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 (this is responsible for much of the damage in CV disease) Angiotensin III Actions of angiotensin II Vasoconstriction Release of aldosterone Alteration of cardiac and vascular structure (“cardiac remodeling”) 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 (these end in -pril) Mechanism of action and overview of pharmacologic effects Reducing levels of angiotensin II Increasing levels of bradykinin 8

Angiotensin-Converting Enzyme Inhibitors Therapeutic uses Hypertension Heart failure Myocardial infarction (MI) Diabetic and nondiabetic nephropathy (slows progression of kidney disease) 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 (this can be significant, can cause syncope with standing) Fetal injury (all drugs the that inhibit the renin-angiotensin can cause fetal harm) Cough Angioedema Hyperkalemia Dysgeusia and rash Renal failure 11

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

Angiotensin II Receptor Blockers (end in –sartan) 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 (no cough as with ACE-inhibitors) 13

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 14

Angiotensin II Receptor Blockers Adverse effects Angioedema Fetal harm Renal failure Possibility of promoting cancer 15

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 16

Aldosterone Antagonists Eplerenone (Inspra) Mechanism of action Selective blockade of aldosterone receptors Therapeutic uses Hypertension Heart failure Adverse effects Hyperkalemia 17

Aldosterone Antagonists Eplerenone (Inspra) (cont’d) Drug interactions Inhibitors of CYP3A4 Drugs that raise potassium levels Use with caution when combined with lithium 18

Aldosterone Antagonists Spironolactone (Aldactone) Mechanism of action Blocks aldosterone receptors Binds with receptors for other steroid hormones (this results in some unusual adverse effects) Therapeutic uses Hypertension Heart failure 19

Aldosterone Antagonists Spironolactone (Aldactone) (cont’d) Adverse effects Hyperkalemia Gynecomastia Menstrual irregularities Impotence Hirsutism Deepening of the voice 20