Drugs for Angina and Ischemic Heart Disease Flashcards
Chronic ischemic heart disease is characterized by`
the partial occlusion of coronary artery
Classic angina
- angina of effort, stable angina
- occlusion of the coronary arteries resulting from the formation of atherosclerotic plaque
- Most common form of angina
- Symptoms occur during exertion or stress
Variant (Prinzmetal) angina:
- episodes of vasoconstriction of coronary arteries
- vasospastic
- Genetic in origin
- symptoms at rest
- Less common than classic angina
Angina is the imbalance between
- O2 demand of the heart and oxygen supply via the coronary arteries
- Heart’s demand for O2>>O2 supply due to partially blocked coronary artery
- Especially during exertion, stress
- results in chest pain
Approaches to treat Angina
- Reduce O2 demand by decreasing cardiac work OR
- increase O2 supply by increasing blood flow through coronary arteries
Ways to increase coronary blood flow to treat angina–surgical and non-surgical approaches
- Coronary artery bypass grafting (most radical)
- Percutaneous transluminal coronary angioplasty (PTCA)
- Atherectomy–tip of catheter shears off the plaque–risk of reocclusion
- Stent–expandable tube used as scafforlding to keep vessel open (drug eluting stents–antiproliferative drugs–cause cell cycle arrest)
To increase coronary blood flow using vasodilators
- useful in vasospastic (Prinzmetal–variant) angina
- to relieve coronary spasm -to restore blood flow into ischemic area
- NOT useful in atherosclerotic (classic) angina–can make it worse– due to coronary steal phenomenon
Coronary steal phemomenonen
- redistribution of blood to non-ischemic areas–associated with the dilation of small arterioles
- Ex: potent arteriolar vasodilators like Dipyridamole
- vasodilation prevents adjacent arteries from providing collateral blood flow exacerbating symptoms in classic angina!! But vasodilator useful for variant angina!
Determinants of myocardial oxygen demand (targets for treatment)
- Heart rate
- Contractility
- Preload
- Afterload
Tachycardia increases HR and can be harmful. Why?
- Tachycardia affects diastole more than systole
- decreased length of diastole so blood flow through coronary artery is impeded
- explains why tachycardia is harmful especially in angina patients
Vasodilator that lacks direct effect on autonomic receptors but may provoke angina attacks
- Hydralazine
- peripheral vasodilator
- releases NO
Drug classes used in chronic ischemic heart disease
- Nitrates (nitrovasodilators)
- Calcium channel blockers
- Beta-blockers
- Newer agent: Ranolazine
Nitrovasodilators
- Nitrogylcerin
- isosorbide dinitrate
- Isosorbide mononitrate (active metabolite of dinatrate)
Endothelium dependent vascular relaxation
- Release of endothelium-derived relaxing factor (EDRF) by Ach leads to relaxation IF endothelium is present
- endothelial NOS produces NO, an endogenous vasorelaxing agent
Endothelial Nitric Oxide Synthase
- activated by Ca2+-calmodulin complex
- then it activates arginine to make citrilline and NO
NO acts on
-Guanylyl cyclase–>act cGMP–>act Protein kinase G–> causes relaxation by dephosphorylating myosin light chain or by opening potassium channels and causing hyperpolarization and reduced calcium entry
MOA of nitrates in Variant angina
1) Nitrate–>NO via ADH2 (frequently thiols)–>
2) Vascular smooth muscle relaxation–>
3) Coronary artery dilation–>
4) Coronary spasm relief
MOA of nitrates in Classic angina
1) 1) Nitrate–>NO via ADH2 (frequently thiols)–>
2) Vascular smooth muscle relaxation–>
3) VENOUS dilation–>
4) Reduced preload–>
5) decreased O2 demand
Multiple effects of NO
- vasodilation
- Prevents platelet aggregation
- inhibits interaction of endothelial cells with blood derived cells (leukocytes)–prevents rolling and transmigration and inflammation by leukocytes
- inhibits smooth muscle proliferation (intimal thickening and reocclusion)
- prevents oxidation damage -prevents LDL oxidation (protects against atherosclerosis)
Sensitivity of vasculature to nitrate induced vasodilation
-veins>large arteries>small arteries and arterioles
Nitrovasodilator beneficial action in angina
- decreased myocardial oxygen demand
- relaxation of vascular smooth muscle
- dilation of veins (major effect): increased venous capacitance, reduced ventricular preload
- dilation of arterioles–higher concentrations of nitrates are needed compared to venous dilation
Dilation of arteries leads to
- reduced arterial pressure and after load
- may dilate large epicardial coronary arteries
- no significant increase in coronary blood flow into the ischemic area in atherosclerotic angina
Nitrates in angina of effort
- decreased preload
- decreased oxygen demand
Nitrates in vasospastic angina
- relaxation of coronary artery vascular smooth muscle
- relieving coronary spasm
Nitrate clinical use
- short acting formulations used to relieve the angina attack
- long acting preparations may be used to prevent attacks
Development of nitrate tolerance
- depletion of thiol compounds -increased generation of oxygen radicals
- reflex activation of sympathetic nervous system (tachycardia, decreased coronary blood supply)
- retention of salt and water
- increased generation of superoxide radical depletes tissues of NO
Reason to avoid oral administration of nitrates
-Rapid denitration by the liver enzymes
Adverse effects of nitrates
- headache (meningeal vasodilation)
- orthostatic hypotension -increased sympathetic discharge
- tachycardia, increased cardiac contractility
- increased renal Na+ and H2O reabsorption
Nitrate drug interactions
- interaction of nitrates with drugs used for treatment of erectile dysfunction (sildenafil, vardenafil, tadalafil)
- combination with nitrates causes severe increase in cGMP and a dramatic drop in BP
- acute MI cases have been reported
-Calcium channel blockers
- non-cardioactive (DHP):
- Amlodipine
- Nifedipine
- Nicardipine
- Cardioactive: Diltiazem, Verapamil
CCB MOA
- Ca2+ mediates smooth muscle contraction; enters cells via voltage dependent calcium channels
- CCBs block Ca2+ entry to relax vascular smooth muscle
- vasculature does NOT have troponin so acts on Myosin-light chain kinase system (Ca2+-calmodulin sensitive)
Anti-anginal mechanisms of CCBs
- Decreased myocardial O2 demand (Classic angina)
- Dilation of peripheral arterioles
- Decreased PVR and after load, decreased BP
- Arterioles more affected than veins (less orthostatic hypotension)
- DHPs are more potent vasodilaters
- Decreased cardiac contractility and heart rate (seen with non-DHPs)
- increased blood supply (operates in variant angina)–dilation of coronary arteries relieves local spasm
Major adverse effects of CCBs
- cardiac depression, cardiac arrest, and acute heart failure (cardioactive CCBs)
- bradyarrythmias, AV block (cardioactive CCBs)
- short acting DHP CCBs–vasodilation triggers reflex sympathetic activation
Nifedipine adverse effects
- immediate release
- increases risk of MI in patients with HTN–slow-release and long-acting DHPs are better tolerated
- causes tachycardia due to hypotension and associated baroreflex
Minor adverse effects of CCBs
- flushing, headache, anorexia, dizziness
- peripheral edema
- constipation
Beta-blockers indicated in angina
- Propranolol
- Nadolol
- Metoprolol
- Atenolol
MOA of B-blockers in angina
- decreased myocardial O2 demand
- decrease HR leads to improved myocardial perfusion and reduced O2 demand at rest and during excercise
- Decrease in contractility
- Decrease in BP leads to reduced afterload
B-blockers adverse effects
- reduced CO
- bronchoconstriction
- impaired liver glucose mobilization
- produce and unfavorable blood lipoprotein profile (increase VLDL and decrease HDL)
- sedation, depression
- withdrawl syndrome associated with sympathetic hyperresponsiveness
B-blocker contraindications
- asthma
- peripheral vascular disease
- Raynaud’s syndrome
- Type 1 diabetics on insulin
- bradyarrhthmias and AV conduction abnormalities
- severe depression of cardiac function
Effects of Nitrates alone in treatment of angina pectoris
- reflex increase in HR
- decrease in arterial pressure
- decrease EDV
- reflex increase contractility
- decrease in ejection time
Effects of B-blockers or CCBs alone in treatment of angina pectoris
- decreases HR, arterial pressure, contractility
- increases EDV and ejection time
Effects of combined nitrates with B-blockers or CCBs in treatment of angina pectoris
- decrease HR, arterial pressure
- no change or decrease in EDV
- no change in contractility, ejection time
Ranolazine MOA
- inhibits late Na+ currents in cardiomyocytes
- ischemic myocardium is often partially depolarized
- Na+ channel in cardiomyocytes is voltage-gated
- Late Na+ current is enhanced in ischemic myocardium and brings about Ca2+ overload and depolarization abnormalities
- Ranolazine normalizes repolarization of cardiac myocytes and reduces mechanical dysfunction
- reduce diastolic tension and compression of coronary vessels in diastole and reduces cardiac contractility and O2 demand
Ranolazine may reduce
- diastolic tension and compression of coronary vessels in diastole
- may reduce cardiac contractility and oxygen demand
Ranalozaine does not affect
- heart rate
- general ionotropic state of myocardium
- coronary blood flow
- peripheral hemodynamics
Ranolazine clinical use
- stable angina which is refractory to standard medications
- decreases angina episodes and improves exercise tolerance in patients taking nitrates, or amlodipine, or atenolol
Ranolazine adverse effects
- QT interval prolongation–may trigger polymorphic ventricular arrhythmias
- constipation
- nausea
- dizziness
- headache
Ranolazine drug interactions
- metabolized by CYP3A4/5–interaction with drugs that modulate the activity of these enzymes
- do not combine with strong CYP3A inhibitors: anti fungal azaleas, verapamil
- inhibits CYP2D6–increases half life of Amitriptyline, Fluoxetine, metoprolol, opioid drugs
- drugs that prolong QT interval–certain anti arrhythmic (Quinidine) and antipsychotic drugs (Thioridazine)–may trigger ventricular arrhythmias
