Renin-angiotensin-aldosterone system

Question 1

What is the action of potassium sparing diuretics?

Answer 1

Influence sodium and water resorption in the collecting duct, weak diuretics

Question 2

What is the action of mineralocorticoids?

Answer 2

Receptor is a nuclear receptor i.e. transcription factor

Mineralocorticoids promote transcription of epithelial sodium channel and sodium/ potassium ATPase genes

Question 3

Spironolactone

Answer 3

Plasma half life ~10 min
Canrenone is an active metabolite, plasma half life 10-35 hours
Inhibits potassium and hydrogen secretion, counteracts potassium loss by other diuretics but may cause hyperkalaemia and acidosis
Non-specific blockade of steroid receptors in other tissues responsible for many side effects
Weak diuretic action, slow onset over several days

Question 4

Use of spironolactone in treating hypertension

Answer 4

Spironolactone is added to other diuretics e.g. thiazides to enhance diuretic effect and limit potassium loss
Updated NICE guidance for selecting anti-hypertensive therapy (ACD rule)- diuretics are often used in combination with other anti-hypertensive drugs, but no longer recommended as first line treatment

Question 5

Use of spironolactone in chronic (congestive) heart failure

Answer 5

Mortality benefit in all grades of LV contractile dysfunction and chronic heart failure
Benefit is additional to ACE inhibitor therapy (aldosterone escape)

Question 6

Eplerenone

Answer 6

More specific MR antagonist than spironolactone, fewer side effects
Specifically indicated in UK for use in heart failure and left ventricular dysfunction after MI
Very weak diuretic action and potential for hyperkalaemia

Question 7

Specific benefit of MR antagonists in CHF

Answer 7

Specific beneficial actions of spironolactone and eplerenone in LV dysfunction
Goes beyond benefits of ACE inhibitors and ARBs, unrelated to diuretic effects
Possible due to effects on fibrosis and cardiac remodelling

Question 8

Actions of ACE inhibitors

Answer 8

Inhibit circulating ACE and tissue ACEs
Principal action is reduced conversion of Ang 1 to Ang 2 in plasma and in tissues
Hence reduction of Ang 2 actions&raquo_space;> vasodilatation, decreased aldosterone release, reduced cell proliferation/ growth
However, Ang 2 is also produced by chymase so ACEIs do no prevent all production of Ang 2

Question 9

ACE inhibitors and bradykinin

Answer 9

ACE is also kininase-II (which degrades kinins)
Hence ACEIs potentiate BK actions- vasodilatation, reduced cell growth/ proliferation
e.g. prevention of LVH in experimental hypertension is BK-dependent
BK accumulation associated with ACEI side effects- persistent unproductive cough, angioedema

Question 10

Use of ACE inhibitors in hypertension

Answer 10

Particularly effective in high-renin form of hypertension (step 1 of ACD rule), less effective in elderly or African/ Caribbean patients
May be combined with another drug e.g. thiazide diuretic or calcium channel blocker
Hypertension associated with renal disease

Question 11

Use of ACE inhibitors in heart failure

Answer 11

Useful in all grades of CHF, usually with a diuretic
Demonstrated benefit post-myocardial infarction even when LV dysfunction is mild
Treatment usually initiated at low dose
Risk of hyperkalaemia so potassium sparing diuretics used with caution in conjunction with ACEIs

Question 12

Use of ACE inhibitors in prophylaxis of cardiovascular events

Answer 12

ACEIs for patients after myocardial infarction may also prevent or reduce risk of further events (secondary prevention)
Increasing use in patients with risk factors for coronary disease (primary prevention)
Mechanism of action unknown, possibly related to cardioprotective effects of BK

Question 13

Angiotensin-II receptors

Answer 13

AT1 receptors mediate most of the cardiovascular actions of Ang 2- vasoconstriction, salt retention, cell growth and proliferation
AT2 receptors roles are unclear, possible inhibition of cell growth, possible behavioural/ central effects

Question 14

Therapeutic uses of AT1 antagonists

Answer 14

Hypertension- alternative under ACD rule for patients who have to discontinue ACE inhibitors due to dry cough
Heart failure- for heart failure and LV dysfunction afetr MI but less evidence of mortality benefit than with ACE inhibitors
Diabetic nephropathy- as an alternative to ACE inhibitors

Question 15

What are the two main types of potassium sparing diuretics?

Answer 15

Competitive mineralocorticoid receptor antagonists (aldosterone antagonists) e.g. spironolactone, eplerenone
Epithelial sodium channel blockers e.g. amiloride and triamterene

Question 16

What are the principal natural agonists at the mineralocorticoid receptor?

Answer 16

Principal natural agonists at mineralocorticoid receptor are aldosterone and 11-deoxycorticosterone