TOR-LOOP 10

Indications

• Oedema associated with heart failure
• Oedema associated with renal disease
• Hypertension

Dosage

Children: Refer to the BNF for Children for specific dosing information in paediatric patients.

Adults: The usual dose for adults is 5 mg once daily, which may be increased if necessary to 20 mg once daily.

Mechanism of action

Torasemide acts by inhibiting the Na+/K+/Cl- pump located on the luminal cell membrane of the medullary thick ascending loop of Henle. This inhibition occurs through the binding of torasemide to a chloride ion-binding site of the transport molecule. Additionally, it influences the renin-angiotensin-aldosterone system by inhibiting the downstream effects of angiotensin II activation, leading to reduced expression of aldosterone synthase and decreased aldosterone receptor binding.

Pharmacodynamics

Administration of torasemide increases urine output, aiding in fluid, acid-base, and potassium management, while also attenuating renal injury and reducing acute renal failure severity. It achieves a long-lasting diuretic effect with less potassium excretion, similar to combination therapy with furosemide and spironolactone, and is effective in lowering extracellular fluid volume and blood pressure in hypertensive patients with chronic kidney disease.

Pharmacokinetics

Torasemide is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring 1 to 2 hours after oral administration. It has a half-life of approximately 3 to 5 hours and is primarily excreted in urine, with a portion metabolized in the liver. Renal impairment may affect its clearance, and caution is advised in such patients.

Contra-indications

• Anuria
• Dehydration
• Severe hypokalaemia
• Hypersensitivity to torasemide or any excipients
• Severe renal failure with creatinine clearance less than 25 mL/minute

Adverse effects

• Asthenia
• Gastrointestinal disturbances
• Anemia
• Confusion
• Dry mouth
• Visual impairment
• Hypotension
• Myocardial infarction
• Cerebral ischemia
• Pancreatitis
• Syncope

Interactions

• Potassium-sparing diuretics (risk of hyperkalaemia)
• Selpercatinib (severe increase in exposure)
• Other diuretics
• ACE inhibitors and angiotensin receptor blockers

Precautions

• Caution in patients with diabetes mellitus
• Gout
• Elderly patients
• Impaired micturition
• Prostatic enlargement
• Hepatorenal syndrome
• Patients with raised intra-ocular pressure

Pregnancy

Manufacturer advises avoiding use due to potential toxicity in animal studies.

Breast-feeding

Manufacturer advises avoiding use; no information available on excretion in breast milk.

Storage

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

Formulations

• Torasemide 2.5 mg tablets
• Torasemide 5 mg tablets
• Torasemide 10 mg tablets
• Torasemide 10 mg per 1 ml solution for injection

Indications

• Constipation
• Dietary fiber supplementation
• Irritable bowel syndrome
• Diverticular disease
• Weight management

Dosage

Children: Refer to appropriate guidelines for specific dosage; generally taken with adequate fluid intake.

Adults: Refer to appropriate guidelines for specific dosage; generally taken with adequate fluid intake.

Mechanism of action

Cellulose acts primarily as a bulk-forming laxative. It absorbs water in the intestines, which increases stool bulk and stimulates peristalsis, thus facilitating bowel movements. Additionally, cellulose is not digestible by human enzymes, leading to fermentation by gut bacteria, which may enhance gut health and alter gut microbiota composition.

Pharmacodynamics

Cellulose increases stool weight and frequency of bowel movements. It works by retaining water in the intestines, leading to softer stools and improved passage through the gastrointestinal tract. The bulking effect of cellulose can help alleviate constipation and promote overall digestive health. It may also play a role in cholesterol reduction and glycemic control through its effects on digestion and absorption of nutrients.

Pharmacokinetics

Cellulose is not absorbed into the bloodstream due to its indigestible nature. Instead, it passes through the gastrointestinal tract, where it adds bulk to the stool. Its fermentation by colonic bacteria produces short-chain fatty acids, which may have beneficial effects on colon health. The onset of action for cellulose as a laxative can vary but is generally within 24 to 72 hours after ingestion.

Adverse effects

• Bloating
• Flatulence
• Diarrhea
• Abdominal discomfort

Precautions

• Use with caution in patients with a history of gastrointestinal disorders.
• Monitor for potential allergic reactions in sensitive individuals.

Pregnancy

Cellulose is generally considered safe during pregnancy as it is a non-toxic, indigestible fiber.

Breast-feeding

Cellulose is also considered safe during breastfeeding; it is excreted in breast milk in negligible amounts.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Powder
• Capsules
• Tablets
• Granules

Indications

• Used as an excipient in solid dosage forms
• Facilitates drug disintegration and dissolution

Dosage

Children: Refer to specific product formulation guidelines as crospovidone is used as an excipient and does not have a direct dosage.

Adults: Refer to specific product formulation guidelines as crospovidone is used as an excipient and does not have a direct dosage.

Mechanism of action

Crospovidone acts by rapidly absorbing water and swelling upon contact with moisture. This action leads to the disintegration of solid dosage forms, thus increasing the surface area of the active ingredients and promoting their dissolution and subsequent absorption in the gastrointestinal tract. It does not affect the pH of the formulation, ensuring that the active ingredients remain stable.

Pharmacodynamics

Crospovidone exhibits properties that enhance the bioavailability of active ingredients in pharmaceutical formulations. Its ability to rapidly disintegrate tablets and capsules leads to quicker release and absorption of the drug into systemic circulation. As a disintegrant, it aids in the effective delivery of drugs that may otherwise be poorly soluble.

Pharmacokinetics

Crospovidone itself is not absorbed systemically when administered orally. It remains in the gastrointestinal tract, where it performs its function as a disintegrant. The pharmacokinetic profile of drugs formulated with crospovidone may be influenced by the enhanced dissolution and absorption rates provided by this excipient.

Pregnancy

Crospovidone is considered to have low toxicity and is generally regarded as safe for use during pregnancy, but specific studies are limited.

Breast-feeding

There is insufficient data on the excretion of crospovidone in human milk, but it is deemed safe for use during breastfeeding.

Storage

Store in a cool, dry place away from light and moisture, in tightly closed containers.

Formulations

• Powder
• Tablets

Indications

• Lactose intolerance
• As a filler or excipient in pharmaceutical formulations

Dosage

Children: Refer to the BNF for Children for specific dosing information based on age and clinical context.

Adults: Refer to the BNF for specific dosing information based on clinical context.

Mechanism of action

Lactose is metabolized in the intestine by the enzyme lactase into its constituent monosaccharides, glucose and galactose. In individuals with lactase deficiency, unabsorbed lactose passes into the colon, where it is fermented by bacteria, leading to gas production and osmotic effects that contribute to diarrhea.

Pharmacodynamics

The pharmacodynamics of lactose are primarily related to its effects on gastrointestinal function. In healthy individuals, lactose is effectively broken down into glucose and galactose, which are absorbed and utilized for energy. In individuals with lactose intolerance, the unabsorbed lactose can cause osmotic diarrhea and colonic fermentation, leading to discomfort and symptoms associated with lactose intolerance.

Pharmacokinetics

Lactose is not absorbed in the gastrointestinal tract until it is hydrolyzed into glucose and galactose by lactase. The absorption of glucose and galactose occurs in the small intestine. The half-life is not applicable as lactose is not typically administered as a medication but is rather ingested as a natural component of food. Its metabolism primarily occurs in the intestine.

Adverse effects

• Bloating
• Diarrhea
• Abdominal pain
• Flatulence

Precautions

• Use with caution in patients with lactose intolerance.
• Consider potential for gastrointestinal upset in sensitive individuals.

Pregnancy

Lactose is generally considered safe for use during pregnancy. However, consult a healthcare professional for individual advice.

Breast-feeding

Lactose is safe to use while breastfeeding, as it is a natural sugar present in breast milk.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Powder
• Granules
• Tablets
• Syrup

Indications

• Primary hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease
• Familial hypercholesterolemia
• Secondary prevention of coronary heart disease

Dosage

Adults: The usual starting dose

Mechanism of action

Lovastatin is a lactone that is hydrolyzed in vivo to its active β-hydroxyacid form, inhibiting HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early step in cholesterol biosynthesis. This inhibition leads to decreased hepatic cholesterol concentrations, prompting upregulation of hepatic LDL receptors, enhancing LDL uptake from the plasma. The result is a reduction in plasma LDL and very low-density lipoprotein (VLDL), consequently lowering the risk of CVD.

Pharmacodynamics

Lovastatin reversibly inhibits HMG-CoA reductase, effectively lowering total cholesterol, LDL-C, apolipoprotein B, and triglyceride concentrations while increasing HDL-C levels. Elevated levels of LDL-C and triglycerides are linked to increased atherosclerosis and CVD risk, whereas higher HDL-C levels correlate with decreased cardiovascular risk. By achieving these lipid profile modifications, lovastatin significantly reduces cardiovascular morbidity and mortality.

Pharmacokinetics

Lovastatin is absorbed from the gastrointestinal tract, with peak plasma concentrations occurring 1 to 2 hours after administration. It is extensively metabolized in the liver, predominantly via the cytochrome P450 system, particularly CYP3A4. The elimination half-life is approximately 2 to 5 hours. Lovastatin is primarily excreted as metabolites in urine and feces. The bioavailability of lovastatin is low due to extensive first-pass metabolism, hence it is often recommended to be taken in the evening for optimal effects.

Contra-indications

• Active liver disease
• Pregnancy
• Breastfeeding
• Hypersensitivity to lovastatin or any of its components

Adverse effects

• Myopathy
• Rhabdomyolysis
• Elevated liver enzymes
• Gastrointestinal disturbances (e.g., nausea, diarrhea)
• Headache
• Muscle cramps
• Dizziness

Interactions

• CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, grapefruit juice) may increase lovastatin levels and risk of myopathy
• CYP3A4 inducers (e.g., rifampicin, carbamazepine) may reduce effectiveness of lovastatin
• Other lipid-lowering agents (e.g., gemfibrozil) may increase risk of myopathy

Precautions

• Use with caution in patients with a history of liver disease
• Monitor liver function tests before and during treatment
• Assess risk of myopathy when used with other medications that affect muscle metabolism
• Consider risk versus benefit in elderly patients

Pregnancy

Lovastatin is contraindicated in pregnancy due to potential harm to the fetus.

Breast-feeding

Lovastatin is contraindicated while breastfeeding as it may pass into breast milk and affect the infant.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 10 mg, 20 mg, 40 mg

Indications

• Used as an excipient in tablet formulations
• Used as a bulking agent in capsule formulations
• Used in food products as a thickener or stabilizer

Dosage

Children: Refer to specific product guidelines as dosage will depend on the formulation and the active ingredients.

Adults: Refer to specific product guidelines as dosage will depend on the formulation and the active ingredients.

Mechanism of action

Microcrystalline cellulose acts as a non-digestible filler that enhances the flow properties of powders during the manufacturing of tablets and capsules. It does not have a direct pharmacological action on the body but ensures that the active ingredients are effectively delivered to the patient.

Pharmacodynamics

As a non-active ingredient, microcrystalline cellulose does not exert pharmacodynamic effects typical of active pharmaceutical ingredients. Its primary role is to provide a stable and consistent matrix for the drug, facilitating the release of the active compound once ingested.

Pharmacokinetics

Microcrystalline cellulose is not absorbed in the gastrointestinal tract; it passes through the digestive system largely unchanged. It adds bulk to the stool, which may aid in promoting regular bowel movements. The substance is excreted in feces, where it contributes to dietary fiber intake.

Pregnancy

Data regarding the use of microcrystalline cellulose during pregnancy is limited. It is advisable to consult with healthcare professionals before use.

Breast-feeding

Microcrystalline cellulose is considered safe during breastfeeding, as it is not absorbed systemically.

Storage

Store in a cool, dry place away from direct sunlight and moisture.

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.

Mechanism of action

Lovastatin is a lactone which is readily hydrolyzed _in vivo_ to the corresponding β-hydroxyacid and strong inhibitor of HMG-CoA reductase, a hepatic microsomal enzyme which catalyzes the conversion of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A ) to mevalonate, an early rate-limiting step in cholesterol biosynthesis. At therapeutic lovastatin doses, HMG-CoA reductase is not completely blocked, thereby allowing biologically necessary amounts of mevalonate to be available. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol, therapy with lovastatin would not be expected to cause an accumulation of potentially toxic sterols. Lovastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increase hepatic uptake of LDL. Lovastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL and a significant reduction in the risk of development of CVD and all-cause mortality. A significant effect on LDL-C reduction was seen within 2 weeks of initiation of lovastatin, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night. When therapy with lovastatin is stopped, total cholesterol has been shown to return to pre-treatment levels. In vitro and in vivo animal studies also demonstrate that lovastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation. Lovastatin has been reported to have beneficial effects on certain cancers. This includes a multi-factorial stress-triggered cell death (apoptosis) and DNA degradation response in breast cancer cells. It has also been shown to inhibit histone deacetylase 2 (HDAC2) activity and increase the accumulation of acetylated histone-H3 and the expression of p21(WAF/CIP) in human cancer cells, suggesting that statins might serve as novel HDAC inhibitors for cancer therapy and chemoprevention. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), atorvastatin, cerivastatin, fluvastatin, pravastatin, lovastatin and simvastatin, reduce atherogenesis and cardiovascular morbidity. Besides, there is growing evidence that statins have immunomodulatory activities. Statins downregulate the expression of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MAC-1) and lymphocyte function-associated antigen-1 (LFA-1), on leucocytes and endothelial cells and, through binding to LFA-1, interfere with ICAM-1-LFA-1 interaction, which is crucial for activation of lymphocytes by antigen-presenting cells, ingress of leucocytes into the inflammation sites and immunologic cytotoxicity. Statins inhibit the inducible expression of major histocompatibility complex class II in several cell types including macrophages and downregulate the expression of T-helper-1 (Th1) chemokine receptors on T cells, leading further to inhibition of activation of lymphocytes and their infiltration into the inflammation sites. Statins block the induction of inducible nitric oxide synthase and the expression of several proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma in macrophages and possess antioxidant effects. These agents inhi

Pharmacodynamics

Lovastatin is an oral antilipemic agent which reversibly inhibits HMG-CoA reductase. It is used to lower total cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, lovastatin reduces the risk of cardiovascular morbidity and mortality. Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD. Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality. Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack. Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks. Clinical studies have shown that lovastatin reduces LDL-C and total cholesterol by 25-40%. The 50% inhibitory dose is known to be of 46 mcg/kg which is translated into a reduction of approximately 30% of plasma cholesterol. **Myopathy/Rhabdomyolysis** Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is dose-related and is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20 to 40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may also be at increased risk for myopathy. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. The risk of myopathy during treatment with lovastatin may be increased with concurrent administration of interacting drugs such as [fenofibrate], [niacin], [gemfibrozil], [cyclosporine], and strong inhibitors of the CYP3A4 enzyme. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with [colchicine], and caution should therefore be exercised when prescribing these two medications together. Real-world data from observational studies has suggested that 10-15% of people taking statins may experience muscle aches at some point during treatment. **Liver Dysfunction** Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials. When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment