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

774 Methyldopa (α-methyl-3,4-dihydroxy-L-phenylalanine), an
analog of 3,4-dihydroxyphenylalanine (DOPA), is metabolized by
the L-aromatic amino acid decarboxylase in adrenergic neurons to
α-methyldopamine, which then is converted to α-methylnorepinephrine.
α-Methylnorepinephrine is stored in the secretory vesicles of
adrenergic neurons, substituting for norepinephrine (NE) itself.
Consequently, when the adrenergic neuron discharges its neurotransmitter,
α-methylnorepinephrine is released instead of norepinephrine.
α-Methylnorepinephrine acts in the central nervous system
(CNS) to inhibit adrenergic neuronal outflow from the brainstem and
probably acts as an agonist at presynaptic α 2
adrenergic receptors in
the brainstem, attenuating NE release and thereby reducing the output
of vasoconstrictor adrenergic signals to the peripheral sympathetic
nervous system.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Absorption, Metabolism, and Excretion. Because methyldopa is a prodrug
that is metabolized in the brain to the active form, its concentration
in plasma has less relevance for its effects than that for many
other drugs. Peak concentrations in plasma occur after 2-3 hours.
The drug is eliminated with a t 1/2
of ~2 hours. Methyldopa is excreted
in the urine primarily as the sulfate conjugate (50-70%) and as the
parent drug (25%). The remaining fraction is excreted as other
metabolites, including methyldopamine, methylnorepinephrine, and
O-methylated products of these catecholamines. The t 1/2
of methyldopa
is prolonged to 4-6 hours in patients with renal failure.
In spite of its rapid absorption and short t 1/2
, the peak effect
of methyldopa is delayed for 6-8 hours, even after intravenous
administration, and the duration of action of a single dose is usually
about 24 hours; this permits once- or twice-daily dosing. The discrepancy
between the effects of methyldopa and the measured concentrations
of the drug in plasma is most likely related to the time
required for transport into the CNS, conversion to the active metabolite
storage of α-methylnorepinephrine and its subsequent release in
the vicinity of relevant α 2
receptors in the CNS. This is a good example
of the potential for a complex relationship between a drug’s pharmacokinetics
and its pharmacodynamics. Patients with renal failure
are more sensitive to the antihypertensive effect of methyldopa, but
it is not known if this is due to alteration in excretion of the drug or
to an increase in transport into the CNS.
Adverse Effects and Precautions. Methyldopa produces sedation that
is largely transient. A diminution in psychic energy may persist in
some patients, and depression occurs occasionally. Methyldopa may
produce dryness of the mouth. Other adverse effects include diminished
libido, parkinsonian signs, and hyperprolactinemia that may
become sufficiently pronounced to cause gynecomastia and galactorrhea.
Methyldopa may precipitate severe bradycardia and sinus
arrest.
Methyldopa also produces some adverse effects that are not
related to its pharmacological action. Hepatotoxicity, sometimes
associated with fever, is an uncommon but potentially serious toxic
effect of methyldopa. At least 20% of patients who receive methyldopa
for a year develop a positive Coombs test (antiglobulin test)
that is due to autoantibodies directed against the Rh antigen on erythrocytes.
The development of a positive Coombs test is not necessarily
an indication to stop treatment with methyldopa; 1-5% of these
patients will develop a hemolytic anemia that requires prompt discontinuation
of the drug. The Coombs test may remain positive for
as long as a year after discontinuation of methyldopa, but the
hemolytic anemia usually resolves within a matter of weeks. Severe
hemolysis may be attenuated by treatment with glucocorticoids.
Adverse effects that are even more rare include leukopenia, thrombocytopenia,
red cell aplasia, lupus erythematosus–like syndrome,
lichenoid and granulomatous skin eruptions, myocarditis, retroperitoneal
fibrosis, pancreatitis, diarrhea, and malabsorption.
Therapeutic Uses. Methyldopa is a preferred drug for treatment of
hypertension during pregnancy based on its effectiveness and safety
for both mother and fetus. The usual initial dose of methyldopa is
250 mg twice daily, and there is little additional effect with doses
>2 g/day. Administration of a single daily dose of methyldopa at bedtime
minimizes sedative effects, but administration twice daily is
required for some patients.
Clonidine, Guanabenz, and Guanfacine
The detailed pharmacology of the α 2
adrenergic agonists
clonidine, guanabenz, and guanfacine is discussed
in Chapter 12. These drugs stimulate the α 2A
subtype of
α 2
adrenergic receptors in the brainstem, resulting in
a reduction in sympathetic outflow from the CNS
(Macmillan et al., 1996). The decrease in plasma concentrations
of NE is correlated directly with the
hypotensive effect (Goldstein et al., 1985). Patients who
have had a spinal cord transection above the level of the
sympathetic outflow tracts do not display a hypotensive
response to clonidine. At doses higher than those
required to stimulate central α 2A
receptors, these drugs
can activate α 2
receptors of the α 2B
subtype on vascular
smooth muscle cells (MacMillan et al., 1996). This
effect accounts for the initial vasoconstriction that is
seen when overdoses of these drugs are taken, and may
be responsible for the loss of therapeutic effect that is
observed with high doses. A major limitation in the use
of these drugs is the paucity of information about their
efficacy in reducing the risk of cardiovascular consequences
of hypertension.
Pharmacological Effects. The α 2
adrenergic agonists
lower arterial pressure by an effect on both cardiac output
and peripheral resistance. In the supine position,
when the sympathetic tone to the vasculature is low, the
major effect is to reduce both heart rate and stroke volume;
however, in the upright position, when sympathetic
outflow to the vasculature is normally increased,
these drugs reduce vascular resistance. This action may
lead to postural hypotension. The decrease in cardiac
sympathetic tone leads to a reduction in myocardial
contractility and heart rate that could promote congestive
heart failure in susceptible patients.
Adverse Effects and Precautions. Many patients experience annoying
and sometimes intolerable adverse effects with these drugs.
Sedation and xerostomia are prominent adverse effects. The xerostomia
may be accompanied by dry nasal mucosa, dry eyes, and