TORSENONE

Indications

• Hypertension
• Heart failure with reduced ejection fraction
• Heart failure with preserved ejection fraction
• Adjunct therapy post-myocardial infarction in patients with heart failure

Dosage

Adults: Initially 25 mg daily, then increased to 50 mg daily within 4 weeks of initial treatment. For patients with concomitant use of moderate CYP3A4 inhibitors, the maximum recommended dose is 25 mg daily.

Mechanism of action

Eplerenone binds to the mineralocorticoid receptor, blocking the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone system (RAAS). This inhibition prevents aldosterone-induced sodium reabsorption in the kidneys and other tissues, leading to decreased blood pressure. Eplerenone is relatively selective for mineralocorticoid receptors compared to glucocorticoid, progesterone, and androgen receptors.

Pharmacodynamics

Eplerenone, as an aldosterone receptor antagonist, leads to sustained increases in plasma renin and serum aldosterone due to the inhibition of the negative feedback mechanism of aldosterone on renin secretion. While plasma renin activity and aldosterone levels may increase, these do not counteract eplerenone's effects on blood pressure, allowing it to effectively manage hypertension and heart failure symptoms.

Pharmacokinetics

Eplerenone is well absorbed following oral administration and undergoes extensive hepatic metabolism, primarily via CYP3A4. It has a bioavailability of approximately 35% due to first-pass metabolism. The drug has a half-life of about 5 hours. Eplerenone is excreted mainly in urine as metabolites, with less than 5% of the dose excreted unchanged. Renal function can affect its pharmacokinetics, necessitating dosage adjustments in patients with renal impairment.

Contra-indications

• Hyperkalaemia

Adverse effects

• Hyperkalaemia
• Hypotension
• Dizziness
• Fatigue
• Renal impairment
• Gastrointestinal disturbances

Interactions

• Cobicistat - Severe (increases exposure)
• Idelalisib - Severe (increases exposure)
• St John's Wort - Severe (decreases exposure)
• Rifampicin - Severe (decreases exposure)
• Cenobamate - Moderate (decreases exposure)
• Amiodarone - Unknown (increases exposure)
• Dronedarone - Unknown (increases exposure)
• Antifungals (azoles) - Unknown (increases exposure)
• Crizotinib - Unknown (increases exposure)
• Imatinib - Unknown (increases exposure)

Precautions

• Use with caution in elderly patients
• Monitor renal function and serum electrolytes, especially potassium
• Consider lower doses in patients with chronic kidney disease
• Avoid concurrent use with potassium-conserving drugs

Pregnancy

Eplerenone is not recommended during pregnancy due to potential risks to the fetus.

Breast-feeding

Eplerenone is excreted in breast milk; caution is advised when used during breastfeeding.

Storage

Store at room temperature, in a dry place, away from direct sunlight.

Formulations

• Tablets: 25 mg, 50 mg

Indications

• Hypertension
• Congestive heart failure
• Edema associated with renal disease
• Acute renal failure

Dosage

Adults: The typical adult

Mechanism of action

Torsemide acts by inhibiting the Na+/K+/Cl- cotransporter in the luminal cell membrane of the medullary thick ascending loop of Henle. This inhibition occurs through binding to a chloride ion-binding site on the transport molecule, reducing sodium, potassium, and chloride reabsorption. Additionally, torsemide affects the renin-angiotensin-aldosterone system by inhibiting the downstream effects of angiotensin II, leading to decreased aldosterone synthesis and receptor activity.

Pharmacodynamics

Torsemide increases urine output, facilitating fluid and electrolyte balance while reducing the risk of renal injury and acute renal failure. It exhibits a long-lasting diuretic effect with less potassium excretion compared to other diuretics, attributed to its influence on the renin-angiotensin-aldosterone system. Torsemide has been reported to lower plasma brain natriuretic peptide levels and improve left ventricular function in patients with heart failure, as well as reduce blood pressure and extracellular fluid volume in hypertensive patients, especially those with chronic kidney disease.

Pharmacokinetics

Torsemide is well absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 1 to 2 hours after oral administration. It is extensively bound to plasma proteins, primarily albumin. The drug undergoes hepatic metabolism, primarily by cytochrome P450 enzymes, with a half-life of approximately 3 to 4 hours. Renal excretion of torsemide and its metabolites is significant, with approximately 80% of the dose eliminated through urine. The pharmacokinetics may be altered in patients with renal impairment.

Adverse effects

• Hypokalemia
• Dehydration
• Electrolyte imbalance
• Hypotension
• Renal impairment
• Gastrointestinal disturbances
• Rash

Interactions

• Aminoglycosides
• Antidiabetic agents
• Antihypertensive drugs
• NSAIDs
• Lithium

Precautions

• Monitor renal function regularly
• Electrolyte levels should be monitored
• Use cautiously in patients with a history of gout
• Caution in patients with diabetes mellitus

Pregnancy

Use in pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited human data available.

Breast-feeding

Use with caution, as it is not known if torsemide is excreted in human milk.

Storage

Store at room temperature, away from moisture and direct light.

Formulations

• Tablets: 5 mg, 10 mg, 20 mg
• Injection: 10 mg/2 ml

Mechanism of action

Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms. Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone, and androgen receptors. Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with the inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulation levels do not overcome the effect of eplerenone on blood pressure. Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, brain) tissues and increases blood pressure through induction of sodium resorption and possibly other mechanisms.

Pharmacodynamics

Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors.

Mechanism of action

As mentioned above, torasemide is part of the loop diuretics and thus, it acts by reducing the oxygen demand in the medullary thick ascending loop of Henle by inhibiting the Na+/K+/Cl- pump on the luminal cell membrane surface. This action is obtained by the binding of torasemide to a chloride ion-binding site of the transport molecule. Torasemide is known to have an effect in the renin-angiotensin-aldosterone system by inhibiting the downstream cascade after the activation of angiotensin II. This inhibition will produce a secondary effect marked by the reduction of the expression of aldosterone synthase, TGF-B1 and thromboxane A2 and a reduction on the aldosterone receptor binding.

Pharmacodynamics

It is widely known that administration of torasemide can attenuate renal injury and reduce the severity of acute renal failure. This effect is obtained by increasing urine output and hence, facilitating fluid, acid-base and potassium control. This effect is obtained by the increase in the excretion of urinary sodium and chloride. Several reports have indicated that torasemide presents a long-lasting diuresis and less potassium excretion which can be explained by the effect that torasemide has on the renin-angiotensin-aldosterone system. This effect is very similar to the effect observed with the administration of combination therapy with [furosemide] and [spironolactone] and it is characterized by a decrease in plasma brain natriuretic peptide and improved measurements of left ventricular function. Above the aforementioned effect, torasemide presents a dual effect .in which the inhibition of aldosterone which donates torasemide with a potassium-sparing action. Torasemide has been shown to reduce extracellular fluid volume and blood pressure in hypertensive patients suffering from chronic kidney disease. As well, some reports have indicated that torasemide can reduce myocardial fibrosis by reducing the collagen accumulation. This effect is suggested to be related to the decrease in aldosterone which in order has been shown to reduce the production of the enzyme procollagen type I carboxy-terminal proteinase which is known to be overexpressed in heart failure patients.