Aldosterone antagonists
MOA
Mechanism & effects of aldosterone action
Renal effect of aldosterone
Mechanism
it acts on intracellular mineralocorticoid receptors
it increases the expression of
Na+ channel in the luminal membrane of the principal cells
Na/K ATPase in the basolateral membrane of the principal cells
Effect
Primary
Na+ reabsorption↑ form the DCT and the collecting duct (via Na+ channel -> Na/K ATPase)
Secondary
K+ and H+ secretion (by increasing lumen negative transepithelial potential difference)
cardiovascular effects of aldosterone
activation of the RAAS system causes cardiovascular remodeling (hypertrophy and fiborsis)
especially, aldosterone promotes collagen synthesis and myocyte hypertrophy in the heart
in the principal cells of the distal convoluted tubule and the collecting duct
Mechanism & effects of aldosterone antagonists
Renal effects of aldosterone antagonists – diuretic action
Mechanism
they competitively inhibit the binding of aldosterone ot the mineralocorticoid receptor
they decrease the expression of
Na+ channel in the luminal membrane of the principal cells
Na/K ATPase in the basolateral membrane of the principal cells
Effect
primary
Secondary
Na+ reabsorption↓ form the DCT and the collecting duct (via Na+ channel -> Na/K ATPase)
K+ and H+ secretion↓ (by decreasing lumen negative transepithelial potential difference)
-> K+ and H+ sparing diuretics
cardiovascular effects of aldosterone antagonists (prevents “aldosterone escape”)
aldosterone antagonists increase the beneficial cardiovascular effects of
ACE inhibitors
angiotensin receptor antagonists
aldosterone antagonists drugs
Spironolactone
General
non-specific aldosterone antagonists
Acts on
mineralocorticoid receptor
steroid receptor
diuretic action / cardiovascular effects
endocrine effects
androgen receptor antagonist
progesterone receptor agonist
pharmacokinetics
Oral bioavailability
0.7
plasma protein binding
High
metabolism
activated by biotransformation
7-thio-spironolactone -> 7-thiomethyl-spironolactone -> canrenone
Elimination
T1/2 of SPL : 1 hour
T1/2 of metabolites of SPL : 16 hours
Clinical use
diuretics
used together with thiazide or loop diuretics (to decrease K+ and H+ effect)
edema (hepatic edema causes secondary hyperaldosteronism)
hypertension
aldosterone antagonist
in hyperaldosteronism
cardiovascular disease
androgen antagonist
Hirsutism & seborrhea in females
Side effect
hyperkalemia -> K+ sparing and if used with other drugs like
metabolic acidosis -> H+ sparing
ACE inhibitors
angiotensin antagonists
NSAID -> decreases PG synthesis, inducing oligouria (K+ retention)
steroid effects (SPL can act on steroid receptor)
Sex steroid effects
Men
gynecomastia (androgen receptor antagonist)
Women
menstrual irregularities (progesterone receptor agonist)
Glucocorticoid effect
increase ACTH by negative feedback
gastric bleeding
peptic ulcer
CNS effects (drowsiness / lethargy)
Others
potassium canrenoate
poorly absorbed -> given i.v.
canrenoic acid lactonizes into canrenone -> more active & persistent
Eplerenone
General
Specific aldosterone antagonist, not acing other steroid receptors, because of its epoxide group
Pharmacokinetic
Oral bioavailability
0.7
Plasma protein binding
Moderate
Elimination
By biotransformation
CYP3A4 converts it into inactive hydroxylated metabolites
T1/2
6 hours
Clinical use
primarily used with cardiovascular indication
hypertension
congestive heart disease and acute myocardial infarct
Side effect
hyperkalemia -> K+ sparing
metabolic acidosis -> H+ sparing
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