Pathophysiological approach of Angina Pectoris

Angina

1. Anti- anginal Drugs Sreenu Thalla Associate Professor Department of Pharmacology

2. Definition Angina pectoris is a primary symptom of myocardial ischemia, which is the severe chest pain that occurs when coronary blood flow is inadequate to supply the oxygen required by the heart.

3. Clinical S ymptoms Patient history is a˝golden standard˝ Retrosternal pain Dyspnea Nausea Arrhythmia Restlessness Pain eased after taking nitrates

4. Clinical Classifications of angina Stable angina pectoris Unstable angina pectoris Prinzmetal’s Variant angina pectoris

5. Physical examination Hypertension Obesity Hyperglycemia Hyperlipidemia

6. 1.Stable angina Is caused by narrowed arteries due to atherosclerosis Occurs when the heart works harder Episodes of pain tend to be alike Usually lasts a short time Is relieved by a rest or angina medicine 2. Unstable angina Often occurs at rest Is more severe and lasts longer than stable angina Episodes of pain tend to be changing in the character, frequency, duration as well as precipitating factors Is caused by episodes of increased coronary artery tone or small platelet clots occurring in the vicinity of an atherosclerotic plaque. Is associated with a high risk of myocardial infarction and death.

7. 3. Variant angina Usually occurs at rest Tend to be severe Is relieved by angina medicine (vasodilators) Is caused by a transient spasm in a coronary artery

8. The difference of Arteriovenous oxygen pressure O 2 demand O 2 supply Wall tension Heart rate Contractility Coronary blood flow Angina Aortic Diastolic pressure Coronary Vascular resistance Ventricular Pressure Ventricular Volume > the duration of diastole Pathophysiology

9. Treatment of angina Lifestyle changes Nitrates Medication β-blockers Calcium channel blockers Surgery : CABG ( coronary artery bypass graft ) PTCA ( percutaneous transluminal coronary angioplasty)

10. Organic nitrates Key structure: -O-NO 2 Nitroglycerin Isosorbide dinitrate Isosorbide mononitrate

11. Pharmacological actions 1. Dilate vascular smooth muscle, decrease myocardiac oxygen consumption dilate veins dilate arteries 2. at minimal effective dose : dilate veins blood returning to heart preload Ventricular volume wall tension 3. at higher dose: dilate arteries peripheral resistance afterload wall tension myocardial oxygen consumption.

12. Increase blood supply to ischemic area Increase sub- endocardium blood flow Redistribution of coronary blood flow Increase embranchment cycle in ischemic area blood flows from epicardium to endocardium dilate veins blood returning to heart dilate arteries ventricular wall tension

13. Protect the ischemic myocytes Inhibit platelet aggregation and adhesion Decrease ischemic damage

14. Mechanisms of action cGMP Nitrates NO cGMP platelet PGI 2 ; CGRP CGRP ： calcitonin gene-related peptide smooth muscle relaxation

15. Nitrates NO Guanylyl cyclase* Guanylyl cyclase GTP cGMP PDE GMP Ca 2+ (intracellular) MLCK* MLC MLC-PO4 MLC Actin Contraction Relaxation Mechanisms of action (MLCK-myosin light chain kinase

16. Pharmakinetics Absorption oral bioavailability 10-20% sublingual route: t 1/2 2~4min Metabolism liver Excretion kidney Clinical uses All types of angina sublingual Acute myocardial infarction iv Congestive heart failure (CHF) load Adverse reactions Respond to vasodilation Flushed appearance Throbbing headache Orthostatic hypotension Tachycardia

17. Beta- adrenoceptor Blocking Drugs Nonselective β- blokers - Propranolol , Pindolol , Timolol Selective β 1 -blokers - Atenolol , Metoprolol , Acebutolol Decrease myocardial oxygen consumption β - blocker decrease heart rate, contractility, and blood pressure decrease myocardial oxygen consumption β - blocker increase in end-diastolic volume, ejection time increase myocardial oxygen consumption total effect: decrease

18. 2. Improve blood supply to the ischemic area Decrease myocardial oxygen consumption Promote the blood supply to the compensative dilating ischemic area Decrease heart rate Increase diastolic perfusion time Blood flow from epicardium to endocardium Increase embranchment cycle in ischemic area 3. Decrease myocardial free fatty acid, improve myocardial metabolism 4. Promote oxygen to dissociate from oxygenated hemoglobin (HbO 2 )

19. β -blockers combines with nitrates Nitrates β- blokers alone alone Heart rate reflex increase decrease Arterial pressure decrease decrease End-diastolic volume decrease increase Contractility reflex increase decrease Ejection time decrease increase synergism

20. Calcium channel-blocking drugs Decrease myocardial oxygen consumption Heart rate and contractility; Vasodilation Antisympathetic action Improve the blood supply to the ischemia Dilate coronary artery Decrease the platelet aggregation Protect ischemic cardiac myocytes Antiatherosclerosis

21. Clinical uses Antianginal effect is similar to β- blokers , but have many virtues Suit for the anginal patient with asthma Variant angina first choice Suit for the anginal patient with surrounding blood vessel spasm Nifedipine Variant angina - strongest action Stable angina - Combined with β- blokers

22. Verapamil Weaker for dilating peripheral vessels Inhibit the heart Used for stable angina and variant angina combined with other drugs Contraindications: heart failure atrioventricular blockade Diltiazem Moderate , used for all types of angina Anginal patient with heart failure Atrioventricular blockade caution

23. Other Antianginal Drugs Dipyridamole Nicorandil Molsidomine ACEI

24. Angina of Effort (stable angina) Nitrates , calcium channel blockers, and β-blockers are all useful in prophylaxis in patients with angina of effort. For maintenance therapy of chronic stable angina, long-acting nitrates, calcium channel-blocking agents, or β-blockers may be chosen. The combination of a β-blocker with a Nitrates or a β-blocker with a calcium channel blocker or two different calcium channel blockers has been shown to be more effective than individual drug used alone. If response to a single drug is inadequate, a drug from a different class should be added to maximize the beneficial reduction of cardiac work while minimizing undesirable effects.

25. Vasospastic Angina Nitrates and the calcium channel blockers are effective drugs for relieving and preventing ischemic episodes in patients with variant angina. Unstable Angina In patients with unstable angina ， anticoagulant and antiplatelet drugs play a major role in therapy. Aggressive therapy with antilipid drugs, heparin, and antiplatelet agents is recommended. In addition, therapy with nitroglycerin and β-blockers should be considered; calcium channel blockers should be added in refractory cases.

26. NEWER DRUGS RANOLAZINE - a drug that has been in development for 20 years. It is a Sodium Channel Blocker. NICORANDIL - a potassium channel activator, and also has a Nitrogen Donating Moeity . IVABRADINE - inhibits the  I f  channel in the sinus node and thereby causes bradycardia without any negative inotropic effects.

27. Thank You