Oral Hypoglycemics, Insulin, and Glucagon PDF

Oral hypoglycemics, Insulin and Glucagon Diabetes mellitus (DM) is a heterogenous disorder involving pathological alterations in glucose, protein and lipid metabolism. The pathological sequela of this condition is intertwined with either a deficiency in insulin secretion or an...

Oral hypoglycemics, Insulin and Glucagon Diabetes mellitus (DM) is a heterogenous disorder involving pathological alterations in glucose, protein and lipid metabolism. The pathological sequela of this condition is intertwined with either a deficiency in insulin secretion or an inability in insulin action (insulin resistance). Pharmacological management of this condition is dependent on the nature of the etiology and the primary therapeutic goal is to maintain a steady blood glucose levels. Insulin Insulin was initially obtained from porcine or bovine sources. Due to the increased tendency for allergies, insulin is now obtained via recombinant DNA technology. Insulin obtained via recombinant DNA technology is like human insulin with a reduced tendency for allergic reactions. Insulin is used in the management of Type 1 and type II diabetes mellitus (especially in clinical settings). i) Pharmacokinetics Insulin is not administered orally because it is destroyed by peptidases in the gastrointestinal tract, and is thus administered, subcutaneously, intravenously, or intramuscularly. Once absorbed, insulin has a half-life of about 5-10 minutes. It is metabolized by insulinase, inactivated in the liver and kidney and excreted in the urine. Insulin formulations (designer insulins) are classified according to their duration of action into ultra-short, short, intermediate, and long-acting. The ultra-short-acting insulins inlude (insulin aspart and insulin lispro), are different from regular insulin (short acting). Intermediate-acting preparations include neutral protamine Hagedorn (NPH) or isophane insulin and Lente insulin (insulin zinc suspension). The longer action preparations include detemir, and glargine. The absorption and pharmacokinetic profile of these insulin preparations were modified via complexation reactions. For instance, insulin is complexed with zinc and protamine to give Lente or isophane insulin (NPH). Similarly, the amino acid sequence or protein structure of human insulin can be altered so that its stability (solubility) in solution is either increased or reduced to alter its duration of action (e.g., reversing proline and lysine gives insulin lispro). Mixed combinations also exist., e.g. NPH and regular insulin in proportions of 70:30 combinations). Other combinations include lispro protamine/lispro (50/50 and 75/25). Insulin glargine has a prolonged action with predictable kinetic profile. 1 Not for Sale or Reprinting (O. Edosuyi. PharmD. Ph.D.) Fig 1: Regulation of insulin secretion and release. Glucose acts here as the primary insulin secretagogue. Notice the action of ATP-sensitive potassium channels and the effect of membrane depolarization that triggers the movement in storage vesicles to move to the membrane to release insulin. Insulin acts by binding to enzyme-linked transmembrane receptors. Receptor occupancy results activation of insulin-dependent glucose transport processes (in adipose tissue and muscle) via a transporter (Glut-4) iii) Side effects Hypoglycaemia, weight gain (because of its anabolic effect), Allergic reactions, injection site reactions, lipoatrophy, (atrophy of subcutaneous fat at the site of insulin injection) and Lipohypertrophy (enlargement of subcutaneous fat depots due to the lipogenic action of insulin). Oral hypoglycaemic agents a) Sulphonylureas. All members are substituted arylsulphonylureas. They are divided into first and second generation. The first generation sulphonylureas (tolbutamide, chlorpropamide) are rarely used because they have a long duration of action (chlorpropamide) and cause severe 2 Not for Sale or Reprinting (O. Edosuyi. PharmD. Ph.D.) hypoglycaemia. The second generation includes, glibenclamide, gliclazide, glipizide, glimepiride. i) Mechanism of action Sulphonylureas act principally on β cells, stimulating insulin secretion and thus reducing plasma glucose. They bind to sulphonylurea receptor domain present on the KATP channels in β-cell plasma membranes, leading to receptor blockage which causes depolarization and Ca2+ entry. They may also reduce hepatic clearance of insulin. Sulphonamides are only useful in patients with functioning pancreatic β-cells. b) Pharmacokinetics Sulphonylureas are well absorbed after oral administration, but food can affect their absorption. They are highly bound to plasma albumin and could interact with highly protein bound drugs (e.g., sulphonamides). They are excreted in the urine; thus, their action is increased in the elderly and in patients with renal impairment. They are contraindicated in pregnancy and in breastfeeding. c) Side effects Hypoglycaemia, weight gain, allergic reactions, there may be Cardiovascular morbidities (due to blockade of KATP channels in the heart), Flushing when administered with alcohol, and hematological aberations. b). Meglitinides They are non-sulphonylureas (have a different chemical structure) insulin secretagogues. They block the sulphonylurea receptor on KATP potassium channels in pancreatic β cells. Examples include repaglinide and nateglinide. They have a short duration of action, rapid elimination, and a low risk of hypoglycaemia. These are administered shortly before a meal to reduce the postprandial rise in blood glucose. They may cause less weight gain. Meglitinides are relatively selective for KATP channels on β cells versus KATP channels in vascular smooth muscle. c). Biguanides Metformin, the only member of this class, increases the activity of the adenosine monophosphate-dependent protein kinase (AMPK), which is activated whenever cellular energy stores are low. Activated AMPK stimulates fatty acid oxidation, glucose uptake, and 3 Not for Sale or Reprinting (O. Edosuyi. PharmD. Ph.D.) non-oxidative metabolism, reduces lipogenesis and gluconeogenesis. The final effect is increased glycogen storage in skeletal muscle, lower rates of hepatic glucose production, increased insulin sensitivity, and lower blood glucose levels. The hepatic effect of metformin is the dominant mode of action and involves suppression of gluconeogenesis. i) Pharmacokinetics Metformin is absorbed primarily from the small intestine. The drug is stable, does not bind to plasma proteins, and is excreted unchanged in the urine. The transport of metformin into cells is mediated in part by organic cation transporters. ii) Side- effects Metformin rarely causes hypoglycaemia in type 2 patients. Gastrointestinal disturbances (e.g., anorexia, diarrhoea, nausea), lactic acidosis. d). Thiazolidinediones (Glitazones) i) Mechanism of action Thiazolidinediones (rosiglitazone and pioglitazone) bind to a nuclear receptor called the peroxisome proliferator-activated receptor-γ (PPARγ). The receptor, PPARγ occurs mainly in adipose tissue, but is also present in muscles and liver. This binding leads to differentiation of adipose cells (this contributes to the unwanted effect of weight gain), increases lipogenesis and enhances uptake of fatty acids and glucose. Glitazones also promotes amiloride-sensitive sodium ion reabsorption in renal collecting ducts, underscoring the adverse effect of fluid retention associated with these agents. Thiazolidinediones effect on blood glucose is slow in onset, the maximum effect being achieved after few months. The final effects lead to reduction in hepatic glucose output and increased glucose uptake into muscle, by enhancing the effectiveness of endogenous insulin. ii) Pharmacokinetics They are given orally and well absorbed. The Thiazolidinediones are metabolized by the liver by hepatic CYPs and may be administered to patients with renal insufficiency. Co- administration with agents like rifampin induces these enzymes and causes a significant decrease in plasma concentrations of rosiglitazone and pioglitazone. iii) Side effects Weight gain and fluid retention, the latter being a major concern, because it can precipitate or worsen heart failure. Headache, fatigue, and gastrointestinal disturbances have also been 4 Not for Sale or Reprinting (O. Edosuyi. PharmD. Ph.D.) reported. Thiazolidinediones are contraindicated in pregnant or breastfeeding women and in children. e). Gliptins (Incretin mimetics) Dipeptidyl peptidase- 4(DPP-4) is an enzyme that is widely distributed in the body, expressed as an ectoenzyme on endothelial cells. DPP-4 cleaves or inactivates of GLP-1(Glucagon- like peptide and GIP (glucose-dependent insulinotropic polypeptide; gastric inhibitory peptide). DPP-4 inhibitors increase the bioavailability of GLP-1 and GIP. Gliptins i.e., sitagliptin and vildagliptin competitively inhibit dipeptidylpeptidase-4 (DPP-4), thereby lowering blood glucose by potentiating endogenous incretins (GLP-1 and GIP) i) Pharmacokinetics Gliptins are absorbed from the small intestine. They do not bind to plasma proteins and are excreted mostly unchanged in the urine. Sitagliptin is excreted in the kidneys. ii) Side effects Nausea, stomach pain, flu-like symptoms, skin reactions. f). GLP-1 agonists i) Mechanism of Action All GLP-1 receptors have a similar mechanism, which is activation of the GLP-1 receptor. GLP-1 receptors are expressed by cells. Binding of agonists to the GLP-1 receptor activates the cAMP-PKA pathway resulting in increased insulin biosynthesis and release. ii) Pharmacokinetics Exenatide is given as a subcutaneous injection twice daily, typically before meals. Exenatide is available as a pen for administration. Liraglutide is given as a subcutaneous injection once daily. iii) Side Effect. Nausea and vomiting and mainly GIT side effects. delayed gastric emptying. g) α-Glucosidase inhibitors i) Mechanism of Action. α-Glucosidase inhibitors reduce intestinal absorption of starch, dextrin, most disaccharides by inhibiting the action of α-glucosidase in the intestinal brush border. Inhibition of this enzyme 5 Not for Sale or Reprinting (O. Edosuyi. PharmD. Ph.D.) slows the absorption of carbohydrates from the GI tract and reduces the rise of postprandial plasma glucose. These drugs also increase the release of the glucoregulatory hormone GLP-1 into the circulation, which may contribute to their glucose-lowering effect. Examples acarbose, miglitol ii) Pharmacokinetics Acarbose is minimally absorbed and the small amount of drug reaching the systemic circulation is cleared by the kidney. iii) Side effects. The main side effects of α -glucosidase inhibitors are GIT related and include flatulence, diarrhea, and abdominal bloating. These side effects are dose dependent and related to the mechanism of action of the drugs, with greater amounts of carbohydrate available in the lower intestinal tract for metabolism by bacteria. Moderate elevations of hepatic transaminases have been reported with acarbose, but symptomatic. α-Glucosidase inhibitors do not stimulate insulin release and therefore do not result in hypoglycemia when used alone. h) Gliflozins. These agents (dapagliflozins, canagliflozin) inhibit the sodium glucose co-transporter (SGLT- 2) in the proximal tubules of the kidney, thus preventing the reabsorption of glucose and reducing blood glucose levels. They bound to plasma proteins and have a short half-life. They can increase the chances of urinary tract infections (especially in women). Agents used to manage hypoglycaemia. Glucagon Glucagon is produced by recombinant DNA technology. Glucagon interacts with a G-protein coupled receptor (GPCR) on the plasma membrane. Glucagon is used to treat severe hypoglycemia, particularly in diabetic patients when the patient cannot safely consume oral glucose and intravenous glucose is not accessible.1 mg of glucagon is administered intravenously, intramuscularly, or subcutaneously but the I/M route is usually used during hypoglycaemic emergencies. The hyperglycemic action of glucagon is transient and may be inadequate if hepatic stores of glycogen are depleted. After the initial response to glucagon, patients should be given glucose or urged to eat to prevent recurrent hypoglycemia. Glucagon also is sometimes used 6 Not for Sale or Reprinting (O. Edosuyi. PharmD. Ph.D.) to relax the intestinal tract to facilitate radiographic examination of the upper and lower gastrointestinal tract. Nausea and vomiting are the most frequent side effects. b). Diazoxide is a vasodilator, with potent hyperglycemic actions when given orally. Hyperglycemia results primarily from inhibition of insulin secretion. Diazoxide interacts with the KATP channel on the cell membrane and either prevents its closing or keeps it open. 7 Not for Sale or Reprinting (O. Edosuyi. PharmD. Ph.D.)