sodium nitroprusside

**Mechanism:** Nitroprusside is a prodrug that spontaneously releases NO (no enzymatic activation needed, unlike nitroglycerin) -> NO activates guanylate cyclase in vascular smooth muscle -> increased cGMP -> activation of protein kinase G -> decreased intracellular Ca2+ / myosin light chain dephosphorylation -> smooth muscle relaxation. Net effect: arterial AND venous dilation (balanced vasodilator), so it decreases both afterload and preload.

**Pharmacokinetics:** IV infusion only. Onset within seconds to ~1-2 min; duration 1-10 min after stopping; half-life ~2 min. Highly titratable; requires continuous arterial BP monitoring (ICU). Solution is light-sensitive (protect from light).

**Clinical uses:** - Hypertensive emergency (e.g., aortic dissection, usually together with a beta-blocker first to prevent reflex tachycardia and increased shear stress; hypertensive encephalopathy; malignant hypertension) - Acute decompensated heart failure / cardiogenic shock with high SVR (reduces preload and afterload) - Acute severe mitral or aortic regurgitation (afterload reduction, bridge to surgery) - Controlled hypotension during surgery

**Metabolism and toxicity (high-yield):** - Nitroprusside contains 5 cyanide (CN-) groups and 1 NO. In RBCs/tissues, it reacts with hemoglobin, releasing NO and cyanide. - Cyanide is converted by hepatic rhodanese (needs thiosulfate as a sulfur donor) to thiocyanate, which is renally excreted. - **Cyanide toxicity:** inhibits cytochrome c oxidase (complex IV) in the electron transport chain -> impaired aerobic respiration -> histotoxic hypoxia, lactic acidosis (anion gap), tachycardia/confusion/seizures/coma, headache, "bitter almond" breath, and bright red venous blood (high venous O2 because tissues can't extract it). Risk factors: high doses (>2 mcg/kg/min), prolonged infusion, hepatic failure, low thiosulfate stores/malnutrition. Treatment: stop infusion; give 100% O2; sodium nitrite (induces methemoglobin, which binds CN- to form cyanomethemoglobin) + sodium thiosulfate (provides sulfur for rhodanese), or hydroxocobalamin (binds CN- to form cyanocobalamin/vitamin B12); hydroxocobalamin is often preferred, especially with smoke inhalation, because nitrites cause methemoglobinemia and hypotension. - **Thiocyanate toxicity:** occurs with prolonged infusion (>24-48 h) or renal failure -> weakness, tinnitus, blurred vision, confusion, psychosis, hypothyroidism (inhibits iodide uptake), seizures. Monitor levels. - **Other adverse effects:** excessive hypotension, reflex tachycardia, methemoglobinemia (minor), headache, nausea. Coronary steal phenomenon / worsened myocardial ischemia (dilation of normal coronary arterioles diverts blood from ischemic regions), so avoid in acute MI. Can raise intracranial pressure via cerebral vasodilation (use caution in intracranial hemorrhage/high ICP). Can inhibit platelet aggregation.

**Comparison pearls:** - Nitroglycerin: predominantly venodilator (preload) at low doses; requires enzymatic bioactivation (mitochondrial ALDH2); tolerance develops. - Hydralazine/minoxidil/fenoldopam/clevidipine/nicardipine: arteriolar dilators. Fenoldopam is a D1 agonist (renal/mesenteric vasodilation). - Nitroprusside is NOT associated with tolerance to the same degree as nitrates in the short term, but tachyphylaxis can occur.

**Board pearl:** "Hypertensive emergency + IV drug with cyanide toxicity" = nitroprusside. Cyanide toxicity -> inhibits complex IV -> treat with hydroxocobalamin or nitrite + thiosulfate. Remember the thiocyanate toxicity in patients with renal failure. In aortic dissection, give a beta-blocker (e.g., esmolol/labetalol) before nitroprusside.