Nitroglycerin binds to the surface of endothelial cells and acts as substrate for formation of nitric oxide (NO). The nitric oxide then moves out of the endothelial cells and binds with its receptor on smooth muscle cell (Fig. 16.1). Once inside the smooth muscle cells, NO converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). The cGMP reduces cytosolic calcium levels by two mechanisms: First, cGMP-dependent protein kinase G is activated which prevents calcium entry into the cell. Second, mitochondrial uptake of calcium is simulated. The overall effect is decreased intracellular calcium levels resulting in smooth muscle cell relaxation [5].

The primary indication of nitroglycerin is the treatment and prevention of acute chest pain associated with angina pectoris. Acute onset of chest pain can be treated with quickly dissolving sublingual tablets (0.3–0.6 mg) or oral spray (0.4–0.8 mg) administered every 5 min until pain is relieved up to three doses within 15 min [6]. Prevention of pain can be achieved with quickly acting sublingual tablets (0.3–0.6 mg) or oral spray (0.4–0.8 mg) just prior to activity, or extended release tablets (isosorbide-5-mononitrate). The IV form of nitroglycerin is indicated for persistent unstable angina that is poorly responsive to oral form, congestive heart failure with acute MI, hypertensive emergency with acute pulmonary edema, and induction of intraoperative hypotension. Start 10–20 mcg/min and titrate up by 5–10 mcg/min every 5–10 min until desired effect. The maximum dose is 500 mcg/min [7]. Not recommended in pediatrics. Pregnancy safety: Category C, not known if it is secreted in breast milk.

Nitroglycerin decreases the anticoagulation effect of heparin, increases the paralytic effect of pancuronium, and potentiates the vasodilatory effect of phosphodiesterase inhibitors which can result in vasodilatory shock. Patients taking ASA >500 mg may have decreased metabolism of nitroglycerin. Nitroglycerin is contraindicated in hypersensitivity to nitrates, glaucoma and hypovolemia, head trauma, constrictive pericarditis, and cardiac tamponade.

The most common side effect is headache, which can be persistent and severe due to dilation of cerebral blood vessels. Other side effects include postural hypotension, tachycardia, syncope, palpitation, anxiety, dizziness, vertigo, anxiety, and weakness. Most of these side effects are related to excessive vasodilation.

Sodium nitroprusside is comprised of five cyanide moieties and one nitrosyl group. Once infused, it converts oxyhemoglobin (Fe⁺⁺) to methemoglobin (Fe⁺⁺⁺) and releases cyanide and NO moieties. Unlike nitroglycerin, SNP directly generates NO, which relaxes vascular smooth muscle by a similar mechanism described above. The cyanide moiety is converted to thiocyanate by thiosulfate sulfurtransferase within the liver. The conversion of cyanide to thiocyanate utilizes sulfur stores. Depletion of sulfur stores by malnutrition or in postoperative patients facilitates accumulation of cyanides and increases the risk of developing cyanide toxicity. The metabolite thiocyanate is excreted in the urine [8].

The rapid onset of action makes SNP ideal for the treatment of hypertensive crisis. The short duration of action allows SNP to be utilized for deliberate hypotension in a variety of surgical procedures, such as major spinal surgery.

The only route of administration of SNP is via an intravenous infusion. The dosing for pediatrics and adults is the same. The initial infusion rate is started low at 0.3 g/kg/min and is titrated up every few minutes to a maximum does of 10 g/kg/min [9]. It is not indicated in patients with renal impairment (creatinine clearance <10 ml/min). The use of higher doses limited to a maximum duration of 10 min. Nitroprusside should not be given to pregnant women. It is not known if SNP and its metabolites are excreted in human milk [6].

The most common side effects are hypotension, palpitations, restlessness, retching, retrosternal discomfort, and muscle twitching which are related to rapid reduction of blood pressure and disappear once infusion is discontinued. Less commonly seen are the following: significant methemoglobinemia whose incidence increases when the maximum recommended dose of 10 g/kg/min is infused for more than 16 h and when medications such as benzocaine and lidocaine that cause methemoglobinemia are concurrently administered. The administration of >2 mcg/kg/min in patients with renal insufficiency or administration at the maximum dose for greater than 24 h can increase the risk of cyanide toxicity [9]. The signs and symptoms of cyanide toxicity (>5 mg/dl) include metabolic acidosis, nausea, mental confusion, and muscle weakness. The degree of pulmonary shunting can also increase due to SNP attenuating the normal physiologic response of pulmonary artery constriction to hypoxia.

Hydralazine reduces afterload by causing arterial vasodilation. The decrease in diastolic blood pressure is greater than the decrease in the systolic blood pressure. Some studies suggest that potassium channels are opened for prolonged period causing hyperpolarization of the smooth muscle cells. Another proposed mechanism involves the production of NO stimulating cGMP as described previously [13]. Lastly, hydralazine has been shown to interfere with the release of calcium from the endoplasmic reticulum which inhibits vasoconstriction.

Hydralazine specifically dilates arteries which minimizes orthostatic hypotension that is associated with other vasodilators. Renal flow is usually maintained or slightly increased by hydralazine making it an ideal medication to use in patients with renal disease; however, clearance is dependent on renal function. Similarly, hydralazine is a first-line medication for the treatment of preeclampsia because it slightly increases uteroplacental blood flow. The reduction of afterload by this drug is beneficial for treatment of congestive heart failure when conventional therapy fails.