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Drug Therapies for Ischemic Heart Disease
- 1. Drugs for IschemicHeart Disease 1
- 2. Ischemic heart disease (IHD) • IHD is an umbrella term that encompasses a spectrum of cardiac disorders caused by myocardial ischemia. • IHD is defined as lack of oxygen and decreased or no blood flow to the myocardium resulting from coronary artery narrowing or obstruction. • Myocardial ischemia is a state of decreased perfusion during which the oxygen supply to the myocardium is insufficient to meet its metabolic demands. 2
- 3. Conventional classification of IHD SIHD is also frequently known as stable coronary artery disease (SCAD) Stable angina is the chief manifestation of SIHD or SCAD Stable & vasospastic angina Symptomatic ischemic cardiomyopathy Microvascular angina 3
- 4. Characteristics of acute coronary syndromes 4
- 5. Pathophysiology Atherosclerosis is the fundamental pathophysiological basis of IHD results in the buildup of plaque in the coronary arteries subsequently lead to stable angina and ACS. Stable angina is caused by narrowing of the coronary artery and limitation of the blood supply to part of myocardium. On the other hand, the sudden rupture of a plaque and the subsequent thrombosis are responsible for 5
- 6. Angina Angina, formally known as angina pectoris, is a term used to describe chest pain. The angina pain may be felt in the jaw, arm, neck, back, or shoulder as well. Angina, caused by a reduced amount of oxygen flowing to the heart, is the primary symptom of IHD and is not a medical condition itself. Angina signifies that the affected individual is at a greater risk of suffering from a heart attack or cardiac arrest. 6
- 7. Angina… The imbalance may be caused by • By an increase in myocardial oxygen demand (which is determined by heart rate, ventricular contractility, and ventricular wall tension) or • By a decrease in myocardial oxygen supply (primarily determined by coronary blood flow & diastolic filling time). 7
- 8. Types of Angina Stable /exertional, typical, classic.../ Angina Variant /Vasospastic, prinzmetal.../ Angina Unstable Angina 8
- 9. Treatment strategy of angina 9
- 10. Organic Nitrates • Glyceryl trinitrate (nitroglycerine) • Isosorbide dinitrate (IDN) • Isosorbide mononitrate (IMN) • Erythrityl trinitrate • Pentaerythritol tetranitrate • Amyl nitrite Nitrates release nitric oxide (NO) within smooth muscle cells, probably through the action of the mitochondrial enzyme aldehyde dehydrogenase-2 (ALDH2). 10
- 11. Nitrates… Nitrates cause vasodilating effects on both peripheral veins and arteries but with more prominent effects on the veins. The enzyme responsible for releasing NO from the nitrates is present mainly in the veins (therefore selective venodilator action). Nitrates primarily reduce cardiac oxygen demand by decreasing preload (left ventricular end‐diastolic pressure). They may modestly reduce afterload, dilate coronary 12
- 12. ADME Drugs Preparation Onset of action Duration of action Nitroglycerin Sublingual tablet or spray 1-3 min 25min Oral, sustained release 35 min 4-8hr Trans-dermal 30 min 10-12 hr Isosorbide dinitrate Sublingual 5 min 1 hr Oral, slow release 30 min 8 hr Isosorbide mononitrate Oral, extended release 30 min >12-24 hr 13
- 13. ADME… Drugs Oral BA(%) Elimination half‐life Metabolism and excretion Nitroglycerin 40 1–3 min Hepatic denitration to dinitrates and mononitrates; renal excretion Isosorbide dinitrate 25 45min; 5h for the activemetabolite,5‐ mononitrate Hepatic denitration followed by glucuronidation; renal excretion Isosorbide mononitrate ~100 5h No significant first‐pass effects; hepatic denitration and renal excretion 14
- 14. Mechanisms of Antianginal Efficacy The major antianginal effect for classic angina is mediated by preload reduction rather than coronary artery dilation. NO-mediated vasodilation of large (venous, arterial) > small (resistance) vessels ⇒ preferential preload reduction without steal effect. Coronary vasodilatory action is mainly responsible for the therapeutic benefit of nitrates in variant/ prinzmetal angina. 15
- 15. Nitrate tolerance • Tolerance has been a major problem with the use of nitrates as chronic antianginal therapy. • Proposed mechanisms I. impaired nitroglycerin bioconversion to 1,2‐glyceryl dinitrate with decreased formation of nitric oxide II. reduced bioactivity of nitric oxide III. activation of the RAAS and sympathetic nervous system in response to nitrate‐induced vasodilation. 16
- 16. Ways to manage tolerance? Nitrate free interval (Need 6-8 hr nitrate free time) to restart activity Exertional angina is prominent during day time: nitrate free interval during night Prinzimetal’s angina is precipitated at morning (circadian catecholamine surges, adrenergic supply from adrenaline is more): nitrate free evening Alternatives (BBs or CCBs) Partially prevented or reversed with a sulfhydryl- regenerating. 17
- 17. Clinical use of nitrates Stable Angina Pectoris Short-acting nitrates for standby therapy • Sublingual GTN is the most commonly used for acute relief • Sublingual ISDN, but not ISMN, is an alternative to GTN Longer-acting nitrates for the prophylaxis of angina • Sustained-release oral preparations (ISDN, ISMN & GTN) • chronic treatment with nitrates is not associated with a 18
- 18. Clinical use of nitrates… Variant (Prinzmetal) Angina long-acting nitrates alone are occasionally efficacious in abolishing episodes of variant angina. additional therapy with Ca2+ channel blockers usually is required. Ca2+ channel blockers, but not nitrates, have been shown to influence mortality and the incidence of MI favorably in variant angina. • they should generally be included in therapy. • But not beta blockers! 19
- 19. Clinical use of nitrates… Unstable Angina Pectoris (ACSs) Resistance to nitrates classifies angina symptoms as “unstable” and is a characteristic feature of ACSs, typically caused by transient or permanent thrombotic occlusion of coronary vessels. Nitrates do not modify this process specifically and are second-line drugs. 20
- 20. Adverse effects of organic nitrates Mainly due to excessive vasodilatation Severe headache (throbbing headache), dizziness, flushing Orthostatic hypotension, reflex tachycardia Syncope (fainting)….cerebral cortex hypo perfusion….loss of consciousness A friend of nitrates is BBs ….reduce reflex tachycardia Serious drug interaction with PDE5 inhibiters Sildenafil (exaggerated response to nitrates, more 21
- 21. β Blockers Only antianginal drug class with proven prognostic benefits in CAD (post MI). They are therefore recommended as first line treatment of patients with stable CAD and unstable angina/ACS. β Blockers are not useful for vasospastic angina and, if used in isolation, may worsen that condition. Standard compounds for the treatment of angina are β1-selective and without intrinsic sympathomimetic activity (e.g., atenolol, bisoprolol, 22
- 22. β Blockers… • The beneficial effects of β-blocking agents are related to their hemodynamic effects— decreased heart rate, blood pressure, and contractility—which decrease myocardial oxygen requirements at rest and during exercise. • Lower heart rate is also associated with an increase in diastolic perfusion time that may increase coronary perfusion. myocardial O2 consumption at rest and during 23
- 23. β Blockers… Moreover, BBs can increase blood flow toward ischemic regions (preventing blood from being shunted away from the ischemic myocardium): “reverse steal or Robin Hood phenomenon”. Undesirable effects: in end-diastolic volume and an in ejection time ( myocardial oxygen requirement) • Combination (nitrate + BBs) • EDV (caused by BB) & reflex tachycardia (caused by nitrates) can be prevented. 24
- 24. β Blockers… Note: • It is important not to discontinue β- blocker therapy abruptly. • The dose should be gradually tapered off over 2 to 3 weeks to avoid rebound angina, MI, and hypertension. 25
- 25. Ca2+ Channel Blockers Calcium influx is increased in ischemia because of the membrane depolarization that hypoxia produces. In turn, this promotes the activity of several ATP- consuming enzymes, thereby depleting energy stores and worsening the ischemia. The Ca++ channel blockers protect the tissue by inhibiting the entrance of Ca++ into cardiac and smooth muscle cells of the coronary and systemic arterial beds. 26
- 26. Ca2+ Channel Blockers… Dihydropyridines: (amlodipine, nifedipine extended R) Their effect for classic angina is mainly by peripheral arterial vasodilation and afterload reduction. Their efficacy in vasospastic angina is due to relaxation of the coronary arteries. Short-acting dihydropyridines should be avoided in CAD because of evidence of increased mortality after an MI. 27
- 27. Nodihydropyridine Ca2+ Channel Blockers Verapamil: more direct negative inotropic and chronotropic effects Cause a reduction in myocardial O2 demand contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities. Diltiazem Diltiazem can relieve coronary artery spasm and is particularly useful in patients with variant angina. 28
- 28. Ca2+ Channel Blockers… Variant Angina Ca2+ channel blockers are effective in about 90% of patients. These agents are considered first-line treatment and may be combined with nitro-vasodilators. Exertional Angina also are effective in the treatment of exertional angina considered the drugs of choice if β blockers do not achieve sufficient symptomatic benefit or are not tolerated • evidence for life-prolonging efficacy is lacking 29
- 29. Ca2+ Channel Blockers… Unstable Angina (ACS) Verapamil and diltiazem are recommended only--- for patients who continue to show signs of ischemia, do not tolerate β blockers, have no clinically significant left ventricular dysfunction, and show no signs of disturbed AV conduction. not to use dihydropyridines without concurrent therapy with β blockers. 30
- 30. Antiplatelet Agents Antiplatelet agents represent the cornerstone of therapy for ACS Aspirin (low dose 75-125 mg), P2Y12 receptor antagonists [clopidogrel, prasugrel, ticagrelor, cangrelor (IV)] ↓ Platelet aggregation by inhibiting COX-1 mediated TxA2 production (aspirin) or ADP receptors (P2Y12 receptor antagonists) 31
- 31. Antiplatelet Agents… Newer thienopyridines (prasugrel, ticagrelor, cangrelor) All three appear superior to clopidogrel in treating patients with ACS; contributing factors likely include faster onset of action and less-variable pharmacokinetics. The hepatic activation of prasugrel is more stable and faster than that of clopidogrel Ticagrelor and prasugrel as the primary choice in patients with ACS and clopidogrel as an alternative 32
- 32. Antithrombotic Agents Heparin, in its unfractionated form and as low- molecular-weight heparin (e.g., enoxaparin), also reduces symptoms and prevents infarction in unstable angina. Fondaparinux, a heparinoid pentasaccharide, antithrombin III-dependent Factor Xa inhibitor has the best efficacy-safety profile of all anticoagulants and is therefore currently first choice. Statins can be added to reduce associated dyslipidemia. 33
- 33. Myocardial Infarction For the treatment of acute ST elevation MI, thrombolytic therapy (streptokinase, urokinase, anistreplase, alteplase, reteplase, tenecteplase etc.) should be instituted as early as possible, preferably within first 3 hours. 10% reduction in mortality can still be attained even if these are administered after 12 hours. Morphine like opioid is administered i.v. to decrease pain and increased sympathetic activity (pain in MI results in the increased sympathetic outflow). 34
- 34. 35
Hinweis der Redaktion
- Indeed, the main symptomatic clinical presentations of SIHD include classical chronic stable angina caused by epicardial stenosis; angina caused by microvascular dysfunction (also known as microvascular angina) angina caused by vasospasm (vasospastic angina), and Symptomatic ischemic cardiomyopathy. Acute coronary syndrome (ACS) is an umbrella term inclusive of unstable angina (UA) or acute myocardial infarction (MI) consisting of ST segment elevation MI (STEMI) or non–ST segment MI (NSTEMI).
- The difference between UA and myocardial infarction is whether the ischemia is severe enough to cause sufficient myocardial damage to release detectable quantities of cardiac troponins. Significant myocardial damage occurs in NSTEMI and STEMI, but not in UA. ST-elevation myocardial infarction is generally due to a complete obstruction of a large coronary artery. The mainstay in these patients is immediate reperfusion by primary angioplasty and stenting or, in the absence of invasive options, fibrinolytic therapy Non–ST-elevation myocardial infarction Due to transient obstruction of larger coronary arteries or occlusion of small branches, leading to disseminated myocardial necrosis. Primary angioplasty is also indicated in these patients. Unstable angina is differentiated from NSTEMI by the absence of increased plasma troponin concentrations.
- The term atherosclerosis comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness). It refers to the process of fatty substances, cholesterol, cellular waste products, calcium, and fibrin (a clotting material in the blood) building up in the inner lining of an artery. The resulting buildup is called plaque
- In some patients, anginal symptoms may occur without any increase in myocardial O2 demand, but rather as a consequence of an abrupt reduction in blood flow, as might result from coronary thrombosis (unstable angina or ACS) or localized vasospasm (variant or Prinzmetal angina).
- Stable angina -common
- In vascular smooth muscle cells, nitric oxide activates guanylate cyclase, which increases cGMP leading to dephosphorylation of myosin light chain and thereby smooth muscle relaxation. Nitric oxide may also activate calcium‐dependent potassium channels, leading to membrane hyperpolarization and thereby smooth muscle cell relaxation
- For use in rectal fissures, intra‐anal administration of nitrates results in decreased sphincter tone and intra‐anal pressure. Nitrates have significant antiplatelet and antithrombotic properties; however, the clinical importance of these potentially beneficial effects is unclear. High dose, This can happen to such an extent that coronary flow is compromised, and the sympathetic increase in myocardial O2 demand overrides the beneficial action of the nitrovasodilators, leading to ischemia.
- Glyceryl dinitrate metabolites of nitroglycerin, which have about one-tenth the vasodilator potency, appear to have half lives of about 40 min.
- The partially denitrated metabolites have much longer half-lives (up to 3 hours). Nitroglycerin metabolites (two dinitroglycerins and two mononitro forms) -The 1,2-dinitro derivative has significant vasodilator efficacy, provides most of the therapeutic effect of orally administered nitroglycerin. Oral isosorbide dinitrate →denitration to two mononitrates (active) Isosorbide mononitrate has improved bioavailability and long duration of action to its stability against hepatic breakdown Ellimination: glutathione-organic nitrate reductase Reduction in liver to denitrated organic compounds glucuronide conjugation and excretion in kidney
- blood flow to ischemic sub-endocardial myocardium may contribute to relief of pain in a typical anginal attack Nonselective vasodilators such as adenosine or dipyridamole can worsen the perfusion of ischemic areas by dilating the relatively constricted arterioles of the healthy myocardium, leading to redistribution of blood flow away from the ischemic myocardium (“steal phenomenon”). Nitrovasodilators, in contrast, do not have a major effect on the smaller resistance arteries (and therefore do not cause steal phenomena).
- Molsidomine is an emerging agent in this category to which tolerance does not develop.
- Patients should be instructed to seek medical attention immediately if three tablets of GTN taken over a 15-min period do not relieve a sustained attack because this situation may be indicative of MI, unstable angina, or another cause of the pain. Sustained-release ISDN and ISMN are typically given in two doses administered 6–7 h apart, followed by a nitrate-free interval of at least 8 h. Nitroglycerin is indicated for either the acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease Isosorbide dinitrate and isosorbide mononitrate are indicated only for the prevention of angina pectoris due to coronary artery disease. This is because the onset of action of isosorbide dinitrate or isosorbide mononitrate is not sufficiently rapid for them to be useful in aborting an acute anginal episode. This is also true for the extended release formulations of nitroglycerin, which are only indicated for prophylaxis of angina pectoris.
- A friend of nitrates is BBs ….reduce reflex tachycardia Palpitation….unpleasant awareness of cardiac activity
- These drugs do not dilate coronary vessels; rather vasoconstriction may occur (unopposed α mediated vasoconstriction due to blockade of β2 mediated vasodilation). These drugs are therefore, contra-indicated in variant angina
- Reversed Robin Hood Syndrome (RRHS) was first described in 2007 as a cause of worsening neurological deficit in the setting of an acute ischemic event. RRHS is the shunting of cerebral blood flow to nonstenotic vascular territories due to impaired vasodilation bought on by hypercapnia.
- Concurrent therapy of a dihydropyridine with a β blocker has proven more effective than either agent given alone in exertional angina, presumably because the β blocker suppresses reflex tachycardia. In contrast, the concurrent administration of verapamil or diltiazem with a β blocker is contraindicated for the potential for AV block, severe bradycardia, and decreased left ventricular function.
- Regular daily use of aspirin In acute MI: reduce mortality by 23% and in combination with streptokinase reduce mortality by 42% and reinfarction by 52% In unstable angina reduce MI and death by 50% In secondary prevention reduce reinfarction by 32% and combined vascular events by 25% Clopidogrel: A 9% reduction in adverse cardiovascular events Initiate a loading dose of 300 mg and then 75 mg once daily In unstable angina combined with aspirin reduces mortality Avoid within first few days of an MI and first 7 days of an ischemic stroke (no clear benefit) Same incidence of bleeding as aspirin but possibly lower GI bleeding
- Thrombin inhibitors, such as hirudin or bivalirudin, directly inhibit even clot-bound thrombin, are not affected by circulating inhibitors, and function independently of antithrombin III. Bivalirudin provides no benefit over heparin in ACS (Valgimigli et al., 2015). Thrombolytic agents such as rTPA are of no benefit in unstable angina. The new oral anticoagulants (factor IIa inhibitor dabigatran and factor Xa inhibitors rivaroxaban, apixaban, and edoxaban) have no established place in the treatment of CAD.
- Pentazocine and pethidine should not be used for this indication since these agents cause tachycardia and can worsen the symptoms.