II. Indications

  1. See ACE Inhibitor for Indications
  2. Intolerance to ACE Inhibitors (esp. cough)
  3. Alternative to ACE Inhibitor when starting a new Antihypertensive
    1. Same indications and efficacy with fewer adverse effects when compared with ACE Inhibitors

III. Contraindications

  1. See ACE Inhibitor for contraindications
  2. ACE inhibitor Induced Angioedema (prior contraindication, debunked)
    1. Angiotensin Receptor Blockers (ARB) do NOT appear to have increased Angioedema risk
    2. ARB Agents do not directly affect bradykinin metabolism (unlike ACE Inhibitors)
      1. ARBs appear safe in those with history of ACE inhibitor Induced Angioedema
    3. ACE InhibitorAngioedema was originally thought to recur with ARB agents in 2 to 10% of patients
      1. Subsequent studies demonstrate no signficant increased risk
      2. Prior recommendation was to avoid ARB if ACE-related reaction was severe
      3. Prior Angioedema observations on ARB were thought residual effects after stopping ACE
        1. Therefore prudent to wait 4-6 weeks before starting ARB after ACE-related Angioedema (see below)
    4. Precautions given to patient to stop ARB immediately and seek emergency care for signs of Angioedema
      1. Wait at least 4 weeks between stopping ACE Inhibitor and starting ARB
      2. (2013) J Allergy Clin Immunol 131:1491-3 [PubMed]
    5. References
      1. Makani (2012) Am J Cardiol 110(3): 383-91 [PubMed]
      2. Rasmussen (2019) J Intern Med 285(5): 553 [PubMed]

IV. Mechanism

  1. See Renin-Angiotensin System
  2. Similar effects to ACE Inhibitors
    1. Antihypertensive effects, renal protective effects and benefits in Congestive Heart Failure
  3. Selectively binds to and inhibits Angiotensin 2 receptor activation
    1. Decreases Aldosterone secretion

V. Preparations: Angiotensin Receptor Blockers

  1. Losartan (Cozaar)
    1. Start: 50 mg orally daily or 25 mg daily if volume depleted (MAX 100 mg/day)
    2. Consider twice daily divided dosing (shorter acting than newer ARBs)
  2. Irbesartan (Avapro)
    1. Start 150 mg orally daily (max 300 mg/day)
  3. Candesartan (Atacand)
    1. Start 8 mg orally daily (maximum 32 mg/day)
    2. Has been used for Migraine Prophylaxis
      1. Messina (2020) J Neurol 267(11):3243-47 +PMID: 32542525 [PubMed]
  4. Eprosartan (Teveten)
    1. Listed for historical reasons - no longer produced by manufacturer
    2. Start 400 mg orally daily (maximum 800 mg/day)
  5. Telmisartan (Micardis)
    1. Start 40 mg orally daily (maximum 80 mg/day)
  6. Valsartan (Diovan)
    1. Start 80 mg orally daily (maximum 320 mg/day)
  7. Olmesartan (Benicar)
    1. Start 20 mg orally daily (maximum 40 mg/day)
  8. Azilsartan (Edarbi)
    1. Start 40 mg orally daily (maximum 80 mg/day)

VI. Preparations: Combination

  1. Amlodipine (and ARB)
    1. Exforge (Amlodipine and Valsartan)
    2. Azor (Amlodipine and Olmesartan)
  2. Hydrochlorothiazide (and ARB)
    1. Most ARB agents are available in combination with Hydrochlorothiazide (Hctz)
  3. Sacubitril and Valsartan (Entresto)
    1. Indicated in Systolic Dysfunction (consider as an alternative to ACE Inhibitor or mono Angiotensin Receptor Blocker)
    2. Sacubitril (Neprilysin Inhibitor) increases vasodilation and Sodium excretion
    3. Risk of Hypotension (Number needed to harm 21)
    4. Risk of Angioedema (Number needed to harm 200)
    5. See Systolic Dysfunction for dosing and references

VII. Protocol: Equivalent dosing (switching between agents)

  1. Losartan (Cozaar) 100 mg daily or divided twice daily
  2. Irbesartan (Avapro) 300 mg daily
  3. Candesartan (Atacand) 16 mg daily
  4. Eprosartan (Teveten) 800 mg daily
  5. Telmisartan (Micardis) 40 mg daily
  6. Valsartan (Diovan) 160 mg daily
  7. Olmesartan (Benicar) 20 mg daily
  8. Azilsartan (Edarbi) 40 mg daily

VIII. Efficacy

  1. Peak effect may require 4-6 weeks
  2. Proteinuria control is equivalent to ACE Inhibitors
    1. Kunz (2008) Ann Intern Med 148:30-48. [PubMed]
  3. Evidence as of 2015 shows similar efficacy of ARBs as ACE Inhibitors in Myocardial Infarction prevention
    1. (2016) Presc Lett 23(3): 13
  4. Avoid in combination with ACE Inhibitors
    1. No advantage to combinations in Hypertension, vascular disease, Diabetes Mellitus, Coronary Artery Disease
    2. Moderate benefit of combination therapy in Congestive Heart Failure
    3. (2013) Prescr Lett 20(3): 13
  5. Reduce cardiovascular death, Cerebrovascular Accident and Myocardial Infarction risk
    1. Higher level cardiovascular protection than Atenolol
      1. However Atenolol is not the best Beta Blocker for cardiovascular disease prevention
      2. Dahlof (2002) Lancet 359:995-1003 [PubMed]
    2. ARBs do not effect Angiotensin II type 2 receptors
      1. Results in less effect on fibrosis and Blood Flow
      2. Unlike ACE Inhibitors, ARBs don't effect nitric oxide
      3. (2005) Prescriber's Letter 12:31-2

IX. Adverse Effects

  1. See ACE Inhibitors (similar adverse effects)
  2. Hyperkalemia
    1. See ACE Inhibitor for related Drug Interactions risking Hyperkalemia
    2. Higher risk with Renal Insufficiency and Diabetes Mellitus
  3. Teratogenicity in second or third trimester
    1. Fetal injury or death
  4. Renal Insufficiency
    1. Renal Artery Stenosis (see monitoring below)
    2. No Creatinine level is absolute contraindication
    3. Baseline Serum Creatinine <3.0 mg/dl is safe for starting ACE Inhibitor (but monitor closely)
    4. Serum Creatinine may normally increase up to 30% over baseline on starting Angiotensin Receptor Blocker
  5. Hypotension
    1. Higher risk when first adding an ACE Inhibitor to a Diuretic
    2. Restart ARB at half prior dose
    3. Decrease or hold dose of any concurrent Diuretic
  6. Angioedema
    1. Far less common than with ACE Inhibitors
    2. ARBs are no longer contraindicated after ACE inhibitor Induced Angioedema (see contraindications above)

X. Safety

  1. Pregnancy: Category X
    1. Stop Angiotensin Receptor Blockers as soon as pregnancy is known
    2. Serious Teratogenicity risk to fetus if continued into second or third trimester
    3. Effects include Anuria, Hypotension, Renal Failure, skull hypoplasia, fetal death
  2. Lactation
    1. Angiotensin Receptor Blockers have unknown safety in Lactation
    2. ACE Inhibitors carry a risk of Hypotension in newborns and most are not compatible with Lactation
  3. Recalls
    1. N-Nitrosodimethylamine (NMDA) or N-nitrosodiethylamine (NDEA) product contamination (FDA recall 2018)
      1. Affected Valsartan (Diovan), Irbesartan (Avapro) and Losartan (Cozaar)
      2. https://www.fda.gov/Drugs/DrugSafety/ucm613916.htm
      3. https://www.fda.gov/Safety/Recalls/ucm624593.htm
      4. https://www.fda.gov/Safety/Recalls/ucm625492.htm
      5. Product contamination may have been for as long as 4 years
      6. Cancer risk 1 in 8000 patients taking Valsartan for 8 years at 320 mg/day
      7. (2018) Presc Lett 25(9): 49

Images: Related links to external sites (from Bing)

Related Studies