Chapter 15: Hypotensive Agents

A multitude of drugs are capable of lowering blood pressure, including volatile anesthetics, sympathetic antagonists and agonists, calcium channel blockers, β-blockers, and angiotensin-converting enzyme inhibitors. This chapter examines agents that may be useful to the anesthesiologist for perioperative control of arterial blood pressure.

As patients age, so too does their vasculature. When a pulse wave is generated by ventricular contraction, it is propagated through the arterial system. At branch points of the aorta, the wave is reflected back toward the heart. In younger patients, the reflected wave tends to augment diastole, improving diastolic pressure. In older patients, the wave arrives sooner, being conducted back by the noncompliant vasculature during late systole, which causes an increase in cardiac workload and a decrease in diastolic pressure (Figure 15–1). Thus, older patients develop increased systolic pressure and decreased diastolic pressure. Widened pulse pressures (the difference between systolic and diastolic pressures) have been associated with both increased incidence of postoperative kidney dysfunction and increased risk of cerebral events in patients undergoing coronary bypass surgery.

β-Blocker therapy should be maintained perioperatively in patients who are being treated with β-blockers as a part of their routine medical regimen. The American College of Cardiology/American Heart Association guidelines for β-blocker use perioperatively should be followed (see Chapter 14). β-Blockers (esmolol, metoprolol, and others) were previously discussed for the treatment of transient perioperative hypertension and are routinely used during anesthesia. This chapter discusses antihypertensive agents other than adrenergic antagonists that are used perioperatively. Antihypertensive agents are critically important for managing hypertensive emergencies (blood pressure >180/120 mm Hg) with signs of organ injury (eg, encephalopathy). Excepting patients with acute aortic dissection, mean arterial pressure should be reduced gradually to prevent organ hypoperfusion (eg, 20% decrease in mean arterial pressure or a diastolic blood pressure of 100–110 mm Hg initially). Prompt treatment of hypertension is also advisable following cardiac and intracranial surgery and other procedures where excessive bleeding is a major concern. Perioperative hypertension is often secondary to pain, anxiety, hypoxemia, hypercapnia, distended bladder, and failure to continue baseline antihypertensive medications. These primary etiologies should be considered and addressed when treating perioperative hypertension.

Blood pressure is the product of cardiac output and systemic vascular resistance. Agents that lower blood pressure reduce myocardial contractility or produce vasodilatation of the arterial and venous capacitance vessels, or both. Agents other than β-adrenergic blockers used to lower blood pressure include nitrovasodilators, calcium antagonists, adrenergic agonists, anesthetic agents, and angiotensin-converting enzyme inhibitors.

Mechanism of Action

Sodium nitroprusside (and other nitrovasodilators) relax both arteriolar and venous smooth muscle. Its primary mechanism of action is shared with other nitrates (eg, hydralazine and nitroglycerin). As nitrovasodilators are metabolized, they release nitric oxide, which activates guanylyl cyclase. This enzyme is responsible for the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP), which controls the phosphorylation of several proteins, including some involved in the control of free intracellular calcium and smooth muscle contraction.

Nitric oxide, a naturally occurring potent vasodilator released by endothelial cells (endothelium-derived relaxing factor), plays an important role in regulating vascular tone throughout the body. Its ultrashort half-life (<5 s) provides nimble endogenous control of regional blood flow. Inhaled nitric oxide is a selective pulmonary vasodilator that is used in the treatment of reversible pulmonary hypertension.

Clinical Uses

Sodium nitroprusside is a potent and reliable antihypertensive. It is usually diluted to a concentration of 100 mcg/mL and administered as a continuous intravenous infusion (0.25–5 mcg/kg/min). Its extremely rapid onset of action (1–2 min) and fleeting duration of action allow precise titration of arterial blood pressure. The potency of this drug requires frequent blood pressure measurements—or, preferably, intraarterial monitoring—and the use of mechanical infusion pumps. Solutions of sodium nitroprusside must be protected from light because of photodegradation.

Metabolism

After parenteral injection, sodium nitroprusside enters red blood cells, where it receives an electron from the iron (Fe²⁺) of oxyhemoglobin. This nonenzymatic electron transfer results in an unstable nitroprusside radical and methemoglobin (Hgb Fe³⁺). The former moiety spontaneously decomposes into five cyanide ions and the active nitroso (N O) group.

The cyanide ions can be involved in one of three possible reactions: (1) binding to methemoglobin to form cyanmethemoglobin; (2) undergoing a reaction in the liver and kidney catalyzed by the enzyme rhodanase (thiosulfate + cyanide → thiocyanate); or (3) binding to tissue cytochrome oxidase, which interferes with normal oxygen utilization (Figure 15–2).

The last of these reactions underlies the development of acute cyanide toxicity, characterized by metabolic acidosis, cardiac arrhythmias, and increased venous oxygen content (as a result of the inability to utilize oxygen). Another early sign of cyanide toxicity is the acute resistance to the hypotensive effects of increasing doses of sodium nitroprusside (tachyphylaxis). Cyanide toxicity is more likely if the cumulative daily dose of sodium nitroprusside is greater than 500 mcg/kg or if the drug is administered at infusion rates greater than 2 mcg/kg/min for more than a few hours. Patients with cyanide toxicity should be mechanically ventilated with 100% oxygen to maximize oxygen availability. The pharmacological treatment of cyanide toxicity depends on providing alternative binding sites for cyanide ions by administering sodium thiosulfate (150 mg/kg over 15 min) or 3% sodium nitrite (5 mg/kg over 5 min), which oxidizes hemoglobin to methemoglobin. A methemoglobin concentration of 10% to 20% is the aim of nitrite administration. Caution should be exercised when inducing methemoglobinemia in patients experiencing cyanide toxicity secondary to combustion as carboxyhemoglobinemia from carbon monoxide poisoning might also be present. Additionally, hydroxocobalamin combines with cyanide to form cyanocobalamin (vitamin B₁₂) and likewise can be administered to treat cyanide poisoning. Cyanocobalamin is excreted by the kidney.

Thiocyanate is slowly cleared by the kidney. Accumulation of large amounts of thiocyanate (eg, in patients with kidney failure) may result in a milder toxic reaction that includes thyroid dysfunction, muscle weakness, nausea, hypoxia, and an acute toxic psychosis. The risk of cyanide toxicity is not increased by kidney failure, however. Methemoglobinemia from excessive doses of sodium nitroprusside or sodium nitrite can be treated with methylene blue (1–2 mg/kg of a 1% solution over 5 min), which reduces methemoglobin to hemoglobin.

Effects on Organ Systems

The combined dilation of venous and arteriolar vascular beds by sodium nitroprusside results in reductions of preload and afterload. Arterial blood pressure falls due to the decrease in peripheral vascular resistance. Although cardiac output is usually unchanged in normal patients, the reduction in afterload may increase cardiac output in patients with congestive heart failure, mitral regurgitation, or aortic regurgitation. In opposition to any favorable changes in myocardial oxygen requirements are reflex-mediated responses to the fall in arterial blood pressure. These include tachycardia and increased myocardial contractility. In addition, dilation of coronary arterioles by sodium nitroprusside may result in an intracoronary steal of blood flow away from ischemic areas that are already maximally dilated.

Sodium nitroprusside dilates cerebral vessels and abolishes cerebral autoregulation. Cerebral blood flow is maintained or increases unless arterial blood pressure is markedly reduced. The resulting increase in cerebral blood volume tends to increase intracranial pressure, particularly in patients with reduced intracranial compliance (eg, brain tumors). This intracranial hypertension can be minimized by slow administration of sodium nitroprusside and institution of hypocapnia.

The pulmonary vasculature also dilates in response to sodium nitroprusside infusion. Reductions in pulmonary artery pressure may decrease the perfusion of some normally ventilated alveoli, increasing physiological dead space. By dilating pulmonary vessels, sodium nitroprusside may prevent the normal vasoconstrictive response of the pulmonary vasculature to hypoxia (hypoxic pulmonary vasoconstriction). Both of these effects tend to mismatch pulmonary ventilation to perfusion, increase venous admixture, and decrease arterial oxygenation.

In response to decreased arterial blood pressure, renin and catecholamines are released during administration of nitroprusside. Renin release can be inhibited with β-blockers. Kidney function is fairly well maintained during sodium nitroprusside infusion, despite moderate drops in arterial blood pressure and renal perfusion.

Mechanism of Action

Nitroglycerin relaxes vascular smooth muscle, with venous dilation predominating over arterial dilation. Its mechanism of action is similar to that of sodium nitroprusside: metabolism to nitric oxide, which activates guanylyl cyclase, leading to increased cGMP, decreased intracellular calcium, and vascular smooth muscle relaxation.

Clinical Uses

Nitroglycerin relieves myocardial ischemia, hypertension, and ventricular failure. Like sodium nitroprusside, nitroglycerin is commonly diluted to a concentration of 100 mcg/mL and administered as a continuous intravenous infusion (0.5–5 mcg/kg/min). In the past glass containers and special intravenous tubing were recommended because of the adsorption of nitroglycerin to polyvinylchloride, but these are now rarely used. Nitroglycerin can also be administered by a sublingual (peak effect in 4 min) or transdermal (sustained release for 24 h) route.

Metabolism

Nitroglycerin undergoes rapid reductive hydrolysis in the liver and blood by glutathione-organic nitrate reductase. One metabolic product is nitrite, which can convert hemoglobin to methemoglobin. Significant methemoglobinemia is rare and can be treated with intravenous methylene blue (1–2 mg/kg over 5 min).

Nitroglycerin reduces myocardial oxygen demand and increases myocardial oxygen supply by several mechanisms:

• The pooling of blood in the large-capacitance vessels reduces the effective circulating blood volume and preload. The accompanying decrease in ventricular end-diastolic pressure reduces myocardial oxygen demand and increases endocardial perfusion.

• Any afterload reduction from arteriolar dilation will decrease both end-systolic pressure and oxygen demand. Of course, a fall in diastolic pressure may lower coronary perfusion pressure and actually decrease myocardial oxygen supply.

• Nitroglycerin redistributes coronary blood flow to ischemic areas of the subendocardium.

• Coronary artery spasm may be relieved.

The beneficial effect of nitroglycerin in patients with coronary artery disease contrasts with the coronary steal phenomenon seen with sodium nitroprusside. Preload reduction makes nitroglycerin an excellent drug for the relief of cardiogenic pulmonary edema. Heart rate is unchanged or minimally increased. Rebound hypertension is less likely after discontinuation of nitroglycerin than following discontinuation of sodium nitroprusside. The prophylactic administration of low-dose nitroglycerin to high-risk patients undergoing surgery and anesthesia has no proven benefit.

The effects of nitroglycerin on cerebral blood flow and intracranial pressure are similar to those of sodium nitroprusside. Headache from dilation of cerebral vessels is a common side effect of nitroglycerin. In addition to the dilating effects on the pulmonary vasculature (previously described for sodium nitroprusside), nitroglycerin relaxes bronchial smooth muscle.

Nitroglycerin (50–100 mcg boluses) has been demonstrated to be an effective (but transient) uterine relaxant that can be beneficial during certain obstetrical procedures if the placenta is still present in the uterus (eg, retained placenta, uterine inversion, uterine tetany, breech extraction, and external version of the second twin). Nitroglycerin therapy has been shown to diminish platelet aggregation.

Hydralazine relaxes arteriolar smooth muscle in multiple ways, including dilation of precapillary resistance vessels via increased cGMP.

Intraoperative hypertension is sometimes controlled with an intravenous dose of 5 to 20 mg of hydralazine. The onset of action is within 15 min, and the antihypertensive effect usually lasts 2 to 4 h. The delayed onset and prolonged duration have made this agent much less attractive than others for perioperative use. Hydralazine can be used to control pregnancy-induced hypertension.

Hydralazine undergoes acetylation and hydroxylation in the liver.

Effects on Organ Systems

The lowering of peripheral vascular resistance causes a drop in arterial blood pressure. The body reacts to a hydralazine-induced fall in blood pressure by increasing heart rate, myocardial contractility, and cardiac output. These compensatory responses can be detrimental to patients with coronary artery disease and are minimized by the concurrent administration of a β-adrenergic antagonist. Conversely, the decline in afterload often proves beneficial to patients in congestive heart failure.

Hydralazine is a potent cerebral vasodilator and inhibitor of cerebral blood flow autoregulation. Unless blood pressure is markedly reduced, cerebral blood flow and intracranial pressure will rise.

Renal blood flow is usually maintained or increased by hydralazine.

Mechanism of Action

Fenoldopam causes rapid vasodilation by selectively activating D₁-dopamine receptors. The R-isomer is responsible for the racemic mixture’s biological activity due to its much greater receptor affinity, compared with the S-isomer.

Clinical Uses

Fenoldopam (infusion rates studied in clinical trials range from 0.01 to 1.6 mcg/kg/min) reduces systolic and diastolic blood pressure in patients with malignant hypertension to an extent comparable to nitroprusside. Side effects include headache, flushing, nausea, tachycardia, hypokalemia, and hypotension. The onset of the hypotensive effect occurs within 15 min, and discontinuation of an infusion quickly reverses this effect without rebound hypertension. Some degree of tolerance may develop 48 h after the infusion. Studies are mixed regarding fenoldopam’s ability to “protect” and “maintain” kidney function in perioperative patients with hypertension at risk of perioperative kidney injury.

Metabolism

Fenoldopam undergoes conjugation without participation of the cytochrome P-450 enzymes, and its metabolites are inactive. Clearance of fenoldopam remains unaltered despite the presence of kidney or hepatic failure, and no dosage adjustments are necessary for these patients.

Effects on Organ Systems

Fenoldopam decreases systolic and diastolic blood pressure. Heart rate typically increases. Low initial doses (0.03–0.1 mcg/kg/min) titrated slowly have been associated with less reflex tachycardia than higher doses. Tachycardia decreases over time but remains substantial at higher doses.

Fenoldopam can lead to rises in intraocular pressure and should be administered with caution or avoided in patients with a history of glaucoma or intraocular hypertension.

As would be expected from a D₁-dopamine receptor agonist, fenoldopam markedly increases kidney blood flow. Despite a drop in arterial blood pressure, the glomerular filtration rate is well maintained. Fenoldopam increases urinary flow rate, urinary sodium extraction, and creatinine clearance compared with sodium nitroprusside.

Dihydropyridine calcium channel blockers (nicardipine, clevidipine) are arterial selective vasodilators routinely used for perioperative blood pressure control in patients undergoing cardiothoracic surgery. Clevidipine, prepared as a lipid emulsion, has a short half- life secondary to rapid metabolism by blood esterases, which facilitates its rapid titration. Clevidipine is infused initially at a rate of 1 to 2 mg/h, with the dose doubled until the desired effect is obtained, up to 16 mg/h. Because of its formulation as a lipid emulsion it is contraindicated in patients with soy or egg allergies and those with impaired lipid metabolism. Unlike verapamil and diltiazem, the dihydropyridine calcium channel blockers have minimal effects on cardiac conduction and ventricular contractility. These calcium channel blockers bind to L-type calcium channel and impair calcium entry into the vascular smooth muscle. L-type receptors are more prevalent on arterial than venous capacitance vessels. Consequently, cardiac filling and preload are less affected by these agents than by nitrates, which might dilate both arterial and venous systems. With preload maintained, cardiac output often increases when vascular tone is reduced by use of dihydropyridine calcium blockers. Nicardipine infusion is titrated to effect (5–15 mg/h).

Another intravenous agent that can produce hypotension perioperatively is the intravenous angiotensin-converting enzyme inhibitor enalaprilat (0.625–1.25 mg). The role of enalaprilat as a nondirect-acting agent in the acute treatment of a hypertensive crisis is limited.