Pharmacology: Drugs used in Angina pectoris

Classification of antianginal agents
first line drugs and newer agents for angina

1. Anti-anginal drugs Department of pharmacology, MMC

2. Objectives To describe classification of drugs used in angina pectoris To explain their mechanism of action, adverse effects, contraindication and important drug interactions

3. Angina pectoris Occurs when myocardial oxygen demand exceeds supply from coronary circulation Drugs used in angina pectoris either increase supply of oxygen and nutrients, or reduce the demand for them, or both Supply of myocardial oxygen can be increased by: dilating coronary arteries slowing the heart (coronary flow, uniquely, occurs in diastole, which lengthens as heart rate falls)

4. Angina pectoris Demand can be decreased by: Reducing afterload ( eg : peripheral resistance) Reducing preload ( eg :-venous filling pressure); according to Starling’s law of the heart, workload and therefore oxygen demand varies with stretch of cardiac muscle fiber Slowing the heart rate

5. Angina pectoris Two forms: Classical , Variant Classical angina: Common form Attacks proved by exercise, emotion and subside when energy demand withdrawn Pathology: severe arteriosclerotic affliction of larger coronary arteries supplying deeper tissues Relieved by rest and reducing myocardial workload

6. Unstable angina Stable angina

7. Angina pectoris Variant angina/ Prinzmetal / vasospastic Uncommon form Attack occurs at rest or during sleep. Unpredictable Due to recurrent localized coronary vasospasm which may be superimposed on atherosclerotic coronary artery disease Drugs are aimed at relieving vasospasm

8. Angina pectoris Unstable angina Rapid increase and severity of attacks May occur even during rest Progressive occlusion of the coronary artery occasionally associated coronary vasospasm High risk of myocardial infarction Antianginal drugs relieve cardiac ischemia but do not alter the course of coronary artery disease No permanent benefit

9. Acute coronary syndrome Rapid worsening of angina: unstable angina and non-ST elevation myocardial infarction Nitrates (limited benefit), antiplatelet drugs, beta blockers , CCB indicated when coronary spasm not relieved by nitrates Thrombolytic/ coronary angioplasty/bypass surgery might be considered in high risk patients

10. Drugs used in angina pectoris Nitrates Beta-blockers Calcium-channel blockers Potassium-channel blockers Others (metabolism modifiers, rate controllers) Short-acting GTN (Glyceryl Trinitrite ISDN (Isosorbide dinitrite - Sublingual ) Propanolol Metoprolol Atenolol Verapamil Diltiazem Amlodipine Nicorandil Trimetazidine Ranolazine Ivabradine Dipyridamole Long-acting Isosorbide dinitrite (oral) Isosorbide mononitrate

11. Drugs used in angina pectoris Two types:- Drugs used to abort or terminate acute attack Eg :- GTN, ISDN(Sublingual) Used for chronic prophylaxis Eg : all other drugs

12. Nitrates Causes direct nonspecific smooth muscle relaxation particularly vascular smooth muscle Reduce Preload Dilate veins more than arteries  peripheral pooling of blood  decreased venous return ( reduced Preload )  end diastolic pressure reduced  less cardiac work Reduce Afterload Produce some arteriolar dilatation decreases total peripheral resistance(TPR)

13. Nitrates At usual doses, tachycardia not prominent At high doses, significant reduction in mean BP  reflex sympathetic stimulation  tachycardia  increased cardiac workload  Precipitation of angina, fainting, cold sweat due to decreased cerebral flow Can be prevented by lying down and raising the foot end

14. Nitrates Redistribution of coronary blood flow relaxation of conducting coronary arteries Favors redistribution of blood flow to ischemic areas of heart

15. Nitrates: Mechanism of Action Nitrates are rapidly converted to nitric oxide (NO) in vascular smooth muscle which activates cytosolic soluble guanylyl cyclase (cGMP)  increased cGMP Causes dephosphorylation of myosin light chain kinases Interferes with activation of myosin  fails to interact with actin  relaxation occurs Raised intracellular cGMP may reduce Ca 2+ entry  relaxation

16. Nitrates Veins express greater amount of mitochondrial aldehyde dehydrogenase which generates NO from GTN – reason for predominant vasodilatory action Platelets: Mild anticoagulant effect Dilates bronchial, gastrobiliary , sphincter of Oddi, & GIT

17. Nitrates Pharmacokinetics: Lipid soluble, well-absorbed from buccal mucosa, intestines and skin Ingested orally, all except ISMN –undergoes extensive first pass metabolism in liver Partly de-nitrated metabolites: less active but longer t1/2 Hydrolyzed by hepatic glutathione -organic nitrate reductase

18. Nitrates Classified into short-acting and long acting Rate of absorption from the site of administration and rate of metabolism govern duration of action

19. Nitrates: Adverse Effects Headache –tolerance develops on continued use Flushing, sweating, palpitations, dizziness, fainting Methemoglobinemia- not seen with clinically used doses Rashes common with pentaerythritol tetranitrate

20. Nitrates: Tolerance Attenuation of hemodynamic and anti-ischemic effect Occurs in dose and duration of exposure dependent manner No significant tolerance develops in intermittent use of SL-GTN Significant with oral, transdermal and continuous IV use, long-acting agents Causes: decreased capacity of vascular smooth muscle to convert nitroglycerine to NO Depletion of sulfhydryl groups may lead to impaired biotransformation of nitrates to NO Enhanced response to vasoconstrictors (angiotensin 2, serotonin, & phenylephrine) To prevent tolerance, use of short acting agents and for short period of time, maintain nitrate-free intervals

21. Nitrates Dependence Withdrawal effects after prolonged exposure result in vasospasm, MI and sudden death Angina threshold is lowered during the nitrate free interval in some patients Can be prevented by adding another class of nitrates and Gradual withdrawal

22. Nitrates: Interactions Sildenafil and other PDE-5 inhibitors- severe hypotension, MI and death Other vasodilators- additive effect

23. Commonly used nitrates Drug Features Route of administration Duration of action GTN (nitroglycerin) Volatile liquid Acts within 1-2 min Indicated for unstable angina, coronary vasospasm, LVF, Hypertension during cardiac surgery Sublingual route Oral Transdermal patch IV infusion 10-30 min 4-8 hr 24 hr ISDN Solid Similar in action to GTN but slightly slower Last dose should not be taken later than 6 pm Sublingual Oral SR oral 20-40 min 2-4 hr 6-10 hr ISMN Active metabolite of ISDN Bioavailability high 10-40 mg oral SR 6-10 hr

24. Nitrates: Uses Angina pectoris Acute coronary syndrome Myocardial Infarction CHF and acute LVF Biliary colic, esophageal spasm Cyanide poisoning

25. Calcium channel antagonist Inhibits voltage sensitive calcium channel (L-Type) located in myocytes Five Types Phenylalkylamines ( eg :-Verapamil) Benzothiazepine ( eg :- Diltriazem ) Dihydropyridines ( eg :-Nifedipine, Amlodipine, Felopidine ) Diarylaminopropylamine ( eg :- Bepridil) Diphenylpiperazine

26. Calcium channel antagonist Pharmacologic Effects CVS Effects Relax arterial smooth muscle Depress rate of SA node pacemaker and slow AV conduction Decrease coronary vascular resistance and increase coronary blood flow Absorption Nearly complete on oral but availability reduced by first pass metabolism Fate Extensively bound to plasma proteins Elimination half-life: 2-6 hr Exceptionally long for Amlodipine followed by nitrendipine and felodipine

27. Calcium channel antagonist Adverse effects Excessive vasodilation and reflex tachycardia Peripheral edema (increase permeability in the arteries but does not affect the veins) Muscle cramps (Nimodipine)

28. Calcium channel antagonist Adverse effects Worsened myocardial ischemia (Dihydropyridines) Worsened heart failure (decrease cardiac contractility) SA or AV nodal dysfunction Prolonged QT (Bepridil)

29. Calcium channel antagonist Worsened Myocardial Ischemia – increase contractility by Dihydropyridine Increase O2 demand Promotes tachycardia Treatment: B-blocker Worsened Heart Failure – don’t give calcium channel blocker

30. Calcium channel antagonist: Therapeutic Uses Variant Angina Exertional Angina Unstable Angina Cardiac Arrhythmias Prophylaxis of migraine or headache (Verapamil) Cerebral vasospasm (Nimodipine) Raynaud’s Disease = reflex vasoconstriction

31. Table: Some Calcium-channel blockers

32. Table: Some Calcium-channel blockers

33. Beta-blockers Decrease severity and frequency of exertional angina Not useful in vasospastic angina Negative chronotropic and negative inotropic effect Decreased myocardial O 2 consumption Therapeutic Uses Unstable Angina Myocardial Infarction

34. Beta-blockers Contraindications Asthma and other bronchospastic conditions, severe bradycardia, atrioventricular blockade,bradycardia -tachycardia syndrome, and severe unstable left ventricular failure

35. Beta-blockers Adverse effects: Fatigue Impaired exercise tolerance Insomnia Worsening of claudication Erectile dysfunction

36. Combination therapy Beta blocker + long acting nitrates Tachycardia due to nitrates prevented by beta-blocker Tendency of B-blocker to cause ventricular dilatation and reduced coronary flow counteracted by nitrates Slow-acting DHP +B-blocker Same effect plus relief of coronary vasospasm Verapamil or diltiazem not used -depressant effect on SA node may add up

37. Combination therapy Nitrates + CCBs: decrease cardiac work and improve coronary perfusion- useful in severe vasospastic angina Nitrates + Beta blockers+ CCBs: Severe cases Verapamil/diltiazem should be avoided in such combinations

38. Newer Anti-anginal agents Direct bradycardic agents, eg , ivabradine Inhibitors of slowly inactivating sodium current, eg , ranolazine Metabolic modulators, eg , trimetazidine Nitric oxide donors, eg , L-arginine Potassium channel activators, eg, nicorandil

39. Newer anti-anginal drugs Ranolazine Act by reducing a late sodium current ( INa ) that facilitates calcium entry Results in reduction in intracellular calcium concentration which help in reducing diastolic tension and thus cardiac load Approved for use in angina but effectiveness in ACS unclear

40. Newer anti-anginal drugs Ranolazine prolongs QT- interval in patients with coronary artery disease while shortens it in patients with long QT-syndrome Not associated with torsades de pointes arrythmia Drug interaction with digoxin and simvastatin by inhibiting its metabolism

41. Newer anti-anginal drugs Trimetazidine Metabolic modulator Partially inhibit the fatty acid oxidation pathway in myocardium Because metabolism shifts to oxidation of fatty acids in ischemic myocardium, the oxygen requirement per unit of ATP produced increases, hence partial inhibition of the enzyme required for fatty acid oxidation (long-chain 3-ketoacyl thiolase , LC-3KAT) appears to improve the metabolic status of ischemic tissue

42. Newer anti-anginal drugs Trimetazidine inhibit LC-3KAT at achievable concentrations and has demonstrated efficacy in stable angina However, it is not approved for use in the USA Perhexiline may shift myocardial metabolism from fatty acid oxidation to more efficient glucose oxidation (like trimetazidine) Currently approved in only few countries not USA

43. Newer anti-anginal drugs Ivabradine:- I f sodium channel blocker Reduce cardiac rate by inhibiting hyperpolarization activated sodium channel in SA node No other significant hemodynamic effects reported Reduce anginal attacks similar to that of Ca 2+ channel blockers and B-blockers Does not act on GI and bronchial SM Approved for use in angina and heart failure outside USA

44. Newer anti-anginal drugs Ivabradine:- I f sodium channel blocker Reduce cardiac rate by inhibiting hyperpolarization activated sodium channel in SA node No other significant hemodynamic effects reported Reduce anginal attacks similar to that of Ca 2+ channel blockers and B-blockers Does not act on GI and bronchial SM Approved for use in angina and heart failure outside USA

45. Newer anti-anginal drugs Nicorandil:- Dual mechanism Activates ATP sensitive K+ channels (KATP) hyperpolarizing vascular smooth muscle Like nitrates acts as a NO donor—relaxes blood vessels by increasing cGMP Arterial dilatation coupled with vasodilatation

46. Nicorandil No significant cardiac effects on contractility and conduction Beneficial effects on angina frequency and exercise tolerance comparable to nitrates and CCBs in stable as well as vasospastic angina

47. Nicorandil Adverse effects: Flushing, palpitation, weakness, headache, dizziness, nausea, and vomiting Large painful aphthous ulcers in the mouth, which heal on stopping nicorandil Unlike nitrates, tolerance does not occur with nicorandil , but it has the potential to interact with sildenafil Dose: 5–20 mg BD

48. Nicorandil Though nicorandil is an alternative antianginal drug, its efficacy and long term effects are less well established May be useful in resistant angina when combined with other drugs When administered i.v. during angioplasty for acute MI, it is believed to improve outcome

49. Dipyridamole Increases total coronary flow by preventing uptake and degradation of adenosine Adenosine is a local mediator involved in autoregulation of coronary flow during ischemia Dilates resistance vessels has no effect on larger coronary vessels Does not reduce cardiac load Fail to relieve anginal symptoms

50. Dipyridamole “Coronary Steal phenomenon” By dilating resistance vessels in non-ischemic zone it diverts the already reduced blood flow away from the ischemic zone Inhibits platelet aggregation by potentiating PGI2 and increasing cAMP in platelets Used for prophylaxis of coronary and cerebral thrombosis in post-MI and poststroke patients, as well as to prevent thrombosis in patients with prosthetic heart valves Dose : 25–100 mg TDS

51. Pharmacologic therapy in Myocardial infarction Ischemic necrosis of a portion of the myocardium due to sudden occlusion of a branch of coronary artery Usual cause: an acute thrombus at the site of atherosclerotic obstruction About ¼ patients die before therapy can be instituted

52. Pharmacologic therapy in Myocardial infarction Pain reliever: nitrates, an opioid analgesic (morphine/pethidine) or diazepam administered parenterally Oxygen Maintenance of blood volume, tissue perfusion and microcirculation:- Fluids

53. Pharmacologic therapy in Myocardial infarction Correct acidosis:- Sod. bicarbonate infusion Prevention and treatment of arrhythmias: Prophylactic i.v. infusion of a β blocker unless contraindicated Tachyarrhythmias may be treated with i.v. lidocaine , procainamide or amiodarone Routine prophylactic lidocaine infusion is not recommended Bradycardia and heart block may be managed with atropine or electrical pacing

54. Pharmacologic therapy in Myocardial infarction Use of diuretics, inotropes and vasodilators in case of heart failure Prevention of thrombus extension, embolism, venous thrombosis by use of anticoagulants Aspirin(162–325 mg) should be given as soon as MI is suspected (if not already being taken on a regular basis)

55. Pharmacologic therapy in Myocardial infarction Thrombolysis and reperfusion: Fibrinolytic agents, i.e. plasminogen activators—streptokinase/ urokinase/alteplase) Prevention of remodeling and subsequent CHF: ACE inhibitors/ARBs

56. Pharmacologic therapy in Myocardial infarction Prevention of future attacks : (a) Platelet inhibitors—aspirin or clopidogrel given on long-term basis are routinely prescribed (b) β blockers—reduce risk of reinfarction, CHF and mortality All patients not having any contraindication are put on a β blocker for at least 2 years (c) Control of hyperlipidemia—dietary substitution with unsaturated fats, hypolipidemic drugs especially statins