Antiischemics

Description about the anti-ischemic drugs and associated mechanisms and side effects

1. Anti Ischemic Drugs PRESENTED BY :- HIMIKA RATHI DEPARTMENT OF PHARMACOLOGY L.M COLLEGE OF PHARMACY 1

2. What is Ischemia? Ischemia is a restriction in blood supply to tissues , causing a shortage of oxygen that is needed for cellular metabolism . Ischemia is generally caused by problems with blood vessels , with resultant damage to or dysfunction of tissue. Ischemia comprises not only insufficiency of oxygen, but also reduced availability of nutrients and inadequate removal of metabolic wastes 2

3. Why Does It Happen? One of the main causes of ischemia is atherosclerosis . That’s where plaque collects in the arteries. Plaque is a hard, sticky substance that’s made mostly of fat . It builds up slowly, but over time, it can harden and narrow your arteries . This slows the blood flow because , blood has less space to move through. I schemia can be also due to blood clot . Plaque itself is a problem. But sometimes, it can bust open and form a clot. This causes a sudden and serious stoppage to your blood flow.. 3

4. What is atherosclerosis? Atherosclerosis is a narrowing of the arteries caused by a buildup of plaque. It’s also called arteriosclerosis or hardening of the arteries. Arteries are the blood vessels that carry oxygen and nutrients from your heart to the rest of your body. As you get older , fat and cholesterol can collect in your arteries and form plaque. The buildup of plaque makes it difficult for blood to flow through your arteries . This buildup may occur in any artery in your body and can result in a shortage of blood and oxygen in various tissues of your body. Pieces of plaque can also break off, causing a blood clot. Atherosclerosis can lead to heart attack, stroke, or heart failure if left untreated. 4

5. Pathophysiology of atherosclerosis Hypercholesterolemia is considered one of the main triggers of atherosclerosis. The increase in plasma cholesterol levels results in changes of the arterial endothelial permeability that allow the migration of lipids, especially LDL-C particles, into the arterial wall. Circulating monocytes adhere to the endothelial cells that express adhesion molecules , Once in the sub endothelial space, the monocytes acquire macrophage characteristics and convert into foamy macrophages. LDL particles in the sub endothelial space are oxidised and become strong chemo attractants. These processes only enhance the accumulation of massive intracellular cholesterol. The end result is a cascade of vascular modifications . Clinical sequelae of atherosclerosis are vessel narrowing with symptoms (angina pectoris) and acute coronary syndromes due to plaque instability. 5

6. ATHEROSCLEROSIS 6

7. ANGINA PECTORIS Angina pectoris , the primary symptom of ischemic heart disease , is caused by transient episodes of myocardial ischemia that are due to an imbalance in the myocardial oxygen supply–demand relationship . Angina pectoris has three patterns : 1) stable, effort-induced, classic, or typical angina ; 2) unstable angina ; and 3 ) Prinzmetal , variant, vasospastic, or rest angina. 7

8. STABLE ANGINA Classic angina is the most common form of angina and, therefore, is also called typical angina pectoris. It is usually characterized by a short-lasting burning, heavy, or squeezing feeling in the chest . Classic angina is caused by the reduction of coronary perfusion due to a fixed obstruction of a coronary artery produced by atherosclerosis . When the pattern of the chest pains and the amount of effort needed to trigger the chest pains do not vary over time, the angina is named “stable angina.” Typical angina pectoris is promptly relieved by rest or nitroglycerin 8

9. Unstable angina Unstable angina is classified between stable angina and MI. In unstable angina , chest pain occurs with increased frequency, duration, and intensity and can be precipitated by progressively less effort. The symptoms are not relieved by rest or nitroglycerin . Unstable angina is a form of acute coronary syndrome and requires hospital admission and more aggressive therapy to prevent progression to MI and death. 9

10. Prinzmetal, variant, vasospastic, or rest angina Prinzmetal angina is an uncommon pattern of episodic angina that occurs at rest and is due to coronary artery spasm .   Prinzmetal’s angina almost always occurs when a person is at rest, usually between midnight and early morning. These attacks can be very painful. Symptoms are caused by decreased blood flow to the heart muscle from the spasm of the coronary artery . Although individuals with this form of angina may have significant coronary atherosclerosis, the angina attacks are unrelated to physical activity, heart rate, or blood pressure. Prinzmetal angina generally responds promptly to coronary vasodilators, such as nitro-glycerine and calcium channel blockers . 10

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12. Imbalance between oxygen demand and oxygen supply 12

13. Causes of decreased myocardial oxygen supply: 1. Progressive narrowing of epicardial coronary arteries by atherosclerotic ( ASO) plaques . 2. Sudden enlargement of ASO plaque. 3. Sudden narrowing or complete occlusion of an epicardial coronary artery by an intracoronary thrombus following rupture or erosion of an ASO plaque. 4 . Coronary artery spasm usually in association with ASO disease e.g. vasospastic ( Prinzmetal) angina . 5 . Other causes: coronary embolism, abnormal coronary rheology slow flow, compression of epicardial coronary artery by myocardial bridge, coronary ectasia . 13

14. Causes of increased myocardial oxygen demands: 1. Heart rate. 2. Arterial pressure. 3. Myocardial inotropic state (contractility ). 4. An increase in LV muscle mass (LVH). 14

15. Anti Ischemic Drugs Anti ischemic drugs include: 1.Nitrates . 2.Beta-adrenergic blockers. 3.Calcium antagonists. 4.Anti platelet drugs. 15

16. The main indication of this group is the relief of anginal pains . Myocardial ischemia is the result of imbalance between myocardial oxygen supply and demand. Anti ischemic drugs produce their beneficial effect by either improving myocardial Oxygen supply or decreasing demand or both . 16

17. Nitrates Mechanism of Action Clinical Indications Contraindications Uses in Acute Coronary Syndromes Nitrate Tolerance 17

18. Three organic nitrates are currently used: 1. Nitroglycerin (NTG). 2. Isosorbide dinitrate (ISDN). 3. Isosorbide mononitrate (ISMN). MECHANISM OF ACTION: Increase coronary blood supply. B . Decrease myocardial oxygen consumption. C. Antiplatelet action 18

19. Molecular Mechanism of Action Nitrates act through endothelial-independent pathway to relax all types of vascular smooth muscle cells to varying degrees. Nitrates are converted to nitric oxide , which then activates guanylate cyclase. Guanylate cyclase, in turn, produces cyclic guanosine monophosphate (cGMP ) which leads to increased levels of intracellular cGMP and vasodilatation through decrease in intracellular calcium level. In platelets, increases in cGMP exert an antiaggregatory action. 19

20. CLINICAL INDICATIONS Chronic stable angina. Treatment and prophylaxis of anginal attacks. Acute coronary syndromes: unstable angina and MI. Congestive heart failure. Diastolic LV dysfunction. Hypertensive emergencies (parenteral nitroglycerin ). Acute pulmonary oedema secondary to LV failure. 20

21. NITRATE PREPARATIONS Nitroglycerin (NTG) Available in many formulations, parenteral, sublingual, buccal , ointment and patch. It has a very short half-life of several minutes ; Veins take up NTG more avidly than arteries. Dosages Sublingual NTG : 0.3-0.6 mg, onset of action is 2-5 minutes and its duration is 20-30 minute . The usual tablet dose is 0.3 mg to 0.4 mg repeated every five minutes for a total of three doses . NTG tablets are both heat and light sensitive. They should be stored in a tightly capped dark bottle in the refrigerator. Prescription should be renewed every three to six months. NTG patch : 0.4-0.8 mg/h, the patch should be applied for only 12-14 hours each day. 21

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23. Isosorbide Dinitrate (ISDN) The most widely used long acting nitrate. Available as short-acting and sustained-release formulation. Onset of action is within 15 to 30 minutes and the duration of action is three to six hours. There is low bioavailability from hepatic metabolism. Dosage:- 10 to 40 mg three times daily. There is no added benefit with 60 and 120 mg doses. Tolerance has limited the usefulness of ISDN as a chronic antianginal agent. Development of tolerance occurs despite higher plasma concentrations of ISDN during maintenance therapy. To prevent the development of tolerance, it is recommended to give ISDN at 8 AM, 1 PM and 6 PM. This regimen can offer antianginal protection for at least six hours. Begin with a dose of 10 mg three times daily and advance to 40 mg three times daily as needed . 23

24. Isosorbide Mononitrate (ISMIN) Onset of action is within 30 minutes, and the duration of action is six to eight hours. It is completely bioavailable. The usual starting dose is 20 mg twice daily to be increased to 40 mg twice daily if necessary. Seven hours interval between doses followed by 17 hours nitrate-free interval. Extended (sustained) release preparation is given once daily and lasts 12 hours. 24

25. CONTRAINDICATIONS Patients who have taken sildenafil (Viagra) within 24 hours because of the risk of severe hypotension . Patients with hypertrophic cardiomyopathy even those without a resting gradient across left ventricular outflow tract. Patients with suspected right ventricular infarction because of risk of hypotension. Use cautiously in patients with severe aortic stenosis or with volume depletion. 25

26. USE OF NITRATES IN ACUTE CORONARY SYNDROMES Unstable Angina IV NTG is preferable because of its short half life and feasibility of rapid dose titration. Tolerance may develop after 24 hours with recurrence of chest pain. Such patients respond to dose increases. Once the patient has been stabilized, IV NTG can be tapered gradually, and intermittent therapy with long-acting oral nitrate can be started about 1-2 hours, before discontinuation of the nitrate infusion . Acute Myocardial Infarction Recent guidelines recommend the use of nitrates for the first 24 to 48 hours in patients with AMI who have an indication for nitrate therapy such as: recurrent ischemia, heart failure or hypertension . The infusion of IV NTG should be initiated at 5 to 10 mcg/min and gradually increased 26

27. . The goal is a 10% reduction in systolic blood pressure for normotensive subjects and approximately a 30% reduction in systolic blood pressure in hypertensive patients, avoiding hypotension. The major concern with continuous infusion of NTG is the development of nitrate tolerance that occurs in most patients within 24 hours. IV NTG is discontinued within 24 to 48 hours. Long acting oral nitrates may be indicated in patients with significant residual ischemia or heart failure. 27

28. NITRATE TOLERANCE Attenuation and sometimes abolition of hemodynamic and antianginal effects of nitrates. Proposed Mechanisms 1. Increased vascular oxygen free radical generation (O2 ¯ ). Superoxide anions inactivate nitric oxide. 2. Depletion of sulfhydryl groups necessary for biotransformation of nitrate to nitric oxide (NO ). 3 . NTG impairs the function of nitric oxide synthase (NOS), reducing NO production . Prevention Intermittent therapy with an adequate nitrate-free interval. It is thought that a nitrate-free interval permits the generation of reduced sulfhydryl groups 28

29. 𝛃-ADRENERGIC BLOCKERS The β-adrenergic blockers decrease the oxygen demands of the myocardium by blocking β1 receptors , resulting in decreased heart rate, contractility , cardiac output, and blood pressure . These agents reduce myocardial oxygen demand during exertion and at rest. As such, they can reduce both the frequency and severity of angina attacks. Agents with intrinsic sympathomimetic activity (ISA) such as pindolol should be avoided in patients with angina and those who have had a MI. Propranolol is the prototype for this class of compounds, but it is not cardio selective . Thus, other β-blockers, such as metoprolol and atenolol are preferred. 29

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34. CONTRAINDICATIONS In vasospastic angina , β-blockers are ineffective and may actually worsen symptoms. β-Blockers should be avoided in patients with severe bradycardia . Nonselective β- blockers should be avoided in patients with asthma . [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.] 34

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36. CALCIUM CHANNEL BLOCKERS Voltage-sensitive Ca2+ channels (L-type or slow channels) mediate the entry of extracellular Ca2+ into smooth muscle and cardiac myocytes and sinoatrial (SA ) and atrioventricular (AV) nodal cells in response to electrical depolarization . Ca2+ is a trigger for contraction, albeit by different mechanisms. Ca2 + channel antagonists, also called Ca 2+ entry blockers , inhibit Ca2+ channel function. These drugs also produce negative inotropic and chronotropic effects in the heart. 36

37. 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 . All calcium channel blockers are, therefore, arteriolar vasodilators that cause a decrease in smooth muscle tone and vascular resistance . In the treatment of effort-induced angina , calcium channel blockers reduce myocardial oxygen consumption by decreasing vascular resistance, thereby decreasing afterload . Their efficacy in vasospastic angina is due to relaxation of the coronary arteries 37

38. A. Dihydropyridine calcium channel blockers Amlodipine an oral dihydropyridine , functions mainly as an arteriolar vasodilator. This drug has minimal effect on cardiac conduction. The vasodilatory effect of amlodipine is useful in the treatment of variant angina caused by spontaneous coronary spasm . Nifedipine is another agent in this class; it is usually administered as an extended-release oral formulation . [ Note: Short-acting dihydropyridines should be avoided in CAD because of evidence of increased mortality after an MI and an increase in acute MI in hypertensive patients.] 38

39. Nondihydropyridine calcium channel blockers Verapamil slows atrioventricular (AV) conduction directly and decreases heart rate, contractility, blood pressure, and oxygen demand. Verapamil has greater negative inotropic effects than amlodipine , but it is a weaker vasodilator . Verapamil is contraindicated in patients with pre-existing depressed cardiac function or AV conduction abnormalities. Diltiazem also slows AV conduction , decreases the rate of firing of the sinus node pacemaker, and is also a coronary artery vasodilator. Diltiazem can relieve coronary artery spasm and is particularly useful in patients with variant angina . 39

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42. ANTIPLATELET THERAPY. 42

43. DRUGS Drugs acting on arachidonic acid metabolism. ↓ Thromboxane A2 synthesis: aspirin small dose (75-325 mg) Prostacyclin analogue: epoprostenol but very short half life. Drugs acting on platelet receptors: Block ADP receptors(P2Y12): Clopidogrel,ticlopidine,prasugrel,ticagrelor . Block GPIIb / IIIa receptors: abciximab-tirofiban-eptifibatide . 43

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45. Ranolazine New alternative drugs for patients who can’t tolerate o ther antianginal drugs. It shortens the cardiac action potential by blocking a plateau Na current. This indirectly decreases Ca influx ,thereby producing a negative ionotropic effect, which decreases the oxygen demand . 45

46. Treatment of angina in patients with concomitant diseases. 46

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50. REFERENCES https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653970 / Lippincott -Illustrated Reviews: Pharmacology Sixth Edition- Karen whalen , pg-281 Goodman & Gilman’s The Pharmacological Basis of THERAPEUTICS https:// www.webmd.com/heart-disease/heart-disease-angina http:// annals.org/aim/fullarticle/1392195/management-stable-ischemic-heart-disease-summary-clinical-practice-guideline-from 50

51. 51 THANK YOU.