1. Angina Pectoris “Chest pain” or angina pectoris is a symptom of ischemic heart disease caused by an imbalance between oxygen requirement of the heart and oxygen supply. Peculiarities of coronary circulation  Functional end arteries  Maximum oxygen extraction  Blood flow mainly during diastole

2. Angina Pectoris o Exertional angina (Stable or effort, or classic): o Myocardial oxygen demand increase triggered by physical activity, pain persists few minutes and subsides with rest (~ 90% of angina cases). o Vasospastic angina (or Prinzmetal, or variant): o Consequence of an abrupt reduction in blood flow due to a vasospasm and characterized by pain at rest. o Unstable (or “crescendo angina”, acute coronary insufficiency, preinfarction angina or intermediate syndrome): o Angina symptoms are more frequent, longer lasting, often occurs at rest and not relieved by nitroglycerine.

5. Antianginal agents o NITRATES / NITRITES o BETA BLOCKERS o CALCIUM CHANNEL BLOCKERS o ANTITHROMBOTIC AGENTS: Aspirin, Heparin o Give 160-325 mg by mouth ASAP. Chewed aspirin is absorbed faster & is preferred. o OTHERS : Ranolazine, Trimetazidine, Nicorandil

6. Antianginal drugs Nitrates / Nitrites : 1.Isosorbide dinitrate 2.Nitroglycerine (Glyceryl trinitrate) 3.Isosorbide mononitrate Nitrates are available in oral tablets, sublingual tablets, intravenous, topical patches and ointment. 4. Amyl nitrite - inhalant

7. Acute attacks Chronic Prophylaxis

8. Organic nitrates exert the majority of their vasodilatory action on venous capacitance vessels at therapeutic dose

10. Antianginal drugs Nitrates : Pharmacokinetics Organic nitrates are highly lipid soluble. Nitrates are denitrated by glutathione reductase in liver (resulting in low bioavailability of about 20%). Nitrates have short half life (5 - 60 minutes). Denitrated metabolites are less active and longer acting are useful in chronic prophylaxis. (isosorbide mononitrate).

11. Antianginal drugs Nitrates / Nitrites : Adverse effects Hypotension, throbbing headache Reflex tachycardia due to a reduction in arterial blood pressure by higher doses of nitrates can result in a paradoxical increase in oxygen demand. Methemoglobinemia is seen with nitrites and rare with nitrates. Tolerance – activation of sympathetic activation and volume expansion. Contraindicated with sildenafil citrate (viagra) and head trauma.

12. Drug interaction between Nitrates and Viagra

13. Nitrates in Angina Pectoris a) Treatment of the acute attack. – Sublingual Nitroglycerin – Sublingual Isosorbide dinitrate – Inhalant Amyl nitrite b) Chronic prophylaxis to reduce attacks – Oral or transdermal Nitroglycerin – Oral Isosorbide dinitrate – Oral Isosorbide mononitrate

14. Effects of nitrates in angina a) In exertional angina b) In variant angina c) In unstable angina: may involve a combination of – Decreased myocardial O 2 demand – Increased myocardial O2 supply – Decreased platelet aggregation d) In Congestive Heart failure: used when symptoms of pulmonary congestion predominate CAUTION: High doses can cause undesirable effects such as reflex tachycardia and reflex increase in cardiac contractility

15. Nitrites in cyanide poisoning Hemoglobin Methemoglobin Cyanomethemoglobin Methemoglobin + Sodium thiocyanate (excreted in urine) Sodium nitrite Cyanide Sodium thiosulfate Hydroxocobalamin is the newly approved antidote for cyanide in US

16. Antianginal drugs BETA RECEPTOR BLOCKERS: They are an important component of treatment of angina pectoris. They reduce the myocardial oxygen demand by decreasing the heart rate and contractility. Increase myocardial perfusion (subendocardial) due to increase diastolic perfusion time. Atenolol, metoprolol and propranolol

18. Antianginal drugs BETA BLOCKERS: These increase survival in especially in patients with history of myocardial infarction. These reduce the load on the heart and the heart’s response to exercise. These are effective in unstable angina and chronic prophylaxis of exertional angina. These are associated with the feeling of coldness in the extremities. CONTRAINDICATED IN VASOSPASTIC ANGINA

19. Antianginal drugs CALCIUM CHANNELS BLOCKERS : CCB Types of calcium channels : L, N, T Calcium channel blockers mainly block L TYPE : SAN, AVN and smooth muscles Amlodipine, Nifedipine, Diltiazem, Verapamil Verapamil and diltiazem block Ca ++ channels both in the heart and in the vessels Dihydropyridines (DHP) like Nifedipine block calcium channels in the vessels only.

21. Antianginal drugs CALCIUM CHANNEL BLOCKERS : CCB CCB cause relaxation of smooth muscles by decreasing the intracellular availability of calcium. Relax mainly arteries. Extravascular smooth muscles – bronchial, biliary and intestinal muscle also relaxed. Block P- glycoprotein, a multi-transporter associated with drug resistance in cancer cells - Verapamil

24. Clinical uses of calcium channel - blocking drugs DrugIndication AmlodipineAngina, hypertension FelodipineHypertension, Raynaud’s disease NicardipineAngina, hypertension NifedipineAngina, hypertension, Raynaud’s disease NimodipineSubarachnoid hemorrhage Diltiazem Angina, hypertension and Supraventricular arrhythmia Verapamil Angina, hypertension, Supraventricular arrhythmias, Migraine

25. Adverse Effects of Ca 2+ channel blockers Headache, dizziness, flushing and peripheral edema (DHP like nifedipine and others) Tachycardia, palpitations and aggravation of myocardial ischemia (nifedipine) Gingival hyperplasia (nifedipine) A-V block, bradycardia, arrhythmias (ver, dil) Constipation (verapamil) Verapamil can double the plasma concentration of digoxin

26. Combination Therapy for Angina To increase effectiveness and reduce adverse effects. Nitrates + β-blockers or CCBs (non-DHP) – Beta-blockers or CCBs can attenuate the nitrate-induced: a) reflex tachycardia b) reflex increase in cardiac contractility – Nitrates can attenuate the beta-blocker-induced: a) increased end diastolic volume b) increased ejection time Nitrates + β-blockers + Ca ++ channel-blockers – In patients with exertional angina that is not controlled by two types of antianginal drugs, but can increase the incidence of adverse effects.

27. Antianginal drugs Ranolazine (Ranexa) is approved for use in the treatment of chronic angina pectoris and acts by reducing calcium overload through alteration of late sodium current. Trimetazidine (Vastarel) is an anti-anginal agent that improves myocardial glucose utilization through inhibition of fatty acid metabolism Nicorandil (Ikorel, Europe) is antianginal agent that acts by stimulation of guanylate cyclase and opening of K+ channel.

28. Antianginal drugs Acute Emergency Treatment of Angina: Myocardial Ischemia Oxygen: – Limits ischemic injury Nitroglycerin: Sublingual – Causes coronary dilation, greater perfusion, reduces preload & afterload Aspirin: – Give 160-325 mg by mouth ASAP. Chewed aspirin is absorbed faster & is preferred. Morphine: – reduces anxiety and relieves pain. Morphine also produces venodilation, which can reduce venous return & reduce preload (oxygen demand)

29. Antianginal drugs Chronic Stable Angina of Effort: Complete treatment : ABCDE – Aspirin & Antianginals drugs – Nitrates sublingual – Beta blocker & BP control – Cholesterol reducing drugs & Cigarette cessation, Calcium channel blockers (if required) – Diabetes & Diet management – Exercise & Education

30. Antianginal drugs o Vasospastic (Variant) Angina: Nitrates Calcium Channel Blockers – NOT Beta-blockers o Unstable Angina Management: Antiplatelet agents (aspirin) (325 mg aspirin initially) – these patients are at a high risk for developing an MI or non-STEMI Anticoagulants (heparin or LMWH) Nitroglycerin (sublingually or by buccal spray; i.v. if pain persists; topical or oral for maintenance) Beta-blocker (reduce heart rate to 50-60 beats/min; caution in patients with evidence of heart failure) Statin or other lipid-lowering agent if applicable (prophylactic therapy)

31. Summary of Antianginal Drugs Drug classAntianginal actions Nitrates and nitrites - Decrease in cardiac O 2 demand by reducing preload - Increase in cardiac O 2 delivery by relieving coronary spasm. Ca ++ channel blocking drugs - Decrease in cardiac O 2 demand by: a) reducing afterload b) reducing cardiac contractility and rate - Increase in cardiac O 2 delivery by relieving coronary spasm. β-blocking drugs - Decrease in cardiac O 2 demand by reducing cardiac contractility and rate