ACE Inhibitors - What are ACE Inhibitors?

ACE inhibitors or angiotensin-converting enzyme inhibitors, are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure though they are also sometimes used in patients with cardiac failure, renal disease or systemic sclerosis.

The first step in the development of (ACE) inhibitors was the discovery of angiotensin converting enzyme (ACE) in plasma by Leonard T. Skeggs and his colleagues in 1956. Brazilian scientist Sergio Ferreira reported in 1965 of a 'bradykinin potentiating factor (BPFs) present in the venom of bothrops jararaca, a South American pit viper. Dr SH Ferreira then proceeded to John Vanes laboratory as a Post-Doc with his already isolated BPFs. The conversion of the inactive angiotensin I to the potent angiotensin II was thought to take place in the plasma. However, in 1967, Kevin K. F. Ng and John R. Vane showed that the plasma (ACE) was too slow to account for the conversion of angiotensin I to angiotensin II ''in vivo''. Subsequent investigation showed that rapid conversion occurs during its passage through the pulmonary circulation.

Bradykinin is rapidly inactivated in the circulating blood and it disappears completely in a single passage through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation due to its conversion to angiotensin II. Furthermore, angiotensin II passes through the lungs without any loss. The inactivation of bradykinin and the conversion of angiotensin I to angiotensin II in the lungs was thought to be caused by the same enzyme. In 1970, Ng and Vane using bradykinin potentiating factor (BPF) provided by Sérgio Henrique Ferreira showed that the conversion of angiotensin I to angiotensin II was inhibited during its passage through the pulmonary circulation.

Bradykinin potentiating factor (BPF) is derived from the venom of the pit viper (''Bothrops jararaca''). It is a family of peptides and its potentiating action is linked to inhibition of bradykinin by ACE. Molecular analysis of BPF yielded a nonapeptide BPF teprotide (SQ 20,881) which showed the greatest (ACE) inhibition potency and hypotensive effect ''in vivo''. Teprotide had limited clinical value, due to its peptide nature and lack of activity when given orally. In the early 1970s, knowledge of the structure-activity relationship required for inhibition of ACE was growing. David Cushman, Miguel Ondetti and colleagues used peptide analogues to study the structure of ACE, using carboxypeptidase A as a model. Their discoveries led to the development of captopril, the first orally-active ACE inhibitor in 1975.

Captopril was approved by the United States Food and Drug Administration in 1981. The first non-sulfhydryl-containing (ACE) inhibitor enalapril was marketed two years later. Since then, at least twelve other ACE inhibitors have been marketed.

In 1991, Japanese scientists created the first ever milk-based ACE inhibitor in the form of a fermented milk drink, using specific cultures to liberate the IPP from the dairy protein. Interestingly, Val-Pro-Pro is also liberated in this process—another milk tripeptide with a very similar chemical structure to IPP. Together, these peptides are now often referred to as lactotripeptides. Shortly after this, in 1996, the first human study confirmed the blood pressure lowering effect of IPP in fermented milk. Although twice the amount of VPP is needed to achieve the same ACE inhibiting activity as the originally discovered IPP, it is assumed that VPP also adds to the total blood pressure lowering effect.

ACE inhibitors can be divided into three groups based on their molecular structure:

Sulfhydryl-containing agents

  • Captopril (trade name Capoten), the first ACE inhibitor
  • Zofenopril

Dicarboxylate-containing agents

This is the largest group, including:

  • Enalapril (Vasotec/Renitec)
  • Ramipril (Altace/Tritace/Ramace/Ramiwin)
  • Quinapril (Accupril)
  • Perindopril (Coversyl/Aceon)
  • Lisinopril (Lisodur/Lopril/Novatec/Prinivil/Zestril)
  • Benazepril (Lotensin)

Phosphonate-containing agents

  • Fosinopril (Monopril) is the only member of this group

Naturally occurring

  • Casokinins and lactokinins are breakdown products of casein and whey that occur naturally after ingestion of milk products, especially cultured milk. Their role in blood pressure control is uncertain.
  • The Lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic ''Lactobacillus helveticus'' or derived from casein have been shown to have ACE-inhibiting and antihypertensive functions.
ACE inhibitors dosages for hypertension
Note: bid = 2 times a day, tid = 3 times a day, d = daily
Drug dosages from Drug Lookup, Epocrates Online.
Name Equivalent daily dose   Start Usual Maximum
Benazepril 10 mg   10 mg 20–40 mg 80 mg
Captopril 50 mg (25 mg bid)   12.5–25 mg bid-tid 25–50 mg bid-tid 450 mg/d
Enalapril 5 mg   5 mg 10–40 mg 40 mg
Fosinopril 10 mg   10 mg 20–40 mg 80 mg
Lisinopril 10 mg   10 mg 10–40 mg 80 mg
Moexipril 7.5 mg   7.5 mg 7.5–30 mg 30 mg
Perindopril 4 mg   4 mg 4–8 mg 16 mg
Quinapril 10 mg   10 mg 20–80 mg 80 mg
Ramipril 2.5 mg   2.5 mg 2.5–20 mg 20 mg
Trandolapril 2 mg   1 mg 2–4 mg 8 mg
Name Equivalent daily dose   Start Usual Maximum
Note: bid = 2 times a day, tid = 3 times a day, d = daily
Drug dosages from Drug Lookup, Epocrates Online.
ACE inhibitors dosages for hypertension

Further Reading

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Last Updated: Nov 18, 2013

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  1. Hans Stoecklin Hans Stoecklin Kenya says:

    I have a saint Bernard dog with a heart problem. Can I give him ACE Hemmer tablets?
    Thanks for your prompt assistance.
    Hans Stoecklin Nairobi Kenya

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