Indications
Alone or with other agents in the management of hypertension.
Captopril, enalapril, fosinopril, lisinopril,
quinapril, ramipril, trandolapril: Management
of HF. Captopril, lisinopril, ramipril,
trandolapril: Reduction of risk of death or development
of HF following MI. Enalapril: Slowed progres sion of left ventricular dysfunction into overt heart failure.
Ramipril: Reduction of the risk of MI, stroke, and
death from cardiovascular disease in patients at risk
(55 yr old with a history of CAD, stroke, peripheral
vascular disease, or diabetes with another cardiovascular
risk factor). Captopril:pprogression of diabetic
nephropathy. Perindopril: Reduction of risk of death
from cardiovascular causes or nonfatal MI in patients
with stable CAD.
Action
ACE inhibitors block the conversion of angiotensin I to
the vasoconstrictor angiotensin II. ACE inhibitors also
prevent the degradation of bradykinin and other vasodilatory
prostaglandins. ACE inhibitors alsoqplasma
renin levels andpaldosterone levels. Net result is systemic
vasodilation. Therapeutic Effects: Lowering
of BP in hypertensive patients. Improved symptoms in
patients with HF (selected agents only).pdevelopment
of overt heart failure (enalapril only). Improved survival
andpdevelopment of overt HF after MI (selected
agents only).prisk of death from cardiovascular
causes or MI in patients with stable CAD (perindopril
only).prisk of MI, stroke or death from cardiovascular
causes in high-risk patients (ramipril only).pprogression
of diabetic nephropathy (captopril only).
Pharmacokinetics
Absorption: Benazepril—37% absorbed after oral
administration. Captopril—60–75% absorbed after
oral administration (pby food). Enalapril—55–75%
absorbed after oral administration. Enalaprilat—IV
administration results in complete bioavailability. Fosinopril—
36% absorbed after oral administration. Lisinopril—
25% absorbed after oral administration
(much variability). Moexipril—13% bioavailability as
moexiprilat after oral administration (pby food). Perindopril—
25% bioavailability as perindoprilat after
oral administration. Quinapril—60% absorbed after
oral administration (high-fat meal maypabsorption).
Ramipril—50–60% absorbed after oral administration.
Trandolapril—70% bioavailability as trandolapril
at after oral administration.
Distribution: All ACE inhibitors cross the placenta.
Benazepril, captopril, enalapril, fosinopril, quinapril,
and trandolapril—Enter breast milk. Lisinopril—
Minimal penetration of CNS. Ramipril—Probably
does not enter breast milk. Trandolapril—Enters
breast milk.
Protein Binding: Benazepril—95%, Fosinopril—
99.4%, Moexipril—90%, Quinapril—97%.
Metabolism and Excretion: Benazepril—Converted
by the liver to benazeprilat, the active metabolite.
20% excreted by kidneys; 11–12% nonrenal (biliary
elimination). Captopril—50% metabolized by the
liver to inactive compounds, 50% excreted unchanged
by the kidneys. Enalapril, enalaprilat—Enalapril is
converted by the liver to enalaprilat, the active metabolite;
primarily eliminated by the kidneys. Fosinopril—
Converted by the liver and GI mucosa to fosinoprilat,
the active metabolite—50% excreted in urine, 50% in
feces. Lisinopril—100% eliminated by the kidneys.
Moexipril—Converted by liver and GI mucosa to
moexiprilat, the active metabolite; 13% excreted in
urine, 53% in feces. Perindopril—Converted by the
liver to perindoprilat, the active metabolite; primarily
excreted in urine. Quinapril—Converted by the liver,
GI mucosa, and tissue to quinaprilat, the active metabolite:
96% eliminated by the kidneys. Ramipril—Converted
by the liver to ramiprilat, the active metabolite;
60% excreted in urine, 40% in feces. Trandolapril—
Converted by the liver to trandolaprilat, the active metabolite;
33% excreted in urine, 66% in feces.
Half-life: Benazeprilat—10–11 hr. Captopril—2
hr (qin renal impairment). Enalapril—2 hr (qin renal
impairment). Enalaprilat—35–38 hr (qin renal
impairment). Fosinoprilat—12 hr. Lisinopril—12
hr (qin renal impairment). Moexiprilat—2–9 hr (q
in renal impairment). Perindoprilat—3–10 hr (qin
renal impairment). Quinaprilat—3 hr (qin renal impairment).
Ramiprilat—13–17 hr (qin renal impairment).
Trandolaprilat—22.5 hr (qin renal impairment).
TIME/ACTION PROFILE (effect on BP—
single dose†)
ROUTE ONSET PEAK DURATION
Benazepril within 1 hr 2–4 hr 24 hr
Captopril 15–60 min 60–90 min 6–12 hr
Enalapril PO 1 hr 4–8 hr 12–24 hr
Enalapril IV 15 min 1–4 hr 4–6 hr
Fosinopril within 1 hr 2–6 hr 24 hr
Lisinopril 1 hr 6 hr 24 hr
Moexipril within 1 hr 3–6 hr up to 24 hr
Perindoprilat within 1–2 hr 3–7 hr up to 24 hr
Quinapril within 1 hr 2–4 hr up to 24 hr
Ramipril within 1–2 hr 3–6 hr 24 hr
Trandolapril within 1–2 hr 4–10 hr up to 24 hr
†Full effects may not be noted for several wks.
Contraindications/Precautions
Contraindicated in: Hypersensitivity; History of angioedema
with previous use of ACE inhibitors (also in
absence of previous use of ACE inhibitors for benazepril);
Concurrent use with aliskiren in patients with diabetes
or moderate-to-severe renal impairment (CCr
60 mL/min); Concurrent use with sacubitril; OB: Can
cause injury or death of fetus—if pregnancy occurs,
discontinue immediately; Lactation: Certain ACE inhibitors
appear in breast milk; discontinue drug or use formula.
Use Cautiously in: Renal impairment, hepatic impairment,
hypovolemia, hyponatremia, concurrent diuretic
therapy; Black patients with hypertension
(monotherapy less effective, may require additional
therapy;qrisk of angioedema); Women of childbearing
potential; Surgery/anesthesia (hypotension may be exaggerated);
Pedi: Safety not established for most agents; benazepril, fosinopril, and lisinopril may be used in A
children 6 yr (captopril and enalapril may be used in
children of all ages); Geri: Initial doseprecommended
for most agents due to age-relatedpin renal function.
Exercise Extreme Caution in: Family history of
angioedema.
Adverse Reactions/Side Effects
CNS: dizziness, drowsiness, fatigue, headache, insomnia,
vertigo, weakness. Resp: cough, dyspnea. CV:
hypotension, chest pain, edema, tachycardia. Endo:
hyperuricemia. GI: taste disturbances, abdominal pain,
anorexia, constipation, diarrhea, nausea, vomiting.
GU: erectile dysfunction, proteinuria, renal dysfunction,
renal failure. Derm: flushing, pruritis, rashes. F
and E: hyperkalemia. Hemat: AGRANULOCYTOSIS,
neutropenia (captopril only). MS: back pain, muscle
cramps, myalgia. Misc: ANGIOEDEMA, fever.
Interactions
Drug-Drug: Concurrent use with sacubitril mayq
risk of angioedema and is contraindicated; do not administer
within 36 hr of switching to/from sacubitril/
valsartan. Excessive hypotension may occur with concurrent
use of diuretics and other antihypertensives.
qrisk of hyperkalemia with concurrent
use of potassium supplements,
potassium-sparing diuretics, or potassium-containing
salt substitutes.qrisk of hyperkalemia, renal
dysfunction, hypotension, and syncope with concurrent
use of angiotensin II receptor blockers or
aliskiren; avoid concurrent use with aliskiren in patients
with diabetes or CCr 60 mL/min; avoid concurrent
use with angiotensin II receptor blockers. NSAIDs
and selective COX-2 inhibitors may blunt the antihypertensive
effect andqthe risk of renal dysfunction.
Absorption of fosinopril may bepby antacids (separate
administration by 1–2 hr).qlevels and mayqrisk
of lithium toxicity. Quinapril maypabsorption of tetracycline,
doxycycline, and fluoroquinolones (because
of magnesium in tablets).qrisk of angioedema
with temsirolimus, sirolimus, or everolimus.
Drug-Food: Food significantlypabsorption of captopril
and moexipril (administer drugs 1 hr before
meals).
Route/Dosage
Benazepril
PO (Adults): 10 mg once daily,qgradually to maintenance
dose of 20–40 mg/day in 1–2 divided doses
(begin with 5 mg/day in patients receiving diuretics).
PO (Children 6 yr): 0.2 mg/kg once daily; may be
titrated up to 0.6 mg/kg/day (or 40 mg/day).
Renal Impairment
PO (Adults): CCr 30 mL/min—Initiate therapy
with 5 mg once daily.
Renal Impairment
PO (Children 6 yr): CCr 30 mL/min—Contraindicated.
Captopril
PO (Adults): Hypertension—12.5–25 mg 2–3
times daily, may beqat 1–2 wk intervals up to 150 mg
3 times daily (begin with 6.25–12.5 mg 2–3 times
daily in patients receiving diuretics) (maximum dose
450 mg/day); HF—25 mg 3 times daily (6.25–12.5
mg 3 times daily in patients who have been vigorously
diuresed); titrated up to target dose of 50 mg 3 times
daily; Post-MI—6.25-mg test dose, followed by 12.5
mg 3 times daily, may bequp to 50 mg 3 times daily;
Diabetic nephropathy—25 mg 3 times daily.
PO (Children): HF—0.3 mg/kg–0.5 mg/kg/dose 3
times daily, titrate up to a maximum of 6 mg/kg/day in
2–4 divided doses; Older Children—6.25–12.5 mg/
dose every 12–24 hr, titrate up to a maximum of 6 mg/
kg/day in 2–4 divided doses.
PO (Infants): HF—0.15–0.3 mg/kg/dose, titrate up
to a maximum of 6 mg/kg/day in 1–4 divided doses.
PO (Neonates): HF—0.05–0.1 mg/kg/dose every 8–
24 hr, mayqas needed up to 0.5 mg/kg every 6–24 hr;
Premature neonates—0.01 mg/kg/dose every 8–12
hr.
Renal Impairment
PO (Adults): CCr 10–50 mL/min—Administer 75%
of dose; CCr 10 mL/min—Administer 50% of dose.
Enalapril/Enalaprilat
PO (Adults): Hypertension—2.5–5 mg once daily,
qas required up to 40 mg/day in 1–2 divided doses
(initiate therapy at 2.5 mg once daily in patients receiving
diuretics); HF—2.5 mg 1–2 times daily, titrated
up to target dose of 10 mg twice daily; begin with 2.5
mg once daily in patients with hyponatremia (serum sodium
130 mEq/L); Asymptomatic left ventricular
dysfunction—2.5 mg twice daily, titrated up to a target
dose of 10 mg twice daily.
PO (Children 1 mo): Hypertension—0.08 mg/kg
once daily; may be slowly titrated up to a maximum of
0.58 mg/kg/day.
IV (Adults): Hypertension—0.625–1.25 mg (0.625
mg if receiving diuretics) every 6 hr; can be titrated up
to 5 mg every 6 hr.
IV (Children 1mo): Hypertension—5–10 mcg/
kg/dose given every 8–24 hr.
Renal Impairment
PO, IV (Adults): Hypertension CCr 10–50 mL/
min—Administer 75% of dose; CCr 10 mL/min—
Administer 50% of dose.
Renal Impairment
PO, IV (Children 1mo): CCr 30 mL/min—Contraindicated.
Fosinopril
PO (Adults): Hypertension—10 mg once daily, may
beqas required up to 80 mg/day. HF—10 mg once
daily (5 mg once daily in patients who have been vigorously
diuresed), may beqover several wk up to 40 mg/
day.
PO (Children 6 yr and 50 kg): Hypertension—
5–10 mg once daily.
Lisinopril
PO (Adults): Hypertension—10 mg once daily, can
bequp to 20–40 mg/day (initiate therapy at 5 mg/day
in patients receiving diuretics); HF—5 mg once daily;
may be titrated every 2 wk up to 40 mg/day; begin with
2.5 mg once daily in patients with hyponatremia (serum
sodium 130 mEq/L); Post-MI—5 mg once daily
for 2 days, then 10 mg daily.
PO (Children 6 yr): Hypertension—0.07 mg/kg
once daily (up to 5 mg/day), may be titrated every 1–2
wk up to 0.6 mg/kg/day (or 40 mg/day).
Renal Impairment
PO (Adults): CCr 10–30 mL/min—Begin with 5 mg
once daily; may be slowly titrated up to 40 mg/day; CCr
10 ml/min—Begin with 2.5 mg once daily; may be
slowly titrated up to 40 mg/day.
Renal Impairment
(Children 6 yr): CCr 30 mL/min—Contraindicated.
Moexipril
PO (Adults): 7.5 mg once daily, may bequp to 30
mg/day in 1–2 divided doses (begin with 3.75 mg/day
in patients receiving diuretics).
Renal Impairment
PO (Adults): CCr 40 mL/min—Initiate therapy at
3.75 mg once daily, may be titrated upward carefully to
15 mg/day.
Perindopril
PO (Adults): Hypertension—4 mg once daily, may
be slowly titrated up to 16 mg/day in 1–2 divided doses
(should not exceed 8 mg/day in elderly patients) (begin
with 2–4 mg/day in 1–2 divided doses in patients
receiving diuretics); Stable CAD—4 mg once daily for
2 weeks, may beq, if tolerated, to 8 mg once daily; for
elderly patients, begin with 2 mg once daily for 1 wk
(may beq, if tolerated, to 4 mg once daily for 1 week,
then,qas tolerated to 8 mg once daily).
Renal Impairment
PO (Adults): CCr 30–60 mL/min—2 mg/day initially,
may be slowly titrated up to 8 mg/day in 1–2 divided
doses.
Quinapril
PO (Adults): Hypertension—10–20 mg once daily
initially, may be titrated q 2 wk up to 80 mg/day in 1–2
divided doses (initiate therapy at 5 mg/day in patients
receiving diuretics); HF—5 mg twice daily initially,
may be titrated at weekly intervals up to 20 mg twice
daily.
Renal Impairment
PO (Adults): CCr 60 mL/min—Initiate therapy at
10 mg/day; CCr 30–60 mL/min—Initiate therapy at 5
mg/day; CCr 10–30 mL/min—Initiate therapy at 2.5
mg/day.
Ramipril
PO (Adults): Hypertension—2.5 mg once daily, may
beqslowly up to 20 mg/day in 1–2 divided doses (initiate
therapy at 1.25 mg/day in patients receiving diuretics).
HF post-MI—1.25–2.5 mg twice daily initially,
may beqslowly up to 5 mg twice daily. Reduction in
risk of MI, stroke, and death from cardiovascular
causes—2.5 mg once daily for 1 wk, then 5 mg once
daily for 3 wk, thenqas tolerated to 10 mg once daily
(can also be given in 2 divided doses).
Renal Impairment
PO (Adults): CCr 40 mL/min—Initiate therapy at
1.25 mg once daily, may be slowly titrated up to 5 mg/
day in 1–2 divided doses.
Trandolapril
PO (Adults): Hypertension—1 mg once daily (2
mg once daily in black patients); HF post-MI—Initiate
therapy at 1 mg once daily, titrate up to 4 mg once daily
if possible.
Renal Impairment
PO (Adults): CCr 30 mL/min—Initiate therapy at
0.5 mg once daily, may be slowly titrated upward (maximum
dose4 mg/day).
Hepatic Impairment
PO (Adults): Initiate therapy at 0.5 mg once daily, may
be slowly titrated upward (maximum dose4 mg/
day).
Availability
Benazepril (generic available)
Tablets: 5 mg, 10 mg, 20 mg, 40 mg. Cost: Generic—
All strengths $10.83/100. In combination
with: amlodipine (Lotrel) and hydrochlorothiazide
(Lotensin HCT). See Appendix B.
Captopril (generic available)
Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg. Cost: Generic—
12.5 mg $77.18/100, 25 mg $83.44/100, 50
mg $143.08/100, 100 mg $190.54/100. In combination
with: hydrochlorothiazide (Capozide). See
Appendix B.
Enalapril (generic available)
Oral solution (mixed berry flavor): 1 mg/mL.
Powder for oral solution (requires reconstitution):
1 mg/mL. Tablets: 2.5 mg, 5 mg, 10 mg, 20
mg. Cost: Generic—2.5 mg $88.33/100, 5 mg
$106.37/100, 10 mg $117.81/100, 20 mg $167.64/100. In combination with: hydrochlorothiazide A
(Vaseretic). See Appendix B.
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