MI+Angina+Drug interactions in case of myocardial infection

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1. Pharmacotherapy of Acute MI and Acute attack of Angina Drug interaction- verapamil/ Diltiazam /Nifedipine with Beta blockers in Angina Dr. Shubham Biswas Junior Resident-2 Pharmacology and Therapeutics King George’s Medical University, Lucknow

2. Contents Definition Prevalence of Acute MI Pathophysiology of MI Criteria for Diagnosis of Acute MI Management of MI Angina Pectoris Classification of Anti-Anginal Drugs Mechanism of Action of Anti-Anginal Drugs Drug Interactions: Calcium channel blockers + Beta Blockers

3. Definition Ischemic heart disease (IHD) is a condition in which there is an inadequate supply of blood and oxygen to a portion of the myocardium, it typically occurs when there is an imbalance between myocardial oxygen supply and demand

4. NSTEMI vs Unstable Angina NSTEMI With evidence of myocardial necrosis (+) Cardiac biomarkers UNSTABLE ANGINA Without evidence of Myocardial necrosis (-) Cardiac biomarkers

5. Prevalence of Acute MI The commonest cause of mortality globally: CVD- 31% In India - 32-40% Recent meta-analysis in 2023 reported global prevalence of MI <60 years : 3.8% >60 years : 9.5% 5 times more in males than females In India, over 3 million per year ( 40%, <50 years of age)

6. Universal definition of Myocardial Infarction “ The clinical definition of MI specifies the presence of acute myocardial injury detected by abnormal cardiac biomarkers in the setting of evidence of acute myocardial ischemia.” Domienik-Karłowicz J, Kupczyńska K, Michalski B, Kapłon-Cieślicka A, Darocha S, Dobrowolski P, Wybraniec M, Wańha W, Jaguszewski M. Fourth universal definition of myocardial infarction. Selected messages from the European Society of Cardiology document and lessons learned from the new guidelines on ST-segment elevation myocardial infarction and non-ST-segment elevation-acute coronary syndrome. Cardiol J. 2021;28(2):195-201. doi : 10.5603/CJ.a2021.0036. Epub 2021 Apr 12. PMID: 33843035; PMCID: PMC8078947.

7. Damage to the endothelial layer Lipids deposition into the intimal layer Inflammatory process T-lymphocytes and monocyte infiltrate the area to ingest the lipid and die Smooth muscle cells in the vessels multiples and form a fibrous cap over the fatty core is called an atheroma Plaque protrudes the lumen causing narrowing of blood vessels and obstruction of blood flow Pathophysiology: If the fibrous cap of the plaque is thick, it can resist the stress of the blood flow If the fibrous cap of the plaque is thin, as the lipid core grows causing rupture of the cap and bleeding in the plaque Formation of thrombus Thrombus may obstruct the blood flow to the coronary artery causing Myocardial Ischemia Myocardial Infarction

8. Diagnosis of Acute MI Classical symptoms : intense and oppressive chest pressure radiating to left arm. Other symptoms : Chest heaviness Radiation to jaw, neck , shoulder, back and arms Nausea and vomiting Diaphoresis Dyspnea lightheadedness

9. Diagnosis of Acute MI: cont.. Usually no signs Tachycardia or bradycardia Extrasystoles S 3 or S 4, mitral regurgitation murmur Lung rales Hypertension or hypotension pallor and distress

10. Criteria for diagnosis of MI Myocardial Injury: Detection of rise and/ or fall of cTn with at least one value above the 99 th percentile “With atleast one of the following” Symptoms of acute Myocardial Ischemia ECG: New ischemic ECG changes; Development of pathological Q waves Imaging: evidence of new loss viable myocardium or new regional wall motion a normality in a pattern consistant with an ischemic etiology

11. Management of Acute MI The patient should ideally be evaluated within 10 minutes of arrival in the ED, with a maximum 20-minute wait permissible for assessment . On arrival in the ED the patient with suspected acute MI should immediately receive : (1) Oxygen by nasal prongs (2) Sublingual nitroglycerin (unless systolic arterial pressure is less than 90 mm Hg or heart rate is less than 50 or greater than 100 beats per minute [bpm])

12. (3) adequate analgesia (with morphine sulfate or meperidine) (4) aspirin, 160 to 325 mg orally. A 12-lead electrocardiogram (ECG) should also be performed. ST-segment elevation (equal to or greater than 1 mV) in contiguous leads provides strong evidence of thrombotic coronary arterial occlusion makes the patient a candidate for immediate reperfusion therapy, either by fibrinolysis or primary percutaneous transluminal coronary angioplasty (PTCA).

13. Hospital Management: The First 24 Hours Monitor continuously by ECG; confirm acute MI with serial ECGs and cardiac marker tests like CK or troponin. Closely monitor for adverse events in the first 24 hours to prevent reinfarction and death. Limit physical activities for 12 hours, manage pain/anxiety with analgesics. Have atropine, lidocaine, pacing patches/pacemaker, defibrillator, and epinephrine ready.

14. Patients surviving large anterior MI or with LV mural thrombus detected by echocardiography are at high embolic stroke risk , potentially reduced by early IV heparin . The patient with evolving acute MI should receive early intravenous β-adrenergic blocker therapy, followed by oral therapy Initiate β-blocker therapy regardless of reperfusion use; studies show reduced morbidity and mortality pre- and post-thrombolytic era.

15. Calcium channel blockers have not been shown to reduce mortality in patients with acute MI, however , Diltiazem might reduce recurrent ischemic events in certain patients. Initiate ACE inhibitor promptly unless contraindicated in MI patients with ST elevation or LBBB without hypotension . Consider continuing ACE inhibitors indefinitely for impaired LV function or CHF . Stop ACE inhibitors if there is no LV dysfunction at 6 weeks. Measure lipid profile and electrolytes at hospital admission.

16. After the First 24 Hours After the initial hospital day, the acute MI patient requires long-term Aspirin  (160 to 325 mg/d) , β-blocker, and ACE inhibitor for 6 weeks . Nitroglycerin should be infused intravenously for 24 to 48 hours, and magnesium sulfate should be given as needed to replete magnesium deficits for 24 hours. For patients receiving alteplase , intravenous heparin for an additional 48 hours is the current practice.

17. coronary angiography and subsequent revascularization should be reserved for survivors of acute MI who have preserved LV systolic function and spontaneous or provoked ischemia. Patients with myocardial ischemia that is spontaneous or provoked in the days to weeks after acute MI, irrespective of whether they received thrombolytic therapy, should undergo elective angiographic evaluation , with subsequent consideration of percutaneous or surgical revascularization

18. During hospitalization for acute MI, closely monitor for complications. Treat pericarditis-related chest pain with high-dose aspirin. Address ischemia-related chest discomfort with nitroglycerin and antithrombotic meds. Consider coronary angiography and revascularization.

19. Patients with heart failure may need diuretics like IV furosemide and afterload-reducing agents. Consider an intra-aortic balloon pump, emergency angiography , and PTCA/CABG in cardiogenic shock . Treat right ventricular infarction with volume expansion (normal saline) and inotropes if hypotension persists.

20. The patient with acute MI and symptomatic sinus bradycardia or atrioventricular block should receive atropine. Temporary pacing should be performed in the patient with : Sinus bradycardia unresponsive to drug therapy, Mobitz type II second-degree atrioventricular block, Third-degree heart block, Bilateral bundle branch block (BBB), Newly acquired BBB, and Right or left BBB in conjunction with first-degree atrioventricular block.

21. Immediate surgical intervention is often required for the patient with failed PTCA with persistent chest pain or hemodynamic instability; persistent or recurrent ischemia refractory to medical therapy who is not a candidate for catheter intervention; cardiogenic shock and coronary anatomy not amenable to PTCA; or a mechanical abnormality leading to severe pulmonary congestion or hypotension, such as papillary muscle rupture (with resultant mitral regurgitation) or ventricular septal defect (VSD).

22. Angina pectoris Pain syndrome due to induction of an adverse oxygen supply/demand situation in a portion of myocardium The most common clinical manifestation of coronary artery disease (CAD)

23. Imbalance between O2 supply and demand in myocardium – Ischemia Due to atherosclerotic coronary artery obstruction

24. Salient features : Associated with exertion or emotional upset Quickly relieved by rest or nitroglycerin Sensation of tightness, squeezing, burning, pressing, choking, aching, bursting, gas, indigestion or an ill- characterized discomfort Clenching a fist over mid-chest

25. Behind or slightly to the left of the mid sternum May radiate to left shoulder and upper arm medial aspect of the elbow Forearm Wrist fourth and fifth fingers right shoulder or arm lower jaw Neck even the back

26. Types of Angina Stable or classical angina Coronary atherosclerotic plaque Exertion cause anginal symptom U nstable angina Rupture of atherosclerotic plaque- coronary thrombosis V ariant/ Prinzmetal / Vasospastic angina Recurrent localized coronary vasospasm

27. Classification of Antianginal Drugs:

28. Organic nitrates activates cytosolic soluble guanyl cyclase ( sGC ) Nitrates Nitric Oxide (NO) ↑ cGMP Dephosphorylation of MLCK Vascular smooth muscle relaxation mALD-2

29. Nitroglycerine (NTG) (0.3-0.6mg) Sublingual NTG is DOC for treatment of an acute attack of angina Isosorbide Dinitrate (ISDN )(5mg sublingual 10-20mg oral) Sublingual route for an acute attack Oral route for long-term prophylaxis of angina Isosorbide Mononitrate (ISMN) (10-40mg oral) Long term prophylaxis

30. Uses: Angina pectoris Acute coronary syndrome Myocardial infarction CHF and acute LVF Biliary colic Esophageal spasm Cyanide poisoning

31. Adverse effects: Fullness in head, throbbing headache Flushing, weakness, sweating, palpitation, dizziness and fainting Methemoglobinemia (severe anemia) Rashes Tolerance Dependence

32. Beta-Blockers ↓ severity & frequency of attack- prolong life expectancy 1 st line drug-stable angina ↓ myocardial O 2 demand Heart rate Myocardial contraction β1 selective & without intrinsic sympathomimetic activity Atenolol (25-50 mg oral) Bisoprolol (5mg oral) Metoprolol (25-100mg oral)(5-15mg iv)

33. Uses: Angina pectoris Hypertension Cardiac arrhythmias Congestive heart failure Pheochromocytoma Glaucoma Hypertrophic obstructive cardiomyopathy Hyperthyroidism Migraine prophylaxis

34. Adverse effects: Bradycardia Negative inotropy ↓ Cardiac output Bradyarrhythmias ↓ AV conduction Bronchoconstriction Fatigue Prolongation of hypoglycemia

35. Calcium Channel Blockers L- type X CCB Blood vessels ↓ in frequency of opening of Ca 2+ channels Vasodilatation Relaxation of vascular smooth muscles ↓ HR ↓ AV conduction ↓ Contraction ↓ Activity of heart Heart

36. Classification: CCB’S Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical.

37. Calcium Channel Blocker Dihydropyridine(DHP) Amlodipine(5-10mg oral), Nifedipine(5-20mg oral) Non- DHP Diltiazem(30-60mg), Verapamil(40-160mg oral)(5mg slow iv) Reflex Tachycardia Should be used with β - blocker Used as mono therapy No Reflex Tachycardia

38. Uses: Angina pectoris Hypertension Cardiac arrythmias Hypertrophic cardiomyotrophy Premature labor Reynaud’s phenomenon

39. Adverse effects: Constipation Bradycardia Hypotension Attenuate conduction defects Precipitate CHF in pts with pre-existing disease Palpitation Ankle edema GERD worsening Difficulty in urine voiding in elderly

40. Ranolazine Chronic angina Improves exercise capacity without affecting BP or HR Inhibits late Na + current in the myocardium ↓Ca 2+ influx through Na + /Ca 2+ exchanger ↓ contractility ↓ O 2 demand Angina relieved

41. Adverse effects: Dizziness Weakness Constipation Postural hypotension Headache Dyspepsia QT Prolongation Dose: 0.5-1.0g bd oral

42. Nicorandil Potassium channel opener Activates ATP sensitive K + channels in vascular smooth muscles Efflux of K + Hyperpolarisation Arterial dilation Venodilation Coronary vasodilation ↓Afterload ↓Preload Also like nitrates

43. Uses: 2 nd line drug in angina During angioplasty for acute MI Dose: 5-20mg bd

44. Adverse effects: Hypotension Headache Buccal and GI ulcers

45. Ivabradine ‘Pure’ heart rate lowering antianginal drug Alternative to β blockers Chronic stable angina Blocks SA node cell ‘f’ (funny) channels ↓HR ↓ O 2 demand

46. Uses: Chronic stable angina Grade II to IV heart failure Dose: Intially 5mg BD and increase to 7.5mg BD if needed Elderly 2.5mg BD

47. Adverse effects: Bradycardia QT prolongation Atrial fibrillation

48. Trimetazidine: pFOX Inhibitors (partial FFA oxidation Inhibitors) (3- KetAcyl Thiolase Enzyme) Decreasing Oxygen Demand without altering Hemodynamics

49. Uses: Angina Post MI patients Dose: 20mg TDS

50. Adverse effects: Gastric burning Dizziness Fatigue Muscle cramps Reversible parkinsonism

51. Platelet-Inhibiting Agents Aspirin (81–162 mg/d) reduces the incidence of MI in chronic stable angina It is recommended in pts with CAD in the absence of contraindications (GI bleeding or allergy) Clopidogrel (75 mg/d) for aspirin-intolerant individuals Ticagrelor, prasugrel , cangrelor

52. Drug interactions Diltiazam and Verapamil with Beta- blockers : Verapamil (and perhaps diltiazem) plus β blockers have the most therapeutic efficacy but also the largest frequency of dangerous adverse cardiac events . Beta-blockers in combination with verapamil and diltiazem causes : Bradycardia AV block Depression of ionotropic state

53. Nifedipine with beta-blockers : When added to β blockers, Nifedipine causes an increase in heart rate , a decrease in blood pressure, and either no change or a slight improvement in most cardiac performance variables. Leon MB, Rosing DR, Bonow RO, Epstein SE. Combination therapy with calcium-channel blockers and beta blockers for chronic stable angina pectoris. Am J Cardiol . 1985 Jan 25;55(3):69B-80B. doi : 10.1016/0002-9149(85)90615-0. PMID: 2857518.