Discovery and development of ACE inhibitors

Discovery and Development of ACE Inhibitors

The discovery and development of ACE inhibitors (Angiotensin-Converting Enzyme inhibitors) represent a significant advancement in the treatment of hypertension and heart failure. These medications work by inhibiting the enzyme responsible for the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, thereby lowering blood pressure and reducing strain on the heart.

Historical Background

The journey to the development of ACE inhibitors began with the study of the renin-angiotensin system (RAS), a hormone system that regulates blood pressure and fluid balance. In the 1950s, researchers identified angiotensin II as a key player in blood pressure regulation. The search for inhibitors of this system led to the discovery of ACE inhibitors.

Discovery of Captopril

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Structure of Captopril

Captopril was the first ACE inhibitor to be developed and approved for clinical use. Its discovery was inspired by the venom of the Brazilian pit viper, Bothrops jararaca, which was found to contain peptides that inhibited ACE. Researchers at Squibb (now part of Bristol-Myers Squibb) synthesized captopril in the late 1970s, and it was approved by the FDA in 1981. Captopril's development marked a breakthrough in cardiovascular medicine, providing a new mechanism to control hypertension.

Development of Enalapril

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Structure of Enalapril

Following the success of captopril, further research led to the development of enalapril, a prodrug that is converted to its active form, enalaprilat, in the body. Enalapril was developed by Merck & Co. and approved in 1985. It offered improved pharmacokinetic properties over captopril, such as a longer half-life, allowing for once-daily dosing.

Introduction of Lisinopril

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Structure of Lisinopril

Lisinopril, another ACE inhibitor, was developed by Merck & Co. and Zeneca (now part of AstraZeneca). It was approved in 1987 and is unique among ACE inhibitors because it is not a prodrug and is excreted unchanged by the kidneys. Lisinopril's long duration of action and favorable side effect profile have made it a widely used medication in the management of hypertension and heart failure.

Mechanism of Action

ACE inhibitors work by blocking the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, thereby reducing blood pressure. This action also decreases the secretion of aldosterone, leading to a reduction in sodium and water retention. The overall effect is a decrease in blood pressure and a reduction in the workload on the heart.

Clinical Applications

ACE inhibitors are primarily used in the treatment of hypertension and heart failure. They are also beneficial in patients with diabetic nephropathy and after myocardial infarction to improve survival. Their use is associated with a reduction in the progression of kidney disease in patients with diabetes.

Side Effects

Common side effects of ACE inhibitors include cough, hyperkalemia, and hypotension. Rarely, they can cause angioedema, a potentially life-threatening condition. Patients with renal artery stenosis or pregnancy should avoid ACE inhibitors due to the risk of adverse effects.

Also see

• Renin-angiotensin system
• Hypertension
• Heart failure
• Angiotensin II receptor blockers