Category:Antihypertensives: Difference between revisions

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The transformative class of the antihypertensive era was the angiotensin-converting enzyme inhibitor. In 1965 the Brazilian physiologist [[wikipedia:Sérgio Henrique Ferreira|Sérgio Ferreira]], working in [[wikipedia:John Vane|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.<ref name="ferreira1965">Ferreira SH. A bradykinin-potentiating factor (BPF) present in the venom of ''Bothrops jararaca''. ''British Journal of Pharmacology and Chemotherapy''. 1965 Feb;24:163-169. PMID 14302350.</ref> A decade later [[wikipedia:Miguel Ondetti|Miguel Ondetti]] and [[wikipedia:David Cushman (scientist)|David Cushman]] at the [[wikipedia:Squibb|Squibb Institute for Medical Research]], working from a model of the active site informed by what was then known of carboxypeptidase A, designed [[Captopril|captopril]], a small orally bioavailable inhibitor of the converting enzyme.<ref name="ondetti1977">Ondetti MA, Rubin B, Cushman DW. Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. ''Science''. 1977 Apr 22;196(4288):441-444. PMID 191908.</ref> Captopril was approved by the U.S. Food and Drug Administration in 1981 and the class expanded quickly: [[Enalapril|enalapril]], [[Lisinopril|lisinopril]], [[Ramipril|ramipril]], [[Benazepril|benazepril]]. The [[:Category:Angiotensin_receptor_blockers|angiotensin receptor blockers]] followed, beginning with [[Losartan|losartan]] in 1995, developed at the DuPont Merck laboratories from a series of imidazole leads first reported by Takeda chemistry.<ref name="carini1991">Carini DJ, Duncia JV, Aldrich PE, Chiu AT, Johnson AL, Pierce ME, Price WA, Santella JB 3rd, Wells GJ, Wexler RR, et al. Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives. ''Journal of Medicinal Chemistry''. 1991 Aug;34(8):2525-2547. PMID 1875347.</ref>

The [[:Category:Calcium_channel_blockers|calcium channel blockers]] entered cardiovascular medicine through a separate door. [[Verapamil|Verapamil]], synthesized in Germany in 1962, was the first agent shown by [[wikipedia:Albrecht Fleckenstein|Albrecht Fleckenstein]] to block the slow inward calcium current of cardiac and vascular smooth muscle.<ref name="fleckenstein1983">Fleckenstein A. History of calcium antagonists. ''Circulation Research''. 1983 Feb;52(2 Pt 2):I3-16. PMID 6297830.</ref> [[Nifedipine|Nifedipine]] and the rest of the dihydropyridine family followed; [[Amlodipine|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 [[:Category:Calcium_channel_blockers|calcium channel blockers]] entered cardiovascular medicine through a separate door. [[Verapamil|Verapamil]], synthesized in Germany in 1962, was the first agent shown by [[wikipedia:Albrecht Fleckenstein|Albrecht Fleckenstein]] to block the slow inward calcium current of cardiac and vascular smooth muscle.<ref name="fleckenstein1983">Fleckenstein A. History of calcium antagonists. ''Circulation Research''. 1983 Feb;52(2 Pt 2):I3-16. PMID 6297830.</ref> [[Nifedipine|Nifedipine]] and the rest of the dihydropyridine family followed; [[Amlodipine|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 medicine 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.<ref name="hot1998">Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, Ménard J, Rahn KH, Wedel H, Westerling S, for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients at high risk of cardiovascular disease: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. ''Lancet''. 1998 Jun 13;351(9118):1755-1762. PMID 9635947.</ref> 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.<ref name="sprint2015">SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, et al. A randomized trial of intensive versus standard blood-pressure control. ''New England Journal of Medicine''. 2015 Nov 26;373(22):2103-2116. PMID 26551272.</ref> 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.<ref name="whelton2018">Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. ''Hypertension''. 2018 Jun;71(6):e13-e115. PMID 29133356.</ref>

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== Classes indexed ==

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

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

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