1. ANTIANGINAL AGENTS

2. Atherosclerotic disease of the coronary arteries, also known as coronary artery disease or ischemic heart disease, is the most common cause of mortality around the world. Patients commonly die either from pump failure due to a myocardial infarction (tissue necrosis) or fatal arrhythmias. Coronary artery disease may present in different forms, such as angina pectoris, acute coronary syndrome, arrhythmias, shortness of breath, and others.

3. Angina Pectoris Angina Pectoris (Latin) = pain in the chest

4. Definition  Sudden, sever, transient, pressing retrostrenal pain.  Radiating to the neck, jaw, left shoulder, and arm.

5. Pathophysiology Anginal pain is precipitated when the oxygen supply to the heart is insufficient to meet oxygen demand. Anginal pain occurs secondary to : 1.Atherosclerosis of the coronary arteries. 2.Vasoconstriction, at an atherosclerosic site of the coronary arteries.

7. Types of Angina Pectoris 1.Stable Angina (Effort angina, Classic Angina). 2.Variant Angina (Prinzmetal’s Angina). 3.Unstable Angina ( Accelarated Angina).

8. Effect of exertion on the balance between oxygen supply and oxygen demand in the healthy heart and the heart with CAD

9. Determinants of the volume of oxygen required by the heart Diastolic factors Blood volume Venous tone Systolic factors Peripheral resistance Heart rateHeart force Ejection time Intramyocardial fiber tension Myocardial O 2 requirement

10. Treatment Strategy 1.increase cardiac oxygen supply 2.decrease oxygen demand

11. Drugs used in angina pectoris Vasodilators Nitrates Short Duration (Sublingual nitroglycerin) Intermediate (Oral) Long Duration (Transdermal) Calcium blockers Cardiac depressants β-blockers Other drugs Metabolism modifiers; rate inhibitors

12. 1- Nitrites & Nitrates  Nitroglycerin.  Amyl Nitrite  Isosorbide dinitrates

13. 1. Nitrites & Nitrates Mechanism of Action Release of nitrite ion NO, Venodilation

15. Nitrites & Nitrates mechanism of action.

16. Therapeutic uses 1.Treatment of acute anginal attacks & for prophylaxis low doses (usually sublingual tablets) for acute attacks & for prophylaxis patches used for prolonged prophylaxis tablets – oral high dose. 2.Treatment of heart failure ( with hydralazine). 3.Treatment of hypertensive emergency.

17. Pharmacokinetics sublingual route(first-pass effect) therapeutic blood level rapidly (few minutes). Total dose administered by this route must be limited to avoid excessive effect. Total duration of effect is brief (15–30 minutes).

18. Pharmacokinetics Long duration: –Oral preparations ( active metabolites). –Transdermal. –Buccal absorption from slow-release preparations Unchanged nitrate compounds t ½ = 2–8 minutes. Partially denitrated metabolites t ½ ≈ 3 hours.

19. Pharmacokinetics The 5-mononitrate metabolite of isosorbide dinitrate is an active metabolite of the latter drug and is available for oral use as isosorbide mononitrate. It has a bioavailability of 100%. Excretion, primarily in the form of glucuronide derivatives of the denitrated metabolites, is largely by way of the kidney.

20. Pharmacokinetics Amyl nitrite and related nitrites are highly volatile liquids. Amyl nitrite is available in fragile glass ampules packaged in a protective cloth covering. The inhalation route provides very rapid absorption and, like the sublingual route, avoids the hepatic first-pass effect. Because of its unpleasant odor and short duration of action, amyl nitrite is now obsolete for angina.

21. Nitroglycerin( Glyceryl trinitrate) Sublingual (duration 30min), Buccal (4hr) Oral spray (30min), Oral tablets (6hr) Topical: ointment (4hr), Transdermal patches (8hr) Intravenous: instant action

22. Adverse Effects Due to vasodilation, vessels relaxed 1. Headache. 2. Facial flushing 3. Orthostatic Hypotension Reflex Tachycardia (lowered Bp => reflex to increase Bp)

23. Tolerance  If tolerance develops, it can be reversed by withholding nitrates (nitrates free interval).  until the sulfhydryl content of VSM has been replenished.

24. Calcium Channel Blockers These agents block the channels that carry slow inward Ca ++ currents in vascular smooth muscle and cardiac muscle Resulting actions include the decrease of conduction velocity, reduction of automaticity, and coronary and peripheral arterial dilitation These effects lead to an increase of coronary blood flow and a decrease in myocardial oxygen demand Examples: nifedipine, verapamil, diltiazem, amlodipine

25. Calcium Channel Blockers Verapamil mainly affects the myocardium => heart rate and contractility. Nifedipine exerts a greater effect on smooth mus­cle in the peripheral vasculature. Diltiazem is intermediate in its actions, => afterload

26. Mechanisms of action Block Ca entry into cell which is important for contractile action in heart. Produce decreased contractility. Vasodilation, (Arteriolar dilation).

27. Mechanisms of action 1)  O 2 Demand - probably “most” important  Decreased HR  Decreased contractility  Decreased afterload (  TPR, BP)  - little effect on venous resistance vs. arterial 2)Increase coronary blood flow (useful in vasospastic angina)

28. Nifedipine: functions mainly as an arteriolar vasodilator. This drug has minimal effect on cardiac conduction or heart rate. Nifedipine is administered orally and has a short half-life (about 4 hours) requiring multiple dosing.

29. Uses nifedipine is useful in the treatment of variant angina caused by spontaneous coronary spasm.

30. Side Effect Can cause flushing, headache, hypotension, and peripheral edema as side effects of its vasodilation activity. may cause reflex tachycardia if peripheral vasodilation is marked resulting in a substantial decrease in blood pressure. Gingival hyperplasia, & dysgeusia

31. Dental Considerations: Calcium Channel Blockers There are no significant drug interactions reported Gingival hyperplasia can occur in patients taking calcium channel blockers; close monitoring and encouragement of optimal oral hygiene is necessary

32. Verapamil Verapamil slows cardiac conduction directly and thus decreases heart rate and oxygen demand, but it is a weaker vasodilator.

33. Side Effect Verapamil is contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities. It also causes constipation. Verapamil should be used with caution in digitalized patients, since it increases digoxin levels.

34. Diltiazem Diltiazem has cardiovascular effects that are similar to those of verapamil. It reduces the heart rate, although to a lesser extent than verapamil, and also decreases blood pressure.

35. Diltiazem In addition, diltiazem can relieve coronary artery spasm and is therefore particularly useful in patients with variant angina. The incidence of adverse side effects is low.

36. Beta-adrenergic Blocking Agents Beta blockers reduce Anginal pain by decreasing cardiac oxygen demand. Reduced oxygen consumption (demand) due to reduced heart rate (esp. during exercise). Reduced blood pressure (esp. systolic) during exercise.

37. Mechanism of action. This is accomplished primarily through blockade of β1 receptors in the heart, which decreases heart rate and contractility. Beta blockers can reduce oxygen demand further by causing a modest reduction in arterial pressure (afterload).

38. Commonly Used Beta-Adrenergic Blockers Propranolol is the prototype of this class of compounds, but other β-blockers, such as metoprolol and atenolol are equally effective. However, agents with intrinsic sympathomimetic activity (eg., pindolol and acebutolol) are less effective and should be avoided.

39. Therapeutic uses The β -blockers reduce the frequency and severity of angina attacks. These agents are particularly useful in the treatment of patients with myocardial infarction and have been shown to prolong survival. The β -blockers can be used with nitrates to increase exercise duration and tolerance Ineffective (or contraindicated) for variant angina (may make attacks worse)

40. Adverse effects Bronchoconstriction (nonselective). Fatigue, insomnia Hypoglycemia (nonselective). Sever myocardial depression & heart failure.

41. contraindication They are contraindicated in patients with: Diabetes, Peripheral vascular disease, Chronic obstructive pulmonary disease.

42. Aspirin & anticoagulants  Unstable Angina : recurrent ischemic episodes at rest  Recurrent thrombotic occlusions  Platelet aggregation  Rx:  aspirin  i.v. heparin  antiplatelet drugs (clopidogrel, others)  nitroglycerin,  blockers; CCBs in refractory pts.

43. IMPLICATIONS FOR DENTISTRY

44. Anginal attacks can be precipitated by physical or emotional stress. Because these situations often arise in the dental operatory, dentists must be aware of the symptoms and treatment of angina.

45. A complete medical history reveals whether a patient is being treated for angina. If so, the dentist should ensure that the patient has medication (e.g., nitroglycerin) available before a procedure is performed Unused tablets should be discarded 6 months after the original bottle has been opened..

46. The use of epinephrine in gingival retraction cord is contraindicated in patients with angina pectoris because of the potential for an excessive workload on the heart. Similar considerations dictate prudence with, although not avoidance of, local anesthetics with adrenergic vasoconstrictors.

47. Orthostatic hypotension might be a problem in patients receiving CCBs, but cardiac depression is not usually clinically significant. Sensations of heat or facial flushing may be evident in these patients.

48. As previously mentioned, gingival inflammation and overgrowth occasionally develop in patients as a result of therapy with CCBs, especially when taken concurrently with other agents that promote gingival enlargement (e.g., phenytoin,cyclosporine). Strict oral hygiene measures, including regular dental prophylaxis, reduce this problem.