Page 200 - Basic _ Clinical Pharmacology ( PDFDrive )

186 SECTION III Cardiovascular-Renal Drugs

before each administration and covered with opaque foil. Infusion well characterized. The remainder is excreted unchanged. Its half-
solutions should be changed after several hours. Dosage typically life is approximately 24 hours, but the relationship between blood
begins at 0.5 mcg/kg/min and may be increased up to 10 mcg/kg/ concentration and hypotensive action is not well established. The
min as necessary to control blood pressure. Higher rates of infu- blood pressure-lowering effect after a rapid injection is established
sion, if continued for more than an hour, may result in toxicity. within 5 minutes and lasts for 4–12 hours.
Because of its efficacy and rapid onset of effect, nitroprusside When diazoxide was first marketed for use in hypertension, a
should be administered by infusion pump and arterial blood dose of 300 mg by rapid injection was recommended. It appears,
pressure continuously monitored via intra-arterial recording. however, that excessive hypotension can be avoided by beginning
with smaller doses (50–150 mg). If necessary, doses of 150 mg
Toxicity may be repeated every 5–15 minutes until blood pressure is low-
ered satisfactorily. Alternatively, diazoxide may be administered
Other than excessive blood pressure lowering, the most serious
toxicity is related to accumulation of cyanide; metabolic acidosis, by intravenous infusion at rates of 15–30 mg/min. Because of
arrhythmias, excessive hypotension, and death have resulted. In a reduced protein binding, smaller doses should be administered
few cases, toxicity after relatively low doses of nitroprusside sug- to persons with chronic renal failure. The hypotensive effects of
gested a defect in cyanide metabolism. Administration of sodium diazoxide are also greater when patients are pretreated with
thiosulfate as a sulfur donor facilitates metabolism of cyanide. β blockers to prevent the reflex tachycardia and associated increase
Hydroxocobalamin combines with cyanide to form the nontoxic in cardiac output.
cyanocobalamin. Both have been advocated for prophylaxis or
treatment of cyanide poisoning during nitroprusside infusion. Toxicity
Thiocyanate may accumulate over the course of prolonged admin- The most significant toxicity from parenteral diazoxide has been
istration, usually several days or more, particularly in patients with excessive hypotension, resulting from the original recommenda-
renal insufficiency who do not excrete thiocyanate at a normal tion to use a fixed dose of 300 mg in all patients. Such hypoten-
rate. Thiocyanate toxicity is manifested as weakness, disorienta- sion has resulted in stroke and myocardial infarction. The reflex
tion, psychosis, muscle spasms, and convulsions, and the diagnosis sympathetic response can provoke angina, electrocardiographic
is confirmed by finding serum concentrations greater than 10 mg/ evidence of ischemia, and cardiac failure in patients with ischemic
dL. Rarely, delayed hypothyroidism occurs, owing to thiocyanate heart disease, and diazoxide should be avoided in this situation.
inhibition of iodide uptake by the thyroid. Methemoglobinemia Occasionally, hyperglycemia complicates diazoxide use, particu-
during infusion of nitroprusside has also been reported. larly in persons with renal insufficiency.
In contrast to the structurally related thiazide diuretics, diazox-
DIAZOXIDE ide causes renal salt and water retention. However, because the
drug is used for short periods only, this is rarely a problem.
Diazoxide is an effective and relatively long-acting potassium
channel opener that causes hyperpolarization in smooth muscle FENOLDOPAM
and pancreatic β cells. Because of its arteriolar dilating property, it
was formerly used parenterally to treat hypertensive emergencies. Fenoldopam is a peripheral arteriolar dilator used for hypertensive
Injection of diazoxide results in a rapid fall in systemic vascular emergencies and postoperative hypertension. It acts primarily as an
resistance and mean arterial blood pressure. At present, it is used agonist of dopamine D receptors, resulting in dilation of periph-
1
orally in the USA for the treatment of hypoglycemia in hyperinsu- eral arteries and natriuresis. The commercial product is a racemic
linism. Diazoxide inhibits insulin release from the pancreas (prob- mixture with the (R)-isomer mediating the pharmacologic activity.
ably by opening potassium channels in the beta cell membrane) Fenoldopam is rapidly metabolized, primarily by conjugation.
and is used to treat hypoglycemia secondary to insulinoma. Its half-life is 10 minutes. The drug is administered by continu-

N ous intravenous infusion. Fenoldopam is initiated at a low dosage
CH 3 (0.1 mcg/kg/min), and the dose is then titrated upward every 15
or 20 minutes to a maximum dose of 1.6 mcg/kg/min or until the
NH
CI S desired blood pressure reduction is achieved.
O 2 As with other direct vasodilators, the major toxicities are reflex
Diazoxide tachycardia, headache, and flushing. Fenoldopam also increases intra-
ocular pressure and should be avoided in patients with glaucoma.
Pharmacokinetics & Dosage
Oral dosage for hypoglycemia is 3–8 mg/kg/day in 3 divided CALCIUM CHANNEL BLOCKERS
doses, with a maximum of 15 mg/kg/day. Diazoxide is similar
chemically to the thiazide diuretics but has no diuretic activity. In addition to their antianginal (see Chapter 12) and antiarrhyth-
It is bound extensively to serum albumin and to vascular tissue. mic effects (see Chapter 14), calcium channel blockers also reduce
Diazoxide is partially metabolized; its metabolic pathways are not peripheral resistance and blood pressure. The mechanism of action