Category:Antihypertensives

An antihypertensive is a medicine that lowers the arterial blood pressure. The category, as a category of useful medicines, did not exist until the middle of the twentieth century, for the simple reason that high blood pressure was not, until then, understood to be a treatable disease. In 1931 the British physician John Hay set down the prevailing view in two sentences that became infamous: "There is some truth in the saying that the greatest danger to a man with a high blood pressure lies in its discovery, because then some fool is certain to try and reduce it."^[1] The reasoning behind the view was not unreasonable on its face: the elevated pressure was thought to be a compensatory response to a narrowed and hardened circulation, and the fear was that lowering it would reduce perfusion of the brain, the heart, and the kidneys to dangerous levels.

The view was dramatized publicly by the death of President Franklin D. Roosevelt on the afternoon of 12 April 1945, of a massive cerebral hemorrhage at the age of sixty-three. His personal physician Howard Bruenn later published the clinical record: pressures in the months before death of 240/130 millimetres of mercury, treated, in the absence of any effective option, with phenobarbital, digitalis, and bed rest, and rising to 300/190 at the time of the fatal stroke.^[2] The case has been reviewed many times in the decades since, both as a clinical history and as an argument that the medical profession had been wrong.

The argument was settled, formally, by Edward Freis and the Veterans Administration Cooperative Study Group on Antihypertensive Agents, working at the Washington VA Hospital. Their first trial, published in 1967, randomized 143 men with diastolic pressures between 115 and 129 millimetres of mercury to either a combination of hydrochlorothiazide, reserpine, and hydralazine, or to placebo; the placebo arm accumulated strokes, heart failure, and aortic dissections at such a rate that the trial was stopped early and the protocol unblinded.^[3] A second VA Cooperative trial, in milder hypertension, confirmed the benefit in 1970.^[4] Observational data accumulating in parallel from the Framingham Heart Study showed that the relationship between blood pressure and cardiovascular events was continuous and monotonic, with no apparent threshold of harm.^[5] The 1931 doctrine was abandoned and clinical attention shifted to which medicines to use, and at what blood-pressure target.

Several medicines were already in hand by 1967. The thiazide diuretics had been introduced in 1957 with chlorothiazide, developed at the Sharp and Dohme research laboratories by Karl Beyer's group from an effort to improve on the existing carbonic anhydrase inhibitors; the new compound preferentially blocked sodium and chloride reabsorption in the distal tubule of the nephron and lowered the blood pressure as efficiently as it cleared the edema of heart failure.^[6] Hydrochlorothiazide, a closer derivative, followed two years later and became the standard of the class. The direct vasodilators had been developed earlier: hydralazine at Ciba in 1949 as an offshoot of antimalarial chemistry, minoxidil at Upjohn in the 1960s. The centrally acting sympatholytic methyldopa was introduced by Merck in 1960. The beta-adrenergic blockers, beginning with propranolol synthesized by James Black at Imperial Chemical Industries in 1964, lowered blood pressure as a side benefit of their antianginal effect, and were quickly recognized as antihypertensive in their own right.^[7]

The transformative class of the antihypertensive era was the angiotensin-converting enzyme inhibitor. In 1965 the Brazilian physiologist Sérgio Ferreira, working in John Vane's laboratory in London, had isolated from the venom of the Brazilian pit viper Bothrops jararaca a series of small peptides that potentiated the action of bradykinin and inhibited the enzyme that converts angiotensin I to angiotensin II; the profound hypotension of a jararaca envenomation is in part the work of these peptides.^[8] A decade later Miguel Ondetti and David Cushman at the Squibb Institute for Medical Research, working from a model of the active site informed by what was then known of carboxypeptidase A, designed captopril, a small orally bioavailable inhibitor of the converting enzyme.^[9] Captopril was approved by the U.S. Food and Drug Administration in 1981 and the class expanded quickly: enalapril, lisinopril, ramipril, benazepril. The angiotensin receptor blockers followed, beginning with losartan in 1995, developed at the DuPont Merck laboratories from a series of imidazole leads first reported by Takeda chemistry.^[10]

The calcium channel blockers entered cardiovascular medicine through a separate door. Verapamil, synthesized in Germany in 1962, was the first agent shown by Albrecht Fleckenstein to block the slow inward calcium current of cardiac and vascular smooth muscle.^[11] Nifedipine and the rest of the dihydropyridine family followed; amlodipine, with its long plasma half-life and gradual onset, provided in 1992 the once-daily dosing and freedom from reflex tachycardia that the immediate-release dihydropyridines had lacked. By the end of the twentieth century five medication classes, the diuretics, the ACE inhibitors, the angiotensin receptor blockers, the calcium channel blockers, and the beta-blockers, were established as the building blocks of essential-hypertension therapy.

The remaining clinical question, and it remains alive, is the treatment target. The early VA trials set a working aim of "below 140/90" by convention. The Hypertension Optimal Treatment trial in 1998 examined diastolic targets between 80 and 90 millimetres of mercury and could not show clear benefit of the lower one.^[12] The Systolic Blood Pressure Intervention Trial in 2015, by contrast, randomized patients at high cardiovascular risk to a systolic target of 120 versus 140 and was stopped early for benefit in the intensive arm, at the cost of a higher rate of hypotension, syncope, and acute kidney injury.^[13] Current American guidelines have settled, for most adults, on a treatment goal of less than 130/80 millimetres of mercury, while acknowledging that the evidence base for any single threshold remains contested and that the absolute benefit of treatment scales with the patient's baseline cardiovascular risk rather than with the blood pressure alone.^[14]

The principal medication classes by which the arterial blood pressure is lowered in modern practice:

• Angiotensin-converting enzyme (ACE) inhibitors: benazepril, enalapril, lisinopril, ramipril
• Angiotensin receptor blockers (ARBs): irbesartan, losartan, olmesartan, telmisartan, valsartan
• Calcium channel blockers (dihydropyridine and non-dihydropyridine): amlodipine, diltiazem, nifedipine, verapamil
• Thiazide diuretics and thiazide-like diuretics: hydrochlorothiazide, chlorthalidone
• Alpha-1 adrenergic blockers (where also used in prostatic hyperplasia): doxazosin, terazosin
• Direct arteriolar vasodilators: hydralazine

Closely related classes whose principal indication is not hypertension but which lower blood pressure as part of their action are collected separately: the beta-adrenergic blockers, the aldosterone antagonists, the loop diuretics when used in resistant hypertension or hypertension complicated by heart failure, and the centrally-acting sympatholytic agents (methyldopa, clonidine, reserpine), the last three of which are now of largely historical interest.

The boundary of this category is "medicine whose principal or clinically important antihypertensive effect contributes to its place in prescribing." A medicine is listed here when blood-pressure lowering is one of its established indications, regardless of how it lowers the pressure. Some medicines listed here are also listed elsewhere because their principal indication is a different cardiovascular problem: the calcium channel blockers are antianginal as well as antihypertensive, the beta-blockers are antianginal and antiarrhythmic, the alpha-1 blockers are also used in benign prostatic hyperplasia. The multi-membership convention of this wiki permits a medicine to sit in every category that describes it. Hypertensive crises, managed with intravenous medicines in the acute setting (sodium nitroprusside, intravenous nicardipine, labetalol, esmolol, clevidipine), are within scope when those medicines have a dedicated page.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.