by egpat 28 May 2024
Metformin chemically belongs to the class of biguanides. We have another drug within this category, phenformin, which is withdrawn from the market, so nowadays only metformin is available. This metformin has a unique action compared with other anti-diabetic agents. A few of the other anti-diabetic agents, such as sulfonylureas, are going to increase the insulin release, but here metformin is not releasing the insulin; instead, it increases the sensitivity of the insulin. This is one of the most important requirements for controlling type 2 diabetes. That's why metformin is the first drug that is indicated to treat type 2 diabetes mellitus.
Apart from this, metformin also shows some weight loss. Other drugs, like sulfonylureas, are going to increase body weight, resulting in weight gain, but this drug is going to reduce body weight to some extent. That's why this drug is preferred for obese patients who are suffering from type 2 diabetes mellitus.
Metformin chemically belongs to the biguanides. Biguanide is a combination of two guanidine moieties. It has two methyl groups on the nitrogen of one guanidine moiety. Therefore, metformin is a N,N-dimethyl biguanide.
Metformin shows important activity in the three important organs. The first one is the liver, where glucose can be produced, which results in increased blood glucose levels. Similarly, in the intestine, glucose can be absorbed through the glucose transporters. Metformin is also reducing carbohydrate absorption and, thereby, glucose absorption in the intestine.
The third target is the muscle. Glucose can be taken into the muscle. Metformin can stimulate this uptake of glucose into the skeletal muscle. In this way, metformin reduces blood glucose levels and increases glucose uptake into the skeletal muscle. Among these, the action of metformin on the liver is mainly responsible for the glycemic control of the drug.
Glucagon is one of the mediators that is going to increase blood glucose levels. It can act on the glucagon receptors expressed in the hepatic cells. These receptors are G-protein-coupled receptors. When glucagon binds to these G-protein-coupled receptors, it activates the adenylyl cyclase system. Now this adenylyl cyclase can convert the ATP into cyclic AMP. This cyclic AMP is an important secondary messenger that can activate the protein kinase A, which is the phosphorylating enzyme that can activate the many types of enzymes responsible for increased glucose production. For instance, they can activate one of the enzymes, the glycogen phosphorylase enzyme, which is responsible for glycogenolysis, the breakdown of the glycogen into glucose. Similarly, they can also increase gluconeogenesis. In this way, glucagon increases blood glucose levels.
The raised blood glucose levels in the liver can increase ATP production in mitochondria. Oxidative phosphorylation in the mitochandria can utilize NADH and release ATP by entering the complex-1 reactions of the electron transport chain.
Metformin can act on these targets to control glucose levels. First, it enters the hepatic cells through organic cation transporter 1 (OCT1). It can inhibit complex-1 reactions, such that it inhibits the production of ATP. Because of reduced ATP levels, AMP levels are increased. This results in an increase in the ratio of AMP to ADP as well as the ratio of ADP to ATP. Now, these raised levels of AMP can inhibit the adenylyl cyclase system, thereby inhibiting glucagon-related activity.
Similarly, increased AMP levels can also activate another enzyme, AMPK, the AMP-dependent protein kinase enzyme, which is again responsible for controlling glucose production within the hepatocytes.
The third target is to control the FBPase enzyme. This is the fructose 1,6-bi phosphatase enzyme, which is required for gluconeogenesis. When this enzyme is inhibited, the glucose production by the hepatocytes is going to be reduced. Through all of these actions, metformin can control glucose levels, and many of these actions just resemble insulin activity. So metformin is going to increase insulin sensitivity, thereby reducing hepatic glucose production.
Metformin can produce lactic acidosis. This is a condition of elevated lactic acid levels in the blood. Normally, the lactic acid levels range from 0.5 to 1 millimoles per liter, but when metformin is used, the lactate levels may be greater than 5 millimoles per liter. Metformin can also increase the ratio between lactate and pyruvate. When lactate levels are increased and pyruvate levels are reduced, which resembles some anaerobic conditions. Even the anionic gap acidosis is increased because of the increased lactic acid levels.
Lactic acidosis can lead to a few of the symptoms, such as myalgia (muscle pain), abdominal pain, malaise, some feeling of weakness, somnolence, increased sleepiness, diarrhea, headache, anorexia (loss of appetite), and hypotension. Along with this, lactic acidosis can also precipitate bronchospasm and bradycardia.
Sometimes this lactic acidosis also increases with other factors. Pyruvate is converted into oxaloacetate by the pyruvate carboxylase enzyme. This oxaloacetate is responsible for gluconeogenesis. Similarly, pyruvate can also be converted into lactate by another enzyme, the lactate dehydrogenase enzyme (LDH).
Metformin can act on these two steps. It can inhibit this pyruvate carboxylase enzyme, such that it can inhibit the conversion of pruvate to oxaloacetate. This elevated level of pyruvate can be converted into lactate. It can also increase NADH levels by inhibiting the electron transport chain complex one reaction, which acts as a co-factor for LDH. Therefore, metformin can increase the conversion of pyruvate to lactate. In this way, metformin can increase lactate levels, resulting in lactic acidosis.
Sometimes other factors can also increase lactic acidosis when they coexist with metformin. For example, iodinated contrast agents can increase lactic acidosis. Excessive alcohol intake can also increase lactic acidosis. Recent surgery may also lead to the development of raised lactic acid levels.
Similarly, a few of the disorders, like congestive heart failure, which produces hypoxia, and hepatic impairment, which reduces lactic acid uptake, may elevate lactic acid levels. People older than 65 also pose more risk.
Metformin is excreted unchanged through the kidneys. In people with renal impairment, metformin levels in the blood may be elevated. So renal functionality should be checked when this drug is used for prolonged periods. When the estimated glomerular filtration rate (eGFR) is less than 30 ml per minute per 1.73 square mm of body surface area, metformin is contraindicated. For people with mild renal impairment, the dose of metformin should be reduced.
Since this metformin is not secreting insulin, it is less likely to produce hypoglycemia. However, when this drug is given with other conditions such as malnutrition or strenuous exercise, alcohol intoxication, adrenal insufficiency, or use with other anti-diabetic agents such as sulfonylureas, hypoglycemic effects can be observed.
Metformin can reduce the absorption of vitamin B12, which may lead to vitamin B12 deficiency. It may not result in anemia, but the levels of vitamin B12 are reduced in the presence of metformin.
A few of the drugs, like acetazolamide, which is a diuretic, and zonisamide, which is an anti-epileptic agent, and topiramate, again, which is an anti-epileptic agent, are going to inhibit the carbonic anhydrase activity. This carbonic anhydrase is required to combine water and carbon dioxide into carbonic acid, or vice versa. When this enzyme is inhibited, it results in increased bicarbonate excretion. This results in increased acid levels within the body, resulting in metabolic acidosis.
When these drugs are given along with metformin, they further increase the acid levels, resulting in lactic acidosis. Similarly, a few of the drugs, like corticosteroids, thiazide diuretics, oral contraceptives, phenytoin, and thyroid agents, are going to increase glucose levels, resulting in hyperglycemia. So when these drugs are given along with metformin, it may result in a loss of glycemic control.
The important side effects of metformin mainly include diarrhea, indigestion, flatulence, nausea, headache, lack of energy, dizziness, and flushing. It can cause taste disturbances, leading to a metallic taste. A decrease in appetite and weight loss can also be observed. It can also cause chills and sweating.
This drug is given in tablet form as well as an extended-release tablet. It's also available as a solution, and the strengths may be variable based on the dosage form. It is available in 500 mg, 850 mg, and 1000 mg strengths.
The dose of metformin should be individualized, and it depends on many factors like age, co-existing conditions, and renal function. Typically, an immediately released metformin tablet is given at an initial dose of 500 mg twice daily or 850 mg once daily. Initially, glycemic control may not be achieved, so the dose should be increased, and the increment should be done after one week of treatment at a rate of 500 mg or 850 mg.
But in the case of extended-release tablets, the dose is somewhat different; the initial dose is 500 mg once daily, and again, the increments can be given after one week of treatment at a rate of 500 mg.
Metfromin increases insulin sensitivity as well as reduces body weight, but it is not secreting insulin. This drug mainly inhibits cyclic AMP-dependent protein kinase A activation. This pathway is stimulated by glucagon and inhibited by metformin. This drug can enter the hepatocytes through the organic cation transporter-1 (OCT1) and inhibit the respiratory chain complex 1 reactions, thereby reducing the conversion of NADH into ATP. When the ATP levels are reduced, it increases the AMP levels, which inhibits glucagon-mediated protein kinase A activation. The raised AMP levels can also stimulate the AMPK, resulting in more glycemic control, and they can also inhibit the FBPase enzyme and fructose 1,6-bi phosphatase enzyme, thereby reducing gluconeogenesis.
This drug can increase lactic acid levels, which may result in myalgia, muscle weakness, and fatigue. This drug should be carefully given with the other drugs that are going to inhibit the carbonic anhydrase activity, which may result in metabolic acidosis. The lactic acidosis produced by metformin may be increased by so many factors, such as iodinated contrasting agents, excessive alcohol intake, post-surgical complications, the age of the patient greater than 65 years, congestive heart failure, and hepatic impairment. All these factors may increase lactic acidosis, and in patients with renal impairment, metformin is not excreted properly, which results in increased metformin levels leading to lactic acidosis.