Anti-Diabetic Medications - Types, Mechanism Of Action, Indications, Side Effects, Contraindications

anti-diabetic medications are used to treat diabetes mellitus a condition characterized by high glucose levels in blood in healthy individuals blood glucose level is tightly regulated by the hormones insulin and glucagon secreted by the pancreatic endocrine cells as a quick review type 1 diabetes commonly starts during adolescence here the pancreatic beta cells are unable to produce enough insulin therefore these individuals suffer from absolute insulin deficiency and they are treated with lifelong insulin injections by contrast type 2 diabetes typically starts in middle ages in these individuals beta cells produce enough insulin but the peripheral cells do not respond as well to it leading to insulin resistance these people are usually treated with oral anti-diabetic medications however with time these individuals may also require insulin therapy depending on how well the blood glucose levels are maintained so in this video we are going to discuss about oral anti-diabetic medications that are mainly used in the treatment of type 2 diabetes mellivus oral hypoglycemics are mainly used in the treatment of type 2 diabetes however the first-line treatment of type 2 diabetes is lifestyle changes such as regular exercising and dietary modifications if these interventions fail to lower the blood glucose levels then the patient will be started on oral hypoglycemic agents which have one or more of the following pharmacological actions increase pancreatic insulin secretion reduce hepatic glucose production increase insulin sensitivity in peripheral tissues reduce gastrointestinal glucose absorption or reduce renal tubular glucose reabsorption anti-diabetic agents can be classified broadly into insulin secretogs and non-insulin secretogs insulin secretogogs induce pancreatic insulin secretion these medications include sulfonylureas meglitenides and incretin based drugs including glp1 agonists and dpp4 inhibitors non-insulin secretogs have various mechanisms of action and these medications include biguanides thiazolidine diones alpha glucosidase inhibitors amyloid analogues and sodium glucose cotransporter 2 inhibitors first let's discuss about non-insulin secretogs under this we had by guanides which includes metformin the first line treatment option for type 2 diabetes mellitus after initiating the lifestyle changes its main mechanism of action is to reduce hepatic gluconeogenesis by activation of adenosine monophosphate activated protein kinase or ampk following administration metformin inhibits the mitochondrial respiratory chain complex in the cells leading to decreased atp levels this results in the activation of ampk which is a key regulator of energy homeostasis within the cells activation of ampk increases the overall cellular catabolism and reduces cellular anabolism it reduces hepatic gluconeogenesis by inhibiting genes responsible for the synthesis of pp carboxy kinase and glucose 6-phosphatus which are key enzymes in the gluconeogenesis pathway it also increases glucose uptake in the peripheral tissues by inducing translocation of glut4 into the cell membrane in addition ampk increases fatty acid oxidation decreases glycogen protein fatty acid and cholesterol synthesis decreases intestinal absorption of glucose and reduces ldl cholesterol while increasing hdl cholesterol which ultimately reduces the risk of cardiovascular events in type 2 diabetics most of the time treatment of type 2 diabetes is started with metformin alone later the disease metformin is given in combination with other oral hypoglycemic agents her insulin it is available in immediate and slow release formulations and is also used in the treatment of polycystic ovarian syndrome and gestational diabetes mellivus if we take pharmacokinetics of metformin it has an oral bioavailability of 50 to 60 and very low plasma protein binding duration of action is six to eight hours metformin is not metabolized in the liver and excreted unchanged in urine via tubular secretion therefore metformin is contraindicated in renal failure now let's see some common side effects of metformin this drug is usually well tolerated by most individuals weight loss is the most common adverse effect gastrointestinal disturbances such as abdominal discomfort nausea and vomiting and diarrhea may occur in some individuals in addition anorexia and metallic taste are some other side effects hypoglycemia does not occur with metformin lactic acidosis is a rare but serious side effect of metformin especially in patients with hepatic and renal failure lactic acid is a product of anaerobic respiration of the cells usually this lactic acid is taken up by the liver and utilized in the process of gluconeogenesis however as metformin inhibits gluconeogenesis excess lactic acid is excreted mainly by the kidneys if an individual with renal impairment takes metformin lactic acid tends to accumulate within the blood causing serious complications therefore metformin is contraindicated in patients with hepatic and renal failure next up we have thiazolidinediones also known as glittazones these medications include pyoglitazone and rosy glittazone which are insulin sensitizers similar to metformin they act as agonists for a nuclear receptor known as the peroxisome proliferator activated receptor gamma or ppar gamma for short normally this receptor is activated when ligands such as free fatty acids bind to it once this happens ppar gamma diffuses into the nucleus and binds with another receptor known as the retinoid x receptor this complex is then able to regulate the transcription of many insulin responsive genes in particular it increases the insulin sensitivity in muscle and adipose tissue by increasing the expression of glut4 it also reduces hepatic gluconeogenesis by down regulating the expression of certain enzymes moreover it regulates fatty acid metabolism by reducing triglyceride levels and increasing both ldl and hdl cholesterol which leads to weight gain and increased risk of cardiovascular disease as these medications are involved at gene transcription level it takes up to one to two months to achieve the desired blood glucose levels if we take pharmacokinetics these drugs have a good oral bioavailability and about 99 of the drug is plasma protein bound therefore the onset of action is slow plasma half-life is three to four hours metabolized by the liver into active metabolites with 70 percent of them excreted in bile and the remainder in urine most common side effect of glitta zones is weight gain they also cause fluid retention and edema which may worsen the symptoms of heart failure especially with concurrent insulin therapy in addition glita zones cause osteopenia and fractures and bones the drug rosy glittazone is not used now because it is associated with an increased risk of cardiovascular events such as myocardial infarction and stroke pioglitazone is also associated with an increased risk of bladder cancer moreover these medications may increase the risk of hepatitis and liver failure therefore liver enzymes should be monitored closely third group of non-insulin secretogs was alpha glucosidase inhibitors which includes the drugs a carbures and miglital alpha glucosidase is an enzyme found in the brush border of small intestine and it breaks down complex carbohydrates like starch into their simpler monosaccharide units like glucose which is eventually absorbed into the blood alpha glucosidase inhibitors prevent this process and they delay the breakdown of carbohydrates this ultimately lowers the postprandial blood glucose levels they can be used alone or can be combined with other oral anti-diabetic agents unlike the other two classes of drugs we discussed so far alpha glucosidase inhibitors can be used to treat both type 1 and type 2 diabetes common side effects include gi disturbances such as gas bloating and diarrhea and very rarely hepatic damage next up we have amyloid analogues amyloid is a peptide hormone secreted alongside insulin by the pancreas amylan lowers blood glucose level by delaying gastric emptying inhibiting glucagon secretion and improving satiety amyloid analogues are structurally similar to amylin and have the same effects on carbohydrate metabolism pramlantite is the main drug in this class unlike the other drugs we've discussed so far pramlantite is an injectable medication not an oral one and it can be used to treat both type 1 and type 2 diabetes common adverse effects include nausea and increased risk of hypoglycemia especially when taken with insulin the last class of medications in non-insulin secretogs are sodium glucose co-transporter 2 or sglt2 inhibitors they include canagliflision and dapogliflosin sglt2s are located in the proximal convoluted tubules of the nephron and are responsible for about ninety percent of the glucose reabsorption by inhibiting these transporters these drugs significantly reduce the glucose reabsorption and promote glycosyria these drugs are not associated with the risk of hypoglycemia most often they are combined with other oral agents and they promote moderate amount of weight loss common side effects include increased risk of urinary infections hypotension due to increased fluid loss along with glucose and moderate increase in ldl cholesterol especially with cannagliflasin now let's discuss about the insulin secretogs which promote insulin secretion from the pancreas under this category first we have sulfonylureas following administration sulfonylureas bind to the sulfonylurea receptor subunit of the atp dependent channels in the pancreatic beta cells by binding they block this potassium channel and as a result potassium accumulates within the cell leading to depolarization of the beta cell membrane then the voltage-gated calcium channels will open up to permit influx of calcium which in turn causes activation and exocytosis of insulin containing granules within the cell in addition to this sulfonylureas have extra pancreatic actions as well they increase insulin receptors on target cells inhibit hepatic gluconeogenesis and stimulate appetite there are two classes of sulfonylureas first generation and the second generation first generation medications include tilbutamide tylasimide and clopropamide second generation drugs are more potent than the first generation and are more commonly used today these include glipizide glyburide and glimepiride these medications are taken orally before meals to reduce blood glucose in type 2 diabetes patients these medications can be used as monotherapy or can be combined with other oral anti-diabetics or insulin and they have a glucose independent action sulfonylureas are metabolized into their inactive metabolites by the liver and excreted in urine therefore these medications must be used with caution in patients with liver disease common adverse effects include hypoglycemia especially with the second generation sulfonylureas as they are more potent weight gain due to stimulation of appetite gi disturbances such as nausea and allergic reactions like rash on rare occasions sulfonylureas can cause a severe skin condition known as steven johnson syndrome moreover first generation sulfonylureas can cause a disulfiram like reaction also known as alcohol intolerance this means that if a person takes alcohol while on sulfonylureas he might experience symptoms like nausea and vomiting flushing dizziness and headache next group of medications are the meglitonides which have a similar action to sulfonyl ureas where they bind and block the atp-dependent potassium channels and subsequently increase the insulin secretion these include repaglinide and nateglinite both of which are taken orally they are rapid acting and have a shorter duration of action compared to sulfonylureas and are taken before each meal to reduce postprandial blood glucose level common adverse effects include hypoglycemia and weight gain if a meal is missed taking the drug should be avoided due to the risk of hypoglycemia last group of insulin secretogs are the incritin-based drugs which include two classes of medications glucagon like peptide 1 agonists or glp-1 agonists and dipeptityl peptidous 4 or dpp4 inhibitors incritins are a group of hormones that are normally secreted by the gi tract in response to high glucose levels they increase insulin secretion from the pancreas in order to reduce blood glucose levels major hormone in this group is glp-1 glp-1 agonists like exenatide and liraglutite act on the same receptor as glp1 and exert their effects these medications are given subcutaneously and they stimulate insulin secretion reduce glucagon release slow down gastric emptying and improve satiety common adverse effects include gi disturbances such as nausea and vomiting loss of appetite weight loss fatigue hypoglycemia and increased risk of pancreatitis the next class of medications dpp-4 inhibitors include cetagliptin veldigliptin and soxoglipton dpp4 is a protease that breaks down glp1 as we have already discussed glp1 is responsible for secretion of a large amount of insulin from the pancreas dpp4 inhibitors prevent the breakdown of glp1 thus it can exert its effects for much longer so the effects of dpp-4 inhibitors are as same as the glp-1 agonists they stimulate insulin secretion reduce glucagon release slow down gastric emptying and improve satiety unlike glp-1 agonists these medications are taken orally common side effects include gi disturbances such as nausea and vomiting nasopharyngitis headache and mild urinary and respiratory infections these medications do not cause weight gain or weight loss so they are weight neutral as far as the contraindications go these medications should not be used in hepatic or renal impairment pregnancy or breastfeeding