Chapter 12: Drugs Used in Ischemic Heart Disease and Congestive Heart Failure

Ischemic heart disease is simply when the oxygen supply to the heart does not match the demand. Often this means that the coronary blood vessels have a reduced diameter limiting the blood flow to the heart.

To reduce myocardial oxygen demand, β-blockers (Chapters 10 and 11) can be used to decrease heart rate and contractility. Calcium channel blockers (Chapter 11) reduce systemic vascular resistance and decrease myocardial contractility. Nitrates (Chapter 11) will produce venous dilation, which will decrease preload and decrease oxygen demand by the heart. Finally, antiplatelet drugs (Chapter 14), such as aspirin, will prevent thrombus formation in the coronary arteries. Lipid-lowering drugs (Chapter 15) have been shown to reduce the risk of heart attacks in patients with coronary artery disease.

Unstable angina is treated with nitroglycerin, antiplatelet, and anticoagulant drugs. Finally, acute myocardial infarction is treated with thrombolytic agents (Chapter 14).

Heart failure occurs when the heart can no longer pump enough blood to meet the demands of the body. After removal or correction of the precipitating cause, further treatment of heart failure involves management of the symptoms. Standard treatment for hospitalized patients has been a loop diuretic (Chapter 11) with a vasodilator that is rapidly acting. Sometimes a drug that increases contractility is also added or used in place of the vasodilator.

Achieving a reduction in cardiac workload can be as simple as reducing physical activity or keeping heart rate low pharmacologically with a β-blocker or by inhibiting the cardiac pacemaker (ivabradine). Alternatively, vasodilator therapy can be used. ACE inhibitors (Chapter 11) are usually used in this instance. ACE inhibitors have been shown to improve symptoms, slow the progression of the heart failure, and prolong survival. The angiotensin II receptor antagonists are also used.

Other vasodilators can also be used to reduce the cardiac workload. Studies have shown that the combination of hydralazine and isosorbide dinitrate can produce improvement in patients with heart failure.

Nitroprusside is used in the treatment of acute heart failure because it reduces both preload and afterload without affecting contractility.

Nesiritide is a recombinant form of human B-type natriuretic peptide, a naturally occurring hormone produced by the ventricle. It produces natriuresis, diuresis, and vasodilation by increasing intracellular cyclic guanosine monophosphate (cGMP) levels. It is used for relief of the dyspnea in patients with heart failure. Neprilysin is an endopeptidase that degrades natriutetic peptide. Inhibition of neprilysin by sacubitril (actually by an active metabolite) increases levels of this peptide, decreasing vasoconstriction and sodium retention. Sacubitril can be used to lower blood pressure and can be used in combination with valsartan (ARB) for heart failure.

Heart failure is associated with retention of sodium and water. Control of the excessive fluid accumulation can relieve symptoms. The first line of attack is to lower dietary intake of sodium. Diuretics are also used to relieve symptoms, but they do not stop the progression of the disease. All classes of diuretics are used; the choice depends on the clinical situation.

CARDIAC GLYCOSIDES

The cardiac glycosides were originally isolated from the Digitalis purpurea plant; a fact that is reflected in their names—digitalis, digoxin, and digitoxin. The term digitalis is a general one that is usually used when referring to the drug digoxin.

These drugs inhibit sodium–potassium–ATPase and enhance release of intracellular calcium from the sarcoplasmic reticulum. This increase in intracellular calcium causes an increase in the force of contraction of the myocytes throughout the heart. In addition to their use in chronic heart failure, both digoxin and digitoxin will slow the ventricular rate in atrial flutter or fibrillation by increasing the sensitivity of the atrioventricular (AV) node to vagal stimulation. This makes them antiarrhythmic drugs as well (see Chapter 13).

As noted in Chapter 2, the therapeutic index is the LD₅₀ divided by the ED₅₀. A low therapeutic index means that the plasma concentration that causes serious toxicity (that is, may be fatal) is only slightly higher than the therapeutic dose. The therapeutic index is between 1.6 and 2.5 for the cardiac glycosides. Toxicity of the cardiac glycosides is more common in patients with low serum potassium levels. This is quite important, because many patients with heart failure are taking “dig. and diuretics” (shorthand for digoxin and a diuretic).

Among these toxic effects, it is the arrhythmias that can be life threatening.

SYMPATHOMIMETICS

These drugs were covered earlier in the autonomic nervous system section (see Chapter 9). Here is a quick review.

Dobutamine is used to increase cardiac output in heart failure and can be used in the treatment of shock. Dobutamine has some α₁ and β₂ agonist effects that play a role in maintaining peripheral vascular resistance. It is only given intravenously, so its use is limited.

DOPAMINE has dopamine receptor agonist activity and, like dobutamine, is used in the treatment of acute heart failure.

In patients with impaired renal function, the use of dopamine (instead of dobutamine) may preserve renal blood flow and, as a result, renal function. Administration of dopamine is also limited to the IV route.

PHOSPHODIESTERASE INHIBITORS

Inamrinone (formerly amrinone) and milrinone inhibit the cyclic adenosine monophosphate (cAMP) phosphodiesterase in cardiac and vascular muscle. This results in a positive inotropic action as well as a vasodilatory effect. There is little increase in heart rate.

Ranolazine is a relatively new drug (approved in 2006) for the treatment of chronic angina. Evidence suggests that ranolazine reduces calcium overload in the ischemic heart muscle cell through inhibition of the late sodium current (I_Na). Myocardial ischemia produces a cascade of complex ionic exchanges that can result in intracellular acidosis, excess cytosolic Ca²⁺, myocardial cellular dysfunction, and, if sustained, cell injury and death. By inhibiting the excess calcium in the cells, cellular function would be maintained. This drug may not belong in this group of drugs that enhance contractility, but it’s a good enough place for now.