Captopril

Captopril (Bristol-Myers Squibb under the trade name Capoten or Inhibace.

Clinical Use

Captopril's main uses are based on its vasodilatation and inhibition of some renal function activities. These benefits are most clearly seen in the following conditions:

1) Hypertension

2) Cardiac conditions such as post myocardial infarction and congestive heart failure

3) Preservation of kidney function in diabetic nephropathy

History

Captopril was developed in 1975 by three researchers at the U.S. drug company Squibb (now Bristol-Myers Squibb): Miguel Ondetti, Bernard Rubin and David Cushman. Squibb filed for U.S. patent protection on the drug in February 1976 and U.S. Patent 4,046,889 was granted in September 1977.

The development of captopril was amongst the earliest successes of the revolutionary concept of structure-based drug design. The renin-angiontensin-aldosterone system had been extensively studied in the mid-20th century and it had been decided that this system presented several opportune targets in the development of novel treatments for hypertension. The first two targets that were attempted were ACE. Captopril was the culmination of efforts by Squibb's laboratories to develop an ACE inhibitor.

Ondetti, Cushman and colleagues built on work that had been done in the 1960s by the British pharmacologist QSAR-based modification that the terminal sulfhydryl moiety of the peptide provided a high potency of ACE inhibition.

Captopril gained FDA approval in June 1981. The drug went generic in the U.S. in February 1996 as a result of the end of market exclusivity for Bristol-Myers Squibb.

Developments from captopril

Limitations of captopril

The ACE inhibitors, with cough being the most common ADR (Rossi, 2006). However, captopril is also commonly associated with rash and taste disturbances (metallic or loss of taste), which are attributed to the unique sulfhydryl moiety (Atkinson & Robertson, 1979).

Captopril also has a relatively poor pharmacokinetic profile. The short half-life necessitates 2–3 times daily dosing, which may reduce patient compliance.

Subsequent ACE inhibitors

The adverse effect and pharmacokinetic limitations of captopril stimulated the development bioavailability. All have a longer half-life and are given once or twice daily, which may improve patient compliance.

Adverse effects

Cough is the most common long-therm aldosterone production.

References

• Atkinson AB, Robertson JIS. Captopril in the treatment of hypertension and cardiac failure. Lancet 1979;2(8147):836–9. PMID 90928
• Patchett AA, Harris E, Tristam EQ, et al. A new class of angiotensin-converting enzyme inhibitors. Nature 1980;288(5788):280–3. PMID 6253826
• Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
• Smith CG, Vane JR. The discovery of captopril. FASEB J 2003;17:788-9. Fulltext. PMID 12724335.

See also

• Captopril challenge test