Anti-Anginal Agent

1. PHM142 Fall 2012 Instructor: Dr. Jeffrey Henderson Anti-Anginal Agent Vanja Adzovic MaggieLeung Tonia Sung Yifan Jiang

2. What is Angina? • Chest pain due to inadequate supply of oxygen to the heart • Causes: • Coronary artery disease (most common) • Coronary artery spasm • Restricted blood flow in the coronary arteries • Two classifications of angina: • 1) stable angina • 2)unstable angina

3. Symptoms • Pain • Pressure • Heaviness on the chest • Tightening and aching across the chest, particularly behind the breastbone. • Other symptoms: • indigestion • weakness • sweating • nausea • cramping • shortness of breath.

4. Treatment Options • Rest (for stable angina only) • Invasive Therapy: • Coronary angioplasty • Coronary artery bypass surgery • Medications • Nitroglycerine • Beta Blockers • Calcium Channel Blockers

5. Nitrates • Most are simple nitric and nitrous esters of polyalcohols • All have same mechanism of action • Vasodilation of vessels  reduces preload and after-load • Effective for acute and chronic angina • Tolerance may develop • Prevent with nitrate-free period (10 – 12 hrs/day) • E.g. Glyceryl trinitrate (nitroglycerin), isosorbide dinitrate (ISDN), amyl nitrate

6. Mechanism of Action • Nitrate conversion to nitric oxide (NO) in target tissue • NO activates cytoplasmic form of guanylate cyclase • Activated guanylate cyclase catalyzes cyclic GMP (cGMP) formation • Increased cGMP decreases intracellular Ca2+ levels • Ca2+-ATPase activation =  Ca2+ efflux, or • Ca2+ channel inhibition = Ca2+ influx, or • Ca2+-activated K+ channel stimulation = hyperpolarization of sarcolemmal membrane • cGMP activates cGMP-dependent protein kinase • cGMP-dependent protein kinase activates myosin light chain phosphatase to prevent smooth muscle contraction

8. Actions of Nitrates • Peripheral Vasodilation • Preload reduction from vein dilation • After-load reduction from arteriole dilation • Increased blood flow to ischemic zone from coronary vessel dilation • Other actions (side effects) • Cutaneous vasodilation (flushing) • Meningeal vessels dilation (headache) • Tachycardia (increased heart rate) • Orthostatic hypotension • Syncope (fainting)

9. Routes of Administration • Large first pass effect due to nitrate reductase in liver • Sublingual administration preferred for rapid, short duration of action • Oral or transdermal administration preferred for longer duration of action • E.g. Nitroglycerin • Sublingual (10 – 30 min) • Oral (6 – 8 hrs) • Transdermal patch (8 – 10 hrs) • E.g. Isosorbide Dinitrate • Sublingual (1½ – 2 hrs) • Oral (6 – 10 hrs) • E.g. Amyl Nitrate • Inhalation (3 – 5 min)

10. β-blockers • Treatment for chronic stable angina • Long term acting, not for immediate relief • Non- selective : block both β-1 and β-2 receptors , can affect the heart, blood vessels, and air passages. eg: Propranolol, Nadolol • Selective : block β-1 receptors , mostly affect the heart and do not affect air passageseg: Atenolol, Metoprolol

11. Mechanism of Action 1. Compete for the binding sites of catecholamines (norepinephrine) on the β –adrenoceptors located on the cardiac myocytes 2. Activation of adenyly cyclase  cAMP & PKA 3. Phosphorylation of Ca2+ channels 4. [Ca2+ ] in cytosol Inhibits sympathetic activities 1 2 3 4

12. Effects of β-blockers • Negative chronotropic effect • Negative inotropic effect Heart rate Strength of contraction Blood pressure Workload of heart Oxygen demand

13. β-blockers (cont’d) Side effects • Bradycardia • Hypotension • Dizziness • Headache • Cold hands and feet Avoid abrupt cessation  may cause rebound and heart attack

14. Calcium-channel blockers • can decrease or prevent angina • indicated when beta-blockers are contraindicated, poorly tolerated or ineffective • may be combined with beta blockers and nitrates, but individual titration of doses required

15. Calcium-channel blockers (cont’d) Examples • dihydropyridines • amlodipine • felodipine • nifedipine • nimodipine • nondihydropyridines • diltiazem • verapamil

16. Mechanism of action • selectively inhibit transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle => inhibit contraction (vasodilatory effects) => increased blood flow to the ischemic area and reduces oxygen demand by decreasing afterload • nondihydropyridines: (compared to dihydropyridines) have more pronounced effect on AV nodal conduction => lower heart rate and contractility => decreases myocardial oxygen demand

17. Calcium-channel blockers (cont’d) Side effects • dihydropyridines: tachycardia (due to reflex sympathetic activity), edema (presumably through pre-capillary vasodilation), hypotension • nondihydropyridines: bradycardia (due to effect on AV node), headache, dizziness

18. Summery • Angina is the manifestation of chest pain due to inadequate supply of oxygen to the heart • The most common anti-anginal agents are nitrates, β-blockers and calcium-channel blockers. NITRATES • Nitrates have the same mechanism of action • Effective for both acute and chronic angina • Nitrate  NO  activate guanylate cyclase  cGMP  activate cGMP protein kinase  phosphorylate proteins  reduce intracellular Ca2+  vasodilation (reduce preload & after-load) • Sublingual administration for rapid and short duration of action due to large first pass effect • Oral or transdermal administration for long lasting action β-BLOCKERS • β-blockers are long term acting and useful to treat chronic stable agina • β-blockers competitively inhibit the β –adrenoceptors on cardiac myocytes block the binding of catecholamines  inhibit the enhanced sympathetic actions • β-blockers has negative chronotropic and inotropic effects which reduce the oxygen demand of the heart CALCIUM-CHANNEL BLOCKERS • usually used when beta-blockers fail • mechanism of action and associated side effects:  • dihydropyridines: vasodilation; tachycardia, edema • nondihydropyridines: vasodilation + lower heart rate and contractility; bradycardia • examples: amlodipine, nifedipine; diltiazem, verapamil

19. References • "Angina." Heartandstroke.ca. N.p., n.d. Web. 14 Oct. 2012. <http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3484055/k.52CA/Heart_disease__Angina.htm>. • "What Is Angina?" - NHLBI, NIH. N.p., n.d. Web. 13 Oct. 2012. <http://www.nhlbi.nih.gov/health/health-topics/topics/angina/> • "Angina Symptoms, Pain, Treatment, Types, Definition - MedicineNet." MedicineNet. N.p., n.d. Web. 14 Oct. 2012. <http://www.medicinenet.com/angina/article.htm>. • Rosenfeld, G. C., & Loose , D. S. (2007). Pharmacology. (4 ed., pp. 84-85). Baltimore, MD: Lippincott Williams & Wilkins. Retrieved from http://books.google.ca/books?id=fm8kmMDjdiAC&pg=PA84&lpg=PA84&dq=antianginal agent nitrate mechanism&source=bl&ots=CUs0AVSsEo&sig=tKvOCi-VOcGgUVYNqcnftCi3hEc&hl=en&sa=X&ei=KMl4UPDnDaT40gGG-YCQDQ&ved=0CCAQ6AEwADge • Gray, J. (2011). Therapeutic choices. (6 ed., pp. 481-482). Ottawa: Canadian Pharmacists Association. • Suzer, O. (2009, January 13). Vasodilators, treatment of angina pectoris. Retrieved from http://www.ctf.edu.tr/farma/onersuzer/pdf/ing/05_Vasodilators_treatment_of_angina.pdf • Gupta, L. K. (2007, June 12). Drugs acting on cardiovascular system: Antianginal drugs. Retrieved from http://nsdl.niscair.res.in/bitstream/123456789/584/1/revised AntiAngina drugs.pdf • O’Rorke, S.T.(2007). Antianhinal Actions of Beta-Adrenocetor Antagonist. American Journal of Pharmaceutical Education, 71 (5). • Natman, E. M., Selwyn, A. P. and Loscalzo, J. (n.d.) Harrison's Online: Part 10. Disorders of the Cardiovascular System. Retrieved from http://accessmedicine.com.myaccess.library.utoronto.ca/content.aspx?aID=9104437&searchStr=calcium+channel+blockers#9104437 • e-CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2012 [updated 2011 September; cited 2012 October 15]. Calcium Channel Blockers [CPhA monograph]. Retrieved from: http://www.e-cps.ca/. Also available in paper copy from the publisher.