The Ballad of Johnny Nitro Nitrates

1.1 "The Ballad of Johnny Nitro": Nitrates Physiology Angina results from an imbalance in oxygen demand & delivery symptoms, need to immediately have vasodilator to oxygen delivery (blasting open obstruction). ischemia (rock looks like anvil). For acute treatment of Prinzmetal angina is d/t coronary vasospasm (John Henry wearing angina medal) muscular Phosphorylation of myosin light chain in vascular smooth muscle cells allows myosin interaction with actin contraction & consequent vasoconstriction (chain around legs & arms of chain gang = myosin light chain; P locks [= phosphate groups] allowing chain to constrict prisoners' legs; baggy blue pants & red shirts constricted at cuffs arterial & venous constriction). Nitric oxide (NO) is produced endogenously by endothelial NO synthase (eNOS) in response to platelet-derived factors, shear stress, acetylcholine, and cytokines. NO increases cGMP in vascular smooth muscle cells (grumpy man controlling steam drill) → Ca. Decreased calcium decreases activity of myosin light chain kinase, resulting in myosin dephosphorylation, preventing myosin interaction with actin (P locks being removed, preventing chains from working & decreasing constriction of prisoners' legs; freed prisoner). cGMP cases venous dilation & venous capacitance; veins are most sensitive preload (Preload tank with↓↓ arrows). Results in cardiac filling & wall stress, pulmonary vascular pressure, CO, which combined add up to decreased myocardial oxygen demand (blacksmith has removed 02 mask). Have some vasodilation of larger arteries → mild SVR Nitrates Exogenous nitrates include nitroglycerin, isosorbide mononitrate (single stick of dynamite), & Isosorbide dinitrate (double stick of dynamite) Organic nitrates are metabolized in vascular smooth muscle cells release of gaseous NO (white NO exhaust emanating from steam drill). Act analogously to endogenously synthesized NO →→ Decreased myocardial O2 demands Oral bioavailability is low. Sublingual is preferred to avoid first pass metabolism for acute symptom relief. Duration of action is very short, and is not suitable for prophylaxis or maintenance therapy Indications: Given orally for maintenance therapy in chronic stable angina (anvil rock; dynamite being thrown into mouth-shaped cave). Isosorbide mononitrate & dinitrate are oral formulations. Doses much higher for sufficient levels to survive first pass metabolism Sublingual formulations for acute symptoms of either Prinzmetal or "angina of effort" (folded shoe tongue on anvil) Acute coronary syndrome (ACS) (broken string guitar). Symptomatic treatment only; no mortality benefit in ACS. ACS includes: unstable angina (episodes of angina at rest, increase in severity, frequency, or duration of chest pain in patients with previously stable angina), NSTEMI, STEMI. Acute treatment of pulmonary edema (guy with lung-shaped sweat stains on shirt), as seen in a hypertensive crisis Lowering BP in HTN crisis (involving the presence of end organ damage) (emergency shut off switch) Adverse effects Orthostatic hypotension, up to syncope d/t venous blood pooling in lower extremities (fainting gal) BP can lead to reflex tachycardia (doc with reflex hammer). To maintain low levels of heart stress, may combine with a B-blocker in some patients to prevent this occurrence (ẞ bugler blocking doctor). Throbbing headaches, flushing d/t vasodilation (guy holding his head, looking a bit sunburned) Prolonged infusion of high dose nitrate may cause methemoglobinemia (rusty wheels on dynamite cart) May develop tolerance to nitrate effects over time (tachyphylaxis) ("We will not tolerate" protester). May be d/t decreased metabolism over time in vascular endothelium (tachycardia, contractility, salt & water retention) Avoid with nitrate free intervals of one day ("We will not tolerate 24h days!") Seen more with continuous exposure as in workplace may see loss of tolerance over weekends, causing headache & dizziness to recur on Mondays; hence the name Monday Disease (Monday clock). Contraindications Do not coadminister with sildenafil (coal filling station) or other PDE5 inhibitors (synergism ↑risk of severe hypotension). Nitrates should be avoided in patients who have taken such rx in last 24 hours d/t risk of hypotension ↓preload should be avoided in hypertrophic obstructive cardiomyopathy (as preload will cause toutflow tract obstruction) & R-sided MI d/t decreased RV preload (want the latter to be enhanced) (large heart-shaped smokestack on train with right side painted white)