- Diabetic nephropathy (Irbesartan, Losartan)
- Stroke and cardiovascular risk reduction
- Congestive heart failure
- See table below for ARB-specific FDA indications.
Formulation & U.S. Cost per unit dose
Onset / time to peak
Treatment of hypertension either alone or in combination with other medications, treatment of NYHA class II-IV heart failure
Metabolized to candesartan by intestinal wall cells
Treatment of hypertension either alone or in combination with other medications
Peak: 1-2 hrs
Metabolized: minimal hepatic
Treatment of hypertension either alone or in combination with other medications, treatment of Type 2 diabetic nephropathy
Onset/Peak: 1-2 hrs
Metabolism: hepatic CYP2C9
Treatment of hypertension either alone or in combination with other medications. Treatment of Type 2 diabetic nephropathy, stroke risk reduction in hypertension and left ventricular hypertension
Losartan 1.5-2 hrs and E 3174 (active metabolite) 6-9 hrs
Metabolism: hepatic (14%) via CYP2C9 and 3A4 to active metabolite E 3174
Highly protein bound to albumin
Treatment of hypertension either alone or in combination with other medications
Peak: 1-2 hrs
Metabolism: hydrolysis in the GI tract to active olmesartan
Treatment of hypertension either alone or in combination with other medications, cardiovascular risk reduction in pts > 55 years old at risk for a major cardiovascular event
Treatment of hypertension either alone or in combination with other medication, cardiovascular risk reduction in patients with left ventricular dysfunction post MI and treatment of heart failure NYHA class II-IV
**Patient Assistant Programs:
https://www.rxhope.com…** Information gathered by Heather Tran and Gladimir Elysee
- Angiotensin receptor blockers (ARBs) are selective blockers of AT1 angiotensin receptors and work by blocking the binding of angiotensin II causing a decrease in systemic vascular resistance.
USUAL ADULT DOSING
- Candesartan: Hypertension: 4-32 mg once daily initially and titrate to effect. Heart failure: Initial: 4 mg once daily. Titrate to effect by doubling dose every 3 weeks. Max dose 32 mg.
- Eprosartan: 600 mg once-daily initially (dose should individualized). Limited data on doses greater than 800 mg.
- Irbesartan: Hypertension: 150 mg once daily initially. Titrate to 300 mg once daily. Nephropathy: Target dose 300 mg once daily.
- Losartan: Hypertension: 50 mg once or twice daily, dose range 25-100 mg. Diabetic nephropathy: Initial: 50 mg once daily. Dose can be increased to 100 mg once daily based on blood pressure response. Stroke reduction: Initial: 50 mg once daily. Max dose 100 mg.
- Olmesartan: 20 mg once daily initially. Titrate to effect after two weeks, the dose may be increased to 40 mg once daily.
- Telmisartan: Hypertension: 40 mg once daily initially. Usual dose 20-80 mg daily Cardiovascular risk reduction: Initial: 80 mg daily
- Valsartan: Hypertension: 80-160 mg once daily initially. Max dose 320 mg daily. Cardiovascular risk reduction: 20 mg twice daily. Target dose 160 mg twice daily Heart failure: Initial: 40 mg twice daily. Typical doses between 80-160 mg twice daily. Max dose 320 mg daily.
DOSING IN SPECIAL POPULATIONS
- CrCl ≥ 30 ml/min: no dosage adjustment is needed.
- For adults, no dosage adjustment needed, unless the patient is also volume-depleted.
- Candesartan, Losartan, Telmisartan: Consider dose reduction with hepatic impairment.
- Eprosartan, Olmesartan, Valsartan: Use standard dose with close monitoring.
- FDA Category D. Avoid in pregnancy.
- Black box warning: can cause injury or death to a developing fetus when used during the second and third trimesters.
- It is not known if losartan or its metabolite are excreted into breast milk; however, significant levels are present in rat milk. Breast-feeding is not recommended during losartan therapy because of the potential for adverse effects in the infant.
ADVERSE DRUG REACTIONS
- Generally well tolerated.
- Dyspepsia and diarrhea
- Myalgia and muscle cramps
- Renal failure (CHF and volume depletion are risk factors)
- Losartan and irbesartan are CYP 1A2, 2C9, and 3A4 substrates. Valsartan and candesartan are only CYP2C9 substrates. Inhibitors and inducers of these CYP isoenzymes may increase and decrease the serum concentrations of these ARBs.
- ACE inhibitors combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, and doubling of serum creatinine.
- Eplerenone, potassium-sparing diuretics and potassium supplements co-administration may result in hyperkalemia.
- Rifampin and phenobarbital may decrease all ARBs serum concentrations. Monitor for therapeutic efficacy and titrate to effect.
- CYP2C9 inhibitors (e.g. azole antifungals, fluoxetine, sertraline, amiodarone, cimetidine) may increase serum concentrations of valsartan and candesartan. Use lowest dose and monitor closely with co-administration.
- CYP1A2 inhibitors (e.g. ciprofloxacin and fluvoxamine) may increase serum concentrations of losartan and irbesartan. Use lowest dose and monitor closely with co-administration.
- CYP3A4 inhibitors (e.g. HIV protease inhibitors, azole antifungals, macrolide antibiotics) may increase serum concentrations of losartan and irbesartan. Use lowest dose and monitor closely with co-administration.
- Only irbesartan and losartan are FDA approves for use in diabetic nephropathy. However, most ARBs are effective in the treatment of diabetic nephropathy     and offer good alternatives for patients intolerant to ACE inhibitor (i.e. cough).
- Compared with ACE inhibitors, ARBs have less common occurrence of cough as a side effect, so are a reasonable alternative either as first choice or if patients develop cough after using ACE inhibitors.
- Although more renal protection data is available with ACE inhibitors, a meta-analysis found that ARBs and ACE inhibitors have comparable efficacy .
- There is evidence that ARBs, like ACE inhibitors, slow the development of diabetic nephropathy, though results from one study were interpreted with caution due to excess cardiovascular deaths in the ARB intervention group .
- However, a meta-analysis which included 5 studies of ARBs in patients with diabetes found no reduction in the incidence of microalbuminuria or macroalbuminuria .
- There is evidence that ARBs, in addition to lifestyle modification, may prevent the development of diabetes. In a study of patients with impaired glucose tolerance and cardiovascular risk factors, a daily dose of valsartan reduced the incidence of diabetes by 14% .
- Viberti G, Wheeldon NM, MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators: Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 106:672, 2002 [PMID:12163426]
Comment: 332 patients with type 2 diabetes and microalbuminuria were randomized to receive valsartan or amlodipine and the valsartan group reverted to normoalbuminuria at a higher rate(29.9% versus 14.5%; P<0.001).
- Arauz-Pacheco C, Parrott MA, Raskin P: The treatment of hypertension in adult patients with diabetes. Diabetes Care 25:134, 2002 [PMID:11772914]
Comment: ARBs can be considered in the management of HTN in adult patients with diabetes.
- Haller H et al: Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 364:907, 2011 [PMID:21388309]
- Bilous R et al: Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med 151:11, 2009 [PMID:19451554]
Comment: In a placebo controlled study for the treatment of diabetic nephropathy in normotensive type 1 and type 2 diabetics, 32 mg/day of candesartan did not prevent microalbuminuria after 4.7 years of follow-up, but may be due to recruitment of mainly patients with well-controlled hypertension who were at low overall vascular risk, which resulted in a low rate of microalbuminuria.
- Tomino Y et al: Antiproteinuric effect of olmesartan in patients with IgA nephropathy. J Nephrol 22:224, 2009 Mar-Apr [PMID:19384840]
Comment: In an observational study, patients were found to have a reduction in urinary protein after a 16 week trial of olmesartan. The reduction in urinary protein was independent of BP lowering properties.
- Lewis EJ et al: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851, 2001 [PMID:11565517]
Comment: Irbesartan is effective in protecting against the progression of nephropathy in patients with type 2 diabetes.
- Parving HH et al: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870, 2001 [PMID:11565519]
Comment: Irbesartan is renoprotective in patients with type 2 diabetes and microalbuminuria.
- Kaliuzhina EV et al: [The effectiveness of eprosartan in patients with chronic glomerulonephritis]. Klin Med (Mosk) 85:58, 2007 [PMID:17926494]
Comment: Limited data of eprosartan in diabetic nephropathy. A small open label study of 15 patients, showed that over 12 weeks showed a potential renal protective (defined as a anti proteinuric and anti hematuric effect) effect at a dose of 600 mg daily.
- Lv J et al: Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst Rev 12:, 2012 [PMID:23235603]
- NAVIGATOR Study Group et al: Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 362:1477, 2010 [PMID:20228403]
- Brenner BM et al: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861, 2001 [PMID:11565518]
Comment: Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study randomized 1513 patients to losartan or placebo and losartan group had lower primary end point of combined doubling of the creatinine concentration, end-stage renal disease, or death.
- Sarafidis PA et al: Effects of renin-angiotensin system blockers on renal outcomes and all-cause mortality in patients with diabetic nephropathy: an updated meta-analysis. Am J Hypertens 21:922, 2008 [PMID:18535536]
Comment: A meta-analysis of 24 studies, (20 using ACEIs and 4 using ARBs) found that the use ACEIs was associated with a trend toward reduction of ESRD incidence (RR 0.70; 0.46-1.05) and use of ARBs with significant reduction of ESRD risk (RR 0.78; 0.67-0.91). Both drug classes were associated with reduction in the risk of doubling serum creatinine.
- Bakris G et al: Antihypertensive efficacy of candesartan in comparison to losartan: the CLAIM study. J Clin Hypertens (Greenwich) 3:16, 2001 Jan-Feb [PMID:11416677]
Comment: When given at the maximum dose, there were statistically significantly (p < 0.05) higher proportions of responders in the candesartan treated patients (62.4% and 56.0%, respectively) than in the losartan group.
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