Anti Anginal hjk bhjkmhjkkmkkkDrugs.pptx

Anti anginal drugs

1. ANTI ANGINAL DRUGS - Dr Garv Ameta CTVS Resident Doctor

2. Angina pectoris is defined as substernal chest pain, pressure, or discomfort that is typically exacerbated by exertion and/or emotional stress, lasts greater than 30 to 60 seconds, and is relieved by rest and nitroglycerin

3. The pain or discomfort may radiate down the arms , up into the neck , into the lower jaw , into the epigastrium , and sometimes into the back . It typically lasts between 5 and 15 minutes. Angina may present in a more atypical fashion or as an angina equivalent and can be characterized by dyspnea, fatigue, weakness , palpitations, or dizziness

4. The primary cause of angina is an imbalance between oxygen supply and oxygen demand in the heart . The most usual cause is coronary artery disease in which atherosclerotic plaque has narrowed the lumen of the vessel that supplies oxygen and nutrients to cardiomyocytes . When there is an increase in oxygen demand, as occurs with exertion, there is an oxygen supply–demand mismatch , such that the oxygen demand is greater than the supply through the narrowed vessel .

5. Even vessels that are in an earlier phases of atherosclerosis , before a severely flow-limiting lesion is present, can contribute to ischemia if the plaque is vulnerable and ruptures . Some patients experience angina due to a reduced oxygen supply when the coronary arteries undergo vasospasm .

6. Other causes of angina include Hypertrophic cardiomyopathy, V alve disease, and especially aortic stenosis; in these cases, again there is a mismatch between supply of oxygen and demand for oxygen by the heart . Tachyarrythmias Pulmonary hypertension (PA compressing Left Main)

7. Coronary artery disease is usually thought of as disease of the large epicardial coronary arteries that course along the surface of the heart, there is now evidence that small intramural coronary arteries or microvessels can be diseased and contribute to myocardial ischemia

8. Recent guidelines for Anti-ischemic medications for patients with stable ischemic heart disease (SIHD) from the American College of Cardiology and the American Heart Association: Level of recommendation, I(B). Beta-blockers should be prescribed as initial therapy for relief of symptoms Level of recommendation, I(B). Calcium channel blockers or long acting nitrates should be prescribed for relief of symptoms when b-blockers are contraindicated or cause unacceptable side effects, or when initial treatment with b-blockers is unsuccessful Level of recommendation, I(B). Sublingual nitroglycerin or nitroglycerin spray is recommended for immediate relief of symptoms

9. Level of recommendation, IIa (B). Ranolazine can be useful when prescribed as a substitute for b-blockers for relief of symptoms if initial treatment with b-blockers leads to unacceptable side effects, or ineffective or contraindicated Level of recommendation, IIa (A). R anolazine in combination with b-blockers can be useful when prescribed for relief of symptoms when initial treatment with b-blockers is not successful

10. Other Anti-ischemic medications used Trimetazidine , Ivabradine Nicorandil Fasudil M ildronate , perhexiline

11. b-Blockers b-Blockers are effective antianginal agents, and their mechanism of action is primarily a reduction in oxygen demand . They decrease heart rate, cardiac contractility, and secondarily reduce blood pressure, which all contribute to a reduction in oxygen demand.

12. The current FDA approved agents are atenolol , metoprolol , nadolol , and propranolol;

13. Mechanism of Action Suppress the activation of the heart by blocking B 1 receptors Decrease the HR, resulting in : decreased myocardial oxygen demand. increased oxygen delivery to the heart . Decrease myocardial contractility, helping to conserve energy or decrease demand . Reduce the work of the heart by decreasing CO and causing a slight decrease in BP ↓ HR, ↓contractility, ↓systolic wall tension, ↑perfusion time

14. These agents are not useful for vasospastic angina and, if used in isolation, may worsen the condition . The decrease in myocardial O 2 consumption is due to a negative chronotropic effect (particularly during exercise ), negative inotropic effect, and a reduction in arterial blood pressure (particularly systolic pressure) during exercise.

15. Side effects of b-blockers include bradycardia , conduction abnormalities, bronchospasm, fatigue, lethargy, depression, nightmares, erectile dysfunction, gastrointestinal upset, worsening of insulin-induced hypoglycemia, cold extremities due to peripheral vasoconstriction , and b-blocker withdrawal syndrome, whereby b-blockers are stopped suddenly and the patient develops worsening angina .

16. Nitrates Nitrates work primarily by decreasing oxygen demand . They reduce preload by causing vasodilation of the venous system , thereby decreasing return of blood to the heart , which decreases volume of the ventricle and ventricular wall stress, and hence oxygen demand . In addition, they cause a small decrease in systemic arterial pressure that also decreases oxygen demand. They also dilate the coronary arteries , which can improve oxygen delivery and help reduce coronary artery vasospasm .

17. Short acting: Glyceryl trinitrate (GNT, Nitogycerine ) Long acting: Isosorbide dinitrate , Isosorbide mononitrate,Erythrityl tetranitrate

18. Nitrates are lipid soluble well absorbed from buccal mucosa, intestine and skin and is available in forms that provide a range of durations of action from 10 – 20 min (sublingual ) to 8 – 10 h (transdermal ). They undergo extensive first past metabolism in liver. Rapidly denitrated by glutathione reductase and mitochondrial aldehyde dehydrogenase . The time to onset of action varies from 1 minute for nitroglycerin to more than 1 hour for isosorbide mononitrate . Isosorbide mononitrate owes its improved bioavailability and long duration of action to its stability against hepatic breakdown. Oral isosorbide dinitrate undergoes denitration to two mononitrates , both of which possess antianginal activity.

19. Mechanism Of Action Relax vascular smooth muscle by their intracellular conversion to nitrite ions, to nitric oxide , activates guanylate cyclase (GC) and increases the cGMP . dephosphorylation of the myosin light chain, vascular smooth muscle

20. Nitrate Tolerance Tolerance develops rapidly. (Due to Depletion of –SH group for Convertion of Nitrate to Nitric acid) The blood vessels become desensitized to vasodilation. Addressed by providing a daily “nitrate-free interval” to restore sensitivity to the drug . This interval is typically 10 to 12 hours, usually at night, because demand on the heart is decreased at that time. Nitroglycerin patches are worn for 12 hours then removed for 12 hours.

21. Adverse Drug Reactions The most common toxic effects of nitrates are the responses These include tachycardia (from the baroreceptor reflex) evoked by vasodilation Orthostatic hypotension (a direct extension of the venodilator effect), and Throbbing headache from meningeal artery vasodilatation Nitrates + Sildenafil can lead to severe hypotension, myocardial infarction and death

22. Calcium Channel Blockers The calcium channel blockers inhibit the movement of calcium across the L-type calcium channels found in cardiac muscle and the smooth muscle of blood vessels. The dihydropyridine calcium channel blockers, such as nifedipine , amlodipine, nisoldipine , felodipine , and nitrendipine , work primarily upon the calcium channels in the smooth muscle of the blood vessels to induce vasodilation . Nondihydropyridine calcium channel blockers such as verapamil and diltiazem also affect the conduction system of the heart, slowing the heart rate , and they can cause bradycardia or conduction abnormalities .

23. Phenyl alkylamine : Verapamil Benzothiazepine : Diltiazem Dihyropyridines : Nifedipine , Nimodipine , Lacidipine , Lercanidipine , Benidipine

24. Nifedipine a dihydropyridine derivative. A rteriolar vasodilator . This drug has minimal effect on cardiac conduction or heart rate. Used in variant angina caused by spontaneous coronary spasm Other members of this class, amlodipine , nicardipine , and felodipine , have similar cardiovascular characteristics except for amlodipine, which does not affect heart rate or cardiac output.

25. Nondihydropyridine derivative/ Verapamil Slows cardiac atrioventricular (AV) conduction directly, and decreases HR, contractility, BP, and oxygen demand. greater - ve inotropic effects than nifedipine , but it is a weaker vasodilator. is extensively metabolized by the liver . C ontraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities. Drug Interaction: verapamil increases digoxin levels . It also causes constipation .

26. Nondihydropyridine derivative/ Deltiazem Its cardiovascular effects similar to verpamil Reduce the HR but lesser than verpamil Reduce BP Relieve coronary artery spasm so used in variant angina First-line agents for treatment of: angina, hypertension, supraventricular tachycardia Short-term management of atrial fibrillation and flutter May cause: hypotension, palpitations, tachycardia or bradycardia, constipation, nausea, dyspnea

27. Adverse drug reactions to CCB’s The calcium channel blockers cause constipation, pretibial edema, nausea, flushing, and dizziness . More serious adverse effects include heart failure, AV blockade, and sinus node depression ; these are most common with verapamil and least common with the dihydropyridines .

28. Verapamil and Diltiazem may be used to treat AV nodal Arrythmias . Calcium blockers are effective as prophylactic therapy in both effort and vasospastic angina . Nifedipine has also been used to abort acute angina in severe atherosclerotic angina , these drugs are particularly valuable when combined with nitrates . In addition to well-established uses in angina, hypertension, andsupraventricular tachycardia, some of these agents are used in migraine , preterm labor, stroke, and Raynaud's phenomenon .

29. Ranolazine (Late Sodium Current Blocker) It is an antianginal agent that does not work through the usual hemodynamic methods to improve oxygen supply or reduce oxygen demand. It blocks the late sodium current toward the later phase of the action potential, reducing intracellular sodium , and subsequently reduces sodium–calcium exchange , having the net effect of reducing calcium overload, which is known to occur in ischemic cardiomyocytes .

30. By reducing calcium overload, the myocardial cells basically relax better during diastole, which improves microvascular perfusion . The drug does not reduce heart rate or blood pressure like b-blockers or calcium channel blockers.

31. Ranolazine is extensively metabolized, mainly by the CYP3A family and also by CYP2D6. It is also a substrate of P- glycoprotein. Ranolazine can prolong the QT interval . Carries some Anti Arrhythmic properties (MER-LIN Trial).

32. Trimetazidine It is a novel antianginal drug acts by nonhaemodynamic mechanism . This antianginal agent partially inhibits fatty acid oxidation and therefore shifts energy metabolism toward the utilization of glucose .

33. Myocardial cell oxygen requirement of the glucose pathways is lower than that of the free fatty acid pathway. It is known that during ischemia, oxidized free fatty acid levels rise within the cardiomyocyte , and this blunts the glucose pathway. Trimetazidine blocks Acyl- CoA b oxidation to Acetyl-CoA , thus favoring the breakdown of glucose to pyruvate to form Acetyl-CoA.

34. It improve cellular tolerance to ischemia by Inhibiting mitochondrial long chain 3-ketoacyl-CoA- thiolase (LC 3 -KAT) a key enzyme in fatty acid oxidation and increasing glucose metabolism in myocardium . Limiting intracellular acidosis and Na + and Ca ++ accumulation during ischemia

35. Nicorandil Nicorandil is an antianginal agent with a dual mode of action . I t activates ATP-sensitive potassium channels causing dilatation of coronary and peripheral resistance vessels , and by activating these channels, it may promote a cardioprotective effect along the same pathways as ischemic preconditioning. In addition , nicorandil has a nitrate moiety that results in systemic arterial and venous vasodilatation. Thus , it reduces preload and afterload (reduction in oxygen demand) at the same time it dilates the coronary arteries (increase in oxygen supply).

36. Side Effects Red , itchy or watery eyes – these can be signs of  conjunctivitis  or a corneal ulcer Painful sores (ulcers) on the eyes, skin or the lining of your mouth Stomach pain, feeling or being sick, loss of appetite, or melena– these are signs of stomach ulcers

37. Ivabradine This antianginal agent is a sinus node inhibitor that slows down the heart rate but does not affect cardiac contractility or have a primary effect on blood pressure . Ivabradine selectively inhibits the hyperpolarization-activated, mixed Na/K inward If current . (Funny Current) This reduces the rate of diastolic depolarization of the pacemaker cells in the sinus node , which decreases rest and exercise heart rate responsiveness. Ivabradine causes on average about 10 beats per minute drop in heart rate

38. Ivabradine is also associated with a peculiar side effect called phosphenes , described as flashes or increased brightness of light in limited areas of the visual field. Bradycardia, Worsening of Cardiac failure. Ivabradine should be used only by patients who are taking a maximally tolerated dosage of a b-blocker or have a contraindication to b-blocker use

39. Fasudil Fasudil is an inhibitor of the Rho kinase pathway, which is an intracellular signaling pathway involved in increasing coronary tone and vasospasm. In some studies Fasudil further dilated the site of coronary vasospasm already treated with nitroglycerin.

40. Enhanced External Counterpulsation A set of inflatable bilateral cuffs are wrapped around the calves, lower thighs, upper thighs, and buttocks, attached to air hoses, and are then inflated and deflated based on the cardiac cycle. During early diastole, the cuffs are inflated from calves to buttocks (in a cranial direction) to 100 to 300 mm Hg, which creates retrograde aortic flow in diastole, increasing coronary artery perfusion pressure and hence coronary flow during diastole (diastolic augmentation)

41. At the completion of diastole, the pressurized air in the cuffs is rapidly removed inducing an afterload-reducing effect . The inflation deflation cycles are typically performed over 1-hour sessions that occur 5 days a week for about 7 weeks.

42. Transmyocardial Revascularization The concept was that drilling laser holes from epicardium to endocardium would create a situation similar to certain reptilian hearts whereby oxygenated blood from the left ventricular cavity would then supply the wall of the left ventricle through channels or sinusoids that traversed the wall . Combined with CABG or PCI.

43. Stem Cell Therapy Human CD34þ stem cells could improve angiogenesis within ischemic myocardium and improve ventricular perfusion and cardiac function.

44. Thank You