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Antianginal drugs.pdf

  1. Antianginal Drugs & newer targets for myocardial infarction PC-630
  2. Anatomy of heart Ischemic heart diseases: (i) Angina (ii) Myocardial infarction
  3. 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
  4. Types of angina q (1)Stable angina q (2)Unstable angina q (3)Variant angina The pathologic physiological mechanism of angina: an imbalance between the myocardial oxygen supply and demand
  5. Pathophysiology
  6. Pathophysiology: Molecular level
  7. 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
  8. 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
  9. Stable angina occurs when myocardial ischaemia is caused by fixed atherosclerotic narrowing of one or more epicardial coronary arteries. In some circumstances, the angina is associated with a coronary spasm and metabolic dysfunction. Vasospastic angina occurs when myocardial ischaemia is caused by a coronary artery spasm with or without endothelial dysfunction. Microvascular angina refers to the absence of an obstructed epicardial coronary artery. Myocardial ischaemia in this case can be caused by microvascular and/or endothelial dysfunction and inflammation.
  10. 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?]
  11. 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)
  12. 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)
  13. 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 approved by the FDA recently
  14. The mechanism of antianginal drugs v(1)Decease myocardial oxygen consumption v(2) Increase myocardial blood and oxygen supply v(3) antiplatelet, antithrombosis
  15. Management with stable coronary artery disease
  16. Management of coronary artery disease
  17. Management of coronary artery disease
  18. Management of coronary artery disease
  19. The schematic shows useful combinations (green lines), combinations that are not recommended (red lines), possible combinations (blue solid lines), and drugs with similar actions (blue dashed lines).
  20. 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
  21. 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
  22. 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
  23. MLCK MLCK-P cGMP MLCK-P NO-induced vasorelaxation
  24. Pharmacological action v(1) decrease myocardiac oxygen consumption Dilate venous decrease blood returning to heart decrease ventricular end-diastolic volume and pressure (large dose) dilate arterial decrease peripheral resistance decrease afterload v(2) increase blood supply to ischemia area v(3) redistribution of coronary blood flow v(4) Inhibition of platelet aggregation, increase the release of PGI2
  25. Clinical uses v(1) all types of angina v(2) acute myocardia infarction v(3) CHF § isosorbide dinitrate used in prophylaxis attack and CHF after myocardia infarction
  26. 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 – 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
  27. • 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 (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 GTN ISDN ISMN Half-life (min) 3 10 280 Plasma clearance (L/min) 50 4 0.1 Apparent volume of distribution (L/kg) 3 4 0.6 Oral bioavailability (%) < 1 20 100 Property Pharmacokinetic Properties of Organic Nitrates
  28. 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)
  29. 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
  30. 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 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)
  31. 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
  32. Calcium antagonists Mechanism of antiangina • (1) dilate coronary arterial • (2) reduction in peripheral vascular resistance • (3) negative chronotropic and inotropic, decrease myocardiac oxygen consumpation • (4) protect cardiac myocytes • (5) antiatherosclrosis
  33. Clinical used Variant angina, Stable angina, Unstable angina
  34. 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
  35. 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)
  36. Relative Cardiovascular Effects of Calcium Channel Blockers (adapted from Goodman & Gilman, 9th ed.) Verapamil ++++ ++++ +++++ +++++ Diltiazem +++ ++ +++++ ++++ Nifedipine +++++ + + 0 Nicardipine +++++ 0 + 0 Compound Coronary vasodilation Suppression of cardiac contractility Suppression of SA node Suppression of AV node
  37. 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)
  38. 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)
  39. Ca++ Channel Blockers: Drug Interactions • b-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)
  40. b-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 b-blockers can cause vasodilation directly – Improve myocardial perfusion by slowing heart rate (more time spent in diastole)
  41. β-adrenoceptor blocking drugs The mechanism of antiangina (1) decrease myocardial oxygen consumpation block β- adrenoceptor inhibit myocardial contractility and heart rate (2) improve blood and oxygen supply to ischamia area (3) lower heart rate, prolong diastolic perfusion time, increase endocardium flow (4) promote oxygen to dissociate from HbO2
  42. qcilinical uses v stable and unstable angina v myocardial infarction
  43. Adverse Effects and Contraindications for b-Blockers • May exacerbate heart failure • Contraindicated in variant angina • 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)
  44. Partial Fatty Acid Oxidation (pFox) Inhibitors • Ranolazine (Ranexa) is approved by the FDA for the treatment of chronic angina in 2006, 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, shown effectiveness in chronic angina • QT prolongation and testicular toxicity are the among the possible toxicities so far
  45. § Ranolazine reduces calcium overload in the ischemic cardiomyocyte through inhibition of the late sodium current (I Na) § Ranolazine is considered as an effective choice as add on antianginal therapy on background of BBs, CCBs or nitrates and also can be uses as first line in patients with absolute or relative contraindication for BBs, CCBs or nitrates § Cost is the major prohibitive factor in some countries for its wider use at this time. Ranolazine
  46. Trimetazidine Trimetazidine improves cellular tolerance to ischemia by inhibiting mitochondrial long chain 3-keto acyl-CoA-thiolase (LC3-KAT), a key enzyme in fatty acid oxidation. It thus reducing fatty acid metabolism and increases glucose metabolism in heart Since oxidation of fatty acid requires more O2, shift back to glucose utilization reduce O2 demand. Trimetazidine is thus labelled as pFOX (fatty acid oxidation pathway) inhibitor. In patients not adequately controlled by long-acting nitrate/BB/CCB, addition of trimetazidine, further reduces anginal attacks and increases exercise tolerence
  47. • Use of more than one class of antianginal agent can reduce specific undesirable effects of single agent therapy Nitrates Alone Reflex Increase Decrease Decrease Reflex increase Decrease Beta-Blockers or Ca Channel Blockers Alone Decrease* Decrease Increase Decrease* Increase Nitrates Plus Beta-Blockers or Ca Channel Blockers Decrease Decrease None or decrease None 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
  48. 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)
  49. 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
  50. Nitrate Resistance Rapid and excessive elevation of plasma and tissue levels of various vasoconstrictor substances (norepinephrine, epinephrine, angiotensin II, endothelin and arginine vasopressin) remain a possible mechanism for nitrate resistance.
  51. Nicorandil Nicorandil is an anti-angina medication that has the dual properties of a nitrate and ATP-sensitive K+ channel agonist. In humans, the nitrate action of nicorandil dilates the large coronary arteries at low plasma concentrations. At high plasma concentrations nicorandil reduces coronary vascular resistance, which is associated with increased ATP-sensitive K+ channel (KATP) opening. However, the effect of nicorandil as a vasodilator is mainly attributed to its nitrate property. Nicorandil is effective in cases where nitrates, such as nitroglycerine, are not effective. Due to its KATP channel agonist action in mitochondria, Nicorandil causes pharmacological preconditioning and provides cardioprotective effects against ischemia.
  52. Side effect of Nicorandil Common: Flushing, palpitations, weakness and vomiting. More recently, perianal, ileal and peristomal ulceration has been reported as a side effect.
  53. Ivabradine o Ivabradine is a direct sinus node inhibitor and only drug in this group o It reduces heart rate by inhibiting the so-called funny channel (f channel) in sinus node. o Funny cationic channels open during early part of slow diastolic (phase 4) depolarization. Thus the resulting inward current (If) determines the slope of Phase 4 depolarization. o Heart rate reduction decreases cardiac oxygen demand and prolongation of diastole tends to improve myocardial perfusion (O2 supply). o Ivabradine has been found to improve exercise tolerance in stable angina and reduce angina frequency.
  54. New hope or Experimental drugs for Angina Mildronate o Mildronate is a fatty acid oxidation inhibitor. o In animal models, mildronate reduced myocardial infarct size. o In one prospective randomized control trial of 512 patients with stable angina, mildronate (1000 and 3000mg) improved total exercise time versus placebo. Perhexiline o Perhexiline is a fatty acid oxidation inhibitor that has been studied for angina in the past and shown to improve exercise and tachycardia (atrial pacing) induced angina. o It was introduced in France in the early 1970s and was remarkable effective at preventing angina. o But it showed peripheral neuropathy and hepatotoxicity in some group of patients.
  55. New hope or Experimental drugs for Angina Molsidomine o Molsidomine is metabolized in the liver to the active metabolite linsidomine. It is an unstable compound that further metabolized to releases NO. o It reduced the level of soluble ICAM-1 (which is a marker for the severity of atherosclerosis). o It causes vasorelaxation of coronary arteries and thereby reduces angina. Phosphodiesterase inhibitors o Phosphodiesterase inhibitors were designed initially to be a therapy for angina. however, the effects were notpromising. o However, there is growing evidence of improved coronary flow with other phosphodiesterase inhibitors like Trapidil, dipyridamole and cilostazol.
  56. New hope or Experimental drugs for Angina Amiodarone/Dronedarone o Amiodarone, approved as an anti-arrhythmic agent, was initially introduced as an antianginal therapy. o In elderly patients with treatment resistance angina, Amiodorane (50- 100mg) is effective when used with their current antianginal drugs. o Dronedarone, which is an iodine-free derivative of amiodarone, with a lesser side effect profile, reduced first cardiovascular hospitalization due to coronary artery disease. Fasudil o Fasudil is a class of rho kinase inhibitors, and the only one currently approved (Japan and China) for the treatment of cerebral vasospasm. o Rho kinase inhibitors result in vascular smooth muscle relaxation through manipulation of the Rho-associated protein kinase (ROCK) pathway, thus they reduce blood pressure. o This agent has not been tested as an angina therapy.
  57. Newer or Experimental drugs for Angina Allopurinol/febuxostat o The exact mechanism of this anti-ischemic effect of allopurinol is unclear, but xanthine oxidase inhibition by Allopurinol can reduce oxidative stress. o Febuxostat is a potent non-purine selective inhibitor of xanthine oxidase and show antioxidative effect similar to Allopuriol. o But one human study is required to find its effect as anti-angina. Testosterone o Testosterone results in coronary artery dilation and increases coronary blood flow in humans. The mechanism appears to be related to ion channels on vascular smooth muscles. o Several small studies have reported the beneficial anti-ischemic effect of testosterone delivered via transdermal, intramuscular, and oral therapy. o However, cardiovascular safety need to be looked as testosterone can increase red blood cells, which increases thrombosis risk.
  58. Adenovirus containing vascular endothelial growth factor (Ad-VEGF121) Reference: Advancements in Pharmacotherapy for Angina. Expert Opin Pharmacother. 2017, April 18 (5):457-469 § Intramyocardial delivery of an adenoviral vector encoding for an angiogenic factor as therapy in refractory angina patients was the Randomized Evaluation of VEGF for Angiogenesis (REVASC). § AdVEGF121 significantly increased exercise time to 1 mm ST- segment depression, with improvements in various quality of life measures.