Drugs Used in Chronic Ischemic Heart Disease -DSA Flashcards
Approach to treating angina pectoris
1 - increase coronary blood flow
2 - reduce myocardial oxygen demand
Determinants of myocardial oxygen demand
Heart rage
contractility
preload
afterload
Drug classes used in chronic IHD
Nitrates - nitrovasodilators
CCB
Beta blockers
Ranolazine
Nitrovasodilators
Nitroglycerin
Isosorbide dinitrate
Isosorbide mononitrate - active metabolite of dinitrate
Nitrovasodilator pharmacokinetics
Significant first-pass metabolism - high nitrate reductase activity in the liver (Nitrate reeducates activity in saturable)
Bioavailability with oral route is low - other routes avoid first pass metabolism
partially denigrated metabolites have activity and longer half-lives
Isosorbide mononitrate is poor substrate of nitrate reductase - high bioavailability
Nitrovasodilator pharmacodynamics - MOA
– Unknown enzymatic reaction releases NO (or other active metabolite – nitrosothiol?)
• The role of mitochondrial aldehyde dehydrogenase 2 (ADH2)
– Thiol compounds are needed to release NO from nitrates
– Vascular smooth muscle relaxation by NO
– Sensitivity of vasculature to nitrate-induced vasodilation:
Veins > Large arteries > Small arteries and arterioles
– No “coronary steal” phenomenon
– Inhibit platelet aggregation
Beneficial action of nitrovasodilators in angina
decreased myocardial oxygen demand
Relaxation of vascular smooth muscle - dilation of veins (major effect) and dilation of arteries
Dilation of veins with nitrovasodilators for treatment of angina
major effect
increased venous capacitance
reduced ventricular preload
Dilations of arteries with nitrovasodilators for treatment of angina
higher concentrations of nitrates are needed compared to venous dilation
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
Nitrate effects in angina of effort
decreased preload
decreased oxygen demand
Nitrate effects on vasospastic angina
relaxation of coronary artery vascular smooth muscle
Relieving coronary artery spasm
Clinical use of nitrovasodilators
short-acting formulations used to relieve 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
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
ED treatment:
– Sildenafil, vardenafil, tadalafil
• Inhibit cGMP-phosphodiesterase-5, increases cGMP
• Minimal effects on hemodynamics when administered alone in men
with coronary artery disease
– Combination with nitrates causes severe increase in cGMP and a dramatic drop in BP
– Acute myocardial infarction cases have been reported
Non-cardioactive calcium channel blockers (dihydropyridines)
Amlodipine - long acting (t1/2 30-50 h)
Nifedipine - short acting (t1/2 4 h)
Nicardipine - short acting (t1/2 2-4 h)
Cardioactive calcium channel blockers (non-dihydropyridines)
Diltiazem
Verapamil
Calcium channel blockers MOA
• Ca2+ mediates smooth muscle contraction; enters cells via voltage-dependent
calcium channels
• CCBs block Ca2+ entry to relax vascular smooth muscle
Anti-Anginal mechanisms of CCBs - decreased myocardial oxygen demand
– Dilation of peripheral arterioles
• Decreased PVR and afterload, decreased blood pressure
• Arterioles more affected than veins (less orthostatic hypotension)
• Dihydropyridines are more potent vasodilators
– Decreased cardiac contractility and heart rate (observed with cardioactive CCBs)
Anti-antinal mechanisms of CCB - increased blood supply
Dilation of coronary arteries relieves local spasms (this mechanism may operate in vasospastic (Prinzmetal) angina and NOT in atherosclerotic angina)
Major adverse effects of CCB
Cardiac depression, cardiac arrest, acute heart failure (cardioactive CCBs)
Bradyarrhythmias, AV block (cardioactive CCBs)
Short acting dihydropyridine CCBs - vasodilation triggers reflex sympathetic activation
Nifedipine - immediate release: increases risk of MI in patient with HTN, slow release and long acting dihydropyridines better tolerated
Minor adverse effects of CCB
Flushing, HA, anorexia, dizziness
Peripheral edema
Constipation
Beta blockers indicated in angina
Propranolol
Nadolol
Metoprolol
Atenolol
Beta blocker MOA in angina
decreased myocardial oxygen demand
– Decrease in HR leads to improved myocardial perfusion and reduced
oxygen demand at rest and during exercise
– Decrease in contractility
– Decrease in blood pressure leads to reduced afterload
Adverse effects of beta-blockers
– Reduced cardiac output
– Bronchoconstriction
– Impaired liver glucose mobilization
– Produce an unfavorable blood lipoprotein profile (increase VLDL and
decrease HDL)
– Sedation, depression
– Withdrawal syndrome associated with sympathetic hyperresponsiveness
Contraindications of beta-blockers
– Asthma – Peripheral vascular disease – Raynaud’s syndrome – Type 1 diabetics on insulin – Bradyarrhythmias and AV conduction abnormalities – Severe depression of cardiac function
Effects of nitrates alone on heart rate, arterial pressure, end-diastolic volume, contractility, and ejection time in angina pectoris
Heart Rate: Reflex increase (not desirable)
Arterial pressure: Decrease
End-diastolic Volume: Decrease
Contractility: Reflex increase (not desirable)
Ejection time: Decrease
Effects of Beta Blockers or CCBs on heart rate, arterial pressure, end-diastolic volume, contractility, and ejection time in angina pectoris
Heart Rate: Decrease Arterial pressure: Decrease End-diastolic Volume: Increase (not desirable) Contractility: Decrease Ejection time: Increase (not desirable)
Effects of nitrates with beta blockers or CCBs on heart rate, arterial pressure, end-diastolic volume, contractility, and ejection time in angina pectoris
Heart Rate: Decrease Arterial pressure: Decrease End-diastolic Volume: none or decrease Contractility: None Ejection time: None
Ranolazine MOA
– Inhibits late Na+ current 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 repolarization abnormalities
– Ranolazine normalizes repolarization of cardiac myocytes and reduces
mechanical dysfunction
Ranolazine does not affect…
- Heart rate
- General inotropic state of myocardium
- Coronary blood flow
- Peripheral hemodynamics
Clinical use of Ranolazine
– Stable angina which is refractory to standard medications
– Decreases angina episodes and improves exercise tolerance in patients taking nitrates, or amlodipine, or atenolol
Adverse Effects of Ranolazine
– QT interval prolongation – may trigger polymorphic ventricular arrhythmias – Constipation – Nausea – Dizziness – Headache
Drug interactions of Ranolazine
– Metabolized by CYP3A4/5 – interaction with drugs that modulate the activity of these enzymes
• Do not combine with strong CYP3A inhibitors: antifungal azoles,
verapamil
– Ranolazine inhibits CYP2D6
• Increases half-life of Amitriptyline, Fluoxetine, Metoprolol, opioid drugs
– Drugs that prolong QT interval – certain antiarrhythmic (Quinidine) and antipsychotic drugs (Thioridazine) – may trigger ventricular arrhythmias
