Cardiovascular Disease, Pharmaceutical Treatment

By the end of the twentieth century, deaths from heart disease topped the list of causes of death in the U.S. with a near seven-fold increase over the previous 100 years to 268 annually per 100,000 of total population. In 1900 only two effective drugs were available for heart disease. Digitalis (which slows the heart when abnormal rhythms are present) had been discovered by William Withering in 1775 when a lady suffering from dropsy was treated successfully by folk doctors with herb tea containing foxglove leaves. Nitrates (which dilate the coronary arteries) had been used for angina (cardiac pain) since 1879. Surprisingly, both these drugs remained in use at the end of the century.

By 1946 it had become apparent that hypertension, or high blood pressure, was the prime predisposing factor in the development of arteriosclerosis and therefore myocardial infarcts (heart attacks). Although a class of drugs called the prostaglandins had been introduced in 1930 for blood pressure control, they were largely ineffective. The ganglion blockers such as guanethidine caused intolerable side effects, and it was not until the 1960s that effective therapy that was well tolerated by patients became available.

Beta-adrenergic blockers. Developed in the 1960s by Sir James Black, the so- called beta blockers such as propanolol and atenolol have an inhibitory effect on adrenaline and so slow the heart and reduce both blood pressure and cardiac contractility.

These actions reduce myocardial oxygen requirements. They are an effective treatment for prevention of angina, hypertension, some disorders of cardiac rhythm, and heart disease secondary to an overactive thyroid. There is evidence of both primary and secondary prevention of cardiac infarcts (when a coronary artery is blocked off and a portion of heart muscle dies when deprived of oxygen.

Calcium channel blockers or antagonists. Introduced in 1968, these drugs induce relaxation of smooth muscles in blood vessels, including the coronary arteries which then dilate, by impeding the inward movement of calcium ions. By reducing vascular resistance, the blood pressure falls. They also have an effect on some abnormalities of cardiac rhythm. This class of drugs includes nifedipine, verapamil, and diltiazem.

Fibrinolytic drugs. The end-point of coronary artery thickening and blockage is a myocardial infarct. A series of controlled studies in the early 1980s (including the GISSI Trial of 1983 in Italy) showed the value of fibrinolytic therapy. These are drugs that break down the protein fibrin, which is the main constituent of blood clots. Streptokinase was the agent first introduced, and tissue Plasminogen Activator (tPA) is now the preferred agent as it is fibrin-specific.

If given intravenously as soon as possible after an acute myocardial infarction, mortality is significantly decreased and damage to the heart muscle minimized. The drug must be given quickly, hence the emphasis in emergency departments on ‘‘door-to-needle time.’’ Survival following an infarct is also improved by the use of the appropriate antiarrhythmic drugs early in treatment. Despite these therapeutic advances, inpatient mortality is between 10 and 20 percent.

Angiotensin-Converting Enzyme (ACE) Inhibitors. The first of these drugs was captopril, introduced in 1980 and soon followed by many others, all similar in action. They inhibit the action of the enzyme which converts angiotensin I to angiotensin II. This peptide is a potent vasoconstrictor and also stimulates the release of aldosterone and vasopressin, both of which increase the blood pressure. Initially, ACE inhibitors were introduced for the treatment of hypertension, but it soon became apparent that they were beneficial for patients in heart failure where the renin-angiotensin-aldosterone system has been activated.

ACE inhibitors are now a crucial component in the treatment of this condition. The effects are related not only to lowering the blood pressure but also to the peripheral vasodilation, which has an ‘‘offloading’’ effect in reducing the cardiac workload.

They also have an effect on remodeling the musculature of the left ventricle of the heart, which becomes thickened in hypertension and some cardiomyopathies (primary disorders of the cardiac muscle). In diabetics, even with normal blood pressure, these drugs exert a strongly renoprotective action which has been shown to delay the onset of kidney failure. Many physicians believe that the ACE inhibitors are among the most important therapeutic advances of the twentieth century.

Diuretics. The treatment of the accumulation of fluid in the legs, abdomen, and lungs is central to the treatment of the failing heart. There was no effective therapy until 1919 when a mercurial compound used intravenously for the treatment of syphilis was found to induce diuresis (excretion of large quantities of urine).

Mercurial diuretics remained the only therapeutic option until effective oral diuretics were developed from 1957 onward. The first of two main groups of drugs were the thiazides, which block the reabsorption of sodium and potassium in the renal tubules. The ‘‘loop’’ diuretics, such as frusemide, also inhibit reabsorption of salts, but they act in the loop of Henle in the kidney. All the diuretics can cause serious electrolyte imbalances and frequent monitoring of blood chemistry is mandatory.

Lipid-lowering agents. By 1980 the Kerala project in Finland had shown that intervention in a population with a high death rate from coronary artery disease associated with high cholesterol levels was very effective, and the Framingham study in Massachusetts had been delivering the same message (among many others) since 1945.

The ion-exchange resin cholestyramine worked, but patients found it difficult to take. More effective and far better tolerated were the statins (e.g., simvastatin). This class of drugs acts to inhibit an enzyme essential for the synthesis of cholesterol.

Antiplatelet drugs and anticoagulants. Aspirin can be described as an old drug reinvented because of the observations, 100 years after its introduction as an analgesic, that it interferes with the activation of platelets, which are essential to the blood clotting process. It reduces mortality if taken at the onset of an acute coronary event and reduces the risks of further infarction if taken long term. Newer antiplatelet drugs include ticlopidine.

Anticoagulants such as warfarin or heparin are more controversial and are not as widely used in the acute phase of myocardial infarction as they were in the 1950s and 1960s. Heparin, however, is of great importance in the crescendo angina syndrome and warfarin is used to prevent blood clots breaking off from the heart and moving around the circulation. This can occur in several circumstances when blood flow through the cardiac chambers is reduced.

By 2000, patients who had been spared the ravages of the tuberculosis and pneumonia that killed so many in 1900 had available a cocktail of drugs to control blood pressure, angina, cholesterol, heart failure, and hinder blood clotting. However, they were getting older, fatter, less active, and were often still smoking.