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 these drugs 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 sensitive endogenous control of regional blood flow.
Inhaled nitric oxide is a selective pulmonary vasodilator that is beneficial and routinely used in the treatment of reversible pulmonary hypertension.
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 (0.5-10 mcg/kg/min). Its extremely rapid onset of action (1-2 min) and fleeting duration of action allow precise titration of arterial blood pressure. A bolus of 1-2 mcg/kg minimizes blood pressure elevation during laryngoscopy but can cause transient hypotension in some patients. 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.
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: binding to methemoglobin to form cyanmethemoglobin; undergoing a reaction in the liver and kidney catalyzed by the enzyme rhodanase (thiosulfate + cyanide → thiocyanate); or binding to tissue cytochrome oxidase, which interferes with normal oxygen utilization (Figure 15-2).
The last of these reactions is responsible for 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). It should be noted that tachyphylaxis implies acute tolerance to the drug following multiple rapid injections, as opposed to tolerance, which is caused by more chronic exposure. Cyanide toxicity is more likely if the cumulative dose of sodium nitroprusside
is greater than 500 mcg/kg administered at an infusion rate faster than 2 mcg/kg/min. Patients with cyanide toxicity should be mechanically ventilated with 100% oxygen
to maximize oxygen
availability. The pharmacological treatment of cyanide toxicity depends on increasing the kinetics of the two reactions by administering sodium thiosulfate (150 mg/kg over 15 min) or 3% sodium nitrate (5 mg/kg over 5 min), which oxidizes hemoglobin to methemoglobin. Hydroxocobalamin
combines with cyanide to form cyanocobalamin
Thiocyanate is slowly cleared by the kidney. Accumulation of large amounts of thiocyanate (eg, in patients with renal 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 renal failure, however. Methemoglobinemia from excessive doses of sodium nitroprusside or sodium nitrate can be treated with methylene blue (1-2 mg/kg of a 1% solution over 5 min), which reduces methemoglobin to hemoglobin.
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 and decrease arterial oxygenation.
In response to decreased arterial blood pressure, renin and catecholamines are released during administration of nitroprusside. Renal function is fairly well maintained during sodium nitroprusside infusion, despite moderate drops in arterial blood pressure and renal perfusion.
Sodium nitroprusside does not directly interact with neuromuscular blocking agents. Nonetheless, a decrease in muscle blood flow caused by arterial hypotension could indirectly delay the onset and prolong the duration of neuromuscular blockade.
Nitroglycerin relaxes vascular smooth muscle, with venous dilation predominating over arterial dilation. Its mechanism of action is presumably 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.
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 (0.5-10 mcg/kg/min). Glass containers and special intravenous tubing are recommended because of the adsorption of nitroglycerin to polyvinylchloride. Nitroglycerin can also be administered by a sublingual (peak effect in 4 min) or transdermal (sustained release for 24 h) route. Some patients seem to require higher than expected doses of nitroglycerin to achieve a given drop in blood pressure, particularly after chronic administration (tolerance). Tolerance may be due to depletion of reactants necessary for nitric oxide formation, compensatory secretion of vasoconstrictive substances, or volume expansion. Dosing regimens that provide for intermittent periods of low or no drug exposure may minimize the development of tolerance.
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 venous return 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
(0.5-2.0 mcg/kg/min) during anesthesia of patients at high risk for perioperative myocardial ischemia remains controversial.
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, an effect enhanced by administration of N-acetylcysteine.
relaxes arteriolar smooth muscle, causing dilation of precapillary resistance vessels via increased cGMP.
Intraoperative hypertension is usually controlled with an intravenous dose of 5-20 mg of hydralazine. The onset of action is within 15 min, and the antihypertensive effect usually lasts 2-4 hr. Hydralazine can be used to control pregnancy-induced hypertension.
Hydralazine undergoes acetylation and hydroxylation in the liver.
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.