ACE inhibitors

Stacy Elder Dalpoas, Pharm.D., BCPS, Lipika Samal, M.D.

INDICATIONS

FDA

Diabetic nephropathy (captopril)
Hypertension (HTN)
Heart Failure with Reduced Ejection Fraction (HFrEF)
Proteinuria
See table for ACE inhibitor-specific FDA indications.

MECHANISM

High affinity for angiotensin converting enzyme (ACE) 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, plasma renin activity increases, reducing aldosterone secretion, and lowering BP.

USUAL ADULT DOSING

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: HFrEF/ HTN/Left ventricular dysfunction after myocardial infarction (LVD after MI): 6.25-12.5 mg three times a day (with diuretic) with goal of 50 mg three times a day for HFrEF. Diabetic nephropathy: 25 mg three times a day.
Enalapril: HFrEF/HTN: 2.5-5 mg once or twice daily, increased up to 40 mg/day every 1-2 weeks in 2.5 mg intervals. IV : 1.25 mg/dose every 6 hours
Fosinopril: HFrEF/HTN: 10 mg daily initially, then titrate to effect (max dose 40 mg daily). Usual dose: 20-40 mg daily.
Lisinopril: HTN: Initial 10 mg daily (no diuretic) or 5 mg daily (if on diuretic). Dose range: 10-40 mg daily. HFrEF: Initial: 2.5-5 mg once daily; titrate by 10 mg increments every 2 weeks to target of 20-40 mg/day. Acute MI: 5mg immediately, uptitrated to 10mg daily
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: 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. HFrEF: 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 first 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) max dose=8mg/day; titrate to desired effect in 1 week intervals.

DOSING IN SPECIAL POPULATIONS

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 (and drugs that act on the renin-angiotensin system) 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

COMMON

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

OCCASIONAL

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

RARE

Hematologic: agranulocytosis, neutropenia
Gastrointestinal: intestinal angioedema
Eosinophilic pneumonitis

DRUG INTERACTIONS

Aliskiren enhances the hyperkalemic and nephrotoxic effect of ACE inhibitors, and use of aliskiren with an ACE inhibitor is contraindicated in patients with diabetes.
Sacubitril is contraindicated with ACE inhibitors due to the increased risk of angioedema.
ACE inhibitors may increase the sensitivity to insulin or other antidiabetic agents.
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, and have no indication for concomitant use. Monitor renal function closely with ACE inhibitor and ARBs co-administration.
Lithium: Lithium concentration may be increased. Monitor concentrations with ACE inhibitor co-administration.
Nephrotic agents (e.g., contrast, NSAIDs, aminoglycosides, amphoB): may increase risk of nephrotoxicity. Monitor renal function closely with co-administration.

PHARMACOKINETIC

Tables/Images

Generic Name	Brand Name	FDA indications	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	10-11 hrs	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®	HFrEF, diabetic nephropathy, hypertension and LVD after MI	Captopril 12.5 mg tab 25 mg tab 50 mg tab 100 mg tab	Captropril 12.5 mg tab $ 1.55 25 mg tab $1.66 50 mg tab $2.89 100 mg tab $3.80	1.7 hrs in healthy adults 3.3 hrs in heart failure 20-40 hrs in anuria	Onset: 15 min Peak effect: 1 hr	Metabolism: 50% metabolized hepatically Excretion >95% in urine with 40-50% unchanged	25-30%
Enalapril	Vasotec®	Treatment of hypertension, asymptomatic left ventricular dysfunction and HFrEF	Enalaprilat inj 1.25 mg/mL Enalapril 2.5 mg tab 5 mg tab 10 mg tab 20 mg tab	Enalaprilat inj 1.25 mg/mL (2 mL vial) $3.41 Enalapril 2.5 mg tab $1.46 5 mg tab $ 1.85 10 mg tab $ 1.94 20 mg tab $2.77	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: 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	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%	>99%
Lisinopril	Zestril® or Prinivil (R)	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 $1.55	12 hrs	Onset:1 hr Time to peak: ~ 6 hrs	Metabolism: Not metabolized Excretion: Unchanged in urine	95%
Perindopril	Aceon®	Treatment of hypertension and reduce mortality/nonfatal MI in patients with stable CAD	Perindopril/ Aceon 2 mg tab 4 mg tab 8 mg tab	Perindopril 2 mg tab $1.90 4 mg tab $2.21 8 mg tab $ 2.69	30-120 hrs	Onset/time to peak: 1-2 hrs	Metabolism: Hepatically hydrolyzed to active metabolite perindoprilat and other active metabolites Excretion: 75% Urine	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 $4.43 10 mg tab $4.43 20 mg tab $4.43 40 mg tab $4.43	Pro drug: (Quinapril) 0.8 hrs Quinaprilat 3 hrs; however half life may be increased with increased CrCl	Onset: 1 hr Peak: 2-4 hr	Metabolism: Hydrolyzed to quinaprilat Excretion: 50-60% in urine	Quinapril and 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 $1.81 5 mg cap $1.89 10 mg cap $2.22	Ramiprilat 13-17 hrs Terminal: >50 hrs	Onset: 1-2 hrs Time to peak: ramipril ~ 1 hr Ramiprilat 2-4 hr	Metabolism: Hepatic metabolism to active metabolite ramiprilat Excretion: 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 $1.24 2 mg tab $1.24 4 mg tab $1.24	Parent drug (trandolapril) 6 hrs Active metabolite (trandolaprilat) 10 hours Terminal: 24 hrs	Onset: 1-2 hr Time to peak effect: Parent: 1 hr Active metabolite: 4-10 hrs	Metabolism: Hepatic metabolism of parent drug to active metabolite trandolaprilat and other inactive metabolites Excretion: 33% urine & 66% feces	80%

COMMENTS

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, to prevent progression of diabetic kidney disease.
ACE inhibitors are not indicated in patients with diabetes who do not have proteinuria or hypertension.
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[8][7][10].
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[2].
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[1]. However, other trials have shown benefit of enalapril in reducing progression of diabetic nephropathy [10].
Patients with diabetic nephropathy randomized to fosinopril achieved a reduced 24 hour urine protein excretion, serum creatinine and BUN[5].
Trandalopril alone and in combination with verapamil decreased the incidence of microalbuminuria over verapamil alone and placebo in type 2 diabetes with hypertension[3].

References

Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009;361(1):40-51. [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.
Schjoedt KJ, Astrup AS, Persson F, et al. Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial. Diabetologia. 2009;52(1):46-9. [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.
Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med. 2004;351(19):1941-51. [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.
Arauz-Pacheco C, Parrott MA, Raskin P, et al. Hypertension management in adults with diabetes. Diabetes Care. 2004;27 Suppl 1:S65-7. [PMID:14693929]
Comment: American Diabetes Association recommendations for management of hypertension in diabetes.
Huang YH, Wang HT, Zhu QZ, et al. [Combination therapy with losartan and fosinopril for early diabetic nephropathy]. Di Yi Jun Yi Da Xue Xue Bao. 2003;23(9):963-5. [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.
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. 2001;134(5):370-9. [PMID:11242497]
Comment: Meta-analysis concluding that ACE inhibitors improve microalbuminuria in normotensive patients with type 1 diabetes mellitus.
Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. The Microalbuminuria Captopril Study Group. Diabetologia. 1996;39(5):587-93. [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%).
Viberti G, Mogensen CE, Groop LC, 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. 1994;271(4):275-9. [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).
Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20):1456-62. [PMID:8413456]
Comment: Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy as compared to other similarly effective treatments.
Ravid M, Savin H, Jutrin I, 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. 1993;118(8):577-81. [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])

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