When diazoxide was first marketed for use in hypertension, a dose of 300 mg by rapid injection was recommended. It appears, however, that excessive hypotension can be avoided by beginning with smaller doses (50–150 mg). If necessary, doses of 150 mg may be repeated every 5–15 minutes until blood pressure is lowered satisfactorily. Alternatively, diazoxide may be administered by intravenous infusion at rates of 15–30 mg/min. Because of reduced protein binding, smaller doses should be administered to persons with chronic renal failure. The hypotensive effects of diazoxide are also greater when patients are pretreated with β blockers to prevent the reflex tachycardia and associated increase in cardiac output.
The most significant toxicity from parenteral diazoxide has been excessive hypotension, resulting from the original recommendation to use a fixed dose of 300 mg in all patients. Such hypotension has resulted in stroke and myocardial infarction. The reflex sympathetic response can provoke angina, electrocardiographic evidence of ischemia, and cardiac failure in patients with ischemic heart disease, and diazoxide should be avoided in this situation. Occasionally, hyperglycemia complicates diazoxide use, particularly in persons with renal insufficiency.
In contrast to the structurally related thiazide diuretics, diazoxide causes renal salt and water retention. However, because the drug is used for short periods only, this is rarely a problem.
Fenoldopam is a peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension. It acts primarily as an agonist of dopamine D1 receptors, resulting in dilation of peripheral arteries and natriuresis. The commercial product is a racemic mixture with the (R)-isomer mediating the pharmacologic activity.
Fenoldopam is rapidly metabolized, primarily by conjugation. Its half-life is 10 minutes. The drug is administered by continuous intravenous infusion. Fenoldopam is initiated at a low dosage (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 desired blood pressure reduction is achieved.
As with other direct vasodilators, the major toxicities are reflex tachycardia, headache, and flushing. Fenoldopam also increases intra-ocular pressure and should be avoided in patients with glaucoma.
In addition to their antianginal (see Chapter 12) and antiarrhythmic effects (see Chapter 14), calcium channel blockers also reduce peripheral resistance and blood pressure. The mechanism of action in hypertension (and, in part, in angina) is inhibition of calcium influx into arterial smooth muscle cells.
Verapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and nitrendipine [withdrawn in the USA]) are all equally effective in lowering blood pressure, and many formulations are currently approved for this use in the USA. Clevidipine is a newer member of this group that is formulated for intravenous use only.