12.03.4 ACE Inhibitors, AT1-Receptor Antagonists, and Aldosterone Receptor Antagonists

The second group of drugs commonly in heart failure are the inhibitors of the renin-angiotensin-aldosterone system, the angiotensin converting enzyme (ACE) inhibitors, AT₁-receptor antagonists, and aldosterone receptor antagonists. Enalapril is an ACE inhibitor, and losartan is an AT-1 receptor antagonist used in heart failure. These drugs have benefits due to venodilation and arteriolar dilation.

In heart failure, drugs that cause venodilation, such as enalapril and losartan, lead to a pooling to the blood in veins. With pooling of blood in the veins, less fluid needs to be dumped in the lungs, and the decreased fluid in the lungs makes breathing easier. Also, decreasing the accumulation of fluid in the lung (caused by the compensatory changes in heart failure), leads to reduced pulmonary resistance making it easier for the heart to pump, and an improved myocardial performance is observed.

Arteriolar dilation with enalapril and losartan also has beneficial effects in heart failure, and these effects are not observed in the normal heart. In the normal heart, cardiac output is independent of peripheral arteriolar resistance. Thus, graphically plotting cardiac output against arterial resistance in the normal heart there is no connection. Regardless of arteriolar resistance, cardiac output is constant (Figure 12.3.3). This is because, in the normal heart, as resistance is increased, so is heart rate, and cardiac output remains unchanged.

Figure 12.3.3 Arteriolar resistance and cardiac out (Copyright QUT, Sheila Doggrell)

However, the situation is very different in the failing heart, as the mechanisms to maintain cardiac output are already turned on, and in the failing heart, heart rate is at a maximum and cannot be increased. Thus, as resistance is increased cardiac output is decreased (Figure 12.3.3). When arteriolar dilators, such as enalapril and losartan are used in heart failure, there is a decrease in arteriolar resistance, and an increase in cardiac output (Figure 12.3.3), but this only applies in the failing heart not the normal heart.

The heart failure, there is excessive accumulation of sodium and water. Aldosterone is the salt and water retention hormone. The levels of aldosterone are elevated in subjects with heart failure. Consequently, antagonists of aldosterone receptors are used in the treatment of heart failure. Spironolactone is an antagonist at aldosterone receptors. In the presence of aldosterone, spironolactone promotes the loss of sodium and water. In a large clinical trial, spironolactone has been shown to decrease the mortality (deaths) and hospitalization of people with heart failure. In the low doses used in the treatment of heart failure, the most common adverse effects of spironolactone are extensions of its beneficial effects. Thus, spironolactone can cause hyperkalemia (retention of too much potassium leading to high potassium levels), and hyponatremia (loss of too much sodium leading to low levels of sodium in the body).