Johns Hopkins Diabetes Guide

ACE inhibitors

Lipika Samal, M.D.; Paul A. Pham, Pharm.D.

INDICATIONS

FDA

MECHANISM[Top]

  • High affinity for angiotensin converting enzyme competing with angiotensin I, the natural substrate, to block its conversion to angiotensin II. Angiotensin II is a potent vasoconstrictor and a negative feedback mediator for renin activity. Thus, as a result of lower angiotensin II plasma levels, blood pressure decreases and plasma renin activity increases.

USUAL ADULT DOSING[Top]

  • Benazepril: 10 mg once daily in patients initial dose (not on a diuretic). Usual dose: 20-40 mg in a single or 2 divided doses.
  • Captopril: CHF/ HTN: 6.25-12.5 mg three times a day (with diuretic) with goal of 50 mg three times a day. Diabetic nephropathy: 25 mg three times a day.
  • Enalapril: CHF/HTN: 2.5-5 mg daily increased up to 40 mg/day every 1-2 weeks in 2.5 mg intervals. IV : 1.25 mg/dose every 6 hours for up to 36 hours
  • Fosinopril: CHF/HTN: 10 mg daily initially, then titrate to effect (max dose 40 mg daily). Usual dose: 20-40 mg daily.
  • Lisinopril: HTN: 10 mg daily (no diuretic) or 5 mg daily (if on diuretic) initially. Dose range: 10-40 mg daily. CHF: Initial: 2.5-5 mg once daily; titrate by 10 mg increments every 2 weeks to target of 20-40 mg/day.
  • Moexipril: Hypertension: 7.5 mg once daily (not on a diuretic) or 3.75 mg once daily (when combined with a diuretic). Administer 1 hr prior to meal. Maintenance: 7.5-30 mg daily in 1-2 divided doses
  • Perindopril Erbumine: HTN: Initial: 4 mg daily; titrate to desired effect every 1-2 weeks to a max dose of 16 mg/day. Usual dose 4-8 mg/day in 2 divided doses. Stable coronary artery disease (CAD): Initial: 4 mg once daily for 2 weeks then increase to 8 mg once daily as tolerated.
  • Quinapril: HTN: 10-20 mg daily initially. Initial dose may be reduced to 5 mg daily (if patient on a diuretic). Range: 10-40 mg once daily. CHF: 5 mg once or twice daily; titrate to desired effect every week to a dose of 20-40 mg daily in 2 divided doses.
  • Ramipril: HTN: 2.5-5 mg once daily (max dose of 20 mg/day). Left ventricular dysfunction (LVD) post-MI: 2.5 mg twice-daily; titrate to 5 mg twice daily as tolerated. Reduced risk of stoke, MI and death Initial: 2.5 mg once daily for 1st week, then 5 mg once daily for weeks 2-4, then titrate to 10 mg once daily as tolerated.
  • Trandolapril: CHF/LVD Initial: 1 mg/day, titrate to 4 mg/day as tolerated. HTN: 1 mg/day initially (may use 2 mg/day in black patients); titrate to desired effect in 1 week intervals.

DOSING IN SPECIAL POPULATIONS[Top]

RENAL

  • CrCl 10-50 ml/min: reduce initial recommended dose by 25%, then titrate to effect.
  • CrCl < 10 ml/min: reduce initial recommended dose by 50%, then titrate to effect.

HEPATIC

  • No dosage adjustment needed.

PREGNANCY

  • FDA pregnancy risk category D. Avoid in pregnancy.
  • ACE inhibitors are teratogenic and have resulted in neonatal morbidity (cardiovascular and CNS) and mortality.

BREASTFEEDING

  • Concentration in milk is about 1% of serum concentration. Avoid ACE inhibitors during breast feeding.

ADVERSE DRUG REACTIONS[Top]

COMMON

  • Cardiovascular: edema, hypotension (use low dose and titrate slowly in volume contracted patients).

OCCASIONAL

  • Drug-related cough (0.5% to 2%)
  • Endocrine/metabolic: gynecomastia, hyperkalemia
  • Rash
  • Renal failure
  • Dermatologic: angioedema of face, lips, and throat (0.1%)
  • Metallic taste (captopril)

RARE

  • Hematologic: agranulocytosis, neutropenia
  • Gastrointestinal: intestinal angioedema
  • Eosinophilic pneumonitis
  • Photosensitivity

DRUG INTERACTIONS[Top]

  • ACE inhibitors may increase the hypoglycemic effects of insulin or other antidiabetic agent.
  • Potassium-sparing diuretics (e.g spironolactone) and trimethoprim: may increase risk of hyperkalemia.
  • Potassium salt: monitor for hyperkalemia with ACE-inhibitor co-administration.
  • ARBs (e.g. losartan, telmisartan): may increase risk of renal failure, diarrhea, hypotension, syncope, and hyperkalemia. Monitor renal function closely with ACE inhibitor and ARBs co-administration.
  • Lithium: lithium concentration may be increased. Monitor concentrations with ACE inhibitor co-administration.
  • Pregabalin: may increase risk of angioedema associated with ACE inhibitors. Use with close monitoring.
  • Antacid: may decrease ACE inhibitor absorption. Separate administration time.
  • Nephrotic agents (e.g contrast, NSAIDS, aminoglycosides, amphoB): may increase risk of nephrotoxicity. Monitor renal function closely with co-administration.

PHARMACOKINETIC[Top]

Tables/Images

Generic Name

Brand Name

FDA indication

Formulation (tab, caps, IV)

U.S. Cost per dose

Half Life

Onset / time to peak

Metabolism/Excretion

Protein binding

Benazepril

Lotensin®

Hypertension alone or in combination with other medications

Benazepril / Losentin
5 mg tab
10 mg tab
20 mg tab
40 mg tab

Benazepril
5 mg tab $1.05
10 mg tab $ 1.05
20 mg tab $1.05
40 mg tab $1.05
Lotensin
5 mg tab $2.29
10 mg tab $2.29
20 mg tab $2.29
40 mg tab $2.29

10-11 hrs

Onset/
time to peak 1-2 hrs

Metabolism:
Pro-drug (benazepril): hepatic cleavage
Active metabolite (benazeprilat): hepatic glucuronide conjugates
Excretion:
Pro-drug (benazepril): 4% renal as glucurondine conjugates
Active metabolite (benazeprilat): 11-12% biliary & 8% renal

Benazepril: ~97%; Benazeprilat: ~95%

Captopril

Capoten®

Congestive heart failure, diabetic nephropathy, hypertension and left ventricular dysfunction with myocardial dysfunction

Captopril
12.5 mg tab
25 mg tab
50 mg tab
100 mg tab

Captropril
12.5 mg tab
$ 0.78
25 mg tab $1.38
50 mg tab $1.56
100 mg tab $1.50

1.9 hrs in healthy patients
2.06 hrs in heart failure
20-40 hrs in anuria

Onset/time to peak: 1 hr

Excretion
>95% in urine with 40-50% unchanged

25-30%

Enalapril

Vasotec®

Treatment of hypertension, asymptomatic left ventricular dysfunction and symptomatic heart failure

Enalaprilat inj 1.25 mg/mL
Enalapril / Vasotec
2.5 mg tab
5 mg tab
10 mg tab
20 mg tab

Enalaprilat inj 1.25 mg/mL (2 mL vial) $7.44
Enalapril
2.5 mg tab $0.80
5 mg tab $ 1.02
10 mg tab $ 1.07
20 mg tab $1.52
Vasotec
5 mg tab $3.78
10 mg tab $4.17
20 mg tab $5,46

Pro-drug (Enalapril) healthy adults 2 hrs; congestive heart failure 3.4-5.8
Active metabolite (enalaprilat) 35-38 hrs

Onset:1 hr
Time to peak:
Oral; 0.5-1.5 hr
IV: 3-4.5 hr

Metabolism:
Pro-drug hepatically metabolized to enalaprilat
Excretion:
60-80% urine and some in feces

50-60%

Fosinopril

Monopril®

Treatment of heart failure and hypertension either alone or in combination with other medications

Fosinopril
10 mg tab
20 mg tab
40 mg tab
Monopril
10 mg tab
20 mg tab
40 mg tab

Fosinopril
10 mg tab $1.19
20 mg tab $1.19
40 mg tab $1.19
Monopril
10 mg tab $1.53
20 mg tab $1.53
40 mg tab $1.70

Active Metabolite (fosinoprilat)
12 hrs

Onset: 1 hr
Time to peak:
3 hrs

Metabolism:
Pro-drug (fosinopril) hydrolyzed in intestinal wall to active metabolite fosinoprilat; also undergoes hepatic metabolism
Excretion:
Urine 45% & feces 50%

95%

Lisinopril

Zestril®

Treatment of hypertension either alone or in combination with other medications, left ventricular dysfunction after MI, acute MI within 24 hrs in stable patients and adjunctive treatment with heart failure

Lisinopril / Zestril
2.5 mg tab
5 mg tab
10 mg tab
30 mg tab
40 mg tab

Lisinopril
2.5 mg tab $0.65
5 mg tab $0.97
10 mg tab $1.00
20 mg tab $1.07
30 mg tab $1.51
40 mg tab $1.56
Zestril
2.5 mg tab $1.02
5 mg tab $1.53
10 mg tab $1.58
20 mg tab $1.69
30 mg tab $2.40
40 mg tab $2.48

11-12 hrs

Onset:1 hr
Time to peak: ~ 7 hrs

Metabolism:
Not metabolized
Excretion:
Unchanged in urine

95%

Perindopril Erbumine

Aceon®

Treatment of hypertension and reduce mortality/nonfatal MI in patients with stable CAD

Perindopril Erbumine / Aceon
2 mg tab
4 mg tab
8 mg tab

Perindopril Erbumine
2 mg tab $1.90
4 mg tab $2.21
8 mg tab $ 2.69
Aceon
2 mg tab $2.11
4 mg tab$2.45
8 mg tab$2.98

Pro-drug: 1.5-3 hrs
Metabolite: 3-10 hrs
Terminal: 30-120 hrs

Onset/time to peak: 1-2 hrs

Metabolism: Hepatic ally hydrolyzed to active metabolite perindoprilate and other active metabolites
Excretion: 75% Urine(4-12% unchanged

Perindopril: 60%; Perindoprilat: 10% to 20%

Quinapril

Accupril®

Treatment of hypertension and heart failure

Quinapril / Accupril
5 mg tab
10 mg tab
20 mg tab
40 mg tab

Quinapril
5 mg tab $1.22
10 mg tab $1.22
20 mg tab $1.22
40 mg tab $1.22
Accupril
5 mg tab $2.05
10 mg tab $2.05
20 mg tab $2.05
40 mg tab $2.05

Pro drug: (Quinopril) 0.8 hrs
Quinaprilat 3 hrs; however half life may be increased with increased CrCl

Onset/time to peak: 1-2 hrs

Metabolism:
Hydrolyzed to quinaprilat
Excretion:
50-60% in urine

Quinapril: 97%; Quinaprilat: 97%

Ramipril

Altace®

Treatment of hypertension alone or in combination with another medication, left ventricular dysfunction after MI and reduce risk of stroke, MI and death

Ramipril/ Altace
1.25 mg cap
2.5 mg cap
5 mg cap
10 mg cap

Ramipril
1.25 mg cap $1.53
2.5 mg cap $1.71
5 mg cap $2.04
10 mg cap $2.10
Altace
1.25 mg cap $1.99
2.5 mg cap $2.35
5 mg cap $2.47
10 mg cap $2.88

Ramiprilat 13-17 hrs
Terminal: >50 hrs

Onset: 1-2 hrs
Time to peak: ramipril ~ 1 hr
Ramiprilat 44%

Metabolism:
Hepatic metabolism of parent drug to active metabolite ramiprilat
Excretion:
Parent and active metabolite: 60% urine and 40% feces

Ramipril: 73%; Ramiprilat: 56%

Trandolapril

Mavik®

Treatment of hypertension alone or in combination with another medication and left ventricular dysfunction after MI

Trandolapril / Mavik
1 mg tab
2 mg tab
4 mg tab

Trandolapril
1 mg tab $1.29
2 mg tab $1.29
4 mg tab $1.29
Mavik
1 mg tab $1.70
2 mg tab $1.70
4 mg tab $1.70

Partent drug (trandolapril) 6 hrs
Active metabolite (trandolaprilat) 10 hours
Terminal: 24 hrs

Onset: 1-2 hours
Time to peak effect: Parent 1 hr
Active metabolite: 4-10 hrs

Metabolism:
Hepatic metabolism of parent drug to active metabolite trandolaprilat
Excretion:
33% urine & 66% feces

80%

COMMENTS[Top]

  • Blood pressure control to goal is advantageous regardless of agent used.
  • Our usual practice is to begin an ACE inhibitor or ARB in people with diabetes found to be hypertensive, proteinuric or both.
  • We do not use ACE inhibitors to "protect the kidneys" in all people with diabetes.
  • Frequently, an antihypertensive from a second drug class must be added to control blood pressure.
  • Numerous trials have shown that ACE inhibitors decrease microalbuminuria and slow progression of diabetic nephropathy in patients with both type 1 and type 2 diabetes[1][2][3].
  • Captopril is the only FDA-approved ACE inhibitor for diabetic nephropathy although other ACE inhibitors may be as effective.
  • Several studies demonstrated that lisinopril is effective in the reducing urinary albumin excretion in diabetes[4].
  • Lisinopril is superior to hydrochlorothiazide in lowering blood pressure, and approximately equal to atenolol and metoprolol in lowering systolic blood pressure. Lisinopril is equivalent to atenolol and metoprolol in lowering diastolic blood pressure.
  • In a well controlled trial of normotensive patients with type 1 diabetes and normoalbuminuria, enalapril 20 mg dose did not slow progression of nephropathy when compared to placebo, but progression of retinopathy was slowed[5]. However, other trials have shown benefit of enalapril in reducing progression of diabetic nephropathy[3].
  • Patients with diabetic nephropathy randomized to fosinopril achieved a reduced 24 hour urine protein excretion, serum creatinine and BUN[6].
  • Trandalopril alone and in combination with verapamil decreased the incidence of microalbuminuria over verapamil alone and placebo in type 2 diabetes with hypertension[7].

References[Top]

  1. Viberti G et al: Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA 271:275, 1994  [PMID:8295285]

    Comment: Randomized, double-blind, placebo-controlled clinical trial of 2 years' duration including 92 patients with insulin-dependent diabetes mellitus and persistent microalbuminuria but no hypertension. Patients randomly allocated to receive either captopril, 50 mg, or placebo twice per day. Progression to clinical proteinuria was significantly reduced by captopril therapy (P = .03 by log-rank test).

  2. Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. The Microalbuminuria Captopril Study Group. Diabetologia 39:587, 1996  [PMID:8739919]

    Comment: 235 normotensive IDDM patients with microalbuminuria participated in double-blind, randomised, placebo-controlled trials to assess the effects of captopril 50 mg twice daily on the progression to overt clinical albuminuria. The risk of progression over 24 months was significantly reduced by captopril (p = 0.004) with a risk reduction of 69.2% (31.7 - 86.1%).

  3. Ravid M et al: Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 118:577, 1993  [PMID:8452322]

    Comment: 94 normotensive, type II diabetic patients with microalbuminuria and normal renal function randomly assigned to receive enalapril, 10 mg per day, or placebo. Difference in rate of change in proteinuria between two groups favored enalapril [P < 0.05])

  4. Schjoedt KJ et al: Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial. Diabetologia 52:46, 2009  [PMID:18974967]

    Comment: At the Steno Diabetes Center, 49 type 1 diabetic patients with diabetic nephropathy participated in double-masked randomised crossover trial with initial washout period followed by three treatment periods of 2 months each, receiving lisinopril 20, 40 and 60 mg once daily in randomised order in addition to slow-release furosemide. Compared with lisinopril 20 mg there was a further reduction in urinary albumin excretion rate of 23% with lisinopril 40 mg and 19% with 60 mg, p < 0.05.

  5. Mauer M et al: Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 361:40, 2009  [PMID:19571282]

    Comment: Multicenter, controlled trial of 285 normotensive patients with type 1 diabetes and normoalbuminuria randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo for 5 years. Authors found that enalapril did not slow nephropathy progression but slowed the progression of retinopathy.

  6. Huang YH et al: [Combination therapy with losartan and fosinopril for early diabetic nephropathy]. Di Yi Jun Yi Da Xue Xue Bao 23:963, 2003  [PMID:13129736]

    Comment: Fifty-seven patients with diabetic nephropathy were divided equally into group A with treatment with losartan (50 mg) and fosinopril (10 mg) daily, group B with daily losartan treatment (50-100 mg), and group C with fosinopril treatment at the daily dose of 10-20 mg for 6-months. Combined use of losartan and fosinopril decreased blood pressure, 24-h urine protein excretion, serum creatinine and BUN to a greater extent than the use of either alone.

  7. Ruggenenti P et al: Preventing microalbuminuria in type 2 diabetes. N Engl J Med 351:1941, 2004  [PMID:15516697]

    Comment: Multicenter double-blind, randomized Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) in subjects with hypertension, type 2 diabetes mellitus, and normal urinary albumin excretion. 1204 subjects randomly assigned to 3 years of trandolapril plus verapamil, trandolapril alone, verapamil alone or placebo. Trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent.

  8. Arauz-Pacheco C et al: Hypertension management in adults with diabetes. Diabetes Care 27 Suppl 1:S65, 2004  [PMID:14693929]

    Comment: American Diabetes Association recommendations for management of hypertension in diabetes.

  9. Lewis EJ et al: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329:1456, 1993  [PMID:8413456]

    Comment: Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy as compared to other similarly effective treatments.

  10. ACE Inhibitors in Diabetic Nephropathy Trialist Group: Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 134:370, 2001  [PMID:11242497]

    Comment: Meta-analysis concluding that ACE inhibitors improve microalbuminuria in normotensive patients with type 1 diabetes mellitus.

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