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Flashcards in Renin-angiotensin-aldosterone system Deck (16)
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What is the action of potassium sparing diuretics?

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


What is the action of mineralocorticoids?

Receptor is a nuclear receptor i.e. transcription factor
Mineralocorticoids promote transcription of epithelial sodium channel and sodium/ potassium ATPase genes



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


Use of spironolactone in treating hypertension

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


Use of spironolactone in chronic (congestive) heart failure

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



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


Specific benefit of MR antagonists in CHF

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


Actions of ACE inhibitors

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 >>> 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


ACE inhibitors and bradykinin

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


Use of ACE inhibitors in hypertension

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


Use of ACE inhibitors in heart failure

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


Use of ACE inhibitors in prophylaxis of cardiovascular events

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


Angiotensin-II receptors

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


Therapeutic uses of AT1 antagonists

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


What are the two main types of potassium sparing diuretics?

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


What are the principal natural agonists at the mineralocorticoid receptor?

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