Continuing Education Activity

Pharmaceutical RAAS blockade is a common and successful strategy in treating several diseases, including hypertension, congestive heart failure, and chronic kidney disease of all types, including diabetic nephropathy. Indications for the use of ARBs are similar to those for ACEIs. However, in patients who cannot tolerate ACEI therapy due to an ACEI-induced cough or angioneurotic edema, ARB therapy is appropriate and suggested as an alternative. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of ARB therapy in the clinical setting related to the essential points needed by members of an interprofessional team managing the care of patients with hypertension and its related conditions and sequelae.

Objectives:

• Identify the mechanism of action of ARBs.
• Summarize the indications for ARB therapy and their place in antihypertensive strategy.
• Review the need for monitoring and follow-up with ARB therapy, including possible adverse reactions.
• Explain the importance of ARB therapy in hypertension management and how it affects therapeutic strategy as it pertains to improving care coordination and communication among the interprofessional team when using these agents to achieve therapeutic outcomes.

Indications

The renin-angiotensin-aldosterone system (RAAS) is intricately involved in the pathophysiology of several diseases, including hypertension, congestive heart failure, and chronic kidney disease of all types, including diabetic nephropathy. Pharmaceutical RAAS blockade has is a common and successful strategy in each of these conditions.[1][2][3] 

Mechanism of Action

Renin secretion is by the juxtaglomerular cells of the kidneys and catalyzes the conversion of angiotensinogen to angiotensin I (ATI) in the liver. ATI is converted to angiotensin II (ATII) by angiotensin-converting enzyme (ACE) and other non-ACE pathways.[2]

ATII is the principal vasoactive peptide in the RAAS and acts on two receptors, AT1 and AT2. ATII activation of AT1 receptors causes an increase in blood pressure due to contraction of vascular smooth muscle, increased systemic vascular resistance, increased sympathetic activity, sodium (Na), and water retention due to increased Na reabsorption in the proximal convoluted tubule.[3] Sodium reabsorption in the proximal convoluted tubule is caused directly by ATII and indirectly by increased aldosterone production in the adrenal cortex, promoting distal Na reabsorption. Chronically high levels of ATII causes smooth muscle and cardiac muscle cell growth and proliferation, endothelial dysfunction, platelet aggregation, enhanced inflammatory responses, and mediation of apoptosis. On the other hand, the effects of ATII binding to AT2 receptors results in vasodilatation due to increased production of nitrous oxide and bradykinin.[4] Furthermore, activation of AT2 receptors leads to renal sodium excretion. Agonism at AT2 receptors has anti-proliferative and cardiovascular protective effects.[3]

RAAS system blockade can take place at several levels. RAAS-blockers include direct renin inhibitors (DRIs), which block the production of renin, ACEIs block conversion of AT1 to AT2 by blocking the angiotensin-converting enzyme, ARBs antagonize the effect of AII on AT1 receptors, and aldosterone antagonists block the effect of aldosterone.[5][6]

Administration

Indications for the use of ARBs are similar to those for ACEIs. However, in patients who cannot tolerate ACEI therapy due to an ACEI-induced cough or angioneurotic edema, ARB therapy is appropriate and suggested as an alternative. Currently available angiotensin receptor blockers, their FDA approved indications, and dosing for these indications are as follows:

Azilsartan

• Available as 40 and 80 mg tablet

Dosing:

• Hypertension: Initial dose: 20 mg by mouth once daily, maximum daily dose: 80 mg

Candesartan 

• Available as 4 mg, 8 mg, 16 mg, 32 mg tablet

Dosing: 

• Hypertension: Initial dose: 16 mg by mouth once daily, maximum daily dose: 32 mg
• Heart failure: Initial dose: 4-8 mg by mouth once daily, maximum daily dose: 32 mg

Eprosartan

• Available as 400 mg, 600 mg tablet

Dosing: 

• Hypertension: Initial dose: 600 mg by mouth once daily, maximum daily dose: 900 mg

Irbesartan

• Available as 75 mg, 150 mg, 300 mg tablet

Dosing: 

• Hypertension: Initial dose: 150 mg by mouth once daily, maximum daily dose: 300 mg
• Diabetic nephropathy: Initial dose: 75 mg by mouth once daily, maximum daily dose: 300 mg

Losartan

• Available as 25 mg, 50 mg, and 10 mg tablet

Dosing:

• Hypertension: Initial dose: 50 mg by mouth once daily, maximum daily dose: 100 mg
• For stroke prevention in hypertensive patients with a history of left ventricular hypertrophy (this does not apply to African-American patients): Initial dose: 50 mg by mouth once daily, maximum daily dose: 100 mg
• For the treatment of proteinuria or diabetic nephropathy: Initial dose: 50 mg by mouth once daily, maximum daily dose: 100 mg

 Olmesartan

• Available as 5 mg, 20 mg, and 40 mg tablet

Dosing:

• Hypertension: Initial dose: 20 mg by mouth once daily. Maximum daily dose: 40 mg

Telmisartan

• Available as 20 mg, 40 mg, and 80 mg tablet

Dosing:

• Hypertension: Initial dose: 40 mg by mouth once daily, maximum daily dose: 80 mg
• To reduce cardiovascular-related mortality in adults age 55 years and older who have risk factors for serious cardiovascular events and who cannot tolerate ACEI, stroke prophylaxis, and myocardial infarction prophylaxis.
• Initial dose: 80 mg by mouth once daily, maximum daily dose: 80 mg

Valsartan

• Available as 40mg, 80 mg, 160 mg and 320 mg tablet

Dosing:

• Hypertension: Initial dose 80-160mg by mouth once daily, a maximum daily dose of 320 mg
• For reducing cardiovascular mortality in otherwise stable patients with a history of left ventricular failure and or left ventricular dysfunction (LVD) following acute myocardial infarction.
• Heart failure: Initial dose: 20 mg by mouth twice a day, maximum daily dose: 160 mg bid
• Heart failure: Initial dose: 20 to 40 mg by mouth twice a day, maximum dose of 160 mg bid

ARBs are available combined with other medications. A few examples are listed below.

• Valsartan and amlodipine
• Irbesartan and hydrochlorothiazide
• Losartan potassium and hydrochlorothiazide
• Valsartan and hydrochlorothiazide
• Valsartan and nebivolol

The combination of valsartan and sacubitril (neprilysin inhibitor) is available and approved for reducing the risk of cardiovascular death, decreasing hospitalization for heart failure in patients with chronic heart failure (NYHA Class II through IV) and patients with reduced ejection fraction.

A few caveats to remember about the use of ARBs:

In patients with volume depletion or in those who are on diuretics, correct volume depletion before starting these agents or start with a lower dose.

Consider using a lower dose in geriatric patients.

Consider every 12-hour dosing in patients who experience diminished blood pressure response towards the end of a 24-hour dosing interval.

Adverse Effects

ARBs are generally well tolerated and have a low incidence of side effects. The incidence of angioedema and cough with ARBs is less than that with ACEIs because ARBs do not increase bradykinin levels though reports of rare cases of both exist with the use of ARBs. ARBs can cause hypotension and/or renal failure in patients whose arterial blood pressure or renal function is highly dependent on the RAAS. For this reason, these drugs are contraindicated in patients with bilateral renal artery stenosis or patients with heart failure who have hypotension.[7][8]

Contraindications

ARB therapy and ACE use during pregnancy reduce perfusion of the fetal kidneys and correlate with renal dysgenesis, fetal oliguric or anuric renal failure, oligohydramnios, skeletal or skull deformities, pulmonary hypoplasia, and death of the fetus. ARBs are FDA classified as a category D risk during pregnancy, and patients who may become pregnant while taking ARBs should understand the importance of birth control. These patients should be educated on different options to control blood pressure should they become pregnant and need to switch to a different antihypertensive therapy. For patients who have become pregnant or think they have become pregnant, ARB therapy should be stopped immediately unless such therapy is considered life-saving for the mother.[8]

No published evidence exists on the safe use of ARBs during breastfeeding, and the effects of potential exposure to a nursing infant are unknown. Newborn infants are at theoretical risk of hypotension due to ARB as these drugs may end up in breast milk. A decision to continue or stop breastfeeding is a necessary discussion between the primary care provider and the patient.  

ARBs may lead to hyperkalemia in patients with renal disease or patients taking agents likely to cause hyperkalemia (K+ supplements, K+ sparing diuretics, ACEIs, DRIs, non-steroidal anti-inflammatory agents), and care should be exercised prescribing ARBs in these patients or avoided altogether.

ARBs potentiate the blood pressure-lowering effect of other antihypertensive drugs and may require adjusting the drug dosage of either the ARB or the other antihypertensive drugs.

The use of ARBs, along with ACEIs or DRIs, comes with a higher incidence of hypotension, acute renal failure, or hyperkalemia. The combined use of these agents is no longer a recommendation and should be avoided.

There are rare reported cases of adverse effects, including urticaria, anaphylaxis, vasculitis, neutropenia, leukopenia, liver function test abnormalities, and others.[9]

Monitoring

ARB therapy puts the patient at an increased risk for hypotension, renal impairment, and hyperkalemia. Therefore patient's blood pressure, renal function, and serum electrolytes should be monitored closely for the duration of ARB use.[10] Primary care providers should pay specific attention to the full medication list. Lithium concentrations may increase with concomitant use of ARBs.[11][12]

Enhancing Healthcare Team Outcomes

The proper and successful management of hypertension often requires a whole-person approach that should include clinicians, mid-level practitioners, nurses, the primary care provider, pharmacists, and specialists to treat a patient with a wide variety of different etiologies of high blood pressure. It may require diversified help from medical specialties since diabetes, heart failure, renal compromise, and obesity often accompany hypertension. This demonstrates an interprofessional team approach to patient care. Although ARB therapy is one of many options in treating hypertension and concomitant conditions of diabetes and or heart failure, early treatment in the face of such a diagnosis has proven to have great success in treating hypertension.[2] [Level 1] If possible, high blood pressure should be diagnosed and treated early as heart disease continues to affect patients at a younger age.[13]

When initiating ARB therapy, a pharmacist should also have involvement to verify dosing, check for drug interactions and contraindications, counsel the patient, and report back to the prescriber if there are any areas of concern. Likewise, nursing should answer patient questions, instruct them on proper administration, and maintain open communication with the prescriber and the pharmacist. This interprofessional team methodology ensures optimal patient results from ARB treatment. [Level 5]

Along with proper pharmacotherapy in treating hypertension, physicians overseeing ARB therapy should encourage patients to begin a weight loss program. Decreased inflammation and a reduction in systolic hypertension are all possible benefits of patients controlling their weight.[14] [Level 2]