Oral hypoglycemic agents
Metformin hydrochloride is a biguanide oral hypoglycemic agent , also known as Glucophage, its hypoglycemic effect is weaker than phenformin, the main role is to reduce the glucagon secretion of A cells ,and to promote the conversion of glucose to glycogen, its characteristic effect including that it does not stimulate pancreatic β-cells to secrete insulin .
The follows are hypoglycemic mechanisms:
1. Increasing the sensitivity of peripheral tissues to insulin, increase insulin-mediated glucose utilization.
2. Increasing glucose utilization of non-insulin-dependent tissues, such as brain, blood cells, kidney medulla, intestine, skin and so on.
3. Inhibiting hepatic gluconeogenesis effect , reducing hepatic glucose output.
4. Inhibiting glucose uptake by intestinal cells.
5. Inhibiting the biosynthesis and storage of cholesterol , lowering blood triglycerides and total cholesterol levels.
Metformin hydrochloride is clinically used for the treatment of type Ⅱ diabetes patients who are not satisfied with simple diet control, especially patients with obesity and hyperinsulinemia, usage of this drug not only displays no hypoglycemic effect, but also there may be weight loss and hyperinsulinemia effect. For some patients with poor efficacy of sulfonylurea ,it may be effective, if it is used with hypoglycemic drugs including sulfonylurea, intestinal glucosidase inhibitors or thiazolidinediones, the results are better than used alone. It can also be used in patients with insulin therapy to reduce the amount of insulin.
At present, domestic manufacturer mainly include the American Shanghai Squibb Pharmaceutical Co., Ltd .
Adverse effects and precautions
Biguanide oral hypoglycemic agents can increase glucose utilization of surrounding tissues and inhibit the intestinal absorption of glucose, and inhibit glycogen gluconeogenesis and hepatic glucose output,it is mainly applied to obesity, dyslipidemia, type II diabetes patients. It almost has no hypoglycemic effect for normal persons , 2 to 3 hours after taking for diabetes patients ,glucose decreases significantly.
Commonly used oral hypoglycemic agents include phenformin and metformin hydrochloride.
The incidence of adverse effects of metformin hydrochloride is higher than tolbutamide , common gastrointestinal reactions are anorexia, nausea, vomiting, abdominal pain, diarrhea, occasional metallic taste in the mouth, bad breath, nausea, loss of appetite and diarrhea and other gastrointestinal reactions, sometimes hypoglycemia is visible .
Since the biguanide drugs enhance sugar anaerobic glycolysis, and inhibit glycogen generation, small number of patients may suffer with ketosis or lactic acidosis, which should be particularly vigilant, but metformin effect is weak , adverse reactions are only 1/50 of other biguanides, and it has rapid clearance, there are no accumulation in the liver, it rarely induces lactic acidosis, sometimes there is mild increase in blood lactate. patients with heart, liver, kidney diseases are prone to these adverse reactions, diabetes patients with these types of complications are hanged. It can reduce the absorption of vitamin B12, but it seldom causes anemia. The following cases are contraindications:
1. Pregnant and lactating women, children under 10 years of age, 80 years of age or older.
2. Diabetic ketoacidosis, diabetic hyperglycemic hyperosmolar syndrome, diabetes lactic acidosis.
3. Severe liver and kidney dysfunction, blood urea nitrogen and creatinine higher than normal, hypovolemic shock, heart failure, AMI, in vivo hypoxic condition such as heart failure, pulmonary insufficiency, or any systemic hypoxia circumstances and other serious heart and lung diseases.
4. Severe infection or trauma, major surgery, clinical hypotension , hypoxia and so on.
5. Complications with severe diabetic nephropathy and retinopathy. When there are symptoms,the drug should be immediately discontinued; cimetidine can reduce the renal excretion of metformin hydrochloride, agar types can reduce the absorption of metformin, patients must check liver and kidney function and cardiac ketones regularly.
6. Alcoholics, vitamin B12 and folate deficiency which are not corrected.
Chemical Properties
White crystal or crystalline powder. Melting point 232 ℃ (218-220 ℃). Soluble in water, dissolved in methanol, slightly soluble in ethanol, insoluble in ether and chloroform. Odorless, bitter taste.
Application
- The product belongs to hypoglycemic agents. It can be used in patients with type Ⅱ diabetes to reduce fasting and postprandial hyperglycemia, HbAlc can be decreased by 1% to 2%, hypoglycemic mechanism of this product may be: I increase the sensitivity of peripheral tissues to insulin, increases insulin-mediated glucose utilization . II increase glucose utilization of non-insulin dependent tissues, such as brain, blood cells, kidney medulla, intestine, skin and the like. III inhibit hepatic gluconeogenesis effect, reduce hepatic glucose output. IV inhibit glucose uptake by intestinal cells.
- Indications: For mild diabetes.
- Metformin hydrochloride is an anti-diabetic agent, reducing blood glucose levels, and improving insulin sensitivity. Its metabolites (including the inhibition of hepatic gluconeogenesis) is activated through LKB1-AMPK (AMP-activated protein kinase) path.
- Hypoglycemic agents, it is used for non-insulin-dependent diabetes. Rat oral LD50 of 1000 mg/kg.
Production method
After the salifying of dimethylamine and the reaction with dicyandiamide , the product is derived.
Description
Metformin is a biguanide with diverse biological activities. Metformin (250 mg/kg, i.p.) increases hepatic AMPK activity and reduces blood glucose by more than 50% in a liver kinase B1-dependent manner in mice fed normal and high-fat diets, respectively, and reduces blood glucose by 40% in
ob/ob mice. It reduces weight gain, hepatic lipid droplet content, and total cholesterol, LDL cholesterol, and triglyceride levels in the plasma of diet-induced obese mice when administered at doses of 10 or 50 mg/kg per day. It also reverses increased hepatic triglyceride and apolipoprotein A5 levels, as well as hepatic steatosis, in a dose-dependent manner in an
ob/ob mouse model of non-alcoholic fatty liver disease (NAFLD). Metformin (250 mg/kg) reduces tumor growth in an HCT116 p53
-\- human colon cancer mouse xenograft model, but has no effect on HCT116 p53
-\- tumors overexpressing recombinant
S. cerevisiae Ndi1 NADH dehydrogenase, a single-subunit ortholog of the multi-subunit mammalian mitochondrial complex I. Formulations containing metformin have been used in the treatment of type 2 diabetes.
Chemical Properties
Crystalline Solid
Originator
Diabetex ,Germania
Uses
1,1-Dimethylbiguanide hydrochloride is used as an antidiabetic agent, used in polycystic ovary syndrome, non-alcoholic fatty liver disease and diabetes mellitus type 2. It may also reduce weight gain in people taking atypical antipsychotics, used in a study to investigate its role in enhancing the secretions of plasma active glucagon-like peptide-1 (GLP-1) levels.
Uses
Anti-diabetic and anti-cancer activity
Uses
An oral hypoglycemic agent
Uses
Metformin hydrochloride may be used as a pharmaceutical primary standard for the determination of the analyte in pharmaceutical formulations and human plasma samples by analytical techniques.
Definition
ChEBI: A hydrochloride resulting from the reaction of metformin with one molar equivalent of hydrogen chloride.
Manufacturing Process
The boiling mixture of 1,000 L xylene, 450 kg dimethylamine and 840 kg dicyanamide was added 365 kg hydrogene chloride. Yield of biguanide, 1,1- dimethyl-, hydrochloride 1,588 kg (96%). Biguanide, 1,1-dimethyl-, hydrochloride may be recrystallysed from methanol.
brand name
Fortamet (Andrx); Glucophage
(Bristol-Myers Squibb); Glumetza (Depomed); Riomet(Ranbaxy).
Therapeutic Function
Oral hypoglycemic
General Description
1,1-Dimethylbiguanide hydrochloride (metformin) is a strong base. It forms well defined salts and possessing excellent coordination capacity with transition metals, forming highly colored bidentate chelate complexes. Metformin (MET) exists in various forms: diprotonated (H
2MET)
2+ in strong acidic solution, monoprotonated (HMET)
+ in weak acid, MET in neutral and deprotonated (MET)
- in strong alkali solution. It is an oral antidiabetic drug. Pharmacokinetics of metformin has been studied. Determination of metformin in human plasma has been described by simple HPLC-UV method. Metformin is reported to increase plasma active glucagon-like peptide-1 (GLP-1) in humans.
Flammability and Explosibility
Non flammable
Biological Activity
Antidiabetic agent; lowers plasma glucose levels and improves insulin sensitivity. Inhibits hepatic gluconeogenesis via activation of the LKB1/AMPK pathway. Displays antiproliferative effects in cancer cell lines.
Biochem/physiol Actions
Metformin is an antidiabetic agent that reduces blood glucose levels and improves insulin sensitivity. Its metabolic effects, including the inhibition of hepatic gluconeogenesis, are mediated at least in part by activation of the LKB1-AMPK (AMP-activated protein kinase) pathway. Activation of this pathway also appears to be involved in the antiproliferative and proapoptotic actions of metformin in cancer cell lines.
Clinical Use
Non-insulin dependent diabetes mellitus
Polycystic ovary syndrome
Veterinary Drugs and Treatments
Metformin may be useful in the adjunctive treatment of non-insulin
dependent diabetes mellitus in cats. Only limited trials of the
drug have been performed in cats, with only very limited success
when the drug is used alone. Studies comparing its safety and efficacy
with other oral antihyperglycemics (e.g., glipizide or insulin)
were not located.
Drug interactions
Potentially hazardous interactions with other drugs
Alcohol: increased risk of lactic acidosis.
Cimetidine: inhibits renal excretion of metformin
Metabolism
Metformin is not metabolised to any great extent, and is
entirely excreted unchanged in the urine.
References
1) Zhou et al. (2001), Role of AMP-activated protein kinase in mechanism of metformin action; J. Clin. Invest., 108 1167
2) Shaw et al. (2005), The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin; Science, 310 1642
3) Shi et al. (2012), Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy; Cell Death Dis., 3 e275
4) Rego et al. (2017) Anti-tumor effects of metformin on head and neck carcinoma cell lines: A systemic review; Oncol. Lett., 13 554
5) Lee et al. (2017) PGC1α Activators Mitigate Diabetic Tubulopathy by Improving Mitochondrial Dynamics and Quality Control; J. Diabetes Res., 2017 6483572
6) Zheng et al. (2012) Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin; Diabetes, 61 217
7) Katila et al. (2017) Metformin lowers α-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson’s disease; Neuropharmacology, 125 396
8) Coll et al. (2020), GDF15 mediates the effects of metformin on body weight and energy balance; Nature, 578 444
