1. Introduction

The history of hypertensive therapy with drugs goes back to around 1900 or even earlier, when physicians began to prescribe a variety of medicines such as sodium thiocyanate, nitrites, alkaloids of ergot, pyrogens, rauwolfia, veratrum virile, barbiturates, bismuth, bromides, hexamethonium, or tetramethylammonium chloride. Most of these agents were ineffective and many were poorly tolerated. The tragic death of President Franklin Roosevelt with a diastolic blood pressure of 180 mm Hg in 1945 underscored the urgency of finding better treatments for hypertension.

After World War II, reserpine and hydralazine became widely used for moderately severe hypertension, often in combination with the newly developed oral diuretics chlorothiazide and hydrochlorothiazide. For malignant hypertension, there was no lifesaving treatment. As a medical student, I watched with awe my senior resident draw up the recommended dose of pentolinium in his syringe and lower the foot of the bed to help reduce the blood pressure. Pentolinium was followed by mecamylamine, then guanethidine and methyldopa, and eventually, in the 1960s, the miracle drug minoxidil that indeed saved many lives. Some doctors were by then also treating even less severe hypertension, but distinguished cardiologists still expressed doubts, and some felt that mild to moderate hypertension should not be treated. It was a time when some family doctors would not tell their patients what their blood pressure was because they did not want to upset them.

After 1948 several trials were initiated, linking hypertension to cardiovascular disease and indicating that even slight elevations of blood pressure were harmful. Hypertension began to be treated more aggressively, with triple therapy (hydrochlorothiazide-reserpine-hydralazine), methyldopa, or prazosin. As the century progressed, antihypertensive treatment was revolutionized by the introduction of more effective and better tolerated drugs.

2. Beta-blockers

The process of discovering beta blockers began in 1948 when Raymond P. Ahlquist published a groundbreaking paper identifying two distinct types of adrenergic receptors: alpha and beta. His work suggested that blocking beta receptors could mitigate the effects of adrenaline on the heart, thus reducing heart rate and blood pressure. The first beta-blocker, dichloro-isoproterenol (DCI), was synthesized in the 1950s but was not clinically useful.

The breakthrough came in the early 1960s, when the British pharmacologist Sir James Black, working at the Imperial Chemical Industries (ICI), discovered propranolol. Introduced in 1964, it revolutionized the treatment of angina and hypertension by effectively reducing heart rate and myocardial oxygen demand. For his contributions, James Black was awarded the Nobel Prize in Physiology or Medicine in 1988.

Beta-blockers work by blocking the effects of adrenaline (epinephrine) on the beta receptors found in the heart and blood vessels. They reduce the heart rate, decrease the force of heart contractions, and lower blood pressure, making them highly effective in treating hypertension, angina, and certain types of arrhythmias. Propranolol was followed by atenolol, metoprolol, and several others, used for hypertension but also for heart failure, post-myocardial infarction management, and migraine prophylaxis. More recent studies however, suggest that while beta blockers effectively lower blood pressure, they may not work as well as other antihypertensives, particularly in reducing stroke risk, so that calcium channel blockers and ACE inhibitors may now be preferred.

3. ACE inhibitors

The angiotensin-converting enzyme (ACE) inhibitors work by blocking the action of angiotensin-converting enzyme, a key component of the renin-angiotensin-aldosterone system (RAAS). This system is responsible for regulating blood pressure and fluid balance in the body. By inhibiting ACE, these drugs prevent the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This leads to vasodilation, reduced blood pressure, and decreased workload on the heart.

These agents were developed when Drs. David Cushman and Miguel Ondetti discovered that peptides in the venom of the Brazilian pit viper, Bothrops jararaca, inhibited ACE and lowered blood pressure. Building on this knowledge, they synthesized in the 1970s the first ACE inhibitor, captopril, designed to closely mimic the structure of the snake venom peptides.

The development of captopril marked a milestone in cardiovascular medicine. It provided a new approach to treating hypertension and heart failure, offering an alternative to the treatments available at the time. Captopril was approved for clinical use in 1981, paving the way for the development of several other ACE inhibitors, such as enalapril, lisinopril, and ramipril.

These drugs are also used for heart failure, post-myocardial infarction management, and preventing the progression of chronic kidney disease. They have spurred further research into the renin-angiotensin-aldosterone system, leading to the development of other classes of drugs, such as angiotensin receptor blockers (ARBs) and direct renin inhibitors.

4. Calcium blockers

Calcium channel blockers (CCBs) inhibit the influx of calcium ions into the smooth muscle cells of the heart and blood vessels. These channels regulate the flow of calcium ions into cells, which results in muscle contraction. By inhibiting these channels, CCBs cause the smooth muscles in the blood vessels to relax (vasodilation), reducing peripheral resistance and thus lowering the blood pressure.

There are two main types of CCBs: dihydropyridines (such as amlodipine and nifedipine) and non-dihydropyridines (such as verapamil and diltiazem). Both types reduce blood pressure but have different effects on the heart and are used in different clinical situations. Dihydropyridines primarily affect the peripheral vasculature and are more effective in reducing systemic blood pressure. Non-dihydropyridines have a more pronounced effect on reducing heart rate and on myocardial contractility, and are often used to manage angina, atrial fibrillation and supraventricular tachycardias.

5. Conclusion

The effective use of antihypertensive drugs has revolutionized medicine and extended people’s lifespans. Oral diuretics and the traditional antihypertensive agents represent the first step in this great journey of discovery, followed by the three classes of drugs discussed here. To have witnessed these seismic advances has been a great privilege, and there is every reason to believe that further progress will result in the total and permanent defeat of this ancient foe of humanity.