Pharmacology of Ischemic Heart Disease.pptx

Pharmacology of Ischemic Heart Disease

1. Pharmacology of Ischemic Heart Disease Haftom G. ( BPharm ., MSc.) Email: [email protected]

2. What is ischemia ? Ischemia is a condition in which the blood flow (and thus oxygen) is restricted or reduced in a part of the body. Cardiac ischemia is the name for decreased blood flow and oxygen to the heart muscle . It is also called coronary artery disease and coronary heart disease. This can ultimately lead to heart attack.

3. Ischemic Heart Disease Myocardial ischemia results from Fixed partial obstruction of an artery or arteries due to atheroma or other pathologies Inappropriate arterial vasospasm Thrombus Myocardial ischemia could be Partial or complete Temporary or permanent (death of a tissue by necrosis or apoptosis) Acute : Myocardial Infarction Chronic : Angina pectoris, Silent Ischemia 3

4. Ischemic Heart Disease If Myocardial ischemia is sufficiently severe and maintained for a long period of time leads to tissue infarction Ischemia with pain preferred than silent, as it gives a warning signal for intervention Myocytes depend on aerobic metabolism, if oxygen remains low; die by apoptosis or necrosis 4

5. Chronic Ischemic Heart Disease Chronic IHD arises as a result of a mismatch between myocardial blood/ oxygen supply and demand Attacks of angina may be precipitated by any stress which increases cardiac work and myocardial oxygen demand The heart extracts approximately 75% of available oxygen even under no stress 5

6. Angina pectoris A ngina pectoris is the principal symptom of ischemic heart disease Characterized by sudden, severe and pressing substernal pain that is usually felt beneath the upper sternum and is often transferred to the surface areas of the body and most often to the left arm and shoulder and even to the side of the face 6

7. Ischemic condition results from Imbalance b/n myocardial oxygen demand & oxygen supplied by coronary vessels. Increased myocardial oxygen demand Determined by Ventricular wall tension , HR , contractility Decreased myocardial oxygen supply Determined by coronary blood flow (CBF) , oxygen-carrying capacity of the blood 7

8. Fig: Pharmacological modifcation of the major determinants of myocardial O2 supply.

9. Types of Angina Stable /exertional, typical, classic/ Angina Underlying Pathology : atherosclerosis in large coronary arteries Episodes precipitated by exercise, cold, stress, emotion, eating Treatment principles : Decrease cardiac load (pre-& after load), increase myocardial blood flow Organic nitrates, β -blockers, CCB, Statins ( atehroma ), antiplatelet drugs (aspirin) 9

10. TYPES…. Vasospastic /Variant, prinzmetals / Angina Cause : transient Vasospasm of coronary Vessels Associated: underlying atheromas Pain can occur at rest Treatment principles :  ed Vasopasm of coronary Vessels Coronary vasodilators ( nitroglycerin ) and CCBs 10

11. TYPES… Unstable / preinfarction , crescendo.../ Angina Chest pains occur with ↑ ed frequency and are precipitated by progressively less effort. Cause : recurrent episodes of small platelet clots. Site: ruptured atherosclerotic plague Precipitated: local Vasospasm Treatment principles : inhibit platelet aggregation & thrombus formation, decrease cardiac load, Vasodilate coronary arteries. 11

12. Therapeutic rationale Decreasing myocardial oxygen demand: Reducing cardiac workload Reducing heart rate Reducing force of myocardial contraction Reducing after load and preload Increasing myocardial oxygen supply : Vasodilators 12

13. Classification of Antianginal Agents Organic nitrates Reduce preloads & after load, dilate coronary arteries. Inhibits platelet aggregation. Ca ++ channel blockers Vasodilate coronary arteries: Reduce after load Some; decrease HR, decrease contractility. ß-adrenergic antagonists Decrease HR, contractility and afterload 13

14. Drug Therapy Other drugs Antiplatelet drugs: e.g., Aspirin Cholesterol lowering agents HMG CoA reductase inhibitors 14

15. Nitrovasodilators Nitrates Glyceryl Tri Nitrate (GTN )- sublingual , buccal , transdermal Isosorbide Mononitrate - sustained release, tablets Isosorbide Dinitrate - sustained release, tablets Nitrites Amyl nitrite Isobutyl nitrite NO containing compounds Sodium nitroprusside 15

16. Mechanism of action Reducing agents such as cysteine or reduced glutathione facilitate the generation of reactive intermediates ( nitrosothiols ) that result in the generation of NO NO activates guanylate cyclase, by binding to iron in the heme group to produce cyclic GMP ( cGMP ) Smooth muscle relaxation: due to 16

17. Mechanism of relaxation by NO 17

18. Pharmacological effects Venodilation (major ↓ preload) Arteriolar dilatation (↓ afterload)  Myocardial work load  se in O 2 demand . Improve perfusion of ischemic myocardium. 18

19. Nitrovasodilators Although venous effects predominate at low doses , nitroglycerin produces a dose-related dilation of both arterial and venous beds Venodilation promotes peripheral pooling of blood and decreases venous return to the heart, reducing left ventricular end-diastolic pressure (preload). Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (afterload). Myocardial oxygen consumption or demand is decreased by both the arterial and venous effects May cause redistribution of coronary blood flow from normal to ischemic tissue . Nitrates (and calcium channel blockers) may also increase myocardial oxygen delivery in variant angina by reversing coronary arterial spasm

20. Pharmacokinetics Parameter GTN ISDN ISMN Half-life (min) 3 10 280 Plasma clearance (L/min) 50 4 0.1 Apparent Vd (L/kg) 3 4 0.6 Oral BA (%) ~0 20 100 20

21. Pharmacokinetics Oral bioavailability is very low Extensive hepatic first pass metabolism . Sublingual effective for the Rx of acute attacks of angina pectoris due to first pass effect Long acting preparations (oral, transdermal, ointment) used to provide prolonged prophylaxis against angina attacks Elimination: glutathione-Organic nitrate reductase Reduction in liver to denitrated organic compounds  glucuronide conjugation and excretion in kidney 21

22. Organic nitrates… Therapeutic uses Treatment & prevention of all types of Angina Variant angina Stable angina Unstable angina 22

23. Indications of Nitroglycerin Sublingual nitroglycerin is the drug of choice for acute treatment of angina due to its rapid onset of action & clinical efficacy Classic Effort-induced Angina pectoris Venodilation with resulting decreased venous return to the heart and the resulting reduction of intracardiac volume result in decreased wall tension & decreased preload result in decreased myocardial oxygen demand. Note : excessive reflex tachycardia & increased contractility due to a reduction in arterial blood pressure by higher doses of nitroglycerin can result in a paradoxical increase in oxygen demand? Vasospastic (Variant or Prinzmetal's ) Angina Relaxes smooth muscle of the epicardial coronary arteries & reduces coronary artery spasm

24. Indications of Nitroglycerin c. Unstable Angina Therapeutic mechanisms are less well established. By dilating epicardial coronary arteries & simultaneously reducing myocardial oxygen demand it may produce beneficial effects. Nitroglycerin's ability to decrease platelet aggregation may also be of importance in unstable angina II. CHF associated with acute myocardial infarction III. Control of blood pressure in hypertension associated with surgical procedures IV. Production of controlled hypotension during surgical procedures

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26. Tolerance Tolerance can develop rapidly Magnitude is a function of dosage and frequency May result from Reduced capacity of the vascular smooth muscle to convert to NO (true vascular tolerance) Activation of mechanisms extraneous to the vessel wall ( pseudotolerance ) Occur with long acting and special formulations 26

27. Tolerance…….. How to overcome tolerance? Using a sustained release preparation which incorporates a “nitrate free period” 27

28. Adverse effects Headache, dizziness and feeling weak Increase dose slowly Postural hypotension (GTN syncope) Lightheadedness Reflex tachycardia Flushing Methemoglobinemia ( Isosorbide dinitrate , rare) Withdrawal from long-term exposure can produce severe ischemia resulting in death or MI 28

29. Contraindications Type 5 PDE inhibitors potentiate the action of nitrates used for angina: Coadministration within 24 hours of taking sildenafil is likely to produce severe hypotension. A few myocardial infarctions have also been reported The interaction with tadalafil (Cialis ®) lasts up to 48 hours due to tadalafil's longer half life Known hypersensitivity Hypotension or uncorrected hypovolemia Increased intracranial pressure (head trauma) Inadequate cerebral circulation Constrictive pericarditis or pericardial tamponade

30. Beta blockers Increase in HR often precipitate angina, drug blunting sympathetic effect on the heart would be antianginal B-blockers are reversible antagonists of the  1 and  2 receptors Cardioselective drugs (  1 ) useful in treating exertional angina attacks ( metoprolol , atenolol ) High dose: selectivity is lost and effect resembles to that of non- selectives Partial agonists (  1 selective) are useful, however, elevate HR at low doses ( pindolol , acebutolol ) Not effective against vasospastic angina due to increased coronary resistance by acting at α adrenergic receptors?? 30

31. Mechanism of action The relevant effect in angina is to block cardiac β1 receptors to produce a: Decreased heart rate Reduced contractility Reduced blood pressure The combination of these effects decreases myocardial oxygen requirements at rest and during exercise . Beta blockers may also be valuable in reducing “silent” ischemia Randomized trials in patients with stable angina have shown better outcome & symptomatic improvement with beta-blockers compared to calcium channel blockers 31

32. Therapeutic Uses Exertional angina Unstable angina; reduce progression to MI. Myocardial infarction: improve mortality Combined with Nitrates &/or Ca ++ channel blockers. Not useful in Variant Angina 32

33. Side Effects: Increase in end-diastolic volume & increased ejection time , which ends up increasing oxygen requirements , which partially offsets the beneficial effects to reduce oxygen demands. This can be balanced by the concomitant use of nitrates Others - fatigue, impaired exercise tolerance, insomnia, unpleasant dreams, erectile dysfunction

34. Contraindications: Asthma & other bronchospastic conditions Severe bradycardia AV block Severe unstable LV failure Beta Bockers are Contraindicated in Vasospastic Angina Sudden cessation of β - blocker therapy may precipitate myocardial infarction

35. Calcium Channel Blockers (CCBs) Increased free calcium in the cytoplasm of vascular smooth muscle cells leads to vasoconstriction The calcium ion, after binding to calcium-binding proteins, activates a myosin light-chain kinase (MLCK), causing phosphorylation of myosin filaments followed by an interaction of these filaments with actin filaments and finally contraction Calcium antagonists block voltage-dependent channels. These channels allow the entry of calcium in response to cell depolarization . 35

36. CCB… Classification:- based on chemical structure. Benzothiazepines : Diltiazem Phenylalkylamines : Verapamil Diarylaminopropylamine ethers: Bepridil Benzimidazole substituted tetralines : mibefradil Dihydropyridines : Nifedipine , nicardipine , Amlodipine, Nimodipine etc. 36

37. CCB… Site of action of Ca ++ -channel blockers. Bind to L-type Ca ++ -channels- prevent Ca ++ influx. different classes bind to different sites on the channel different types of L-type channels exist. Bepridil ; also blocks Na + and K + channels Mibefradil : also blocks T-type channels 37

38. Pharmacological Effects Vascular smooth muscle Decreased intracellular ca ++ in arterial Smooth muscle  Relaxation Decreased after load Little or No effect on venous beds No effect on preload. 38

39. Nifedipine Mechanisms of Action: vascular selective L-type calcium channel blocker In CLASSIC ANGINA : Dilates peripheral arterioles which ( reduces afterload ) against which the heart works Reduced work of the heart reduces myocardial energy consumption and oxygen requirements In PRINZMETAL's or VASOSPASTIC ANGINA : Dilates the main coronary arteries and coronary arterioles , both in normal and ischemic regions Is a potent inhibitor of coronary artery spasm , whether spontaneous or ergonovine -induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm In HYPERTENSION?

40. Nifedipine Indications: For prophylactic treatment of: Angina of effort Vasospastic angina Hypertension For treating patients with AV node conduction disturbances needing a calcium channel blocker (e.g. for angina or hypertension) nifedipine may be a safer choice compared to verapamil or diltiazem because it does not significantly decrease AV node conduction in situ

41. Verapamil Indications: Vasospastic & Effort-Associated angina (prophylactic treatment) Hypertension Paroxysmal Supraventricular Tachycardia (PSVT) : a drug of choice for prophylaxis A drug of 2nd choice after adenosine for acute treatment (adenosine has been shown to produce better outcomes when used for acute conversion of PSVT to sinus rhythm) Control of ventricular rate in patients with chronic atrial fibrillation/flutter .

42. Verapamil Indications: Vasospastic & Effort-Associated angina (prophylactic treatment) Hypertension Paroxysmal Supraventricular Tachycardia (PSVT) : a drug of choice for prophylaxis A drug of 2nd choice after adenosine for acute treatment (adenosine has been shown to produce better outcomes when used for acute conversion of PSVT to sinus rhythm) Control of ventricular rate in patients with chronic atrial fibrillation/flutter .

43. Verapamil Contraindications: Severe hypotension 2nd or 3rd degree AV block Cardiogenic shock Severe CHF Sick sinus syndrome (unless client has artificial pacemaker) Severe LV dysfunction

44. Diltiazem Indications: Vasospastic & Classic Angina (prophylactic treatment) Hypertension Control of ventricular rate in atrial fibrillation of flutter Contraindications: Hypotension AV block (2nd- or 3rd-degree) or sick sinus syndrome, except in the presence of a functioning ventricular pacemaker Acute MI Pulmonary congestion Lactation

45. Ranolazine Mechanism of Action: It reduces Na influx during ventricular depolarization by blocking a “late Na plateau current” caused by Na channels that do not inactivate, or that re-open The reduction in intracellular Na results in a consequent reduction of intracellular Ca due to the activity of the Na/ Ca exchanger The reduction in intracellular Ca reduces contractility, which reduces ischemic injury Ranolazine also dose-dependently increases QTc by blocking the cardiac IKr It has no significant effect on blood pressure or heart rate

46. Ranolazine Indications: Ranolazine is not recommended as first-line therapy for patients with chronic stable angina due to the potential risk of QTc prolongation & increased cost compared to traditional antianginal drug regimens It is considered as an option for those who cannot tolerate any of the traditional agents due because of hemodynamic or other side effects It can also be used as “add on” therapy with traditional agents. Ranolizine increases exercise duration similar to other antianginal agents

47. Ranolazine Side Effects: Dizziness , nausea, constipation, and headache Dose-dependent QTc prolongation (concern for pro-arrhythmia)

48. Summary of Maintenance Therapy for Angina Acute Emergency Treatment of Angina: Myocardial Ischemia Oxygen Nitroglycerin Aspirin Morphine : Reduces central anxiety and relieves pain . Pain affects heart rate, contractility & systolic blood pressure, which increase oxygen demand . Morphine also produces venodilation

49. Summary of Maintenance Therapy for Angina Chronic Stable Angina of Effort: Mono or combination antianginal therapy with: Long-acting Nitrates Calcium Channel Blockers Beta Blockers Alternative 2nd line drug: Ranolazine HOWEVER a More Complete Treatment (2) Includes: ABCDE A spirin, A CE inhibitors & A ntianginals (listed above) B eta blocker & B P control C holesterol drug & C igarette cessation D iabetes & D iet management E xercise & E ducation

50. Summary of Maintenance Therapy for Angina Vasospastic (Variant) Angina: Mono or combination therapy with: Nitrates Calcium Channel Blockers NOT Beta-blockers

51. Summary of Maintenance Therapy for Angina Unstable Angina Management: Antiplatelet agents ( A spirin , Clopidogrel , Glycoprotein 3b-2a inhibitors ) (325 mg aspirin initially) In unstable angina, a thrombus full of platelets partially occludes a vessel Anticoagulants (heparin or Enoxaparin) Nitroglycerin (sublingually or by buccal spray; i.v. if pain persists; topical or oral for maintenance) Beta-blocker (reduce heart rate to 50-60 beats/min; caution in patients with evidence of HF) ACE-inhibitor Statin or other lipid-lowering agent if applicable (prophylactic therapy )