1. Antianginal Drugs Donald Blumenthal, Ph.D. Department of Pharmacology & Toxicology Don.Blumenthal@pharm.utah.edu Recommended Reading Goodman & Gilman Online (11th ed.), Chapt. 31 (www.accessmedicine.com) Harrison’s Online, Chapt 244: (www.accessmedicine.com) Katzung (9th ed.), Chapt. 12 Additional Resources Used to Prepare Lecture Clinical Pharmacology Online (cpip.gsm.com) Hurst's The Heart: Manual of Cardiology (11th ed.) Part 6 (www.accessmedicine.com)

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3. Learning Objectives Know the major classes of drugs used to treat angina and their clinically important mechanisms of action Know the major contraindications, toxicities, and drug interactions of each class of antianginal drugs Know the drugs of choice for treating different forms of angina Know which antianginal drug combinations are beneficial and which are ill-advised

4. Angina Pectoris Angina pectoris is the principle symptom of ischemic heart disease The condition is characterized by sudden, severe substernal pain or pressure The primary cause of angina is an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels –This imbalance may be due to: »a decrease in myocardial oxygen delivery »an increase in myocardial oxygen demand »or both

5. Factors Affecting Myocardial Oxygen Delivery Coronary artery blood flow is the primary determinant of oxygen delivery to the myocardium –Myocardial oxygen extraction from the blood is nearly complete, even at rest Coronary blood flow is essentially negligible during systole and is therefore determined by: –Perfusion pressure during diastole (aortic diastolic pressure) –Duration of diastole –Coronary vascular resistance »Coronary vascular resistance is determined by numerous factors including: Atherscelorosis Intracoronary thrombi Metabolic products that vasodilate coronary arterioles Autonomic activity Extravascular compression

6. Factors Affecting Myocardial Oxygen Demand The major determinants of myocardial oxygen consumption include: –Ventricular wall stress »Both preload (end-diastolic pressure) and afterload (end-systolic pressure) affect ventricular wall stress –Heart rate –Inotropic state (contractility) –Myocardial metabolism (glucose vs fatty acids) A commonly used non-invasive index of myocardial oxygen demand is the “double product”: –[Heart rate] X [Systolic blood pressure] –Also known as the rate-pressure product

7. Stable Angina Stable angina is also known as: –Exertional angina –Typical or classic angina –Angina of effort –Atherosclerotic angina The underlying pathology is usually atherosclerosis (reduced oxygen delivery) giving rise to ischemia under conditions where the work load on the heart increases (increased oxygen demand) Anginal episodes can be precipitated by exercise, cold, stress, emotion, or eating Therapeutic goals: Increase myocardial blood flow by dilating coronary arteries and arterioles (increase oxygen delivery), decrease cardiac load (preload and afterload; decrease oxygen demand), decrease heart rate (decrease oxygen demand), [alter myocardial metabolism?]

8. Unstable Angina Unstable angina is also known as: –Preinfarction angina –Crescendo angina –Angina at rest Associated with a change in the character, frequency, and duration of angina in patients with stable angina, and episodes of angina at rest Caused by recurrent episodes of small platelet clots at the site of a ruptured atherosclerotic plaque which can also precipitate local vasospasm May be associated with myocardial infarction Therapeutic rationale: Inhibit platelet aggregation and thrombus formation (increase oxygen delivery), decrease cardiac load (decrease oxygen demand), and vasodilate coronary arteries (increase oxygen delivery)

9. Vasospastic Angina Vasospastic angina is also referred to as: –Variant angina –Prinzmetal's angina Caused by transient vasospasm of the coronary vessels Usually associated with underlying atheromas Chest pain may develop at rest Therapeutic rationale: Decrease vasospasm of coronary vessels (calcium channel blockers are efficacious in >70% of patients; increase oxygen delivery)

10. History of Antianginal Drugs Amyl nitrate and nitroglycerin were found to provide transient relief of angina in the mid-to late 1800s Subsequently many other vasodilators were introduced for the treatment of angina, but double- blinded clinical trials showed many were no better than placebo –Some of the classic studies of the placebo effect were carried out in patients with angina Beta-adrenergic blockers and calcium channel blockers were developed during the early 1960’s and are now also widely used in the prophylactic therapy of angina pFox inhibitors, the first new drugs for angina in more than 20 years, are likely to be approved by the FDA in the near future

12. Pharmacology of Antianginal Agents Three major classes of agents are used individually or in combination to treat angina: Organic nitrates –Vasodilate coronary arteries –Reduce preload and aferload Calcium channel blockers –Vasodilate coronary arteries –Reduce afterload –The non-dihydropyridines (verapamil and diltiazem) also decrease heart rate and contractility Beta-adrenergic blockers –Decrease heart rate and contractility –Decrease afterload 2° to a decrease in cardiac output –Improve myocardial perfusion 2° to a decrease in heart rate *All of these may also reduce platelet aggregation A new class of drugs, pFox inhibitors, are in the final stages of approval for chronic angina –Reduce myocardial oxygen consumption by shifting metabolism from fatty acid to glucose metabolism –No hemodynamic effects

13. Organic Nitrates / Nitrovasodilators All of these agents are enzymatically converted to nitric oxide (NO) in the target tissues –NO is a very short-lived endogenous mediator of smooth muscle contraction and neurotransmission Veins and larger arteries appear to have greater enzymatic capacity than resistance vessels, resulting in greater effects in these vessels NO activates a cytosolic form of guanylate cyclase in smooth muscle –Activated guanylate cyclase catalyzes the formation of cGMP which activates cGMP- dependent protein kinase –Activation of this kinase results in phosphorylation of several proteins that reduce intracellular calcium and hyperpolarize the plasma membrane causing relaxation

14. Mechanism of Action of Nitrovasodilators Nitric Oxide activates converts Guanylate Cyclase* GTP cGMP activates cGMP-dependent protein kinase Activation of PKG results in phosphorylation of several proteins that reduce intracellular calcium causing smooth muscle relaxation Nitrates become denitrated by glutathione S-transferase to release

15. Effects of Nitrovasodilators Peripheral vasodilation: –Dilation of veins predominates over that of arterioles Increased coronary blood flow: –Large epicardial coronary arteries are dilated without impairing autoregulation in small coronary vessels –Collateral flow may be increased –Decreased preload improves subendocardial perfusion –Although organic nitrates can relax vasospastic coronary arteries, they have little or no effect on total coronary blood flow in patients with typical angina due to atherosclerosis –Dilation of coronary arteries can paradoxically result in aggravation of angina - a phenomenon known as “coronary steal” Inhibition of platelet function: –May contribute to their effectiveness in the treatment of unstable angina

16. Hepatic first-pass metabolism is high and oral bioavailability is low for nitroglycerin (GTN) and isosorbide dinitrate (ISDN) –Sublingual or transdermal administration of these agents avoids the first-pass effect Isosorbide mononitrate (5-ISMN) is not subject to first- pass metabolism and is 100% available after oral administration Hepatic blood flow and disease can affect the pharmacokinetics of GTN and ISDN GTNISDN5-ISMN Half-life (min)310280 Plasma clearance (L/min)5040.1 Apparent volume of distribution (L/kg)340.6 Oral bioavailability (%)< 120100 Property Pharmacokinetic Properties of Organic Nitrates

17. Routes of Administration Amyl nitrate is a gas at room temperatures and can be administered by inhalation –Rapid onset, short duration (3-5 min) GTN and ISDN have a rapid onset of action (1-3 min) when administered sublingually, but the short duration of action (20-30 min) is not suitable for maintenance therapy IV nitrogylcerin can be used to treat severe recurrent unstable angina Slowly absorbed preparations of nitrovasodilators (oral, buccal, transdermal) can be used to provide prolonged prophylaxis against angina (3-10 hrs), but can lead to tolerance (tachyphylaxis)

18. Tolerance and Dependence with Nitrovasodilators Continuous or frequent exposure to nitrovasodilators can lead to the development of complete tolerance –Transdermal GTN may provide therapeutic levels of drug for 24 hours or more, but efficacy only lasts 8-10 hrs –Nitrate-free periods of at least 8 hrs (e.g.- overnight) are recommended to avoid or reduce tachyphylaxis The mechanism of tolerance is not completely understood but appears to relate to the enzymes involved in converting the nitrates to NO, or to the enzyme that produces cGMP Industrial (occupational) exposure to organic nitrates has been associated with “Monday disease” and physical dependence manifest by variant angina occurring 1-2 days after withdrawal –Has resulted in myocardial infarction in some patients –No evidence that dependence occurs in normal therapy, even with high doses

19. Adverse Effects of Nitrovasodilators The major acute adverse effects of nitrovasodilators are due to excessive vasodilation –Orthostatic hypotension –Tachycardia –Severe throbbing headache –Dizziness –Flushing –Syncope Organic nitrates are contraindicated in patients with elevated intracranial pressure Sildenafil (Viagra) and other PDE-5 inhibitors used for erectile dysfunction can potentiate the actions of nitrovasodilators because they inhibit the breakdown of cGMP (they should not be taken within 6 hours of taking a nitrovasodilator) –See the movie “Something’s Gotta Give” (Jack Nicholson & Diane Keaton)

20. Chemistry of Ca ++ Channel Blockers Five major classes of Ca ++ channel blockers are known with diverse chemical structures: –Benzothiazepines: Diltiazem –Dihydropyridines: Nicardipine, nifedipine, nimodipine, amlodipine, and many others »There are also dihydropyridine Ca ++ -channel activators (Bay K 8644, S 202 791) –Phenylalkylamines: Verapamil –Diarylaminopropylamine ethers: Bepridil –Benzimidazole-substituted tetralines: Mibefradil

21. Effects on Vascular Smooth Muscle Ca ++ channel blockers inhibit L-type and/or T-type voltage-dependent Ca ++ channels Little or no effect on receptor-operated channels or on release of Ca ++ from SR “Vascular selectivity” is seen with the Ca ++ channel blockers –Decreased intracellular Ca ++ in arterial smooth muscle results in relaxation (vasodilatation) -> decreased cardiac afterload (aortic pressure) –Little or no effect of Ca ++ -channel blockers on venous beds -> no effect on cardiac preload (ventricular filling pressure) –Specific dihydropyridines may exhibit greater potencies in some vascular beds (e.g.- nimodipine more selective for cerebral blood vessels, nicardipine for coronary vessels) –Little or no effect on nonvascular smooth muscle

22. Effects on Cardiac Cells Magnitude and pattern of cardiac effects depends on the class of Ca ++ channel blocker Negative inotropic effect (myocardial L-type channels) –Reduced inward movement of Ca ++ during action potential plateau phase –Dihydropyridines have very modest negative inotropic effect –Mibefradil (T-type) has no negative inotropic effect Negative chronotropic/dromotropic effects (L- and T-type channels) –Verapamil, diltiazem, and mibefradil depress SA node and AV conduction –Dihydropyridines have minimal direct effects on SA node and AV conduction (but they can cause reflex tachycardia)

23. Relative Cardiovascular Effects of Calcium Channel Blockers (adapted from Goodman & Gilman, 9th ed.) Verapamil++++++++++++++++++ Diltiazem++++++++++++++ Nifedipine+++++++0 Nicardipine+++++0+0 CompoundCoronary vasodilation Suppression of cardiac contractility Suppression of SA node Suppression of AV node

24. Desired Therapeutic Effects of Calcium Channel Blockers for Angina Improve oxygen delivery to ischemic myocardium –Vasodilate coronary arteries –May inhibit platelet aggregation –Particularly useful in treating vasospastic angina Reduce myocardial oxygen consumption –Decrease afterload (no effect on preload) –Non-dihydropyridines also lower heart rate and decrease contractility –(* Dihydropyridines may aggravate angina in some patients due to reflex increases in heart rate and contractility)

25. Ca ++ Channel Blockers: Toxicities Adverse effects are typically direct extensions of their therapeutic effects and are relatively rare –Major adverse effects: »Depression of contractility and exacerbation of heart failure »AV block, bradycardia, and cardiac arrest –Minor adverse effects »Hypotension, dizziness, edema, flushing Patients with ventricular dysfunction, SA node or AV conduction disturbances, WPW syndrome, and systolic blood pressures below 90 mm Hg should not be treated with verapamil or diltiazem Immediate-release forms of dihydropyridines may increase mortality in patients with myocardial ischemia Bepridil is associated with several serious toxicities including DILQT syndrome (which can lead to the ventricular proarrhythmia, torsades de pointes)

26. Ca ++ Channel Blockers: Drug Interactions  -blockers in combination with verapamil, diltiazem, or bepridil –Bradycardia, AV block, depression of inotropic state Some channel blockers (verapamil, diltiazem) can cause an increase in plasma digoxin levels –AV block can also occur with concurrent treatment with channel blockers and digitalis Quinidine in combination with some calcium channel blockers –Results in decreased clearance of both and an increased risk of bradycardia and AV nodal block Bepridil in combination with other drugs that are known to cause DILQT syndrome (e.g. quinidine, sotalol)

27.  -Adrenergic Blockers in the Treatment of Angina Though most beta-blockers do not cause coronary vasodilation like the nitrovasodilators or calcium channel blockers, beta-blockers are important in the treatment of angina because of their effects on the heart Desired effects of beta-blockers –Reduce myocardial oxygen consumption by reducing contractility and heart rate »Reducing cardiac output also reduces afterload »Some  -blockers can cause vasodilation directly or by acting as  -blockers –Improve myocardial perfusion by slowing heart rate (more time spent in diastole)

28. Adverse Effects and Contraindications for  -Blockers May exacerbate heart failure Contraindicated in patients with asthma Should be used with caution in patients with diabetes since hypoglycemia-induced tachycardia can be blunted or blocked May depress contractility and heart rate and produce AV block in patients receiving non- dihydropyridine calcium channel blockers (i.e. verapamil and diltiazem)

29. Partial Fatty Acid Oxidation (pFox) Inhibitors Ranolazine (Ranexa, piperazine acetamide) is under review by the FDA for the treatment of chronic angina, acute coronary syndromes (ACS), and long-term prevention of ACS –First new antianginal drug in more than 25 years Acts by partially inhibiting fatty acid oxidation in the myocardium, thus shifting metabolism to glucose which requires less oxygen to metabolize No hemodynamic effects MARISA and CARISA clinical trials have studied more than 3300 angina patients and healthy volunteers; ERICA and MERLIN trials are ongoing for safety FDA advisory committee (12/9/2003) recommended use only in refractory cases of angina until safety concerns have been addressed –QT prolongation and testicular toxicity are the among the possible toxicities so far

30. Use of more than one class of antianginal agent can reduce specific undesirable effects of single agent therapy Nitrates Alone Reflex Increase Decrease Reflex increase Decrease Beta-Blockers or Channel Blockers Alone Decrease* Decrease Increase Decrease* Increase Nitrates Plus Beta-Blockers or Channel Blockers Decrease None or decrease None Undesireable effects are shown in italics * Dihydropyridines may cause the opposite effect due to a reflex increase in sympathetic tone Heart Rate Afterload Preload Contractility Ejection time Effect Combination Therapy of Angina

31. Antianginal Combination Therapies Good Ones: –A dihydropyridine calcium channel blocker and a beta- blocker (coronary vasodilation, decreased afterload, lower heart rate, suppression of reflex tachycardia) –A nitrovasodilator and a beta-blocker (coronary vasodilation, decreased preload, lower heart rate, suppression of reflex tachycardia) –A nitrovasodilator and a non-dihydropyridine calcium channel blocker (coronary vasodilation, decreased preload and afterload, lower heart rate, suppression of reflex tachycardia) –A nitrovasodilator, a dihydropyridine calcium channel blocker, and a beta-blocker (coronary vasodilation, decreased preload and afterload, lower heart rate, suppression of reflex tachycardia) Bad Ones: –A beta-blocker and non-dihydropyridine calcium channel blocker (bradycardia, AV block, depressed LV function)

32. Additional Considerations in Treating Angina Modify risk factors associated with atherosclerosis (smoking, hypertension, hyperlidemia) –Statins can reduce coronary artery disease in some patients Patients with stable angina who are refractory to drug therapy may require surgical revascularization (bypass) or angioplasty –Patients with vasospastic angina are not good candidates for these surgical procedures Unstable angina is an acute coronary syndrome that may require maximally tolerated doses of conventional antianginal drugs, and additional drugs including: –Antiplatelet drugs (aspirin, platelet glycoprotein IIB/IIIA inhibitors, and/or platelet ADP antagonists) –Thrombolytic drugs (tissue plasminogen activator, streptokinase, or similar fibrinolytic agent) –Heparinoid anticoagulants including heparin or low molecular weight heparins –Surgical revascularization or angioplasty is often required in these patients