1. Calcium Channel Blockers & Anti-angina Agents PRCL 628: Medical Pharmacology Robert J. DiDomenico, PharmD, FCCP Clinical Associate Professor Cardiovascular Clinical Pharmacist OBJECTIVES For each of the anti-angina drugs/drug classes, students should be able to: 1.Describe the mechanism of action. 2.Compare and contrast the pharmacokinetic and drug interaction profiles within each class. 3.Compare and contrast the clinical effects. 4.List the common and/or serious adverse effects.

2. Calcium Channel Blockers & Anti-angina Agents PRCL 628: Medical Pharmacology Required Reading: 1.Katzung BG. Chapter 12. Vasodilators & the Treatment of Angina Pectoris. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=55821915. http://www.accessmedicine.com/content.aspx?aID=55821915 Suggested Reading: 1.Michel T, Hoffman BB. Chapter 27. Treatment of Myocardial Ischemia and Hypertension. In: Knollmann BC, ed. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=16667490. http://www.accessmedicine.com/content.aspx?aID=16667490

3. Abrams J. N Engl J Med 2005;352:2524-33

4. Prinzmetal or Variant Angina Coronary Artery Vasospasm http://www.uofmmedicalcenter.org/healthlibrary/Article/40420

5.  Oxygen Supply ≠  /  Oxygen Demand  /  Arterial pO 2  /  Diastolic filling time  Coronary blood flow  /  Heart rate  /  Myocardial contractility  /  Ventricular wall tension Chronic Angina

6. Treatment of Angina Nonpharmacologic –Percutaneous coronary intervention –Correction of anemia –Correction of hypoxemia Pharmacologic –Beta-blockers –Calcium channel blockers –Nitrates –Ranolazine

7. Parker JD, Parker JO. N Engl J Med 1998;338:520-31. (Nitroglycerin)

8. Trevor AJ, Katzung BG, Masters SB. Chapter 12. Drugs Used in the Treatment of Angina Pectoris. In: Trevor AJ, Katzung BG, Masters SB, eds. Pharmacology: Examination & Board Review. 9th ed. New York: McGraw-Hill; 2010. http://www.accesspharmacy.com/content.aspx?aID=6543820. http://www.accesspharmacy.com/content.aspx?aID=6543820

9. Figure 1. Pathways of organic nitrate bioactivation in vascular cells. Münzel T et al. Circulation Research 2005;97:618-628 Copyright © American Heart Association

10. Nitrates Pharmacodynamic Effects Beneficial effects –  Oxygen demand  Ventricular volume  Arterial pressure  Ejection time –  Perfusion Coronary vasodilation  Collateral blood flow  LVEDP Deleterious effects –  Oxygen demand Reflex tachycardia Reflex  in contractility –  Perfusion  Diastolic perfusion time due to tachycardia –Nitrate tolerance Requires 8 – 12 hour “nitrate-free” interval

11. Nitrates Adverse Effects & Notable Drug Interactions Common adverse effects –Headache –Reflex tachycardia –Orthostatic hypotension Drug interactions –Phosphodiesterase inhibitors Potentiate effects of nitrates & may precipitate severe hypotension & MI –Sildenafil (Viagra, Revatio) –Vardenafil (Levitra, Staxyn) –Tadalafil (Cialis, Adcirca)

12. Pharmacokinetics of Nitrate Dosage Forms NitrateDosage formOnset (minutes) DurationCommon Dose Short-acting Nitroglycerin Sublingual Translingual spray Intravenous 1 – 3 1 – 4 1 – 2 10 – 60 min 3 – 5 min 0.4 – 0.6mg PRN 0.4mg/spray PRN 5 – 10mcg/min titrated to effect Long-acting Nitroglycerin Isosorbide dinitrate Isosorbide mononitrate Topical ointment Transdermal patch Oral 20 – 60 20 - 60 15 – 40 30 – 60 2 – 8 hours 2 – 6 hours 6 – 8 hours (Ismo) 8 – 12 hours (Imdur) 0.5 – 1 inch q4-6h 0.2 – 0.4 mg/hr 5 – 60mg TID 20mg BID 30 – 120mg daily

13. Figure 2. Molecular mechanisms of nitrate tolerance. Münzel T et al. Circulation Research 2005;97:618-628 Copyright © American Heart Association

14. Katzung BG. Chapter 12. Vasodilators & the Treatment of Angina Pectoris. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=55821915. http://www.accessmedicine.com/content.aspx?aID=55821915

15. Trevor AJ, Katzung BG, Masters SB. Chapter 12. Drugs Used in the Treatment of Angina Pectoris. In: Trevor AJ, Katzung BG, Masters SB, eds. Pharmacology: Examination & Board Review. 9th ed. New York: McGraw-Hill; 2010. http://www.accesspharmacy.com/content.aspx?aID=6543820. http://www.accesspharmacy.com/content.aspx?aID=6543820 X

16. http://www.drugdevelopment-technology.com/projects/istaroxime/istaroxime4.html

17. Calcium Channel Blockers Pharmacodynamic Effects  Myocardial oxygen demand Smooth muscle relaxation = vasodilation –Arterioloes > veins Nimodipine selective for cerebral vessels  Contractility –Nondihydropyridines (diltiazem, verapamil) –Dihydropyridines (e.g., nifedipine) Minimal effect at therapeutic doses  Heart rate –Nondihydropyridines Clinical uses –Angina –Hypertension –Raynaud’s Dihydropyridines –Pulmonary HTN Nifedipine/DHPs –Supraventricular tachycardias Diltiazem Verapamil

18. Calcium Channel Blockers Pharmacokinetics & Dosing DrugDosage formBioavail- ability (%) Onset (minutes) Half- life (hours) Duration (hours) Common Dose DiltiazemIR tablet SR capsule XR/CD capsule IV 40 – 6530 – 60 1 – 2 hrs 3 3 – 106 12 24 1 – 3 30 – 90mg q6h 60 – 180mg BID 120 – 480mg/day 15 – 20mg, 5-15mg/hr VerapamilIR tablet SR tab/cap IV 20 – 351 – 2 hrs 5 – 11 hrs 1 – 5 4 – 126 – 8 12 - 24 < 0.5 40 – 160mg TID 120-480mg/day 2.5 – 10mg NifedipineIR capsule SR tablet 45 – 7020 30 2 – 76 – 8 24 10 – 30mg q6-8h 30 – 240mg daily AmlodipineTablet65 – 906 – 12 hrs30 – 50242.5 – 10mg daily FelodipineER tablet15 – 202 – 5 hrs11 – 16242.5 – 20mg daily

19. Calcium Channel Blockers Adverse Effects & Notable Drug Interactions Adverse effects –Peripheral edema –Flushing –Hypotension –Reflex tachycardia Dihydropyridines Nifedipine > others –Nondihydropyridines Bradycardia Heart block Heart failure Inhibit CYP3A4 –Statins –Cyclosporine –Tacrolimus Inhibits p-glycoprotein (verapamil) –P-glycoprotein substrates (e.g., digoxin)

20. Carbone F, et al. Swiss Med Wkly. 2013;143:w13874. http://www.smw.ch/content/smw-2013-13874/

21. Ranolazine Clinical Effects & Precautions  Ventricular wall tension (diastole) No effect on heart rate & blood pressure Small risk for QTc prolongation Drug interactions –Substrate CYP3A4, CYP2D6, PGP –Inhibits CYP3A4, CYP2D6, PGP –Avoid/contraindicated Azole antifungals Strong CYP3A4 inducers & inhibitors High-risk QTc prolonging drugs

22. Summary of Anti-Angina Effects on Myocardial Oxygen Supply & Demand Drug/ClassHRBPWall Tension Contract- ility O 2 Supply Beta-blockers // CCBs Verap/Dilt Dihydropyridines //     Nitrates // Ranolazine  Cavallari LH, DiDomenico RJ. Chapter 7: Ischemic Heart Disease In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT, eds. Pharmacotherapy Principles & Practice, 3 rd ed.. Chicago: McGraw-Hill, 2013.