. One advantage of reserpine is
that it is considerably less expensive than other antihypertensive
drugs; thus, it is still used in developing nations.
Metyrosine
Metyrosine (DEMSER) is (–)-α-methyl-L-tyrosine. Metyrosine inhibits
tyrosine hydroxylase, the enzyme that catalyzes the conversion of
tyrosine to DOPA and the rate-limiting step in catecholamine biosynthesis
(see Chapter 8). At a dose of 1-4 g/day, metyrosine
decreases catecholamine biosynthesis by 35-80% in patients with
pheochromocytoma. The maximal decrease in synthesis occurs only
after several days and may be assessed by measurements of urinary
catecholamines and their metabolites.
Metyrosine is used as an adjuvant to phenoxybenzamine and
other α adrenergic blocking agents for the management of pheochromocytoma
and in the preoperative preparation of patients for resection
of pheochromocytoma. Metyrosine carries a risk of crystalluria, which
can be minimized by maintaining a daily urine volume of >2 L. Other
adverse effects include orthostatic hypotension, sedation, extrapyramidal
signs, diarrhea, anxiety, and psychic disturbances. Doses must be
titrated carefully to achieve significant inhibition of catecholamine
biosynthesis and yet minimize these substantive side effects.
Ca 2+ CHANNEL ANTAGONISTS
Ca 2+ channel blocking agents are an important group of
drugs for the treatment of hypertension. The general