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

glomerular filtration are maintained, and plasma renin
activity increases. Unlike minoxidil, hydralazine, diazoxide,
and other arteriolar vasodilators, sodium nitroprusside
usually causes only a modest increase in heart
rate and an overall reduction in myocardial O 2
demand.
Absorption, Metabolism, and Excretion. Sodium nitroprusside is an
unstable molecule that decomposes under strongly alkaline conditions
or when exposed to light. The drug must be protected from light
and given by continuous intravenous infusion to be effective. Its onset
of action is within 30 seconds; the peak hypotensive effect occurs
within 2 minutes, and when the infusion of the drug is stopped, the
effect disappears within 3 minutes.
The metabolism of nitroprusside by smooth muscle is initiated
by its reduction, which is followed by the release of cyanide
and then NO (Bates et al., 1991). Cyanide is further metabolized by
liver rhodanase to form thiocyanate, which is eliminated almost
entirely in the urine. The mean elimination t 1/2
for thiocyanate is 3
days in patients with normal renal function, and it can be much
longer in patients with renal insufficiency.
Therapeutic Uses. Sodium nitroprusside is used primarily
to treat hypertensive emergencies but also can be used in
many situations when short-term reduction of cardiac
preload and/or afterload is desired. Nitroprusside has
been used to lower blood pressure during acute aortic
dissection; improve cardiac output in congestive heart
failure, especially in hypertensive patients with pulmonary
edema that does not respond to other treatment
(see Chapter 28); and decrease myocardial oxygen
demand after acute MI. In addition, nitroprusside is used
to induce controlled hypotension during anesthesia in
order to reduce bleeding in surgical procedures. In the
treatment of acute aortic dissection, it is important to
administer a β adrenergic receptor antagonist with nitroprusside,
because reduction of blood pressure with nitroprusside
alone can increase the rate of rise in pressure in
the aorta as a result of increased myocardial contractility,
thereby enhancing propagation of the dissection.
Sodium nitroprusside is available in vials that contain 50 mg.
The contents of the vial should be dissolved in 2-3 mL of 5% dextrose
in water. Addition of this solution to 250-1000 mL of 5%
dextrose in water produces a concentration of 50-200 μg/mL.
Because the compound decomposes in light, only fresh solutions
should be used, and the bottle should be covered with an opaque
wrapping. The drug must be administered as a controlled continuous
infusion, and the patient must be closely observed. The majority of
hypertensive patients respond to an infusion of 0.25-1.5 μg/kg/min.
Higher rates of infusion are necessary to produce controlled hypotension
in normotensive patients under surgical anesthesia. Patients who
are receiving other antihypertensive medications usually require less
nitroprusside to lower blood pressure. If infusion rates of 10 μg/kg/min
do not produce adequate reduction of blood pressure within 10 minutes,
the rate of administration of nitroprusside should be reduced to
minimize potential toxicity.
Toxicity and Precautions. The short-term adverse effects of nitroprusside
are due to excessive vasodilation, with hypotension and the consequences
thereof. Close monitoring of blood pressure and the use
of a continuous variable-rate infusion pump will prevent an excessive
hemodynamic response to the drug in the majority of cases.
Less commonly, toxicity may result from conversion of nitroprusside
to cyanide and thiocyanate. Toxic accumulation of cyanide
leading to severe lactic acidosis usually occurs when sodium nitroprusside
is infused at a rate >5 μg/kg/min but also can occur in some
patients receiving doses ~2 μg/kg/min for a prolonged period. The
limiting factor in the metabolism of cyanide appears to be the availability
of sulfur-containing substrates in the body (mainly thiosulfate).
The concomitant administration of sodium thiosulfate can
prevent accumulation of cyanide in patients who are receiving
higher-than-usual doses of sodium nitroprusside; the efficacy of the
drug is unchanged (Schulz, 1984). The risk of thiocyanate toxicity
increases when sodium nitroprusside is infused for more than
24-48 hours, especially if renal function is impaired. Signs and
symptoms of thiocyanate toxicity include anorexia, nausea, fatigue,
disorientation, and toxic psychosis. The plasma concentration of
thiocyanate should be monitored during prolonged infusions of nitroprusside
and should not be allowed to exceed 0.1 mg/mL. Rarely,
excessive concentrations of thiocyanate may cause hypothyroidism by
inhibiting iodine uptake by the thyroid gland. In patients with renal failure,
thiocyanate can be removed readily by hemodialysis.
Nitroprusside can worsen arterial hypoxemia in patients with
chronic obstructive pulmonary disease because the drug interferes
with hypoxic pulmonary vasoconstriction and therefore promotes
mismatching of ventilation with perfusion.
Diazoxide. Diazoxide was used in the treatment of hypertensive
emergencies but fell out of favor at least in part due to the risk of
marked falls in blood pressure when large bolus doses of the drug
were used. Other drugs are now preferred for parenteral administration
in the control of hypertension. Diazoxide also is administered
orally (PROGLYCEM) to treat patients with various forms of hypoglycemia
(see Chapter 43).
NONPHARMACOLOGICAL THERAPY
OF HYPERTENSION
Nonpharmacological approaches to the treatment of
hypertension may be sufficient in patients with modestly
elevated blood pressure. Such approaches also can augment
the effects of antihypertensive drugs in patients
with more marked initial elevations in blood pressure.
The indications and efficacy of various lifestyle modifications
in hypertension are reviewed in a summary
statement from the Joint National Committee (Chobanian
et al., 2003).
• Reduction in body weight for people who are modestly
overweight or frankly obese may be useful
(Horvath et al., 2008).
• Restricting sodium consumption lowers blood pressure
in some patients. The Dietary Approaches to
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION