ANGIOTENSIN II RECEPTOR BLOCKER (ARB) DOSING

• ACRONYMS AND DEFINITIONS

• ARB - Angiotensin II receptor blocker
• CrCl - Creatinine clearance
• GFR - Glomerular filtration rate
• HCTZ - Hydrochlorothiazide
• P = drugs with pediatric dosing

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• ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs)

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• Kidney disease
• While ARBs are beneficial in treating and preventing kidney disease, their inhibitory effects on the RAAS system can be detrimental when kidneys are severely compensated, leading to elevations in potassium, serum creatinine, and BUN. The risk of adverse effects depends on the degree of kidney disease and concurrent medical problems (e.g. heart failure, diabetes). To help avoid these issues, ARBs should be started at the lowest dose possible and titrated slowly in patients with significant kidney disease.
• The STOP ACEi study (N=411) published in 2022 randomized patients with GFR < 30 ml/min to discontinue or continue their ACE inhibitor or ARB. The primary outcome was GFR at 3 years. At the end of the study, there was no significant difference in GFR between the groups (discontinue - 12.6 ml/min, continue - 13.3 ml/min, p=0.42). End-stage kidney disease or the initiation of renal replacement therapy occurred in 62% of discontinue patients and 56% of continue patients (HR 1.28, 95%CI [0.99 - 1.65]) [PMID 36326117].


• Azilsartan (Edarbi®)
• No dose adjustment necessary
• Candesartan (Atacand®)
• Use caution
• Irbesartan (Avapro®)
• No dose adjustment necessary unless patient is volume depleted
• Losartan (Cozaar®)
• No dose adjustment necessary unless patient is volume depleted
• Olmesartan (Benicar®)
• No initial dose adjustment is recommended
• Telmisartan (Micardis®)
• No initial dose adjustment is necessary
• Valsartan (Diovan®)
• CrCl ≥ 30 ml/min: no dose adjustment necessary
• CrCl < 30 ml/min: has not been studied

• Liver disease dosing
• Azilsartan (Edarbi®)
• Child-Pugh A or B: no dose adjustment necessary
• Child-Pugh C: has not been studied
• Candesartan (Atacand®)
• Child-Pugh B: starting dose should be 8 mg/day when treating hypertension
• Child-Pugh C: has not been studied
• Irbesartan (Avapro®)
• No dose adjustment necessary
• Losartan (Cozaar®)
• Child-Pugh A or B: use starting dose of 25 mg once daily
• Child-Pugh C: has not been studied
• Olmesartan (Benicar®)
• No initial dose adjustment is recommended
• Telmisartan (Micardis®)
• Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency
• Valsartan (Diovan®)
• Child-Pugh A or B: no dose adjustment necessary
• Child-Pugh C: has not been studied

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• DRUG INTERACTIONS

• NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).


• All ARBs
• ACE inhibitors - see combining ARBs and ACE inhibitors
• Aliskiren (Tekturna®) - Aliskiren should not be prescribed with ARBs in patients with diabetes or decreased kidney function (GFR<60ml/min)
• Lithium - ARBs can increase lithium levels. This combination should be avoided, or lithium levels should be checked frequently if they are taken together.
• Medications that can raise potassium levels - ARBs may raise potassium levels and cause hyperkalemia. When taken with other potassium-raising medications, the risk is increased. While it is often appropriate to combine ARBs with other potassium-raising drugs, patients and providers should be aware of the potential risks. See RAAS inhibitor-induced hyperkalemia for recommendations on addressing hyperkalemia in ARB-treated patients.
• Examples of medications that may raise potassium levels include:
• Aldosterone antagonists (spironolactone and eplerenone)
• ACE inhibitors
• Aliskiren (Tekturna®)
• Cyclosporine (Neoral®)
• ENaC inhibitors (triamterene, amiloride)
• Finerenone (Kerendia®)
• Heparin - heparin raises potassium secondarily by inhibiting aldosterone synthesis. LMWH does not appear to have the same effect. [3]
• Penicillin G potassium injection (1 million units contains 1.68mEq of potassium)
• Potassium supplements (K-Dur®, etc)
• Tacrolimus (Prograf®)
• Trimethoprim (part of Bactrim® and Septra®)
• Voclosporin (Lupkynis®)
• NSAIDS (Advil®, Aleve®, etc.) - NSAIDS can attenuate the effect of ARBs. This is more of a concern when NSAIDS are taken on a chronic basis. Cases of decreased kidney function have been reported when NSAIDS were taken with ARBs. The risk appears to be greater with advanced age, dehydration, and underlying kidney disease.
• Salt substitutes (No-Salt®, etc.) - Salt substitutes typically contain a high amount of potassium (16.4 mEq per 1/4 teaspoon). Since ARBs can raise potassium levels, caution should be used when consuming salt substitutes.


• Telmisartan (Micardis®)
• Digoxin - telmisartan has been shown to increase digoxin levels. When taken together, digoxin levels should be monitored.
• Ramipril (Altace®) - Ramipril, an ACE inhibitor, should not be taken with telmisartan. Telmisartan has been shown to significantly increase ramipril levels.

• Metabolism and clearance
• Azilsartan (Edarbi®)
• CYP2C9 - substrate
• Candesartan (Atacand®)
• No significant liver metabolism
• Irbesartan (Avapro®)
• CYP2C9 - substrate
• Losartan (Cozaar®)
• CYP2C9 - substrate
• CYP3A4 - substrate
• P-glycoprotein - substrate
• Olmesartan (Benicar®)
• OATP - substrate
• Telmisartan (Micardis®)
• CYP2C19 - inhibitor
• OATP - substrate
• Valsartan (Diovan®)
• OATP - substrate

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• PRICE ($) INFO

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• BIBLIOGRAPHY

• 1 - Manufacturer's Package Insert for each drug listed
• 2 - PMID 28827377 - Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents, Pediatrics (2017)
• 3 - PMID 22560830 - Use and safety of unfractionated heparin for anticoagulation during maintenance hemodialysis, Am J Kidney Dis (2021)