Study Notes on the Renin-Angiotensin-Aldosterone System

Chapter 47: Drugs Acting on the Renin-Angiotensin-Aldosterone System

Overview of the Renin-Angiotensin-Aldosterone System (RAAS)

• Physiology of the Renin-Angiotensin-Aldosterone System

  • Types of Angiotensin:

  • Angiotensin I: Inactive form, precursor for Angiotensin II.

  • Angiotensin II: Highly active form, exerting several physiological effects.

  • Angiotensin III: Lesser understood, has some actions similar to Angiotensin II.

  • Actions of Angiotensin II: Significantly influences cardiovascular system.

  • Vasoconstriction: Increases systemic vascular resistance.

  • Release of aldosterone: Promotes retention of sodium and water, increases blood volume.

  • Alteration of cardiac and vascular structure: Promotes remodeling, can lead to hypertrophy.

Actions of Aldosterone

• Functions:

  • Regulation of Blood Volume and Blood Pressure: Enhances sodium reabsorption in kidneys.

  • Pathologic Cardiovascular Effects: Excessive aldosterone can lead to hypertension and heart failure.

Formation and Regulation of Angiotensin II

• Renin: Enzyme released by kidneys.

  • Catalyzes the conversion of Angiotensinogen (produced by the liver) into Angiotensin I.

• Angiotensin-Converting Enzyme (ACE): Converts Angiotensin I to Angiotensin II.

  • Regulation of Renin Release is crucial for proper function of RAAS.

• Regulation of Blood Pressure:

  • The system helps to regulate blood pressure in conditions such as:

  • Hemorrhage

  • Dehydration

  • Sodium depletion.

  • Mechanisms:

  • Constricts renal blood vessels.

  • Promotes renal retention of sodium and water, and excretion of potassium.

  • Local production of angiotensin II in tissues adds to systemic effects.

Angiotensin-Converting Enzyme (ACE) Inhibitors

Mechanism of Action and Overview

• Effects:

  • Reduce levels of angiotensin II in the body.

  • Increase levels of bradykinin, a vasodilator.

Pharmacokinetics

• Overview of absorption and metabolism of ACE inhibitors, typically administered orally, with some exceptions.

Therapeutic Uses

• Clinical Applications for ACE Inhibitors:

  • Hypertension management.

  • Treatment of heart failure.

  • Post-myocardial infarction (MI).

  • Diabetic and nondiabetic nephropathy management.

  • Prevention of MI, stroke, and death in high cardiovascular risk patients.

Adverse Effects

• Common Side Effects:

  • First-dose hypotension: Sudden drop in blood pressure.

  • Cough: Due to increased bradykinin.

  • Fetal Injury: Contraindicated in pregnancy.

  • Angioedema: Swelling of deeper layers of the skin; potentially life-threatening.

  • If symptoms such as edema of the tongue, lips, or eyes occur, immediate emergency care is necessary.

  • Hyperkalemia: Elevated potassium levels in the blood.

  • Renal Failure: Impaired kidney function.

  • Neutropenia: Decrease in white blood cells.

Drug Interactions

• ACE inhibitors may interact with:

  • Diuretics

  • Other antihypertensive agents

  • Potassium-raising drugs

  • Lithium

  • Nonsteroidal anti-inflammatory drugs (NSAIDs)

Preparations, Dosage, and Administration

• Except for enalaprilat (which is administered intravenously), all ACE inhibitors are typically taken orally.

• Most are available in single-drug formulations with specific guidelines for administration regarding meals, except for captopril and moexipril.

Angiotensin II Receptor Blockers (ARBs)

Mechanism of Action and Overview

• Pharmacological Effects:

  • Block access of angiotensin II to its receptors, leading to:

  • Dilation of arterioles and veins.

  • Prevention of pathological cardiac changes induced by angiotensin II.

  • Decrease in aldosterone release.

  • Increased excretion of sodium and water.

  • Unlike ACE inhibitors, ARBs do not increase bradykinin levels, thus avoiding cough as a side effect.

Therapeutic Uses

• Clinical Applications for ARBs:

  • Hypertension treatment.

  • Heart failure management.

  • Post-myocardial infarction (MI).

  • Management of diabetic nephropathy.

  • Indicated for patients unable to tolerate ACE inhibitors.

  • Prevention of MI, stroke, and death due to cardiovascular causes in high-risk patients.

  • May prevent development of diabetic retinopathy.

  • Recent studies show ineffectiveness for primary prevention of nephropathy in normotensive diabetic patients.

Adverse Effects

• Common Side Effects:

  • Angioedema: Risk, similar to ACE inhibitors but generally less frequent.

  • Fetal Harm: Use in pregnancy is contraindicated.

  • Renal Failure: Potential risk including acute kidney injury.

  • Lower incidence of cough due to lack of bradykinin accumulation in the lungs compared to ACE inhibitors.

Direct Renin Inhibitors

• Aliskiren (Tekturna):

  • Mechanism: Binds tightly with renin and inhibits the cleavage of angiotensinogen to angiotensin I.

  • Side Effects:

  • Angioedema.

  • Cough.

  • Gastrointestinal effects.

  • Hyperkalemia.

  • Fetal injury and potentially fetal death.

Aldosterone Antagonists

Eplerenone (Inspra)

• Mechanism of Action:

  • Selective blockade of aldosterone receptors.

• Therapeutic Uses:

  • Management of hypertension.

  • Treatment of heart failure.

• Pharmacokinetics:

  • Absorption is not affected by food, allowing flexible dosing.

• Adverse Effects:

  • Hyperkalemia: Risk of elevated potassium levels.

Drug Interactions

• Caution required with:

  • Inhibitors of CYP3A4.

  • Drugs that raise potassium levels.

  • Lithium: Use with caution.

Spironolactone (Aldactone)

• Mechanism of Action:

  • Blocks aldosterone receptors and binds to receptors for other steroid hormones.

• Therapeutic Uses:

  • Used in the treatment of hypertension and heart failure.

• Adverse Effects:

  • Hyperkalemia: Increased risk of potassium accumulation.

  • Gynecomastia: Breast tissue development in men.

  • Menstrual Irregularities: Altered menstrual cycles.

  • Impotence: Sexual dysfunction.

  • Hirsutism: Increased hair growth in women.

  • Deepening of the Voice: Can occur due to hormonal changes.