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.
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.
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 as a result of increased Na reabsorption in the proximal convoluted tubule. Sodium reabsorption in the proximal convoluted tubule is caused directly by ATII and indirectly by increased aldosterone production in the adrenal cortex which promotes 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, effects of ATII binding to AT2 receptors results in vasodilatation due to increased production of nitrous oxide and bradykinin. Furthermore, activation of AT2 receptors leads to renal sodium excretion. Agonism at AT2 receptors has anti-proliferative and cardiovascular protective effects.
RAAS system blockade can take place at several levels. RAAS-blockers include direct renin inhibitors (DRIs) block production of renin, ACEIs block conversion of AT1 to AT2 by blocking angiotensin-converting enzyme, ARBs antagonize the effect of AII on AT1 receptors and aldosterone antagonists block the effect of aldosterone.
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:
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 as Entrestoand 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 for patients with reduced ejection fraction.
A few caveats to remember about the use of ARBs:
In patients with volume depletion or those who are on diuretics, correct volume depletion prior to starting these agents or start with a lower dose.
Consider using a lower dose in geriatric patients.
Consider q12-hour dosing in patients who experience diminished blood pressure response towards the end of a 24-hour dosing interval.
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.
ARB therapy, as well as ACE use, during pregnancy, reduces perfusion of the fetal kidneys and are associated 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 be advised on 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.
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 the 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 adjustment of drug dosage of either the ARB or the other antihypertensive drugs.
Use of ARBs along with ACEIs or DRIs comes with a higher incidence of hypotension, acute renal failure or hyperkalemia. Combination use of these agents is to be avoided.
There are rare reported cases of adverse effects including urticaria, anaphylaxis, vasculitis, neutropenia, leukopenia, liver function test abnormalities and others.
ARB therapy puts the patient at an increased risk for hypotension, renal impairment, and hyperkalemia and therefore patient's blood pressure, renal function, and serum electrolytes should be monitored closely for the duration of ARB use. Primary care providers should pay specific attention to the full medication list. Lithium concentrations may increase with concomitant use of ARBs.
The proper and successful management of hypertension often requires a whole-person approach that should include a nurse, primary care provider, pharmacist, and specialty physicians able to treat a patient in a wide variety of different causes and etiologies of high blood pressure. It may require diversified help from medical specialties as diabetes, heart failure, renal compromise, and obesity often accompany patients with hypertension. Although ARB therapy is one of many options in the treatment of 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. (Level I) If possible, high blood pressure should be diagnosed and treated early as heart disease continues to affect patients at a younger age.
Along with proper pharmacotherapy in the treatment of 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. (Level ll)
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