Captopril

Captopril (rINN) /kptprl/ is an angiotensinconverting enzyme (ACE) inhibitor used for the
treatment of hypertension and some types of congestive
heart failure. Captopril was the rst ACE inhibitor
developed and was considered a breakthrough both
because of its novel mechanism of action and also
because of the revolutionary development process.
Captopril was discovered and developed at Squibb and
Sons Pharmaceuticals based on concepts pioneered by
Nobel Laureate John Vane and is now marketed by
Bristol-Myers Squibb under the trade name Capoten.[1]

It has also been investigated for use in the treatment of

cancer.[4]

2 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 led 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 among the earliest successes of the revolutionary concept of ligand-based drug
design. The renin-angiontensin-aldosterone system had
been extensively studied in the mid-20th century, and this
system presented several opportune targets in the development of novel treatments for hypertension. The rst
two targets that were attempted were renin and ACE.
Captopril was the culmination of eorts by Squibbs laboratories to develop an ACE inhibitor.
Ondetti, Cushman, and colleagues built on work that had
been done in the 1960s by a team of researchers led by
John Vane at the Royal College of Surgeons of England.
The rst breakthrough was made by Kevin K.F. Ng[5][6][7]
in 1967, when he found the conversion of angiotensin I
to angiotensin II took place in the pulmonary circulation
instead of in the plasma. In contrast, Sergio Ferreira[8]
found bradykinin disappeared in its passage through the
pulmonary circulation. The conversion of angiotensin I
to angiotensin II and the inactivation of bradykinin were
thought to be mediated by the same enzyme.

Drosophila ACE in complex with captopril (purple), PDB entry

2x8z[2]

In 1970, using bradykinin potentiating factor (BPF) provided by Sergio Ferreira,[9] Ng and Vane found the conversion of angiotensin I to angiotensin II was inhibited during its passage through the pulmonary circulation. BPF was later found to be a peptide in the venom
of a lancehead viper (Bothrops jararaca), which was a
collected-product inhibitor of the converting enzyme.
Captopril was developed from this peptide after it was
found via QSAR-based modication that the terminal
sulfhydryl moiety of the peptide provided a high potency
of ACE inhibition.

Clinical use

Captoprils main uses are based on its vasodilation and

inhibition of some renal function activities. These benets are most clearly seen in: 1) Hypertension 2) Cardiac conditions such as congestive heart failure and after
myocardial infarction 3) Preservation of kidney function
in diabetic nephropathy
Additionally, it has shown mood-elevating properties in
some patients. This is consistent with the observation that
animal screening models indicate putative antidepressant
activity for this compound, although one study has been
negative. Formal clinical trials in depressed patients have
not been reported.[3]

Captopril gained FDA approval on April 6, 1981. The

drug became a generic medicine in the U.S. in February
1996, when the market exclusivity held by Bristol-Myers
Squibb for captopril expired.
The development of captopril has been claimed as an
1

8 SEE ALSO

instance of 'biopiracy' (commercialization of traditional 5.2 Subsequent ACE inhibitors

medicines), since no benets have owed back to the indigenous Brazilian tribe who rst used pit viper venom as The adverse eect and pharmacokinetic limitations of
an arrowhead poison.[10]
captopril stimulated the development of enalapril and
subsequent ACE inhibitors. These were specically designed to lack the sulfhydryl moiety believed to be responsible for rash and taste disturbance.[16] Most subsequent ACE inhibitors are given as prodrugs, to improve
oral bioavailability. All have longer half-lives and are
given once or twice daily, which may improve patient
compliance.

6 Adverse eects
Captopril synthesis of Shimazaki, Watanabe, et al.

Chemical synthesis

A chemical synthesis of captopril by treatment of Lproline with (2S)3-acetylthio-2-methylpropanoyl chloride under basic conditions (NaOH), followed by aminolysis of the protective acetyl group to unmask the drugs
free thiol, is depicted in the gure at right.[11]

Pharmacokinetics

Main article: ACE inhibitor Adverse eects

Adverse eects of captopril include cough due to increase in the plasma levels of bradykinin, angioedema,
agranulocytosis, proteinuria, hyperkalemia, taste alteration, teratogenicity, postural hypotension, acute renal
failure, and leukopenia.[17] Except for postural hypotension, which occurs due to short and fast mode of action
of captopril, most of the side eects mentioned are common for all ACE inhibitors. Among these, cough is the
most common adverse eect. Hyperkalemia can occur,
especially if used with other drugs which elevate potassium level in blood, such as potassium-sparing diuretics.
Other side eects are:
Itching
Headache

Unlike the majority of ACE inhibitors, captopril is

not administered as a prodrug (the only other being
lisinopril).[12] About 70% of orally administered captopril is absorbed. Bioavailability is reduced by presence
of food in stomach. It is partly metabolised and partly
excreted unchanged in urine.[13]

Tachycardia
Chest pain
Palpitations
Weakness

5
5.1

Developments from captopril

Limitations of captopril

7 Overdose

Captopril (as other ACE inhibitors) overdose can be anThe adverse drug reaction (ADR) prole of captopril is tagonized with naloxone.[18][19]
similar to other ACE inhibitors, with cough being the
most common ADR.[14] However, captopril is also commonly associated with rash and taste disturbances (metallic or loss of taste), which are attributed to the unique thiol 8 See also
moiety.[15]
Captopril also has a relatively poor pharmacokinetic prole. The short half-life necessitates two or three times per
day dosing, which may reduce patient compliance.

Captopril challenge test

Captopril suppression test

References

[1] Bryan, Jenny (2009). From snake venom to ACE inhibitor the discovery and rise of captopril. Pharmaceutical Journal. Retrieved 2015-01-08.
[2] Akif, M.; Georgiadis, D.; Mahajan, A.; Dive, V.;
Sturrock, E. D.; Isaac, R. E.; Acharya, K. R. (2010).
High-Resolution Crystal Structures of Drosophila
melanogaster Angiotensin-Converting Enzyme in
Complex with Novel Inhibitors and Antihypertensive
Drugs. Journal of Molecular Biology 400 (3): 502517.
doi:10.1016/j.jmb.2010.05.024. PMID 20488190.
[3] Novel Pharmacological Approaches to the Treatment of
Depression
[4] Attoub
2008).
growth
6572.

S, Gaben AM, Al-Salam S et al. (September

Captopril as a potential inhibitor of lung tumor
and metastasis. Ann. N. Y. Acad. Sci. 1138:
doi:10.1196/annals.1414.011. PMID 18837885.

[15] Atkinson, AB; Robertson, JI (1979). Captopril in

the treatment of clinical hypertension and cardiac failure. Lancet 2 (8147): 8369. doi:10.1016/S01406736(79)92186-X. PMID 90928.
[16] Patchett, AA; Harris, E; Tristram, EW; Wyvratt, MJ; Wu,
MT; Taub, D; Peterson, ER; Ikeler, TJ; Ten Broeke, J;
Payne, L. G.; Ondeyka, D. L.; Thorsett, E. D.; Greenlee,
W. J.; Lohr, N. S.; Hosommer, R. D.; Joshua, H.; Ruyle,
W. V.; Rothrock, J. W.; Aster, S. D.; Maycock, A. L.;
Robinson, F. M.; Hirschmann, R.; Sweet, C. S.; Ulm, E.
H.; Gross, D. M.; Vassil, T. C.; Stone, C. A. (1980). A
new class of angiotensin-converting enzyme inhibitors.
Nature 288 (5788): 2803. doi:10.1038/288280a0.
PMID 6253826.
[17] Captopril (ACE inhibitor): side eects. lifehugger. 0709-2008. Retrieved 2009-05-02. Check date values in:
|date= (help)
[18] Goldfranks toxicologic emergencies, Lewis R. Goldfrank,Neal Flomenbaum, page 953.

[5] Ng KKF and Vane JR: Conversion of angiotensin I to angiotensin II. Nature 1967, 216, 762-766.

[19] Meylers Side Eects of Analgesics and Antiinammatory Drugs, Jerey K. Aronson, page 120.

[6] Ng KKF and Vane JR: Fate of angiotensin I in the circulation. Nature, 1968, 218, 144-150.

10 External links

[7] Ng KKF and Vane JR: Some properties of angiotensin

converting enzyme in the lung in vivo. Nature, 1970, 225,
1142-1144.
[8] Ferreira SH and Vane JR: The disappearance of
bradykinin and eledoisin in the circulation and vascular
beds of the cat. Br. J. Pharm. Chemother.,1967,30, 417424.
[9] Smith CG, Vane JR (May 2003). The discovery of captopril. FASEB J. 17 (8): 7889. doi:10.1096/fj.030093life. PMID 12724335.
[10] Ellsworth B., Brazil to step up crackdown on biopiracy
in 2011, Ruters, Dec. 22, 2010
[11] Shimazaki, M.; Hasegawa, J.; Kan, K.; Nomura, K.;
Nose, Y.; Kondo, H.; Ohashi, T.; Watanabe, K. (1982).
Synthesis of captopril starting from an optically active
.BETA.-hydroxy acid. Chem. Pharm. Bull. 30 (9):
31393146. doi:10.1248/cpb.30.3139.
[12] Brown, NJ; Vaughan, DE (1998).
Angiotensinconverting enzyme inhibitors. Circulation 97 (14):
141120.
doi:10.1161/01.cir.97.14.1411.
PMID
9577953.
[13] Duchin, KL; McKinstry, DN; Cohen, AI; Migdalof,
BH (1988). Pharmacokinetics of captopril in healthy
subjects and in patients with cardiovascular diseases. Clinical pharmacokinetics 14 (4): 24159.
doi:10.2165/00003088-198814040-00002.
PMID
3292102.
[14] Rossi S, editor. Australian Medicines Handbook 2006.
Adelaide: Australian Medicines Handbook; 2006.

U.S. Patent 4,046,889

RxList monograph: Capoten
U.S. National Library of Medicine: Drug Information Portal - Captopril

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