Angiotensin II Receptor Antagonists

Synonyms: AIIRAs, AT1 receptor antagonists, angiotensin receptor blockers, ARB, AIIRAs

This class of drug inhibits the effects of angiotensin II and therefore reduces blood pressure and cardiac afterload. Angiotensin II receptor antagonists (AIIRAs) are licensed for the management of hypertension, heart failure and diabetic nephropathy and have similar properties as angiotensin-converting enzyme (ACE) inhibitors.¹

• Angiotensinogen is converted into angiotensin I by renin, which is released from the renal juxtaglomerular apparatus in response to reduced blood pressure or reduced plasma sodium concentration.
• ACE catalyses the conversion of angiotensin I to angiotensin II.
• Angiotensin II stimulates angiotensin receptors and causes vasoconstriction and secretion of aldosterone.
• Aldosterone increases reabsorption of sodium and water in the distal tubule of the kidney.^2,3

The renin-angiotensin-aldosterone system controls blood pressure and plasma sodium concentration.

• AIIRAs block angiotensin receptors, resulting in vasodilation and reduced adrenal secretion of aldosterone and therefore lower blood pressure and reduced afterload.
• Angiotensin receptor blockers do not inhibit the breakdown of bradykinin but are less likely to be associated with the same side effects such as cough and angioedema that are associated with ACE inhibitors.
• Pharmacokinetic profile permits single daily dosing.¹

For all indications, the use of AIIRAs is currently restricted to alternative, second line therapy for patients who are unable to tolerate ACE inhibitors (e.g.due to cough).^4,5,6,7

Hypertension

Treatment of hypertension decreases the frequency of stroke, coronary events, heart and renal failure. Current guidelines now suggest that an AllRA should be used to initiate treatment in patients with hypertension under the age of 55 if an ACE inhibitor is not well tolerated.⁵ Patients that most benefit from first line treatment of hypertension with ACE inhibitor or AIIRA include:⁸

• Young, Caucasian patients in whom hypertension is often related to high renin levels
• Patients with chronic renal disease, to slow progression of renal impairment
• All patients with type II diabetes mellitus due to its cardiac and renal protective effects
• Type II diabetics with established nephropathy

AIIRAs have equivalent blood pressure lowering efficacy to ACE inhibitors. The dose of AIIRAs should be up titrated to the maximum recommended dose to achieve blood pressure targets.¹ Most hypertensive patients require combination therapy to control blood pressure. AIIRAs can be safely combined with thiazide diuretics and/or calcium channel blockers if necessary.⁸ Initial trials suggested that combining an ACEI and an ARB may be of benefit.⁹ However, a subsequent review of the available literature was critical of these trials, and suggested that they were unable to distinguish a true pharmacological interaction from a simple additive effect. Further work on the safety of this combination was needed and it was suggested, at least for hypertensive patients who did not suffer from renal failure, it was better to follow existing British Hypertension Society guidelines and add a diuretic or calcium channel blocker to an ACEI or ARB if necessary.¹⁰

Heart failure

Drug therapy is necessary for most patients with heart failure due to left ventricular systolic dysfunction. Diuretics, ACE inhibitors and beta-blockers are most commonly used.¹¹ However it has been shown that AIIRAs significantly reduce mortality and hospitalisation for patients who are intolerant of ACE inhibitors.¹² Recent evidence also suggests that patients under specialist care may benefit from combination treatment with beta-blocker, ACE inhibitor plus AIIRA, which had previously been considered harmful.¹³ ACE inhibitor or AIIRA therapy is recommended, for use in the early management of patients with symptomatic or asymptomatic ventricular dysfunction.¹¹

Diabetic nephropathy⁸

Although all antihypertensive therapy slows the progression of diabetic nephropathy, ACE inhibitors and AIIRAs exert additional, independent benefits, particularly in type II diabetes. Recent guidelines state that diabetics with persistent, significant microalbuminuria/ proteinuria benefit from ACE inhibitor/ AIIRA therapy, regardless of blood pressure.
ACE inhibitors/ AIIRAs have renoprotective effects beyond that of simple blood pressure control.
A combination of ACE and AIIRA is occasionally used in nephropathy (both diabetic and non-diabetic). A meta-analysis has shown that this results in a significant decrease in proteinuria. Whilst this finding is interesting, further research is required to find out whether this decrease is maintained in the and whether any clinical benefit results in terms of long-term preservation of renal function.¹⁴

• Bilateral renal artery stenosis: causes severe and progressive renal failure.¹
• Pregnancy: drugs that disrupt the renin-angiotensin-aldosterone system during the second or third trimesters interfere with foetal blood pressure control and renal function and have been associated with foetal kidney and skull maldevelopment.
• Breast-feeding: insufficient data regarding secretion of the drug in milk and its potential effects.¹⁵

• Aortic/ mitral stenosis/ obstructive hypertrophic cardiomyopathy: risk of hypotension and syncope.
• Renovascular disease and renal impairment.
• Women of child-bearing age.

The AIIRAs are generally very well tolerated and no specific side-effects have yet been identified. However, consider reduced drug doses in patients at high risk of the following,

• Hypotension
• Renal impairment
• Hyperkalaemia.

• Check U&E, creatinine and blood pressure before starting AIIRAs.
• Stop potassium-sparing diuretics and potassium supplements (concurrent low-dose spironolactone therapy needs careful monitoring).
• Stop NSAIDs if possible to minimise risk of renal impairment.
• It is not usually necessary to withhold diuretics but see instructions below.
• Initiate treatment at low dose and warn patients to lie down for 2-4 hours because of the risk of first-dose hypotension.
• Treatment can be started in the community for the majority of patients but if there is significant risk of first-dose hypotension or renal failure the patient may benefit from initiation in hospital. Risk factors include:
  • Creatinine >150 μmol/L
  • Urea >12 mmol/L
  • Sodium <130 mmol/L
  • Systolic blood pressure < 100mmHg
  • Diuretic dose > 80mg frusemide or 2mg bumetanide daily
  • Suspected renal artery stenosis eg if known peripheral vascular disease
  • Age > 70 years and frail
  • Hypovolaemia
  • Unstable heart failure
  • Concurrent, high-dose vasodilator therapy
• If hospital admission is not possible, diuretics should be withheld for at least 24 hours and treatment initiated at home. Blood pressure must be monitored carefully for 2 hours.
• Titrate dose up over a minimum of 4 weeks until target dose or target blood pressure is reached.
• Titrate more cautiously in high-risk patients.

Current guidelines recommend the same monitoring schedule as is required for ACE inhibitors.

• Serum creatinine and potassium should be checked after 3 weeks of AIIRA therapy but consider more frequent monitoring if at high-risk of renal impairment or hyperkalaemia.⁶
• Continue to monitor at increasing intervals until stable on optimum dose
• Monitor 6 to 12 monthly thereafter.