Drugs Used In Angina & Chronic Ischemic Heart Disease Flashcards
Categories of drugs used in chronic IHD
Nitrates (nitrovasodilators)
Calcium channel blockers
Beta-blockers
Ranolazine
What nitrates are used in chronic IHD?
Nitroglycerin
Isosorbide dinitrate
Isosorbide mononitrate
What calcium channel blockers are used in IHD?
Non-cardioactive (dihydropyridines):
Amlodipine
Nifedipine
Nicardipine
Cardioactive:
Diltiazem
Verapamil
What beta blockers are used in chronic IHD?
Propranolol
Nadolol
Metoprolol
Atenolol
Chronic ischmic heart disease is characterized by partial occlusion of a coronary artery. What are the 2 types of IHD?
Classic angina (angina of effort, stable angina): occlusion of coronary aa. resulting from formation of atherosclerotic plaque — MOST COMMON form; symptomatic during exertion or stress
Variant (prinzmetal) angina: episodes of vasoconstriction of coronary aa.; likely genetic in origin, symptoms occur at rest. Much less common than classic
Surgical approaches to treat angina pectoris
Coronary artery bypass grafting
Percutaneous transluminal coronary angioplasty (PTCA)
Atherectomy - tip of catheter shears off plaque (risk of reocclusion)
Stent - expandable tube used as scaffolding to keep vessel open (drug eluting stents may be more effective long term)
In which type of angina are vasodilators useful?
Useful in tx of vasospastic (prinzmetal) angina — to relieve coronary spasm and restore blood flow to ischemic area
Note: vasodilators are NOT useful in atherosclerotic/CLASSIC angina — d/t “coronary steal” phenomenon = redistribution of blood to non-ischemic areas (associated with dilation of small arterioles)
Nitrovasodilators have significant first pass metabolism d/t high nitrate reductase activity in the ____; nitrate reductase activity is saturable.
Bioavailability with oral route is low, so other routes are often used. Partially denitrated metabolites may still have activity and longer half-lives. ______ is a nitrovasodilator that is known to be a poor substrate of nitrate reductase and thus characterized by higher bioavailability
Liver
Isosorbide mononitrate
MOA of nitrates in angina
Unknown enzymatic reaction releases NO (or other active metabolite); requires mitochondrial aldehyde dehydrogenase 2 (ADH2)
Thiol compounds are needed to release NO from nitrates. In vascular smooth muscle, NO dilates veins and, at high concentrations, large arteries. Dilation of veins increases capacitance and reduces ventricular preload; dilation of arteries may reduce afterload and dilate large epicardial coronary aa, but there is no substantial increase in blood flow into ischemic area in atherosclerotic angina
Inhibition of platelet aggregation
T/F: there is no “coronary steal” phenomenon with nitrates
True
Rank the vasculature in terms of sensitivity to nitrate-induced vasodilation
Veins > large arteries > small arteries and arterioles
Describe development of tolerance/limiting factors to use of nitrates
Depletion of thiol compounds
Increased generation of superoxide radicals
Reflex activation of SNS (tachycardia, decreased coronary blood supply)
Retention of salt and water
Clinical use of nitrates
Short-acting formulations are used to relieve acute angina attack [nitroglycerin sublingual or spray, isosorbide dinitrate sublingual or spray]
Long-acting preparations may be used to prevent attacks [nitroglycerin oral or ointment or patch, isosorbide dinitrate oral, isosorbide mononitrate oral—-longest MOA]
Adverse effects of nitrates
Headache (d/t meningeal vasodilation; nitrates are contraindicated with increased ICP)
Orthostatic hypotension
Increased sympathetic dishcarge — tachycardia, increased cardiac contractility
Increased renal Na and H2O reabsorption
Drug interactions with nitrates
Nitrates interact with drugs used to tx ED — sildenafil, vardenafil, tadalafil [severe increases in cGMP with dramatic drop in BP; acute MIs have been reported]
Of the calcium channel blockers used in angina, which is considered long acting?
Amlodipine — t1/2 of 30-50 hours
[Nifedipine and Nicardipine are considered short acting at t1/2 of 4 hr and 2-4 hrs respectively]
Of the calcium channel blockers, which has the greatest effect on decreasing automaticity at SA node and decreasing conduction at AV node?
Verapamil (closely followed by diltiazem
Of the calcium channel blockers used in angina, which one provides the most vasodilation?
Amlodipine
Anti-anginal mechanisms of calcium channel blockers
Decreased myocardial O2 demand (helps with atherosclerotic angina) by:
Dilation of peripheral arterioles (decreased PVR and afterload, decreased BP, arterioles > veins so less orthostatic hypotension, dihydropyridines more potent vasodilators)
Decreased cardiac contractility and HR (with cardioactive CCBs)
In addition —
Increases blood supply to help with variant angina via dilation of coronary arteries to relieve local spasm
Adverse effects of CCBs used in angina
Major:
Cardioactive CCBs may cause cardiac depression, cardiac arrest, acute heart failure, bradyarrhythmias, atrioventricular block; short acting dihydropyridine CCBs may cause reflex sympathetic activation. Nifedipine increases risk of MI in pts with HTN — slow release and long acting dihydropyridines are better tolerated in those pts
Minor:
Flushing, HA, anorexia, dizziness, peripheral edema, constipation
MOA of beta blockers used in angina
Decreasing HR —> improved myocardial perfusion and reduced O2 demand at rest and during exercise
Decrease contractility —> decreased O2 demand
Decrease in BP —> reduced afterload
AEs associated with beta blockers used for angina
Reduced cardiac output Bronchoconstriction Impaired liver glucose mobilization Increase VLDL, decrease HDL Sedation, depression Withdrawal syndrome associated with sympathetic hyperresponsiveness
Contraindications to beta blockers
Asthma Peripheral vascular disease T1D on insulin Bradyarrhythmias and AV conduction abnormalities Severe depression of cardiac function
Effects of nitrates alone on HR, arterial pressure, EDV, contractility, and ejection time
HR: reflex increase (undesirable)
Arterial pressure: decrease
EDV: decrease
Contractility: reflex increase (undesirable)
Ejection time: decrease
Effects of beta blockers or CCBs on HR, arterial pressure, EDV, contractility, and ejection time
HR: decrease
Arterial pressure: decrease
EDV: increase (undesirable)
Contractility: decrease
Ejection time: increase (undesirable)
Effects of combined nitrates with beta blockers or CCBs on HR, arterial pressure, EDV, contractility, and ejection time
HR: decrease
Arterial pressure: decrease
EDV: none or decrease
Contractility: none
Ejection time: none
MOA of ranolazine (new agent used in angina)
[ischemic myocardium is often partially depolarized and Na+ channel is voltage gated. Late Na+current is enhanced in ischemic myocardium and brings about Ca++ overload and repolarization abnormalities]
Ranolazine normalizes repolarization of cardiac myocytes and reduces mechanical dysfunction by inhibiting late Na+ current in cardiomyocytes
May reduce diastolic tension and compression of coronary vessels in diastole; may reduce cardiac contractility and oxygen demand
Effect of ranolazine on HR, coronary blood flow, and peripheral hemodynamics
No effect!!
Clinical use of ranolazine
Stable angina which is refractory to standard meds
Decreases angina episodes and improves exercise tolerance in pts taking nitrates, amlodipine, or atenolol
In summary: approaches to tx of variant angina
Management is primarily focused on prevention of episodes
CCBs are first choice drugs; if those are contracindicated d/t low BP, bradycardia, or AV block — Long-acting nitrates are used
In summary: approaches to tx of stable (atherosclerotic) angina
First line: lipid-lowering therapy, lifestyle modification, immediate release nitrates, antiplatelet therapy (ASA)
Second: beta-blocker or alternative (CCB or long acting nitrate)
Add CCB or BB (if not first drug); if BP is low use long acting nitrate or ranolazine
Consider triple therapy (BB + CCB + long acting nitrate or ranolazine)
Last line therapy: consider CABG surgery
