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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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