DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
BENAZEPRIL
CAPTOPRIL
ENALAPRIL
ENALAPRILAT
FOSINOPRIL
LISINOPRIL
CH 2 CH 2
CH 2 CH 2
C
H
CH 2 CH 2
CH 2 CH 2 CH 2 CH 2
COOC 2 H 5
H
H
C N
H
COOC 2 H 5
C
H
CH 3 CH 2 COOCHCH(CH 3 ) 2
NH 2
COOH (CH 2 ) 4
H
CH 2 CH 2 C N C C
H
O
P
O
O
H
CH 3
C C N
H O
CH 3
H
O
C
H
C
O
O
C
O
N
N
N
MOEXIPRIL
CH 2 CH 2
N
CH 2
COOH
COOH
CH 3
HSCH 2 C C N
H
N
COOH
H
N
CH 2
COOH
COOH
COOH
COOH
COOC 2 H 5
COOH
H
C N C C N
CH 3
OCH 3
OCH 3
PERINDOPRIL
COOH
COOC 2 H 5 CH 3
H
CH 3 CH 2 CH 2 C N C C N
H H
H H O
QUINAPRIL
CH 3 CH 2 OOC CH 3
COOH
H
CH 2 CH 2 C N C C N
H H O
RAMIPRIL
COOH
COOC 2 H 5 CH 3
H
CH 2 CH 2 C N C C N
H H
H H O
TRANDOLAPRIL
COOH
COOC 2 H 5 CH 3
H
CH 2 CH 2 C N C C N
Figure 26–9. Chemical structures of selected ACE inhibitors. Captopril, lisinopril, and enalaprilat are active molecules. Benazepril,
enalapril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are relatively inactive until converted to their corresponding
diacids. The structures enclosed within red boxes are removed by esterases and replaced with a hydrogen atom to form the
active molecule in vivo (e.g., enalapril to enalaprilat or ramipril to ramiprilat).
H
H
O
H
H
O
H
All ACE inhibitors block the conversion of AngI to AngII and
have similar therapeutic indications, adverse- effect profiles, and contraindications.
Although captopril and enalapril are indistinguishable
with regard to antihypertensive efficacy and safety, the
Quality- of- Life Hypertension Study Group reported that captopril
may have a more favorable effect on quality of life (Testa et al.,
1993). Because hypertension usually requires lifelong treatment,
quality- of- life issues are an important consideration in comparing
antihypertensive drugs. ACE inhibitors differ markedly in tissue distribution,
and it is possible that this difference could be exploited to
inhibit some local (tissue) RAS while leaving others relatively intact.
Captopril (CAPOTEN, others). Captopril, the first ACE inhibitor to be
marketed, is a potent ACE inhibitor with a K i
of 1.7 nM. It is the
only ACE inhibitor approved for use in the U.S. that contains a
sulfhydryl moiety. Given orally, captopril is absorbed rapidly and
has a bioavailability ~75%. Bioavailability is reduced by 25-30%
with food, so captopril should be given 1 hour before meals. Peak
concentrations in plasma occur within an hour, and the drug is
cleared rapidly with a t 1/2
~2 hours. Most of the drug is eliminated
in urine, 40-50% as captopril and the rest as captopril disulfide
dimers and captopril–cysteine disulfide. The oral dose of captopril
ranges from 6.25-150 mg two to three times daily, with 6.25 mg