1. Chapter 44 Drugs Acting on the Renin-Angiotensin-Aldosterone System

2. Drugs Acting on the Renin-Angiotensin-Aldosterone System • Physiology of the renin-angiotensin-aldosterone system • Angiotensin-converting enzyme inhibitors • Angiotensin II receptor blockers • Aldosterone antagonists

3. Physiology of the Renin-Angiotensin-Aldosterone System • Type of angiotensin • Angiotensin I • Angiotensin II • Angiotensin III • Actions of angiotensin II • Vasoconstriction • Release of aldosterone • Alteration of cardiac and vascular structure

4. Physiology of the Renin-Angiotensin-Aldosterone System • Actions of aldosterone • Regulation of blood volume and blood pressure • Pathologic cardiovascular effects

5. Fig. 44–1. Regulation of blood pressure by the renin-angiotensin-aldosterone system.

6. Physiology of the Renin-Angiotensin-Aldosterone System • Formation of angiotensin II by renin and angiotensin-converting enzyme (ACE) • Renin • Catalyzes the formation of angiotensin I from angiotensinogen • Regulation of renin release • Angiotensin-converting enzyme (kinase II) • Catalyzes the conversion of angiotensin I (inactive) to angiotensin II (highly active)

7. Physiology of the Renin-Angiotensin-Aldosterone System • Regulation of blood pressure by the renin-angiotensin-aldosterone system • Helps regulate blood pressure in the presence of hemorrhage, dehydration, or sodium depletion • Acts in two ways • Constricts renal blood vessels • Acts on the kidney to promote retention of sodium and water and excretion of potassium • Tissue (local) angiotensin II production

8. Angiotensin-Converting Enzyme Inhibitors • Mechanism of action and overview of pharmacologic effects • Reducing levels of angiotensin II • Increasing levels of bradykinin • Pharmacokinetics

9. Angiotensin-Converting Enzyme Inhibitors • Therapeutic uses • Hypertension • Heart failure • Myocardial infarction (MI) • Diabetic and nondiabetic nephropathy • Prevention of MI, stroke, and death in patients at high cardiovascular risk MI = myocardial infarction.

10. Fig. 44–2. Overview of ACE inhibitor actions and pharmacologic effects.

11. Angiotensin-Converting Enzyme Inhibitors • Adverse effects • First-dose hypotension • Fetal injury • Cough • Angioedema • Hyperkalemia • Dysgeusia and rash • Renal failure • Neutropenia

12. Angiotensin-Converting Enzyme Inhibitors • Drug interactions • Diuretics • Antihypertensive agents • Drugs that raise potassium levels • Lithium • Nonsteroidal anti-inflammatory drugs

13. Angiotensin-Converting Enzyme Inhibitors • Preparations, dosage, and administration • Except for enalaprilat, all ACE inhibitors are administered orally • All available in single-drug formulations • Except for captopril and moexipril, all oral formulations may be administered without regard to meals

14. Angiotensin II Receptor Blockers • Mechanism of action and overview of pharmacologic effects • Block access of angiotensin II • Cause dilation of arterioles and veins • Prevent angiotensin II from inducing pathologic changes in cardiac structure • Reduce excretion of potassium • Decrease release of aldosterone • Increase renal excretion of sodium and water • Do not inhibit kinase II • Do not increase levels of bradykinin

15. Fig. 44–3. Elevation of glomerular filtration pressure by angiotensin II.

16. Angiotensin II Receptor Blockers • Therapeutic uses • Hypertension, heart failure, myocardial infarction • Diabetic nephropathy • If unable to tolerate ACE inhibitors: protection against MI, stroke, and death from cardiovascular (CV) causes in high-risk patients • Migraine headache • May prevent development of diabetic retinopathy • New data show that ACE inhibitors and angiotensin II receptor blockers (ARBs) are not effective for primary prevention of nephropathy in normotensive diabetic patients

17. Angiotensin II Receptor Blockers • Adverse effects • Angioedema • Fetal harm • Renal failure • Possibility of promoting cancer

18. Direct Renin Inhibitors • Aliskiren (Tekturna) • Binds tightly with renin and inhibits the cleavage of angiotensinogen to angiotensin I • Side effects • Angioedema, cough, GI effects, hyperkalemia, fetal injury, and death

19. Aldosterone Antagonists • Eplerenone (Inspra) • Mechanism of action • Selective blockade of aldosterone receptors • Therapeutic uses • Hypertension • Heart failure • Pharmacokinetics • Absorption is not affected by food • Adverse effects • Hyperkalemia

20. Aldosterone Antagonists • Eplerenone (Inspra) (cont’d) • Drug interactions • Inhibitors of CYP3A4 • Drugs that raise potassium levels • Use with caution when combined with lithium

21. Aldosterone Antagonists • Spironolactone (Aldactone) • Mechanism of action • Blocks aldosterone receptors • Binds with receptors for other steroid hormones • Therapeutic uses • Hypertension • Heart failure

22. Aldosterone Antagonists • Spironolactone (Aldactone) (cont’d) • Adverse effects • Hyperkalemia • Gynecomastia • Menstrual irregularities • Impotence • Hirsutism • Deepening of the voice