Classification Therapeutic: antihypertensives

Pharmacologic: ACE inhibitors

Pregnancy Category C (first trimester), D (second and third trimesters)

Indications

Alone or with other agents in themanagement of hypertension. hypertension.

Captopril, enalapril, fosino-pril, lisinopril, quinapril, ramipril, tran-dolapril:
Management of CHF. Captopril, li-sinopril,
ramipril, trandolapril: Reduction of risk of death or development of CHF following MI.
Enalapril: Slowed progression of left ven-tricular
dysfunction into overt heart failure. Ra-mipril: Reduction of the risk of MI, stroke, and death fromcardiovascular disease in
patients at risk (>55 years old with a history of CAD, stroke, peripheral vascular disease, or diabetes with
another cardiovascular risk factor). Cap-topril: Decreased progression of diabetic ne-phropathy. Perindopril: Reduction of
risk of death fromcardiovascular causes or non-fatal MI in patients with stable CAD.

Action

ACE inhibitors block the conversion of angioten-sin

I to the vasoconstrictor angiotensin II. ACE inhibitors
also prevent the degradation of bra-dykinin
and other vasodilatory prostaglandins. ACE inhibitors also increase plasma renin levels and reduce aldosterone levels. Net
result is sys-temic vasodilation. Therapeutic Effects: Low-ering of blood pressure in hypertensive patients. Improved
symptoms in patients with CHF (se-lected agents only). Decreased development of overt heart failure (enalapril only).
Improved survival and reduced development of overt CHF afterMI (selected agents only). Decreased risk of death from
cardiovascular causes or MI in patients with stable CAD (perindopril only). De-creased risk of MI, stroke, or death from car-
diovascular causes in high-risk patients (rami-pril only). Decreased progression of diabetic nephropathy
(captopril only).

Pharmacokinetics
Absorption: Benazepril—37% absorbed after oral administration. Captopril—60–75% ab-sorbed
after oral administration (_by food). Enalapril—55–75% absorbed after oral ad-ministration.
Enalaprilat—IV administration results in complete bioavailability. Fosino-pril—36%absorbed after oral administration.
Lisinopril—25%absorbed after oral administration (much variability). Moexipril—13% bioavailability as moexiprilat after
oral adminis-tration (_by food). Perindopril—25% bioavailability
as perindoprilat after oral administration. Quinapril—60%absorbed after oral administration (high-fatmealmay_absorption).
Ramipril—50–60%absorbed after oral administration. Trandolapril—70%bioavail ability as trandolaprilat after oral
administration.

Distribution: All ACE inhibitors cross the placenta. Benazepril, captopril, enalapril, fosinopril, quinapril, and
trandolapril—Enter breastmilk. Lisinopril—Minimal penetration of CNS. Ramipril—Probably does not enter breastmilk.
Trandolapril—Enters breastmilk. Protein Binding: Benazepril—95%, Fosinopril—99.4%, Moexipril—90%, Quinapril—
97%.
Metabolismand 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 comsin pounds,
50%excreted unchanged by the kidneys. Enalapril, enalaprilat—Enalapril is converted by the liver to enalaprilat, the
activemetabolite; primarily eliminated by the kidneys. Fosinopril—Converted by the liver and GI mucosa to fosinoprilat, the
activemetabolite—50%excreted in urine, 50%in feces. Lisinopril—100%eliminated by the kidneys. Moexipril—Converted
by liver and GImucosa to moexiprilat, the activemetabolite; 13%excret-ed in urine, 53%in feces. Perindopril—Con-verted
by the liver to perindoprilat, the active metabolite; primarily excreted in urine. Quina-pril—Converted by the liver,
GImucosa, 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% ex-creted in urine, 66% in feces. Half-life: Benazeprilat—10–11 hr. Captopril—2
hr (increased in renal impairment). Enalapril—2 hr (increased in renal impairment). Enalaprilat—35–38 hr (increased in
renal impairment). Fosinoprilat—12 hr. Lisi-nopril—12 hr (increased in renal impair-ment). Moexiprilat—2–9 hr (increased
in re-nal impairment). Perindoprilat—3–10 hr (increased in renal impairment). Quinapri-lat—3 hr (increased in renal
impairment). Ra-miprilat—13–17 hr (increased in renal im-pairment). Trandolaprilat—10 hr (increased in renal
impairment).

Contraindications/Precautions
Contraindicated in: Hypersensitivity; History of angioedema with previous use of ACE inhibi-tors; OB: Can cause injury
or death of fetus; Lac-tation: Certain ACE inhibitors appear in breast milk discontinue drug or use formula. Use Cautiously
in: Renal impairment, hepatic impairment, hypovolemia, hyponatremia, con-current diuretic therapy; Black patients with hy-
pertension (monotherapy less effective,may re-quire additional therapy; higher risk of angioedema);Women of child bearing
potential; Surgery/anesthesia (hypotension may be exag-gerated); Pedi: Safety not established formostagents; benazepril,
fosinopril, and lisinopril may be used in children 6 yr (captopril and enalapril may be used in children of all ages); Geri:
Initial dosage reduction recommended for most agents due to age-related decline in 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, consti-pation, 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: Excessive hypotension may occur with concurrent use of diuretics and other antihypertensives._risk of
hyperkalemia with concurrent use of potassium supplements potassium-sparing diuretics, potassium containing salt
substitutes, or angiotensin II receptor antagonists. Antihypertensive re-sponse may be_by NSAIDs. Absorption of fo-
sinoprilmay be_by antacids (separate administration by 1–2 hr)._levels and may_risk of lithium toxicity. Quinapril
may_ab-sorption of tetracycline, doxycycline, and fluoroquinolones (because of magnesium in tablets).

Drug-Food: Food significantly_absorption of captopril and moexipril (administer drugs 1hr before meals).

Route/Dosage
1. Fosinopril
PO (Adults): Hypertension—10mg once dai-ly,may be increased as required up to 80mg/day. CHF—10mg once daily (5 mg
once daily in patients who have been vigorously diuresed); may be increased over several weeks up to 40 mg/day. PO
(Children 6 yr and >50 kg): Hypertension—5–10 mg once daily.

2. Perindopril
PO (Adults): Hypertension—4mg once daily, may be slowly titrated up to 16mg/day in 1–2 divided doses (should not
exceed 8mg/day in elderly patients) (begin with 2–4mg/day in 1–2 divided doses in patients receiving diuretics); Stable
CAD—4 mg once daily for 2 weeks; may be increased, if tolerated, to 8 mg once daily; for elderly patients, begin with 2mg
once daily for 1week (may be increased, if tolerated, to 4mg once daily for 1 week, then, increase as toleratin ed to 8 mg
once daily).
Renal Impairment
PO (Adults): CCr 30–60ml/min—2mg/day initially;may be slowly titrated up to 8mg/day in 1–
2 divided doses.

3. Quinapril
PO (Adults): Hypertension—10–20mg once daily initially,may be titrated q 2 wk up to 80 mg/day in 1–2 divided doses
(initiate therapy at 5mg/day in patients receiving diuretics). CHF—5mg twice daily initially;may be titrated at weekly
intervals up to 20 mg twice daily.
Renal Impairment
PO (Adults): CCr >60ml/min—Initiate ther-apy at 10mg/day; CCr 30–60ml/min—Initiate therapy at 5 mg/day; CCr 10–30
ml/min—Ini-tiate therapy at 2.5 mg/day.

4. Ramipril

PO (Adults): Hypertension—2.5 mg once daily;may be increased slowly up to 20mg/day in 1–2 divided doses (initiate
therapy at 1.25 mg/day in patients receiving diuretics). CHF post-MI—1.25–2.5mg twice daily initially;may be increased
slowly up to 5mg twice daily. Re-duction 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, then in-creased as tolerated to 10 mg once daily (can also be given in 2 divided doses).
Renal Impairment
PO (Adults): CCr <40 ml/min—Initiate ther-apy at 1.25 mg once daily; may be slowly titrated up to 5 mg/day in 1–2
divided doses.
5. Trandolapril
PO (Adults): Hypertension—1mg once daily (2mg once daily in black patients); CHF post-MI—Initiate therapy at 1 mg
once daily, titrate up to 4 mg once daily if possible.
Renal Impairment
PO (Adults): CCr <30ml/min—Initiate ther-apy at 0.5mg once daily;may be slowly titrated upward (maximumdose =
4mg/day).
Hepatic Impairment
PO (Adults): Initiate therapy at 0.5mg once daily;may be slowly titrated upward (maximum dose = 4mg/day).