Pathways

Spirapril is an angiotensin-converting enzyme (ACE) inhibitor for the conversion of angiotensin I into angiotensin II. Angiotensin II is a critical circulating peptide hormone that has powerful vasoconstrictive effects and increases blood pressure. Spirapril is used to treat hypertension, high blood pressure, congestive heart failure, and chronic renal failure as it decreases blood pressure. Spirapril is converted into spiraprilat through the liver after being ingested which travels in the blood to inhibit ACE which is from the lungs. Angiotensin has many vasoconstrictive effects by binding to angiotensin II type 1 receptor (AT1) in blood vessels, kidneys, hypothalamus, and posterior pituitary. In blood vessels, AT1 receptors cause vasoconstriction in the tunica media layer of smooth muscle surrounding blood vessels increasing blood pressure. Less angiotensin II that is circulating lowers the constriction of these blood vessels. AT1 receptors in the kidney are responsible for the production of aldosterone which increases salt and water retention which increases blood volume. Less angiotensin II reduces aldosterone production allowing water retention to not increase. AT1 receptors in the hypothalamus are on astrocytes which inhibit the excitatory amino acid transporter 3 from up-taking glutamate back into astrocytes. Glutamate is responsible for the activation of NMDA receptors on paraventricular nucleus neurons (PVN neurons) that lead to thirst sensation. Since angiotensin II levels are lowered, the inhibition of the uptake transporter is not limited decreasing the amount of glutamate activating NMDA on PVN neurons that make the individual crave drinking less. This lowers the blood volume as well. Lastly, the AT1 receptors on posterior pituitary gland are responsible for the release of vasopressin. Vasopressin is an anti-diuretic hormone that cases water reabsorption in the kidney as well as causing smooth muscle contraction in blood vessels increasing blood pressure. Less angiotensin II activating vasopressin release inhibits blood pressure from increasing. Overall, Spirapril inhibits the conversion of angiotensin I into angiotensin II, a powerful vasoconstrictor and mediator of high blood pressure so decreasing levels of angiotensin will help reduce blood pressure from climbing in individuals.

Spirapril (trade name: Renormax) belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Spirapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form spiraprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.

Spirapril (trade name: Renormax) belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Spirapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form spiraprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.

Spironolactone is a potassium-sparing diuretic. It acts by competing with aldosterone for its receptor inside the principal cells of the late distal tubule and collecting tubule. Aldosterone increases sodium reabsorption and potassium excretion by up-regulating the expression of basolateral sodium-potassium ATPases as well as luminal (apical) sodium and potassium channels. Sodium in the nephron lumen enters the principal cells through the luminal sodium channels, where it is then actively pumped out into the interstitium by sodium-potassium ATPases. This causes the interstitium to become hyperosmotic and establishes an osmotic gradient, facilitating water reabsorption through aquaporin channels. On the other hand, potassium is actively pumped from the interstitium into the principle cell. It then diffuses from inside the cell into the nephron lumen via potassium channel, driven by an electrochemical gradient established by sodium leaving the lumen. Potassium entering the nephron lumen is subsequently excreted in the urine. Spironolactone inhibits sodium and water reabsorption as well as potassium excretion by blocking the actions of aldosterone as described above.

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.