21. Drugs acting on the renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system

This system is better known as RAAS. It plays a central role in the control of Na+ excretion, sympathetic activity, fluid volume and vascular tone.

Renin is produced by the juxtaglomerular apparatus in the kidney. It’s an enzyme that converts angiotensinogen produced by the liver into angiotensin I. Angiotensin I doesn’t have any important biological activity, so it’s converted into angiotensin II by the enzyme angiotensin-converting enzyme, also called ACE. ACE is a membrane-bound enzyme found on the surface of endothelial cells, especially in the lung.

Angiotensin II acts on two receptors, AT1 and AT2. They have opposite effects, although AT2 is much less active than AT1, so only AT1 is clinically important. AT1 has the following effects:

• Vasoconstriction, especially in the efferent arterioles of the glomeruli
• Increased noradrenaline release from the brain
• Increased proximal tubular reabsorption of Na+
• Stimulates secretion of aldosterone
• Stimulates growth of heart and vascular cells

Angiotensin II activates NF-κB, the famous inflammatory transcription factor. This stimulates inflammation, fibrosis and hypertrophy in the heart, which contributes to heart disease.

Angiotensin II is a very potent hypertensive molecule – it’s 40 times as potent as noradrenaline. It mainly constricts vessels in the skin, splanchnic organs and the kidney.

There are multiple points at which the RAAS can be inhibited:

• Renin release – inhibited by β blockers
• Renin activity – inhibited by renin inhibitors
• ACE – inhibited by ACE inhibitors
• Angiotensin II receptors – inhibited by AT1-receptor blockers
• Aldosterone receptors – inhibited by aldosterone-receptor antagonists

No RAAS-affecting drugs should be used in pregnant women.

RAAS plays an important role in cardiovascular disease, the major cause of mortality in the western world. By modifying RAAS can we decrease:

• Hypertension
  • By reducing systemic vascular resistance and reducing aldosterone-mediated fluid retention
• Heart disease
  • By reducing inflammation, fibrosis, hypertrophy in the heart, by decreasing hypertension, and by being renoprotective
• Chronic kidney disease
  • RAAS-inhibitors slow the progression of chronic kidney disease by increasing renal blood flow and through other mechanisms

Renin inhibitors

The only important renin inhibitor is aliskiren. It’s an orally active non-peptide molecule that binds to the active site of renin and blocks it.

It’s used to treat primary (essential) hypertension. It's rarely used.

ACE inhibitors

ACE inhibitors are often abbreviated as ACEI. They all end in -pril. The most important ones are captopril, enalapril, lisinopril and ramipril. They have many beneficial effects:

• Reduce sympathetic activity
• Reduce total peripheral resistance
• Reduce aldosterone secretion
• Increase perfusion of the kidneys
• Reduce afterload and preload
• Reduce myocardial hypertrophy
• Reduce ADH secretion

Indications

They’re the first line treatment of non-complicated hypertension, especially when there is also diabetes or cardiovascular disease. It’s also used to treat heart failure and as secondary prevention against myocardial infarction after the patient has had one.

They’re also renoprotective, meaning that they have beneficial effects on renal diseases. For this reason they’re indicated in diabetic nephropathy and other chronic kidney diseases.

Side effects

• Hypotension
  • The initial depressor effect can be strong
• Dry cough
  • Dose-independent, goes away after treatment.
  • Probably due to accumulation of bradykinin
• Hyperkalaemia
  • Especially in patients who take K+-sparing diuretics
• Skin rash
• Angioedema
• Acute kidney injury

Interactions

• Antacids – decrease their oral bioavailability
• K+-sparing diuretics and K+ supplements – may worsen a potential hyperkalaemia

Angiotensin II receptor Blockers

The ARBs block the AT1 receptor selectively, reversing the effects of angiotensin II. They all end in -sartan. The most important ones are:

• Losartan
• Valsartan
• Candesartan
• Irbesartan

Indications

They have mostly the same effects and indications as ACEI, however they’re mostly used as alternatives in case ACEIs aren’t tolerated or ACEIs gives side effects.

Side effects

• Hypotension
• Hyperkalaemia
• Acute kidney injury

Dry cough and angiooedema occurs much less frequently with ARBs than with ACE inhibitors.

Aldosterone antagonists

Aldosterone antagonists are used as diuretics and are covered in their own topic.

Renal effects of ACE inhibitors and ARBs

You might’ve noticed that ACE inhibitors and ARBs are both renoprotective and nephrotoxic. Their beneficial effects in slowing the progression of chronic kidney disease are significant, especially in the setting of diabetic nephropathy. Because these drugs decrease the angiotensin-mediated vasoconstriction in the kidneys, they increase the renal blood flow, which partly explains the renoprotective effect. However, these drugs have multiple renoprotective effects, not all of which are well understood.

However, decreasing the angiotensin-mediated vasoconstriction can be harmful in some cases. The effective filtration pressure in the glomerulus depends on the degree of vasoconstriction of the efferent arteriole; when this vasoconstriction decreases, the effective filtration pressure also decreases. This may decrease the glomerular filtration rate. If this decrease is large enough, acute kidney injury occurs.

Luckily, acute kidney injury due to RAS inhibitors is rare. It occurs mostly in patients who simultaneously take other nephrotoxic drugs (especially NSAIDs) and patients who have diseases which decrease renal perfusion, like heart failure, pre-existing kidney disease, hypovolaemia, renal artery stenosis, etc. In these patients, RAS inhibitors should be given with care and their renal function should be monitored in the early stages.