Historically the treatment for what was called the "hard pulse disease" consisted in reducing the quantity of blood by bloodletting or the application of leeches.This was advocated by The Yellow Emperor of China, Cornelius Celsus, Galen, and Hippocrates. A major breakthrough was achieved with the discovery of the first well-tolerated orally available agents. The first was chlorothiazide, the first thiazide diuretic and developed from the antibiotic sulfanilamide, which became available in 1958. Subsequently beta blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers and renin inhibitors were developed as antihypertensive agents.