LACTOR TABS

Indications

• Heart failure
• Hypertension
• Edema associated with liver cirrhosis
• Nephrotic syndrome
• Primary hyperaldosteronism

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: Initially 100–200 mg daily, then increased if necessary to a maximum of 400 mg daily, adjusted according to response.

Mechanism of action

Spironolactone and its active metabolites bind competitively to the mineralocorticoid receptor in the distal convoluted renal tubule, antagonizing aldosterone's effects. This leads to increased sodium and water excretion while retaining potassium. Additionally, spironolactone has antiandrogenic effects, reducing testosterone synthesis and impacting androgen receptor activity.

Pharmacodynamics

Spironolactone promotes diuresis while sparing potassium, which is crucial for maintaining electrolyte balance. It raises renin and aldosterone levels, while also demonstrating progestogenic and anti-androgenic properties. The drug exhibits anti-inflammatory effects and has low affinity for glucocorticoid receptors, making it suitable for managing fluid retention without causing significant potassium loss.

Pharmacokinetics

Spironolactone is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1 to 3 hours post-administration. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, resulting in active metabolites. The drug has a half-life of about 1.4 hours, but its effects can last longer due to its active metabolites. Renal clearance is significant, and dosage adjustments may be necessary in patients with renal impairment.

Contra-indications

• Severe renal impairment
• Acute renal insufficiency
• Hyperkalaemia

Adverse effects

• Hyperkalaemia
• Acidosis
• Agranulocytosis
• Alopecia
• Breast neoplasm benign
• Breast pain
• Confusion
• Dizziness
• Electrolyte imbalance
• Gastrointestinal disorder
• Gynaecomastia
• Hepatic function abnormality
• Hypertrichosis
• Leg cramps
• Leucopenia
• Libido disorder
• Malaise
• Menstrual disorder
• Nausea
• Severe cutaneous adverse reactions
• Skin reactions
• Thrombocytopenia

Interactions

• Digoxin (increases concentration)
• Lithium (unknown, may increase concentration)
• Mitotane (unknown, may decrease effects)

Precautions

• Monitor potassium levels before treatment, during initiation, and after any dose changes
• Use with caution in renal impairment, low blood pressure, ischaemic heart disease, and diffuse vascular disease
• Consider potential risks during pregnancy and breastfeeding

Pregnancy

Use only if potential benefit outweighs risk; concerns about feminisation of male fetus in animal studies.

Breast-feeding

Metabolites present in milk, but the amount is probably too small to be harmful.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets (25 mg, 50 mg, 100 mg)
• Oral suspension
• Solution for injection

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

Aldosterone is a key hormone in the renin-angiotensin-aldosterone system. By binding to the mineralocorticoid receptor at the distal tubules and collecting duct, it causes sodium reabsorption and potassium secretion, increases vascular stiffness and remodelling, and activates pro-inflammatory pathways. Spironolactone and its active metabolites are aldosterone antagonists that produce a potassium-sparing diuretic effect. They competitively bind to receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule. Spironolactone can exert antiandrogenic effects by several mechanisms: it can destroy testicular CYP and decrease 17alpha-hydroxylase activity, resulting in decreased testosterone synthesis; and it can inhibit 5alpha-dihydrotestosterone binding to cytosolic androgen receptor in the prostate. Spironolactone exhibits antiandrogenic effects in males and females. The mechanism of antiandrogenic activity of spironolactone is complex and appears to involve several effects of the drug. Spironolactone decreases testosterone biosynthesis by inhibiting steroid 17alpha-monooxygenase (17alpha-hydroxylase) activity, possibly secondary to destruction of microsomal cytochrome P-450 in tissues with high steroid 17alpha-monooxygenase activity (e.g., testes, adrenals). The drug also appears to competitively inhibit binding of dihydrotestosterone to its cytoplasmic receptor protein, thus decreasing androgenic actions at target tissues. Spironolactone-induced increases in serum estradiol concentration also may contribute to its antiandrogenic activity, although such increases may not occur consistently; such increases appear to result from increased conversion of testosterone to estradiol. Spironolactone may have variable effects on serum 17-hydroxyprogesterone concentrations, possibly decreasing its production by inhibiting steroid 17alpha-monooxygenase activity or decreasing its conversion (with resultant accumulation) to androstenedione by inhibiting cytochrome P450-dependent 17alpha-hydroxyprogesterone aldolase (17,20-desmolase) activity. Serum progesterone concentrations may increase with the drug secondary to decreased hydroxylation (via steroid 17alpha-monooxygenase) to 17-hydroxyprogesterone. In children, compensatory increases in lutropin (luteinizing hormone, LH) and follicle-stimulating hormone (FSH) secretion can occur, probably secondary to the drug's antiandrogenic effects (i.e., a feedback response to decreasing serum testosterone concentrations and/or peripheral androgenic activity). MEDICATION (VET): Spironolactone is used most frequently and is a competitive antagonist of aldosterone. Aldosterone is elevated in animals with congestive heart failure in which the renin-angiotensin system is activated in response to hyponatremia, hyperkalemia, and reductions in blood pressure or cardiac output. Aldosterone is responsible for increasing sodium and chloride reabsorption and potassium and calcium excretion from renal tubules. Spironolactone competes with aldosterone at its receptor site, causing a mild diuresis and potassium retention. High concentrations of spironolactone have been reported to interfere with steroid biosynthesis by inhibiting 11 beta- and 18-, 21-, and 17 alpha-hydroxylase.

Pharmacodynamics

Spironolactone has a potassium-sparing diuretic effect. It promotes sodium and water excretion and potassium retention. It increases renin and aldosterone levels. Spironolactone is a mineralocorticoid receptor antagonist and has a low affinity for the glucocorticoid receptor. It also exhibits progestogenic and anti-androgenic actions as it binds to the androgen receptor and, to a lesser extent, estrogen and progesterone receptors. Spironolactone exhibits anti-inflammatory effects.

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.