1. Cardiac Pharmacology Ted Williams Pharm D Candidate OSU/OHSU College of Pharmacy

2. The big, scary picture CNS Baroreflex I-1 α 2 Vagus Nerve Preload Afterload α 1 GI Vasculature B1 ANP Aldosterone B2 Renin NO M2 - B1 + Conductivity Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ ATII Na↑ PG Na↑ Ca↑ Mg↑ K↑ H2O ADH/Vasopressin

3. Breaking it Down • Direct Cardiac Agents • Peripheral Vascular Agents • Renal Agents

4. Reality Check • The pharmacology really isn’t that simple, but it is a helpful framework

5. Direct Cardiac Agents • Beta Blockers (BB) • Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB) • Digitalis Glycoside (De-GOX-in) • Aldosterone antagonists • Well explain why this is here later

6. Peripheral Vascular Agents • Dihydropyridine CCB • Nitrates • Hydralazine • Phosphodiesterase Inhibitors • Alpha 1 Antagonists

7. Renal Agents • ACE Inhibitors • Angiotensin 2 Inhibitors • Diuretics • Carbonic Anhydrase Inhibitors • Loop • Thiazide Diuretics • Aldosterone Antagonists • Potassium Sparing Diuretics

8. Mixed Bag • Selective I-1 Imidazoline Receptor Agonists

9. Hypertension in 30 seconds • Excessive vascular volume • Low Compliance of vasculature • Increased activity of the ReninAnginotensin System

10. Ischemic Heart Disease in 30 Seconds • Cardiac Muscle has insufficient oxygen • Two Solutions • Reduce cardiac Oxygen demand • Increase Preload • Reduce Contractility • Reduce Afterload • Increase cardiac oxygen supply • Increase Coronary Flow • Increase Oxygen extraction

11. Heart Failure in 30 Seconds • Chronic overwork of the heart muscle causes hypertrophic remodeling • Reduced cardiac output • Fluid retention

12. Cardiac Fluid Dynamics in 30 Seconds Contractility Preload Afterload + + - Heart Rate Stroke Volume + + Cardiac Output

13. ReninAngiotensin Pathway

14. Direct Cardiac Agents – BB • Selectivity • Beta 1 Selective • Beta 1/2 Non-Selective • Alpha 1, Beta 1/2 Non-Selective • Alpha 2, Beta 1/2 Non-Selective • Intrinsic Sympathomimetic Activity (ISA) • ISA • No long term mortality benefit Post MI • Non-ISA do have benefit post MI • Non-ISA

15. Beta Blocker Targets CNS Baroreflex Preload Afterload I-1 α 2 Vagus Nerve α 1 GI Vasculature B1 ANP Aldosterone B2 Renin NO M2 - B1 + Conductivity Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ ATII Na↑ PG Na↑ Ca↑ Mg↑ K↑ H2O ADH/Vasopressin

16. Beta Blocker Targets • Beta 1 blockade • “Cardioselective” • Inhibits sympathetic contractility, inotropy, and conductivity of the heart • Inhibits sympathetic renin secretion in the kidneys • Best Tolerated Beta 1 Blockers • Atenolol • Acebutolol • Bisoprolol • Metoprolol

17. Beta Blocker Targets • Beta 2 blockade • Beta 2 receptors inhibit smooth muscle contractions in the lungs and GI tract • Beta 2 blockade is useful for restricting hepatic blood flow for patient with Liver Cirrhosis, but generally not a therapeutic effect for CVD • Commonly Used Beta 2 Blockers • Propranolol • Nadolol

18. Beta Blockers and Hypertension • Primarily a function of Beta 1 Blockade • Inhibition of sympathetic cardiac stimulation of the SA node • Inhibition of Renin secretion • Secondary effects of Beta 2 Blockade • Vasodilation of GI Vasculature • Place in Therapy • Second line monotherapy for uncomplicated hypertension • Important agent for Hypertension with other cardiovascular co-morbidities • Stroke • MI • CHF

19. Beta Blockers and Ischemic Heart Disease • Reduces Cardiac Oxygen Demand by limiting maximum stimulation (Heart Rate) • Place in Therapy • First Line for Stable Angina • Decreases Morbidity (Reduced Symptoms) • Decreases Mortality (Prolongs life) • Only Non-ISA

20. Beta Blockers and Heart Failure Contractility Preload Afterload + + - Heart Rate Stroke Volume + + Cardiac Output

21. Beta Blockers and Heart Failure • Particular Effects • Decreased Heart Rate • Decreased Contractility • Decreased Afterload • Increased Preload • Increased Stroke Volume via Preload • Net Effect • Increased Cardiac Output • Place in Therapy • Stage B, C (myocardial damage present) • Improves Morbidity

22. Targets for Mixed Alpha/Beta Blockers CNS Baroreflex Preload Afterload I-1 α 2 Vagus Nerve α 1 GI Vasculature B1 ANP Aldosterone B2 Renin NO M2 - B1 + Conductivity Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ ATII Na↑ PG Na↑ Ca↑ Mg↑ K↑ H2O ADH/Vasopressin

23. Targets for Mixed Alpha/Beta Blockers • Alpha 1 Blockade • Peripheral Vasodilation by inhibition of Gq Signaling pathway • Additional Reduced Afterload • Place In therapy • Heart Failure in particular • Examples • Carvedilol (alpha-1, beta 1/2) • Labetalol (alpha-1, beta 1/2) • Alpha 2 Blockade • CNS Inhibition the inhibition of the baroreflex • Inhibits sympathetic increases in blood pressure • PNS inhibition of the negative feedback on vagal cardiac stimulation • Alpha 2 Agonists • Stimulates Negative feedback on Beta 1 neurons controlling Heart Rate • Enhances Beta Blockade • Celiprolol (alpha-2 agonist, beta-1 blockade)

24. Non-DHP CCB Targets CNS Baroreflex Preload Afterload I-1 α 2 Vagus Nerve α 1 GI Vasculature B1 ANP Aldosterone B2 Renin NO M2 - B1 + Conductivity Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ ATII Na↑ PG Na↑ Ca↑ Mg↑ K↑ H2O ADH/Vasopressin

25. Non-DHP CCB Targets • Use dependent tissue selectivity • Binds to the open state of the channel • The more often the channel opens, the more drug exposure and therefore the more tissue “selective” • Peripheral vasodilation present, but not as strong as with DHP CCB • Cardioselective • Verapamil • Diltiazem

26. Non-DHP CCB and Hypertension • First line monotherapy, with a few restrictions • BPReductions primarily due to decreased heart rate and contractility reducing cardiac output

27. Non-DHP CCB and Ischemic Heart Disease • Reduces Contractility • Reduces Heart Rate • Second line behind Beta Blockers for symptom relief • Not strongly supported to improve prognosis • First line for vasospastic Angina • Use with extreme caution in combination with beta blockers due to risk of AV Block

28. Non-DHP CCB and Heart Failure Contractility Preload Afterload + + - Heart Rate Stroke Volume + + Cardiac Output

29. Non-DHP CCB and Heart Failure • Specific Effects • Decreased Contractility • Decreased Conductivity • Decreased Automaticity • Net Effects • Decreased cardiac output • Increases Edema via peripheral vasodilation, a major no-no for HF patients • Place in Therapy • Contraindicated in Systolic Heart Failure (most common kind of Heart Failure) • Should be discontinued by Stage C Heart failure, even with compelling indications

30. Digitalis Targets CNS Baroreflex Preload Afterload I-1 α 2 Vagus Nerve α 1 GI Vasculature B1 ANP Aldosterone B2 Renin NO M2 - B1 + Conductivity Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ ATII Na↑ PG Na↑ Ca↑ Mg↑ K↑ H2O ADH/Vasopressin

31. Digitalis Targets • Increases cardiac contractility by increasing calcium levels • Cellular target is Sodium Potassium ATPase which is loosely coupled with Sodium Calcium Exchanger • Sympatholytic suppression of ReninAngiotensin System • Increases ParasympatheticVagal Tone • Reduces Preload • Reduces Heart Rate

32. Digitalis And Hypertension • Neutral Effects on Blood Pressure • …Move along, nothing to see here

33. Digitalis And Ischemic Heart Disease • The improved cardiac function of Digitalis glycoside is only present in the hypertrophied heart. • Mason, D. Digitalis and Angina Pectoris. Chest 1973;64;415-416

34. Digitalis And Heart Failure Contractility Preload Afterload + + - Heart Rate Stroke Volume + + Cardiac Output

35. DigitalisAnd Heart Failure • Heart Failure is the only real use… • Specific Effects • Increased Contractility dominates • Decreased Preload • Decreased Heart Rate • Net Effect • Increased Cardiac Output • Symptom management only • No improvement in mortality • Although RADIANCE and PROVED demonstrated worsening outcomes when Digitalis was discontinued

36. Aldosterone Antagonists Targets CNS Baroreflex Preload Afterload I-1 α 2 Vagus Nerve α 1 GI Vasculature B1 ANP Aldosterone B2 Renin NO M2 - B1 + Conductivity Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ ATII Na↑ PG Na↑ Ca↑ Mg↑ K↑ H2O ADH/Vasopressin

37. Aldosterone Antagonists Targets • Blocks Collagen deposition (fibrosis) in the myocardium • Minor Potassium sparing diuresis by blocking sodium reabsorption in the distal convoluted tubules and collecting ducts (potassium sparing) • Examples • Spironolactone • Eplerenone

38. AldosteroneAntagonistsAnd Hypertension • Minor blood pressure effects due to diuresis • Side effects limit efficacy • Gynecomastia in men due to testosterone production antagonism

39. AldosteroneAntagonistsAnd Ischemic Heart Disease • Where’s the MOA?

40. Aldosterone AntagonistsAnd Heart Failure • Decrease in Preload due to decreased blood pressure • Real benefit is the inhibition of myocardial fibrosis • 25mg QD with no titration

41. Peripheral Vascular Agents • Dihydropyridine CCB (DHP-CCB) • Nitrates • Hydralazine • Phosphodiesterase Inhibitors (PDE) • Alpha 1 Antagonists

42. DHP-CCB Targets CNS Baroreflex Preload Afterload I-1 α 2 Vagus Nerve α 1 GI Vasculature B1 ANP Aldosterone B2 Renin NO M2 - B1 + Conductivity Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ ATII Na↑ PG Na↑ Ca↑ Mg↑ K↑ H2O ADH/Vasopressin

43. DHP-CCB Targets • State Dependent Binding • Bind to the inactive state of the channel • The less active the tissue, the greater selectivity for the tissue • Arterial vascular smooth muscle relaxation • Reducing Afterload • Some Baroreflex triggering

44. DHP-CCB and Hypertension • First line monotherapy • Preferred over Non-DHP for patients with HF • Preferred over Non-DHP for patients taking BB

45. DHP-CCB and Ischemic Heart Disease • Reduces Afterload • Second line after Beta Blockers • Improves morbidity only • Mortality benefit not adequately demonstrated • Preferred in patients with HF over Non-DHP

46. DHP-CCB and Heart Failure Contractility Preload Afterload + + - Heart Rate Stroke Volume + + Cardiac Output

47. DHP-CCB and Heart Failure • Reduces Afterload • Minor effects on Contractility, Heart Rate, and Conductivity • Net effect is a reduction of cardiac output • Increases Edema via peripheral vasodilation, a major no-no for HF patients

48. Nitrate Targets CNS Baroreflex Preload Afterload I-1 α 2 Vagus Nerve α 1 GI Vasculature B1 ANP Aldosterone B2 Renin NO M2 - B1 + Conductivity Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ ATII Na↑ PG Na↑ Ca↑ Mg↑ K↑ H2O ADH/Vasopressin

49. Nitrate Targets • PeripheralVasodiation by promoting Nitric Oxide Release • Veins • Arteries • Arterioles • Decrease Preload

50. Nitrate And Hypertension • Not particularly helpful