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Chapter 44

Drugs Acting on the Renin-Angiotensin-Aldosterone System

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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

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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

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Physiology of the Renin-Angiotensin-Aldosterone System

Actions of aldosterone Regulation of blood volume and blood pressure Pathologic cardiovascular effects

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

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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)

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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

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Angiotensin-Converting Enzyme Inhibitors

Mechanism of action and overview of pharmacologic effects Reducing levels of angiotensin II Increasing levels of bradykinin

Pharmacokinetics

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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.

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

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Angiotensin-Converting Enzyme Inhibitors

Adverse effects First-dose hypotension Fetal injury Cough Angioedema Hyperkalemia Dysgeusia and rash Renal failure Neutropenia

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Angiotensin-Converting Enzyme Inhibitors

Drug interactions Diuretics Antihypertensive agents Drugs that raise potassium levels Lithium Nonsteroidal anti-inflammatory drugs

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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

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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

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

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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

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Angiotensin II Receptor Blockers Adverse effects

Angioedema Fetal harm Renal failure Possibility of promoting cancer

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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

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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

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Aldosterone Antagonists Eplerenone (Inspra) (cont’d)

Drug interactions• Inhibitors of CYP3A4• Drugs that raise potassium levels• Use with caution when combined with lithium

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Aldosterone Antagonists Spironolactone (Aldactone)

Mechanism of action• Blocks aldosterone receptors• Binds with receptors for other steroid hormones

Therapeutic uses• Hypertension• Heart failure

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Aldosterone Antagonists Spironolactone (Aldactone) (cont’d)

Adverse effects• Hyperkalemia• Gynecomastia• Menstrual irregularities• Impotence• Hirsutism• Deepening of the voice