19.2 Drugs Affecting the Renin-Angiotensin-Aldosterone System

The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and fluid balance under normal conditions. In heart failure, though, the RAAS becomes overactivated, which drives vasoconstriction and fluid retention that make the failing heart work even harder.

Three drug classes target different steps in this cascade: ACE inhibitors, ARBs, and aldosterone antagonists. All three improve symptoms, reduce hospitalizations, and increase survival in heart failure patients.

Renin-Angiotensin-Aldosterone System (RAAS) Drugs in Heart Failure Treatment

Renin-angiotensin-aldosterone system in heart failure

When cardiac output drops in heart failure, the kidneys interpret this as low blood flow and ramp up renin secretion. That kicks off a cascade: renin converts angiotensinogen into angiotensin I, which ACE then converts into angiotensin II, a potent vasoconstrictor. Angiotensin II also triggers the adrenal glands to release aldosterone, which tells the kidneys to hold onto sodium and water.

In the short term, this raises blood pressure and maintains perfusion. But in heart failure, the system stays chronically activated, creating a vicious cycle:

• Sustained vasoconstriction increases afterload on an already struggling heart
• Sodium and water retention increases blood volume and preload, worsening congestion
• Over time, angiotensin II and aldosterone promote ventricular remodeling, where the heart muscle thickens and stiffens, further reducing function
• Patients experience progressive symptoms: worsening dyspnea, peripheral edema, and fatigue

Blood Pressure Regulation and Fluid Homeostasis

Understanding the normal RAAS pathway helps you see exactly where each drug class intervenes. Here's the cascade step by step:

1. The juxtaglomerular apparatus in the kidneys detects decreased renal perfusion pressure or decreased sodium delivery to the distal tubule
2. The kidneys release renin into the bloodstream
3. Renin cleaves angiotensinogen (produced by the liver) into angiotensin I
4. Angiotensin-converting enzyme (ACE), found primarily in the lungs, converts angiotensin I into angiotensin II
5. Angiotensin II causes vasoconstriction and stimulates aldosterone release from the adrenal cortex
6. Aldosterone acts on the distal tubules and collecting ducts to promote sodium and water reabsorption

A negative feedback loop normally keeps this in check: once blood pressure and volume are restored, renin secretion decreases. In heart failure, the persistent low cardiac output overrides this feedback, keeping the system locked in an "on" state.

ACE inhibitors and ARBs for heart failure

ACE Inhibitors (captopril, enalapril, lisinopril) block ACE, preventing the conversion of angiotensin I to angiotensin II. With less angiotensin II circulating, you get vasodilation, reduced aldosterone secretion, and decreased fluid retention.

• Proven to improve symptoms, reduce hospitalization rates, and prolong survival in heart failure
• ACE also breaks down bradykinin, so blocking ACE causes bradykinin to accumulate. This is why a dry, persistent cough develops in up to 10-15% of patients. It's the most common reason patients switch to an ARB.
• Other side effects: hypotension, hyperkalemia, renal dysfunction, and angioedema (rare but potentially life-threatening)
• Key drug interactions: potassium supplements, potassium-sparing diuretics (risk of hyperkalemia), and NSAIDs (can blunt the antihypertensive effect and worsen renal function)

ARBs (losartan, valsartan, candesartan) work one step downstream. Instead of blocking angiotensin II production, they block its action at AT1 receptors. The clinical benefits are similar to ACE inhibitors.

• Used primarily as an alternative when patients can't tolerate ACE inhibitor-induced cough, since ARBs don't affect bradykinin metabolism
• Side effects and drug interactions are largely the same as ACE inhibitors, though cough and angioedema are significantly less common

Aldosterone Antagonists (spironolactone, eplerenone) block aldosterone at mineralocorticoid receptors in the kidneys, reducing sodium and water reabsorption.

• Added to ACE inhibitors or ARBs in patients with moderate-to-severe heart failure (NYHA Class III-IV) to improve symptoms and survival
• Hyperkalemia is the most significant risk, especially when combined with ACE inhibitors or ARBs. Potassium levels and renal function require close, ongoing monitoring.
• Spironolactone can cause gynecomastia and breast tenderness due to its antiandrogenic effects. Eplerenone is more selective for the mineralocorticoid receptor and has a lower incidence of these hormonal side effects.

Nursing considerations for RAAS medications

• Baseline and ongoing assessment: Check blood pressure, heart rate, serum creatinine, eGFR, and serum potassium before starting therapy and at regular intervals throughout treatment
• Potassium monitoring is critical. All three drug classes can raise potassium levels. The risk compounds with combination therapy. Watch for signs of hyperkalemia: muscle weakness, paresthesias, and cardiac rhythm changes.
• First-dose hypotension: Patients starting ACE inhibitors or ARBs, especially those who are volume-depleted or on diuretics, may experience a significant drop in blood pressure with the first dose. Consider holding or reducing the diuretic dose beforehand, and monitor closely after the initial dose.
• Hold and notify the prescriber if systolic blood pressure falls below the facility-specific threshold (commonly $<$ 90 mmHg) or if potassium rises above 5.0 mEq/L
• Advise patients to avoid potassium supplements and potassium-containing salt substitutes unless specifically prescribed
• Educate patients to report swelling of the face, lips, tongue, or throat immediately, as angioedema can progress to airway obstruction and requires emergency intervention
• Reinforce the importance of not stopping these medications abruptly, as they provide long-term survival benefits even when patients feel well
• Collaborate with the healthcare team to titrate doses based on blood pressure response, symptom improvement, and lab values. The goal is to reach evidence-based target doses when tolerated.

Patient education for RAAS-targeting drugs

1. Explain that these medications reduce strain on the heart and slow disease progression. Patients should understand they're taking them for long-term benefit, not just symptom relief.
2. Stress the importance of taking medications exactly as prescribed and not stopping without talking to their provider, even if they feel fine.
3. Teach home blood pressure and heart rate monitoring. Have patients keep a log and bring it to follow-up appointments.
4. Advise rising slowly from sitting or lying positions to minimize orthostatic hypotension and fall risk.
5. Instruct patients to report a persistent dry cough (common with ACE inhibitors), any facial or throat swelling, dizziness, or difficulty breathing right away.
6. Remind patients to avoid over-the-counter NSAIDs (ibuprofen, naproxen) without provider approval, since these can reduce the effectiveness of RAAS drugs and harm kidney function.
7. Emphasize regular follow-up appointments and lab work. Potassium and kidney function need to be checked periodically, and patients should understand why these labs matter.
8. Encourage a heart-healthy lifestyle: sodium intake $<$ 2 g/day, regular physical activity as tolerated, stress management, and smoking cessation.