Pharmacology: Drugs affecting the renin-angiotensin-aldosterone system

Physiology of RAAS and angiotensin can be found here.

Classification of drugs

The simplest way would be to classify drugs that affect the RAAS is to divide them into drugs that inhibit renin, angiotensin converting enzyme or angiotensin receptors, and aldosterone.

Combination therapy with two drugs affecting the renin-angiotensin system (ACE inhibitors, angiotensin-II receptor antagonists, and aliskiren is not recommended due to an increased risk of hyperkalaemia, hypotension, and renal impairment, compared to use of a single drug. 

Drugs that inhibit renin

Aliskiren – direct renin inhibitor

Drugs that inhibit angiotensin converting enzyme

ACE inhibitors

Indications: All grades of heart failure, hypertension 1st line non Afro-Carribbean or <55y, secondary prevention in myocardial infarction with left ventricular dysfunction (improves prognosis), diabetic nephropathy and CKD (improves prognosis and renal protective)

Anaesthetic pearl: Conflicting data on whether it does cause refractory hypotension in the perioperative period. Survey by the SPACE trial investigators in 2018 showed a large number of anaesthetists would prefer to hold on the day of surgery, but many would still continue. SPACE is still running and aims to investigate whether continuing or temporarily stopping ACEi/ARB reduces injury to the heart, and other complications, after major planned surgery.

From a kinetic point of view ACE inhibitors may be divided into three groups:

  • Group 1. Captopril – an active drug that is metabolized to active metabolites.
  • Group 2. Enalopril, ramipril – prodrugs, which only become active following hepatic metabolism to the diacid moiety.
  • Group 3. Lisinopril – an active drug that is not metabolized and is excreted unchanged in the urine.

Starting the drug

Transient hypotension may occur at start of treatment therefore first dose at night. Monitor renal function, electrolytes and BP.

Effects

CVS: Reduces SVR significantly -> Fall in BP. Reduced after load can lead to increase in cardiac output in heart failure patients. HR may increase, baroreceptor reflexes unaffected.

Renal: Blocks normal function of angiotensin II at glomerulus so if renal perfusion pressure falls, renal failure may follow. Therefore, do not use ACEi in renal artery stenosis or single kidney with unilateral renal artery stenosis. Renal vasodilation may occur in normal kidneys -> Natriuresis. Check electrolytes.

Metabolic: High renin as no negative feedback from aldosterone. Hyperkalaemia and raised U&E especially in mild renal impairment.

Side effects and interactions:

  • Persistent dry cough: Increased bradykinin which are normally broken down by ACE. NSAIDs may alleviate this cough but at the expense of reduced antihypertensive effects
  • Hyperkalaemia: Especially with combined with potassium sparing diuretics, due to reduction in aldosterone release
  • Unexplained hypoglycaemia: In diabetes Type 1 and 2.
  • Renal failure: If combined with NSAIDs. See physiology article at start of this page to understand why
  • Angioedema in 0.2%: More common in black patients
  • Agranulocytosis and thrombocytopaenia
  • Loss of taste, rash, pruritus, fever, apthous ulceration
Angiotensin II receptor antagonists (ARBs)

Usually used for hypertension where dry cough is unacceptable during ACEi therapy.

Examples: Losartan, candesartan

Mechanism of action: Specific angiotensin II (type AT1) receptor antagonist at all sites within the body. Blocks negative feedback on angiotensin II on renin secretion -> increased renin -> increased angiotensin II, but with little effect due to comprehensive blockade. AT2 is not block – may be cardioprotective.

Effects the same as ACEi with less bradykinin increase as it has no effect on angiotensin converting enzyme

Contraindications: Bilateral renal artery stenosis and pregnancy

Aldosterone antagonists

Examples: Spironolactone and eplerenone (competitive aldosterone antagonists)

Mechanism of action – blocks aldosterone receptors which leads to reduced K+ excretion and increased Na+ excretion which leads to a diuresis. This is limited as only 2% of Na+ reabsorption is aldosterone controlled.

Effects:

Hyperkalaemia – careful in renal impairment and in combination with ACEi or other potassium sparing drugs

Hyponatraemia

Hormonal – Has anti androgenic effects and can cause gynaecomastia in men, menstrual irregularity in women. Contraindicated in Addison’s disease.

References:

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