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

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 2

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 3

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

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

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) 6

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 7

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

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. 9

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

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

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

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 13

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 14

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

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 16

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

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 18

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 19

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

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

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