Page 199 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 11 Antihypertensive Agents 185

population (see Chapter 4). As a consequence, rapid acetylators Pharmacokinetics & Dosage
have greater first-pass metabolism, lower blood levels, and less
antihypertensive benefit from a given dose than do slow acety- Pharmacokinetic parameters of minoxidil are listed in Table 11–2.
lators. The half-life of hydralazine ranges from 1.5 to 3 hours, Even more than with hydralazine, the use of minoxidil is associated
but vascular effects persist longer than do blood concentrations, with reflex sympathetic stimulation and sodium and fluid reten-
possibly due to avid binding to vascular tissue. tion. Minoxidil must be used in combination with a β blocker
and a loop diuretic.
N
Toxicity
N
Tachycardia, palpitations, angina, and edema are observed when
doses of co-administered β blockers and diuretics are inadequate.
N NH 2
H Headache, sweating, and hypertrichosis (the latter particularly
Hydralazine bothersome in women) are relatively common. Minoxidil illus-
trates how one person’s toxicity may become another person’s
Usual dosage ranges from 40 to 200 mg/d. The higher dosage therapy. Topical minoxidil (as Rogaine) is used as a stimulant to
was selected as the dose at which there is a small possibility of hair growth for correction of baldness.
developing the lupus erythematosus-like syndrome described in
the next section. However, higher dosages result in greater vaso-
dilation and may be used if necessary. Dosing two or three times SODIUM NITROPRUSSIDE
daily provides smooth control of blood pressure.
Sodium nitroprusside is a powerful parenterally administered
Toxicity vasodilator that is used in treating hypertensive emergencies as
well as severe heart failure. Nitroprusside dilates both arterial and
The most common adverse effects of hydralazine are headache,
nausea, anorexia, palpitations, sweating, and flushing. In patients venous vessels, resulting in reduced peripheral vascular resistance
with ischemic heart disease, reflex tachycardia and sympathetic and venous return. The action occurs as a result of activation
stimulation may provoke angina or ischemic arrhythmias. With of guanylyl cyclase, either via release of nitric oxide or by direct
dosages of 400 mg/d or more, there is a 10–20% incidence— stimulation of the enzyme. The result is increased intracellular
chiefly in persons who slowly acetylate the drug—of a syndrome cGMP, which relaxes vascular smooth muscle (see Figure 12–2).
characterized by arthralgia, myalgia, skin rashes, and fever that In the absence of heart failure, blood pressure decreases, owing
resembles lupus erythematosus. The syndrome is not associated to decreased vascular resistance, whereas cardiac output does not
with renal damage and is reversed by discontinuance of hydrala- change or decreases slightly. In patients with heart failure and low
zine. Peripheral neuropathy and drug fever are other serious but cardiac output, output often increases owing to afterload reduction.
uncommon adverse effects.
+ NO
MINOXIDIL
CN – CN –
Minoxidil is a very efficacious orally active vasodilator. The effect
results from the opening of potassium channels in smooth muscle Fe 2+
membranes by minoxidil sulfate, the active metabolite. Increased
potassium permeability stabilizes the membrane at its resting – –
potential and makes contraction less likely. Like hydralazine, min- CN CN
oxidil dilates arterioles but not veins. Because of its greater poten- –
tial antihypertensive effect, minoxidil should replace hydralazine CN
when maximal doses of the latter are not effective or in patients Nitroprusside
with renal failure and severe hypertension, who do not respond
well to hydralazine. Pharmacokinetics & Dosage

O Nitroprusside is a complex of iron, cyanide groups, and a nitroso
moiety. It is rapidly metabolized by uptake into red blood cells
H N N NH 2
2
with release of nitric oxide and cyanide. Cyanide in turn is metab-
olized by the mitochondrial enzyme rhodanese, in the presence of
N
a sulfur donor, to the less toxic thiocyanate. Thiocyanate is dis-
tributed in extracellular fluid and slowly eliminated by the kidney.
N
Nitroprusside rapidly lowers blood pressure, and its effects
disappear within 1–10 minutes after discontinuation. The drug is
given by intravenous infusion. Sodium nitroprusside in aqueous
Minoxidil solution is sensitive to light and must therefore be made up fresh