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

maximum recommended dose of hydralazine is 200 mg/day to minimize
the risk of drug-induced lupus syndrome.
K ATP
Channel Openers: Minoxidil
The discovery in 1965 of the hypotensive action of
minoxidil was a significant advance in the treatment of
hypertension, because the drug has proven to be efficacious
in patients with the most severe and drug-resistant
forms of hypertension.
Locus and Mechanism of Action. Minoxidil is not active
in vitro but must be metabolized by hepatic sulfotransferase
to the active molecule, minoxidil N-O sulfate; the
formation of this active metabolite is a minor pathway in
the metabolic disposition of minoxidil. Minoxidil sulfate
relaxes vascular smooth muscle in isolated systems
where the parent drug is inactive. Minoxidil sulfate activates
the ATP-modulated K + channel. By opening K +
channels in smooth muscle and thereby permitting K +
efflux, it causes hyperpolarization and relaxation of
smooth muscle (Leblanc et al., 1989).
Pharmacological Effects. Minoxidil produces arteriolar
vasodilation with essentially no effect on the capacitance
vessels; the drug resembles hydralazine and diazoxide
in this regard. Minoxidil increases blood flow
to skin, skeletal muscle, the gastrointestinal tract, and
the heart more than to the CNS. The disproportionate
increase in blood flow to the heart may have a metabolic
basis, in that administration of minoxidil is associated
with a reflex increase in myocardial contractility
and in cardiac output. The cardiac output can increase
markedly, as much as 3- to 4-fold. The principal determinant
of the elevation in cardiac output is the action of
minoxidil on peripheral vascular resistance to enhance
venous return to the heart; by inference from studies
with other drugs, the increased venous return probably
results from enhancement of flow in the regional vascular
beds, with a fast time constant for venous return to
the heart (Ogilvie, 1985). The adrenergically mediated
increase in myocardial contractility contributes to the
increased cardiac output but is not the predominant
causal factor.
The effects of minoxidil on the kidney are complex.
Minoxidil is a renal artery vasodilator, but systemic hypotension produced
by the drug occasionally can decrease renal blood flow. Renal
function usually improves in patients who take minoxidil for the
treatment of hypertension, especially if renal dysfunction is secondary
to hypertension (Mitchell et al., 1980). Minoxidil is a very potent
stimulator of renin secretion; this effect is mediated by a combination
of renal sympathetic stimulation and activation of the intrinsic
renal mechanisms for regulation of renin release.
Discovery of K + channels in a variety of cell types and in
ATP
mitochondria is prompting consideration of K + channel modulators
ATP
as therapeutic agents in myriad cardiovascular diseases (Pollesello
and Mebazaa, 2004) and may provide explanations for some of the
effects of minoxidil noted in the previous section. Various K + channels
possess different regulatory sulfonylurea receptor subunits and
ATP
thus exhibit tissue-specific responses. Recent studies suggest that certain
actions of K + channel openers can be influenced by hypercholesterolemia
and by concurrent administration of sulfonylurea
ATP
hypoglycemic agents (Miura and Miki, 2003).
Absorption, Metabolism, and Excretion. Minoxidil is well absorbed
from the GI tract. Although peak concentrations of minoxidil in
blood occur 1 hour after oral administration, the maximal hypotensive
effect of the drug occurs later, possibly because formation of
the active metabolite is delayed.
The bulk of the absorbed drug is eliminated by hepatic metabolism;
~20% is excreted unchanged in the urine. The major metabolite
of minoxidil is the glucuronide conjugate at the N-oxide position
in the pyrimidine ring. This metabolite is less active than minoxidil,
but it persists longer in the body. The extent of biotransformation of
minoxidil to its active metabolite, minoxidil N-O sulfate, has not
been evaluated in humans. Minoxidil has a plasma t 1/2
of 3-4 hours,
but its duration of action is 24 hours or occasionally even longer. It
has been proposed that persistence of minoxidil in vascular smooth
muscle is responsible for this discrepancy. However, without knowledge
of the pharmacokinetic properties of the active metabolite, an
explanation for the prolonged duration of action cannot be given.
Adverse Effects and Precautions. The adverse effects of minoxidil
can be severe and are divided into three major categories: fluid and
salt retention, cardiovascular effects, and hypertrichosis.
Retention of salt and water results from increased proximal
renal tubular reabsorption, which is in turn secondary to reduced renal
perfusion pressure and to reflex stimulation of renal tubular α adrenergic
receptors. Similar antinatriuretic effects can be observed with
the other arteriolar dilators (e.g., diazoxide and hydralazine). Although
administration of minoxidil causes increased secretion of renin and
aldosterone, this is not an important mechanism for retention of salt
and water in this case. Fluid retention usually can be controlled by
the administration of a diuretic. However, thiazides may not be sufficiently
efficacious, and it may be necessary to use a loop diuretic, especially
if the patient has any degree of renal dysfunction. Retention of
salt and water in patients taking minoxidil may be profound, requiring
large doses of loop diuretics to prevent edema formation.
The cardiac consequences of the baroreceptor-mediated activation
of the sympathetic nervous system during minoxidil therapy
are similar to those seen with hydralazine; there is an increase in
heart rate, myocardial contractility, and myocardial O 2
consumption.
Thus, myocardial ischemia can be induced by minoxidil in patients
with coronary artery disease. The cardiac sympathetic responses are
attenuated by concurrent administration of a β adrenergic blocker.
The adrenergically induced increase in renin secretion also can be
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION