Pathways

Spironolactone is a steroidal, non specific, orally administered aldosterone antagonist used mainly for its antihypertensive effects. This drug is used to treat heart failure, hyperaldosteronism, hypertension, adrenal hyperplasia, edema, and nephrotic syndrome. It has also been shown to decrease proteinuria. Spironolactone can be found under the brand names Aldactazide, Aldactone, and Carospir. The main target of spironolactone is the distal convoluted tubule in the nephron of the kidneys where it competitively inhibits mineralocorticoid receptors (MRs) in the principal cells to promote sodium (Na+) and water (H2O) excretion and potassium (K+) retention. Once spironolactone is bound to the MR, it blocks aldosterone from binding which inhibits aldosterone dependent sodium potassium exchange channels and results in the antihypertensive effects seen by causing alterations to the Na+:K+ ratio. Aldosterone is a mineralocorticoid hormone responsible for contributing to the regulation of blood pressure, sodium reabsorption, and potassium excretion and therefore, plays a role in blood pressure via the RAAS pathway. In the principal cells of the distal convoluted tubule, sodium and water reabsorption occur, along with potassium excretion. The sodium channel (ENaC) transports Na+ from the tubule lumen into the principal cells, then the NA+/K+ ATPase pumps the Na+ into the interstitium where it reabsorbed into the blood. K+ ions are pumped into the principal cell from the interstitium via the Na+/K+ ATPase, then the K+ channel transports K+ from the cell into the lumen where it is excreted in urine. Water reabsorption is linked to Na+ reabsorption and occurs via the aquaporins. Activation of the RAAS system leads to increased production of aldosterone, which is produced by the adrenal cortex in the zone glomerulosa. Following binding of aldosterone, the mineralocorticoid receptors undergo dimerization and activation and move into the nucleus where they undergo transcription. Protein is then synthesized in the cytosol. This effect on gene transcription leads to an upregulation of sodium channels in the apical membrane and Na+/K+ ATPase in the basolateral membrane, aiding an increase in Na+ and water reabsorption and K+ excretion. This change in ion concentrations leads to an increased effective circulating volume. By blocking the binding of aldosterone, the RAAS system. This prevents the aldosterone effects on gene transcription, therefore, there is a decrease in Na+ channels and Na+/K+ ATPase in the membrane. Sodium reabsorption decreases, the concentration of Na+ in the lumen becomes high and as a result, water reabsorption also decreases. The effects on Na+/K+ ATPase results in reduced K+ excretion. This effect of spironolactone is important for treating conditions like hypertension because the increased water excretion in urine leads to decreased blood plasma volume, lowering blood pressure. One of the limitations of aldosterone blockage with spironolactone is the increased risk of hyperkalaemia and increased serum creatinine levels. The maximal hypotensive effects seen from spironolactone often require 3-4 weeks to be fully expressed and may persist 1-2 weeks after discontinuation, this is because spironolactone is a prodrug with multiple active metabolites with long half lives such as canrenone which is metabolized in the liver by hepatocytes. Spironolactone has also been shown to have antiandrogenic activity as well contributing to off label uses. Spironolactone has moderate affinity for progesterone and androgen receptors which increases the likelihood of side effects such as loss of libido, menstrual irregularities, gynecomastia, and impotence, Structurally, spironolactone contains elements of progesterone leading to those progestognenic and antiandrogenic adverse effects. Some side effects of using spironolactone may include feeling dizzy, experiencing muscle cramps, feeling tired and low in energy, and experiencing breast pain and enlargement.

Stanozolol is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Stanozolol passes through the liver and is then excreted from the body mainly through the kidney.