INDICATIONS

MECHANISM

• Angiotensin receptor blockers (ARBs) are selective blockers of angiotensin (AT1) receptors and work by blocking the binding of angiotensin II causing a decrease in systemic vascular resistance. By direct blockade of the angiotensin receptors, ARBs are thought to be associated with fewer side effects related to bradykinin than ACE Inhibitors.

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

ADVERSE DRUG REACTIONS

DRUG INTERACTIONS

• 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. Combination therapy has not been associated with significant benefit.
• 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.

COMMENTS

• Only irbesartan and losartan are FDA approved for use in diabetic nephropathy. However, most ARBs are effective in the treatment of diabetic nephropathy[9][10][8][11] 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, one meta-analysis found that ARBs and ACE inhibitors have comparable efficacy[5] while another meta-analysis found no reduction in the incidence of microalbuminuria or macroalbuminuria with use of ARBs[1].
• In general, ACE inhibitors and ARBs are used relatively interchangeably for patients who have diabetes and hypertension and are the preferred blood pressure agents in the setting of microalbuminuria.
• 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[2].
• 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%[3].

References

1. Lv J, Perkovic V, Foote CV, et al. Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst Rev. 2012;12:CD004136.  [PMID:23235603]
2. Haller H, Ito S, Izzo JL, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364(10):907-17.  [PMID:21388309]
3. NAVIGATOR Study Group, McMurray JJ, Holman RR, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362(16):1477-90.  [PMID:20228403]
4. Bilous R, Chaturvedi N, Sjølie AK, et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med. 2009;151(1):11-20, W3-4.  [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.
   

5. Sarafidis PA, Stafylas PC, Kanaki AI, 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. 2008;21(8):922-9.  [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.
   

6. Kaliuzhina EV, Zibnitskaia LI, Surkova LG, et al. [The effectiveness of eprosartan in patients with chronic glomerulonephritis]. Klin Med (Mosk). 2007;85(8):58-61.  [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.
   

7. Arauz-Pacheco C, Parrott MA, Raskin P. The treatment of hypertension in adult patients with diabetes. Diabetes Care. 2002;25(1):134-47.  [PMID:11772914]

   Comment: ARBs can be considered in the management of HTN in adult patients with diabetes.
   

8. 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. 2002;106(6):672-8.  [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).
   

9. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-60.  [PMID:11565517]

   Comment: Irbesartan is effective in protecting against the progression of nephropathy in patients with type 2 diabetes.
   

10. Parving HH, Lehnert H, Bröchner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870-8.  [PMID:11565519]

    Comment: Irbesartan is renoprotective in patients with type 2 diabetes and microalbuminuria.
    

11. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-9.  [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.
    

12. Tomino Y, Kawamura T, Kimura K, et al. Antiproteinuric effect of olmesartan in patients with IgA nephropathy. J Nephrol. 2009;22(2):224-31.  [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.
    

13. Bakris G, Gradman A, Reif M, et al. Antihypertensive efficacy of candesartan in comparison to losartan: the CLAIM study. J Clin Hypertens (Greenwich). 2001;3(1):16-21.  [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.