1. Drugs in the Therapy of Angina Dr. Thomas Abraham PHAR417: Fall 2004

2. Regulation of vascular smooth muscle contractility by Nitric oxide:  Acetylcholine (via M 2 /M 3 receptors) and bradykinin (via B1/B2 receptors) causes endothelial cells on arteries and veins to release nitric oxide (NO).  Released NO travels through the wall of the blood vessel to reach the smooth muscle cells to initiate biological response.  NO binds and activates cytosolic guanylate cyclase, which converts GTP to cGMP.

3. Role of Nitric Oxide In Vascular smooth muscle relaxation.  The overall effect of the cGMP-PKG system is to cause smooth muscle relaxation by decreasing intracellular calcium levels to decrease actin-myosin interactions: - phosphorylates and inactivate PLC and the IP 3 channel. decreased production of IP 3 and decreased effectiveness of IP 3 to release calcium from SR stores. - activate the SR Ca 2+ -ATPase. increased rate of removal of calcium from the cytoplasm.  Organic nitrates mimic the effects of NO to cause smooth muscle relaxation.

4.  Angina pectoris is caused by accumulation of metabolic byproducts in myocardial tissue and results because oxygen demand by the myocardium far exceeds the oxygen (blood) supply.  Oxygen supply and demand mismatch are primarily due to atherosclerotic occlusion of coronary arteries (exertional, stable angina). Angiospasms (variant angina) is also responsible for cardiac ischemia.  Theoretically the supply to demand mismatch can be corrected by - improving blood flow to the myocardium - decreasing myocardial oxygen demand Pathophysiology of Angina

5. Nitrate vasodilators in Angina Therapy  Are polyol organic esters of nitric acid: - the nitrate esters (R-- C—O—NO 2 ) - the nitrite esters (R—C—O—NO)  Amyl nitrite is volatile – administered as a gas.

6.  Greater potency of erythrityl tetranitrate and nitroglyerin relative to other organic nitrates may be due to more rapid bioactivation. Nitrate vasodilators in Angina Therapy  Fully nitrated polyols are non-polar and lipid soluble: allows rapid absorption from inhalational, dermal and sublingual sites. - NTG sublingual, transdermal (patch and ointment), spray - Amyl nitrite inhalational - Isosorbide dinitrate sublingual, chewable  Degradation of the nitrates in the presence of glutathione generates the NO free radical, which causes vasodilation.

7.  Rapid onset of action after sublingual admin. due to by-pass of liver first time through. Sublingual administration in acute attacks and prophylaxis of acute attacks.  Oral administration of nitrates has longer onset time but longer duration of action.  Transdermal delivery (NTG patch) onset time of ~1hour and duration of 4-8 hours.  Tolerance to all nitrate compounds develops after prolonged use and treatment has to be interrupted every ~8 hours.  Tolerance may be due to decreased production of NO from nitrate drugs or due to the production of oxygen free radicals (O 2 - ) which react with NO to form peroxynitrates that are not vasodilators. Nitrate vasodilators in Angina Therapy

8.  Nitrates dilate veins preferentially over arteries leading to decreased left and right heart end-diastolic pressure (decreased preload) with small change in TPR. - heart rate unchanged or slightly increased due baroreceptor reflex mechanism. - Cardiac output decreases due to lower ventricular end- diastolic pressure.  Lower doses dilate arterial vessels of skin, meninges – flushing, headache  Higher doses (1) decrease systolic and diastolic pressure: decrease TPR; (2) decrease C.O.; (3) cause venous blood pooling; (4) reflex sympathetic nerve activity. Nitrate vasodilators in Angina Therapy

9.  Appear to alleviate anginal pain by restoring myocardial oxygen supply/demand via - decreasing myocardial work due to decreased afterload and preload. - Ischemic regions of heart may have improved blood flow to subendocardial regions due to decreased preload that decreases ventricular wall tension.  Adverse effects: (cardiovascular) headache, dizziness, weakness, postural hypotension, flushed skin, tachycardia, rash. Nitrate vasodilators in Angina Therapy

10. Drug Interactions Nitrates are contraindicated in patients on sildenafil (Viagra®) due to increased potential for hypotensive episode via PDE5 inhibition. Therapeutic Use Used in exertional and variant angina to restore myocardial oxygen supply/demand. Nitrates are used in congestive heart failure Improve coronary blood flow after MI Nitrate vasodilators in Angina Therapy

11. Other agents in Angina Therapy  -blockers: metoprolol, timolol, atenolol have been shown effective in reducing anginal attacks by decreasing myocardial oxygen demand. Calcium-channel blockers: amlodipine, bepridil, nicardipine improve coronary blood flow to increase myocardial oxygen supply