Empagmet 12.5 / 500

Indications

• Type 2 diabetes mellitus
• Gestational diabetes
• Management of pre-existing diabetes in pregnant women

Dosage

Children: For children aged 10 years and older, the usual starting dose is 500 mg taken with food, with gradual increases based on clinical response. Refer to the BNF for Children for specific dosing recommendations.

Adults: The initial dose is usually 500 mg to 1,000 mg taken orally with food, and the dosage may be gradually increased based on glycemic control and tolerance, with a maximum daily dose typically not exceeding 2,000 mg.

Mechanism of action

Metformin decreases hepatic glucose production and increases peripheral glucose utilization. It does not stimulate insulin release from the pancreas, making it antihyperglycemic rather than hypoglycemic. The drug also interacts with SIRT1, a protein involved in bile acid metabolism, contributing to its effects on glucose homeostasis.

Pharmacodynamics

Metformin improves glycemic control in patients with type 2 diabetes by reducing fasting and postprandial plasma glucose levels. It acts by decreasing intestinal absorption of glucose, increasing insulin sensitivity, and enhancing peripheral glucose uptake and utilization, without causing hypoglycemia.

Pharmacokinetics

Metformin is absorbed from the gastrointestinal tract and is excreted unchanged in the urine. It has a half-life of about 6 hours and does not undergo significant metabolism. The drug's pharmacokinetics can be affected by renal function, and caution is advised in patients with renal impairment.

Contra-indications

• Severe renal impairment (creatinine clearance less than 25 mL/minute)
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• Hypersensitivity to metformin or any of its components

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Lactic acidosis (rare)
• Hepatic disorders (rare)
• Oedema (rare)
• Acute generalised exanthematous pustulosis (very rare)
• Thrombocytopenia (very rare)

Interactions

• Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists may require monitoring and adjustments
• Antacids containing magnesium and aluminium salts may reduce the absorption of metformin
• Concomitant use with other antihyperglycemic agents requires careful monitoring for hypoglycemia

Precautions

• Caution in patients with hepatic impairment
• Monitor liver function regularly during treatment
• Patients should be advised to discontinue use in the event of significant illness, especially dehydration or infections

Pregnancy

Avoid use during pregnancy. Women planning to become pregnant should discontinue metformin and consult a healthcare provider for safer alternatives.

Breast-feeding

Avoid use during breastfeeding. Metformin is excreted in breast milk, and its effects on a nursing infant are unknown.

Storage

Store in a cool, dry place, below 25°C. Protect from light.

Formulations

• Metformin hydrochloride 500 mg tablets
• Metformin hydrochloride 850 mg tablets
• Metformin hydrochloride 1000 mg tablets

Indications

• Type 2 diabetes mellitus as monotherapy (if metformin is inappropriate)
• Type 2 diabetes mellitus in combination with insulin or other antidiabetic drugs (if existing treatment fails to achieve adequate glycaemic control)
• Symptomatic chronic heart failure

Dosage

Adults: 10 mg once daily, increased to 25 mg once daily if necessary and tolerated.

Mechanism of action

Empagliflozin inhibits the SGLT2 transporters in the proximal tubules of the kidneys. By blocking the co-transport of sodium and glucose into the blood, it increases glucosuria, leading to lower blood glucose levels. Additionally, it may offer cardiovascular benefits by mechanisms yet to be fully elucidated, including effects on myocardial sodium/hydrogen exchangers and diuretic actions.

Pharmacodynamics

Empagliflozin effectively reduces blood glucose levels through increased urinary glucose excretion, necessitating once-daily dosing due to its prolonged action. Patients should be monitored for ketoacidosis, as it can occur even in the absence of significantly elevated blood glucose. The drug also poses a risk of urogenital infections due to the elevated glucose levels in urine.

Pharmacokinetics

Empagliflozin is absorbed after oral administration, with peak plasma concentrations occurring within 1.5 hours. It has a volume of distribution of approximately 73 liters and is primarily excreted via urine. Renal function should be monitored, as impaired renal function may affect drug efficacy and safety.

Contra-indications

• Diabetic ketoacidosis
• Severe renal impairment (eGFR < 30 mL/min)
• Hypersensitivity to empagliflozin or any of the excipients

Adverse effects

• Genital infections
• Urinary tract infections
• Dehydration
• Hypotension
• Diabetic ketoacidosis (rare)
• Fournier's gangrene (necrotizing fasciitis of the genitalia)

Interactions

• Antiepileptics (unknown effect on exposure)
• Rifamycins (unknown effect on exposure)
• Insulin and insulin secretagogues (may require dose adjustments)

Precautions

• Monitor for signs of diabetic ketoacidosis, particularly in patients with risk factors
• Consider temporary interruption in patients with complicated urinary tract infections
• Caution in elderly patients due to risk of hypotension and volume depletion
• Monitor renal function periodically

Pregnancy

Empagliflozin is not recommended during pregnancy due to potential risks to the fetus. Consult a healthcare provider for alternatives.

Breast-feeding

Empagliflozin is not recommended for use while breastfeeding. The effects on a nursing infant are unknown.

Storage

Store below 30°C. Protect from moisture. Keep out of reach of children.

Formulations

• Tablets: 10 mg, 25 mg

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

• Energy source
• Dietary fiber supplement
• Source of vitamins and minerals
• Antioxidant support

Dosage

Children: Corn can be introduced to children as part of a balanced diet. There is no specific paediatric dosage; it should be given according to age-appropriate dietary guidelines.

Adults: Corn can be consumed in various forms as part of a balanced diet. There is no specific adult dosage; intake should be based on dietary preferences and nutritional needs.

Mechanism of action

The primary component of corn is starch, which is a polysaccharide composed of glucose units. Upon ingestion, starch is broken down into glucose by enzymes such as amylase in the digestive system. The glucose is then absorbed into the bloodstream, providing energy to cells throughout the body. Corn also contains antioxidants such as lutein and zeaxanthin, which may help protect against oxidative stress and support eye health.

Pharmacodynamics

Corn is mainly metabolized for energy due to its high carbohydrate content. The dietary fiber in corn aids in digestion and promotes satiety. Additionally, the presence of vitamins and minerals contributes to overall health, supporting various bodily functions including immune response and bone health. The antioxidants in corn may help reduce inflammation and lower the risk of chronic diseases.

Pharmacokinetics

The digestion and absorption of corn depend on its form (whole kernel, cornmeal, corn syrup, etc.). Generally, carbohydrates are digested and absorbed relatively quickly, with glucose appearing in the bloodstream shortly after consumption. The fiber content can slow digestion and help maintain stable blood sugar levels. The bioavailability of nutrients from corn can vary based on processing methods, such as cooking or milling.

Pregnancy

Corn is generally considered safe during pregnancy. It provides essential nutrients such as fiber, vitamins, and minerals, but should be consumed in moderation as part of a balanced diet.

Breast-feeding

Corn is safe for consumption while breastfeeding. It can provide important nutrients, but it's advisable to monitor for any allergic reactions in infants.

Storage

Store corn in a cool, dry place. Fresh corn should be kept in the refrigerator and consumed within a few days for optimal freshness.

Formulations

• Fresh corn
• Canned corn
• Frozen corn
• Cornmeal
• Corn syrup
• Corn oil

Indications

• Type 2 diabetes mellitus
• Polycystic ovary syndrome (PCOS)

Dosage

Children: The

Adults: The usual starting dose of metformin for adults is 500 mg taken orally twice a day or 850 mg once daily, with gradual increases based on tolerance and blood glucose levels. The maximum recommended daily dose is 2000-3000 mg, depending on the formulation used.

Mechanism of action

Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing intestinal absorption of glucose, and increasing insulin sensitivity, which enhances peripheral glucose uptake and utilization. It is known to inhibit mitochondrial complex I activity, leading to increased AMP:ATP ratios that activate AMP-activated protein kinase (AMPK), a key regulator of glucose metabolism. This activation results in reduced hepatic glucose output and improved cellular glucose uptake.

Pharmacodynamics

Metformin exerts its effects primarily by enhancing insulin sensitivity and reducing glucose production by the liver. Unlike sulfonylureas, which increase insulin secretion, metformin does not cause hyperinsulinemia. Its ability to lower fasting plasma glucose and glycosylated hemoglobin (HbA1c) levels makes it a cornerstone in the management of type 2 diabetes. Clinical studies have shown significant reductions in fasting plasma glucose and HbA1c levels in patients treated with metformin.

Pharmacokinetics

Metformin is absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring 2-3 hours after ingestion. It has a bioavailability of approximately 50-60% when administered orally. The drug is primarily eliminated unchanged by the kidneys, and its clearance is proportional to renal function. The half-life of metformin is about 6.5 hours. Accumulation may occur in cases of renal impairment, necessitating caution in patients with reduced renal function.

Adverse effects

• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Lactic acidosis
• Vitamin B12 deficiency

Interactions

• dolutegravir+metformin: Moderate (increases exposure)
• cimetidine+metformin: Moderate (increases exposure)
• risdiplam+metformin: Moderate (increases concentration)
• vandetanib+metformin: Moderate (increases exposure)
• bictegravir+metformin: Unknown (increases exposure)
• guanfacine+metformin: Unknown (increases concentration)
• mexiletine+metformin: Unknown (affects exposure)
• pitolisant+metformin: Unknown (increases exposure)
• ribociclib+metformin: Unknown (increases exposure)

Precautions

• Renal impairment
• Dehydration
• Excessive alcohol intake

Pregnancy

Metformin is classified as a Category B medication. It is often used during pregnancy for managing gestational diabetes but should be administered under medical supervision.

Breast-feeding

Metformin is excreted in breast milk, but is generally considered safe for use during breastfeeding. Consult with a healthcare provider for specific guidance.

Storage

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

Formulations

• Tablets
• Extended-release tablets
• Oral solution

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines in cases of methanol poisoning in pediatric patients.

Adults: In cases of methanol poisoning, immediate medical attention is required. Treatment typically involves the administration of fomepizole or ethanol as antidotes, along with supportive care and correction of metabolic acidosis. Dosing should be guided by clinical protocols.

Mechanism of action

Methanol is metabolized in the liver by alcohol dehydrogenase to formaldehyde, which is further oxidized to formic acid. Formic acid is responsible for many of the toxic effects of methanol, including metabolic acidosis and visual impairment. The severity of toxicity can depend on individual susceptibility and the activity of metabolic pathways, particularly those involving folic acid metabolism, which is necessary for formate metabolism.

Pharmacodynamics

Methanol toxicity manifests through its metabolic products, primarily formic acid, which decreases blood pH, leading to metabolic acidosis. This acidosis can cause complications such as respiratory distress and cardiovascular instability. The accumulation of formic acid also impacts mitochondrial function and can lead to cellular hypoxia and damage, particularly in the optic nerve, resulting in visual impairment or blindness.

Pharmacokinetics

Methanol is rapidly absorbed through the gastrointestinal tract and can cross the blood-brain barrier. It is metabolized primarily in the liver, with a significant portion converted to formaldehyde and then to formic acid. The elimination half-life of methanol varies and can be prolonged in cases of intoxication due to saturation of metabolic pathways. The time to peak concentrations can vary significantly; toxicity can develop long after initial ingestion, complicating management.

Adverse effects

• Metabolic acidosis
• Visual impairment
• Headaches
• Nausea
• Vomiting
• Dizziness
• Coma
• Death

Precautions

• Use with caution in individuals with liver impairment
• Monitor for signs of toxicity, especially in cases of suspected overdose

Pregnancy

Methanol is classified as a teratogen and should be avoided during pregnancy due to the risk of fetal toxicity and developmental harm.

Breast-feeding

Methanol is not recommended while breastfeeding due to potential harmful effects in the nursing infant.

Storage

Store in a cool, dry place away from light and heat. Keep container tightly closed and out of reach of children.

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.

Indications

• Topical antiseptic for skin disinfection
• Surgical scrubs and hand sanitizers
• Wound care management
• Pharmaceutical excipient in solid and liquid formulations

Dosage

Children: Refer to specific product guidelines for pediatric dosing recommendations, as doses can vary based on formulation and intended use.

Adults: Refer to specific product guidelines for dosing recommendations, as doses can vary based on the formulation and intended use.

Mechanism of action

Povidone acts by forming a complex with iodine when used as an antiseptic, which releases iodine slowly to exert its antimicrobial effect. The iodine disrupts microbial cell walls and interferes with protein synthesis, leading to cell death. Additionally, as a polymer, povidone can enhance drug solubility and stability by forming a hydrophilic matrix.

Pharmacodynamics

Povidone has a broad spectrum of antimicrobial activity against bacteria, viruses, and fungi. Its antiseptic properties are primarily due to the release of iodine, which is effective in reducing microbial load and preventing infection. The polymer's ability to bind to various substances allows it to be utilized in formulations that require improved stability and solubility.

Pharmacokinetics

Povidone is not absorbed systemically when applied topically, as it remains localized at the site of application. Its pharmacokinetics are largely dependent on the formulation and route of administration, with the polymer being metabolized by hydrolysis and excreted in urine as low-molecular-weight compounds. The release and activity of iodine are influenced by the concentration of povidone and the presence of organic matter.

Adverse effects

• Local irritation
• Allergic reactions
• Skin rashes
• Hypersensitivity reactions

Precautions

• Use with caution in patients with known allergies to iodine or povidone-iodine
• Avoid use in deep puncture wounds or serious burns

Pregnancy

Povidone is generally considered safe for use during pregnancy, but it is advisable to consult a healthcare professional before use.

Breast-feeding

Povidone is considered safe during breastfeeding, but it is recommended to consult a healthcare professional.

Storage

Store at room temperature, away from moisture and heat. Keep the container tightly closed.

Formulations

• Topical solution
• Ointment
• Surgical scrub
• Gauze impregnated with povidone-iodine

Dosage

Children: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Adults: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Mechanism of action

The mechanism of action for purified compounds varies widely depending on the specific substance. Generally, purified drugs exert their effects by interacting with specific biological targets, such as receptors, enzymes, or ion channels, leading to a desired therapeutic effect. This interaction can involve binding to receptors to activate or inhibit signaling pathways, modulating enzymatic activity, or altering physiological processes.

Pharmacodynamics

Pharmacodynamics describes the effects of a drug on the body and the relationship between drug concentration and effect. For purified drugs, this can involve dose-response relationships and the time course of their action. The purified form often enhances potency and reduces variability in response among patients, which can lead to more predictable therapeutic outcomes. The overall effect is determined by the drug's affinity for its target, the efficacy of the drug-receptor interaction, and the downstream signaling pathways activated as a result of this interaction.

Pharmacokinetics

Pharmacokinetics involves the absorption, distribution, metabolism, and excretion (ADME) of a drug. For purified substances, absorption can be more efficient due to the absence of impurities that may affect solubility or stability. Distribution may also be enhanced, leading to higher bioavailability. Metabolism can be influenced by the structure of the purified compound, as it may be metabolized more readily by liver enzymes. Excretion typically occurs through the kidneys or liver, depending on the molecular characteristics of the purified drug.

Pregnancy

Consult with a healthcare professional, as the safety of purified forms of medications during pregnancy may vary depending on the specific substance.

Breast-feeding

Consult with a healthcare professional, as the safety of purified forms of medications during breastfeeding may vary depending on the specific substance.

Storage

Store in a cool, dry place, away from light and moisture, and keep out of reach of children.

Indications

• Nutritional supplement
• Source of energy in dietary formulations
• Excipients in pharmaceutical formulations

Dosage

Children: Refer to specific product guidelines, as doses can vary based on formulation and intended use.

Adults: Refer to specific product guidelines, as doses can vary based on formulation and intended use.

Mechanism of action

Starch serves primarily as a source of energy when metabolized. In the gastrointestinal tract, enzymes such as amylase break down starch into maltose and glucose, which are then absorbed into the bloodstream. The glucose can then be utilized by the body for energy or stored as glycogen in the liver and muscles.

Pharmacodynamics

The pharmacodynamic effects of starch are mainly related to its role as a carbohydrate source. It contributes to the regulation of blood glucose levels and provides energy for cellular functions. Its digestibility and the rate at which it raises blood glucose can vary based on its source and processing method.

Pharmacokinetics

Starch is not absorbed in its intact form. It undergoes enzymatic hydrolysis in the digestive system, where it is broken down into simpler sugars such as glucose. The absorption of glucose occurs primarily in the small intestine, with subsequent entry into the bloodstream. The onset of glucose availability varies depending on the type of starch and the presence of other nutrients.

Pregnancy

Starch is generally considered safe during pregnancy as it is a carbohydrate and a common food source.

Breast-feeding

Starch is typically safe for breastfeeding mothers, as it is a major component of many foods consumed during lactation.

Storage

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

Formulations

• Powder
• Granules
• Suspension

Mechanism of action

The vast majority of glucose filtered through the glomerulus is reabsorbed within the proximal tubule, primarily via SGLT2 (sodium-glucose linked co-transporter-2) which is responsible for ~90% of the total glucose reabsorption within the kidneys. Na⁺/K⁺-ATPase on the basolateral membrane of proximal tubular cells utilize ATP to actively pump Na+ ions into the interstitium surrounding the tubule, establishing a Na⁺ gradient within the tubular cell. SGLT2 on the apical membrane of these cells then utilize this gradient to facilitate secondary active co-transport of both Na+ and glucose out of the filtrate, thereby reabsorbing glucose back into the blood – inhibiting this co-transport, then, allows for a marked increase in glucosuria and decrease in blood glucose levels. Empagliflozin is a potent inhibitor of renal SGLT2 transporters located in the proximal tubules of the kidneys and works to lower blood glucose levels via an increase in glucosuria. Empagliflozin also appears to exert cardiovascular benefits - specifically in the prevention of heart failure - independent of its blood glucose-lowering effects, though the exact mechanism of this benefit is not precisely understood. Several theories have been posited, including the potential inhibition of Na⁺/H⁺ exchanger (NHE) 1 in the myocardium and NHE3 in the proximal tubule, reduction of pre-load via diuretic/natriuretic effects and reduction of blood pressure, prevention of cardiac fibrosis via suppression of pro-fibrotic markers, and reduction of pro-inflammatory adipokines.

Pharmacodynamics

Empagliflozin lowers blood glucose levels by preventing glucose reabsorption in the kidneys, thereby increasing the amount of glucose excreted in the urine. It has a relatively long duration of action requiring only once-daily dosing. Patients should be monitored closely for signs and symptoms of ketoacidosis regardless of blood glucose level as empagliflozin may precipitate diabetic ketoacidosis in the absence of hyperglycemia. As its mechanism of action is contingent on the renal excretion of glucose, empagliflozin may be held in cases of acute kidney injury and/or discontinued in patients who develop chronic renal disease. The overexcretion of glucose creates a sugar-rich urogenital environment which increases the risk of urogenital infections in both male and female patients - monitor closely for signs and symptoms of developing infection.

Mechanism of action

Metformin is widely used to treat hyperglycemia. However, metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type II diabetes through an unknown mechanism. Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver. Both metformin-treated wild-type C57 mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels. However, metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice. Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport. Hepatic SIRT1 mutation elevates Foxa2 acetylation levels, which promotes Foxa2 binding to and activating genes involved in bile acids metabolism, impairing hepatic and systemic bile acid homeostasis. Our data clearly suggest that hepatic SIRT1 mediates metformin effects on systemic bile acid metabolism and modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis. Metformin is antihyperglycemic, not hypoglycemic. It does not cause insulin release from the pancreas and does not cause hypoglycemia, even in large doses. Metformin has no significant effects on the secretion of glucagon, cortisol, growth hormone or somatostatin. Metformin reduces glucose levels primarily by decreasing hepatic glucose production and by increasing insulin action in muscle and fat. ... May decrease plasma glucose by reducing the absorption of glucose from the intestine. /Salt not specified/ Metformin potentiates the effect of insulin by mechanisms not fully understood. Metformin does not stimulate pancreatic beta cells to increase secretion of insulin; insulin secretion must be present for metformin to work properly. It is postulated that metformin decreases hepatic glucose production and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. /Salt not specified/ People with Type 2 diabetes mellitus (T2DM) have reduced bone mineral density and an increased risk of fractures due to altered mesenchymal stem cell (MSC) differentiation in the bone marrow. This leads to a shift in the balance of differentiation away from bone formation (osteogenesis) in favour of fat cell development (adipogenesis). The commonly used anti-diabetic drug, metformin, activates the osteogenic transcription factor Runt-related transcription factor 2 (Runx2), which may suppress adipogenesis, leading to improved bone health. Here we investigate the involvement of the metabolic enzyme, AMP-activated protein kinase (AMPK), in these protective actions of metformin. The anti-adipogenic actions of metformin were observed in multipotent C3H10T1/2 MSCs, in which metformin exerted reciprocal control over the activities of Runx2 and the adipogenic transcription factor, PPARgamma, leading to suppression of adipogenesis. These effects appeared to be independent of AMPK activation but rather through the suppression of the mTOR/p70S6K signalling pathway. Basal AMPK and mTOR/p70S6K activity did appear to be required for adipogenesis, as demonstrated by the use of the AMPK inhibitor, compound C. This observation was further supported by using AMPK knockout mouse embryo fibroblasts (MEFs) where adipogenesis, as assessed by reduced lipid accumulation and expression of the adipogeneic transcription factor, C/EBPbeta, was found to display an absolute requirement for AMPK. Further activation of AMPK in wild type MEFS, with either metformin or the AMPK-specific activator, A769662, was also associated with suppression of adipogenesis. It appears, therefore, that basal AMPK activity is required for adipogenesis and that metformin can inhibit adipogenesis through AMPK-dependent or -independent mechanisms, depending on the cellular context.

Mechanism of action

Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (also called gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization. It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism. The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control. After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios. These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism. Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit _fructose-1,6-bisphosphatase_ enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting _adenylate cyclase_ and decreasing the production of cyclic adenosine monophosphate (cAMP), a derivative of ATP used for cell signaling. Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin. In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose. In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years. Metformin is widely used to treat hyperglycemia. However, metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type II diabetes through an unknown mechanism. Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver. Both metformin-treated wild-type C57 mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels. However, metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice. Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport. Hepatic SIRT1 mutation elevates Foxa2 acetylation levels, which promotes Foxa2 binding to and activating genes involved in bile acids metabolism, impairing hepatic and systemic bile acid homeostasis. Our data clearly suggest that hepatic SIRT1 mediates metformin effects on systemic bile acid metabolism and modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis. Metformin is antihyperglycemic, not hypoglycemic. It does not cause insulin release from the pancreas and does not cause hypoglycemia, even in large doses. Me

Pharmacodynamics

**General effects** Insulin is an important hormone that regulates blood glucose levels. Type II diabetes is characterized by a decrease in sensitivity to insulin, resulting in elevations in blood glucose when the pancreas can no longer compensate. In patients diagnosed with type 2 diabetes, insulin is unable to exert adequate effects on tissues and cells (i.e. insulin resistance) and insulin deficiency may also be present. Metformin reduces hepatic production of glucose, decreases the intestinal absorption of glucose, and enhances insulin sensitivity by increasing both peripheral glucose uptake and utilization. In contrast with drugs of the sulfonylurea class, which lead to hyperinsulinemia, the secretion of insulin is unchanged with metformin use. **Effect on fasting plasma glucose (FPG) and Glycosylated hemoglobin (HbA1c)** HbA1c is an important periodic measure of glycemic control used to monitor diabetic patients. Fasting plasma glucose is also a useful and important measure of glycemic control. In a 29-week clinical trial of subjects diagnosed with type II diabetes, metformin decreased the fasting plasma glucose levels by an average of 59 mg/dL from baseline, compared to an average increase of 6.3 mg/dL from baseline in subjects taking a placebo. Glycosylated hemoglobin (HbA1c) was decreased by about 1.4% in subjects receiving metformin, and increased by 0.4% in subjects receiving placebo only.

Mechanism of action

... The metabolic mechanisms of methanol toxicity /are/ reviewed. ... It is noted that the most severe toxicity occurs many hours following peak blood and tissue methanol concentrations so that these do not necessarily provide an accurate indication of toxicity. Individual differences are seen both in this latent period and in individual susceptibility to methanol. This susceptibility may depend on the activity of folic acid requiring metabolic reactions involved in formate metabolism, formate being an intermediate produced during methanol oxidation and responsible for many toxic effects of methanol. Studies of the characteristics of methanol poisoning in non-primates and monkeys are examined. Despite the ingestion of lethal doses of methanol, non-primates generally do not develop significant metabolic acidosis nor impairment of vision, and no consistent histopathology has been demonstrated in these species. In monkeys, results suggest that the latent period represents a period of compensated metabolic acidosis; when compensatory mechanisms are exhausted, blood pH begins to drop. Formate accumulates and produces acidosis in the methanol poisoned monkey, but not in the rat, apparently due to a slower rate of formate metabolism to carbon dioxide in the monkey. ... Studies demonstrating the role of alcohol dehydrogenase in methanol metabolism in the monkey are reported; however, the catalase/peroxidative system which participates in methanol metabolism in rats apparently does not function in the monkey. Formaldehyde and formate metabolism are also examined. The regulation of the rate of formate metabolism is governed by regulation of the hepatic tetrahydrofolate concentrations. ... Further research is needed to determine what step or process it is which places the primate at a distinct liability in the metabolic disposition of one carbon moieties. Methanol toxicity is observed in monkeys and humans but is not seen in rats or mice. The expression of methanol poisoning is related to the ability of an animal to metabolize formate to carbon dioxide. Since the rate of formate oxidation is related to hepatic tetrahydrofolate content and the activites of folate dependent enzymes, studies were designed to determine hepatic concentrations of hepatic tetrahydrofolate and activites of folate dependent enzymes of human liver and livers of species considered insensitive to methanol poisoning. An excellent correlation between hepatic tetrahydrofolate and maximal rates of formate oxidation has been observed. In human liver, levels were only 50% of those observed for rat liver and similar to those found in monkey liver. Total folate was also lower (60% decreased) in human liver than that found in rat or monkey liver. Interestingly, mouse liver contains much higher hepatic tetrahydrofolate and total folate than rat or monkey liver. This is consistent with higher formate oxidation rates in this species. A second important observation has been made. 10-Formyltetrahydrofolate dehydrogenase activity, the enzyme catalyzing the final step of formate oxidation to carbon dioxide, was markedly reduced in both monkey and human liver. Thus, two mechanisms may be operative in explaining low formate oxidation in species susceptible to methanol toxicity, low hepatic tetahydrofolate levels and reduced hepatic 10-formyltetrahydrofolate dehydrogenase activity. Formic acid, the toxic metabolite of methanol, has been hypothesized to produce retinal and optic nerve toxicity by disrupting mitochondrial energy production. It has been shown in vitro to inhibit the activity of cytochrome oxidase, a vital component of the mitochondrial electron transport chain involved in ATP synthesis. Inhibition occurs subsequent to the binding of formic acid to the ferric heme iron of cytochrome oxidase, and the apparent inhibition constant is between 5 and 30 mM. Concentrations of formate present in the blood and tissues of methanol-intoxicated humans, non-human primates and rodent m