Mineralocorticoid receptor antagonists

An important drug in the present context is the mineralocorticoid receptor antagonist spironolactone (7.74, Fig. 7.12). Among its many metabolic reactions, spironolactone is readily hydrolyzed at the thioester bond (Fig. 7.12, Reaction a) to form deacetyl-spironolactone (7.75, Fig. 7.12), a metabolite found in a variety of tissues [155 -157]. This thiol compound, which is also a potent mineralocorticoid antagonist, promotes the mechanism-based inactivation of hepatic, adrenal, and testicular cytochrome P450 isozymes. There is now good evidence to indicate that this behavior is the result of microsomal 5-oxidation (see Chapt. 7 in [7]). When spironolactone was incubated with liver microsomes from rats pretreated with dexamethasone (an inducer of CYP3A), the sulfinic and sulfonic acid derivatives were characterized [158]. Perhaps the importance of the 5-deacetylation of spironolactone... 

Inhibitors of Na+channels in the collecting ducts Mineralocorticoid-receptor antagonists Side effects of diuretics INTRODUCTION... 

Delyani, J.A. (2000) Mineralocorticoid receptor antagonists the evolution of utility and pharmacology. Kidney International, 57, 1408-1411. 

Kolkhof, P., Flamme, I., Figueroa Perez, L., Baerfacker, L., Hartmann, E., Rinke, M. and Schafer, S. (2006) Cardiac and renal protection by a new mineralocorticoid receptor antagonist in salt-sensitive arterial hypertension. European Heart Journal, 27 (Suppl 1), 110. 

The sample of patients selected for a clinical trial may not be representative of the entire population of patients with that disease. Patients entered into a trial usually are selected according to the severity of their disease and other characteristics inclusion criteria) or are excluded because of coexisting disease, concurrent therapy, or specific features of the disease itself (exclusion criteria). It always is important to ascertain that the clinical characteristics of an individual patient correspond with those of patients in the trial. For example, the Randomized Aldactone Evaluation Study (RALES) showed that treatment with the mineralocorticoid-receptor antagonist spironolactone was associated with a 30% reduction in death in patients with severe congestive heart failure. Hyperkalemia, a potential adverse effect, was seen only rarely in this study, which excluded patients with serum creatinine levels >2.5 mg/dL. With the expanded use of spironolactone after RALES was published, numerous patients, many of whom did not meet the RALES inclusion criteria, developed severe hyperkalemia. Therefore, knowledge of the criteria for selecting the patients in a trial must inform the application of study results to a given patient. 

Aldosterone antagonists potassium-sparing diuretics (mineralocorticoid receptor antagonists)... 

Mineralocorticoid receptor antagonists for the treatment of hypertension and diabetic nephropathy 12JMC7957. 

ACE inhibitors do not completely block aldosterone synthesis. Since this steroid hormone is a potent inducer of fibrosis in the heart, specific antagonists, such as spironolactone and eplerenone, have recently been very successfully used in clinical trials in addition to ACE inhibitors to treat congestive heart failure [5]. Formerly, these drugs have only been applied as potassium-saving diuretics in oedematous diseases, hypertension, and hypokalemia as well as in primary hyperaldosteronism. Possible side effects of aldosterone antagonists include hyperkalemia and, in case of spironolactone, which is less specific for the mineralocorticoid receptor than eplerenone, also antiandrogenic and progestational actions. 

The answer is c. (Hardmanr pp 706-708.) Spironolactone is an aldosterone antagonist that acts on the mineralocorticoid receptor It is a Kksparing diuretic. It can also function as an androgen antagonist, which could explain the gynecomastia and erectile dysfunction. Women with hirsutism are sometimes treated with spironolactone. 

Spironolactone and eplerenone block the mineralocorticoid receptor, the target site for aldosterone. In the kidney, aldosterone antagonists inhibit sodium reabsorption and potassium excretion. However, diuretic effects are minimal, suggesting that their therapeutic benefits result from other... 

Corticosteroids Glucocorticoids Mineralocorticoids Corticosteroid antagonists Receptor antagonists Synthetic inhibitors... 

Figure 12.6 Mechanism of action of mineralocortjcoid receptor antagonists in the collecting tubule. Aldosterone enters the tubular cell by the basolateral surface and binds to a specific mineralocorticoid receptor (MNR) in the cytoplasm. The hormone receptor complex triggers the production of an aldosterone-induced protein (AlP) by the cell nucleus (NUC). The AIP acts on the sodium ion channel (ic) to augment the transport of Na+across the basolateral membrane and in to the cell. An increase in AIP activity leads to the recruitment of dormant sodium ion channels and Na pumps (P) in the cell membrane. AIP also leads to the synthesis of new channels and pumps within the cell. The increase in Na+conductance causes electrical changes in the luminal membrane that favour the excretion of intracellular cations, such as K+and H-h. Spironolactone competes with aldosterone for the binding site on the MNR and forms a complex which does not excite the production of AIP by the nucleus.

Spiro compounds 202 and 203 are antagonists of the mineralocorticoid receptor. This limits the production of excess aldosterone, which, in turn, leads to increased sodium uptake and potassium loss. This condition, known as Conn s syndrome, is associated with hypertension <2005W02005110992>. Amine 204 is a seratonergic 5-HY5-HT2 agonist for the treatment of glaucoma <2003W003051352>. 

These diuretics act by reducing sodium reabsorption in the collecting duct, and hence increasing potassium retention. Spironolactone acts as a competitive antagonist of aldosterone, blocking its stimulatory effects on sodium reabsorption via the mineralocorticoid receptor. Amiloride and triamterene both inhibit ENaC, The danger of this group of diuretics is that they can induce hyperkalemia, which is particularly lilcely to occur in patients with kidney disease. 

Eplerenone is a selective aldosterone receptor antagonist that binds to the mineralocorticoid receptor (MR), blocking the binding of aldosterone. It is indicated in the treatment... 

Antagonists of mineralocorticoid receptors (primary site of action is late distal tubule and collecting duct) + I + (+) I I NC NC NC NC... 

ANTAGONISTS OF MINERALOCORTICOID RECEPTORS (ALDOSTERONE ANTAGONISTS, K+-SPARING DIURETICS)... 

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