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Pharmacology of antidiabetic drugs

This document summarizes a lecture on pharmacology of antidiabetic drugs. It begins with an introduction to diabetes mellitus and its classification into four main types: type 1 characterized by insulin deficiency; type 2 characterized by insulin resistance and relative insulin deficiency; type 3 characterized by other specific causes; and type 4 or gestational diabetes. It then discusses the mechanisms and pharmacokinetics of various classes of antidiabetic drugs including insulin, sulfonylureas, meglitinides, biguanides, thiazolidinediones, alpha-glucosidase inhibitors and incretin mimetics. Adverse effects including hypoglycemia are also summarized.

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Pharmacology of Antidiabetic drugs Lecture by Dr. T.S. Mohamed Saleem M.Pharm., Ph.D Assistant Professor & Head, Department of Pharmacology Annamacharya College of Pharmacy, Rajampet 25-04-2017 Dr.T.S.Mohamed Saleem 1
Introduction  The endocrine pancreas - 1 million islets of Langerhans  Four hormone-producing cells are present  Insulin - the storage and anabolic hormone of the body;  Islet amyloid polypeptide (IAPP, or amylin) - modulates appetite, gastric emptying, and glucagon and insulin secretion;  Glucagon - hyperglycemic factor that mobilizes glycogen stores;  Somatostatin - a universal inhibitor of secretory cells;  gastrin, which stimulates gastric acid secretion; and pancreatic peptide 25-04-2017 Dr.T.S.Mohamed Saleem 2
Diabetes mellitus • An elevated blood glucose associated with • absent or inadequate pancreatic insulin secretion, • With or without concurrent impairment of insulin action • Classified into four categories: • type 1, insulin-dependent diabetes; • type 2, non–insulin-dependent diabetes; • type 3, other; MODY • type 4, gestational diabetes mellitus 25-04-2017 Dr.T.S.Mohamed Saleem 3
Type 1 Diabetes Mellitus • The hallmark of type 1 diabetes is selective beta cell (B cell) destruction and severe or absolute insulin deficiency. • Type 1 diabetes is further subdivided into immune and idiopathic causes. • The immune form is the most common form of type 1 diabetes. • Susceptibility appears to involve a multifactorial genetic linkage, but only 10–15% of patients have a positive family history. 25-04-2017 Dr.T.S.Mohamed Saleem 4
Type 1 • For persons with type 1 diabetes, insulin replacement therapy is necessary to sustain life. • Interruption of the insulin replacement therapy can be life-threatening and can result in diabetic ketoacidosis or death. • Diabetic ketoacidosis is caused by insufficient or absent insulin and results from excess release of fatty acids and subsequent formation of toxic levels of ketoacids. 25-04-2017 Dr.T.S.Mohamed Saleem 5
Type 2 Diabetes Mellitus • Tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. • Insulin is produced by the beta cells in these patients, it is inadequate to overcome the resistance, and the blood glucose rises. • The impaired insulin action also affects fat metabolism, resulting in increased free fatty acid flux and triglyceride levels and reciprocally low levels of high-density lipoprotein (HDL). 25-04-2017 Dr.T.S.Mohamed Saleem 6
Type II • Individuals with type 2 diabetes may not require insulin to survive, but 30% or more will benefit from insulin therapy to control blood glucose. • It is likely that 10–20% of individuals in whom type 2 diabetes was initially diagnosed actually have both type 1 and type 2 or a slowly progressing type 1 called latent autoimmune diabetes of adults (LADA), and they ultimately require full insulin replacement. • Dehydration in individuals with untreated or poorly controlled type 2 diabetes can lead to a life-threatening condition called nonketotic hyperosmolar coma . 25-04-2017 Dr.T.S.Mohamed Saleem 7
Type 3 Diabetes mellitus • The type 3 designation refers to multiple other specific causes of an elevated blood glucose: • Pancreatectomy, • Pancreatitis, • Nonpancreatic diseases, • Drug therapy, etc. • MODY 25-04-2017 Dr.T.S.Mohamed Saleem 8
Type 4 Diabetes Mellitus • Gestational diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy. • Gestational diabetes is diagnosed in approximately 7% of all pregnancies in the USA. • During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester. • Risk assessment for diabetes is suggested starting at the first prenatal visit. • High-risk women should be screened immediately. • Screening may be deferred in lower-risk women until the 24th to 28th week of gestation. 25-04-2017 Dr.T.S.Mohamed Saleem 9
INSULIN • Insulin is a small protein with a molecular weight in humans of 5808. • It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges • Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus of beta cells and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C- peptide by removal of four amino acids 25-04-2017 Dr.T.S.Mohamed Saleem 10
Insulin is shown as the shaded (orange color) peptide chains, A and B. Differences in the A and B chains and amino acid modifications for the rapid-acting insulin analogs (aspart, lispro, and glulisine) and long-acting insulin analogs (glargine and detemir) are discussed in the text. 25-04-2017 11 Dr.T.S.Mohamed Saleem Structureofhumanproinsulin(C-peptideplusAandBchains)andinsulin
• Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues • Granules within the beta cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin. • The entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units. 25-04-2017 Dr.T.S.Mohamed Saleem 12
Insulin Secretion • Insulin is released at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. • Other stimulants such as other sugars (eg, mannose), amino acids (especially gluconeogenic amino acids, eg, leucine, arginine), hormones such as glucagon-like polypeptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, cholecystokinin, high concentrations of fatty acids, and β-adrenergic sympathetic activity are recognized. 25-04-2017 Dr.T.S.Mohamed Saleem 13
• Stimulatory drugs are sulfonylureas, meglitinide and nateglinide, isoproterenol, and acetylcholine. • Inhibitory signals are hormones including insulin itself and leptin, α-adrenergic sympathetic activity, chronically elevated glucose, and low concentrations of fatty acids. Inhibitory drugs include diazoxide, phenytoin, vinblastine, and colchicine. 25-04-2017 Dr.T.S.Mohamed Saleem 14
figure 25-04-2017 15 Dr.T.S.Mohamed Saleem
25-04-2017 16 Dr.T.S.Mohamed Saleem
Insulin Degradation • The liver and kidney are the two main organs that remove insulin from the circulation. • Liver normally clears - 60% of the insulin • Kidney removing 35–40% • Subcutaneous insulin injections, this ratio is reversed • Liver normally clears - 60% of the insulin • Kidney removing 35–40% • The half-life of circulating insulin is 3–5 minutes. • Basal insulin values of 5–15 μU/mL (30–90 pmol/L) are found in normal humans, with a peak rise to 60–90 μU/mL (360–540 pmol/L) during meals. 25-04-2017 Dr.T.S.Mohamed Saleem 17
The Insulin Receptor • Identified in the primary target tissues, ie, liver, muscle, and adipose tissue • High specificity and affinity in the picomolar range • Increase in glucose uptake; • increased glycogen synthase activity • increased glycogen formation; • multiple effects on protein synthesis, lipolysis, and lipogenesis; • activation of transcription factors that enhance DNA synthesis and cell growth and division 25-04-2017 Dr.T.S.Mohamed Saleem 18 Translocation of glucose transporter (GLUT 4)
25-04-2017 Dr.T.S.Mohamed Saleem 19
Insulin Preparations • Rapidacting, with very fast onset and short duration; • Short-acting, with rapid onset of action; • Clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf life. • Intermediate-acting; • turbid suspension at neutral pH with protamine in phosphate buffer (neutral protamine Hagedorn [NPH] insulin) • Long-acting, with slow onset of action • Insulin glargine and insulin detemir are clear, soluble long- acting insulins 25-04-2017 Dr.T.S.Mohamed Saleem 20
25-04-2017 Dr.T.S.Mohamed Saleem 21
Rapid-acting and short-acting insulin preparations • Modification of the amino acid sequence of regular insulin produces analogs that are rapid-acting insulins. • Insulin lispro - lysine and proline at positions 28 and 29 in the B chain are reversed. • Peak levels - 30 to 90 minutes, as compared with 50 to 120 minutes for regular insulin. • Mimic the prandial (mealtime) release of insulin and to control postprandial glucose. • Administered in the 15 minutes proceeding a meal or within 15 to 20 minutes after starting a meal 25-04-2017 Dr.T.S.Mohamed Saleem 22
Intermediate-acting insulin • Neutral protamine Hagedorn (NPH) insulin - addition of zinc and protamine to regular insulin. • insulin isophane • less soluble, resulting in delayed absorption and a longer duration of action 25-04-2017 Dr.T.S.Mohamed Saleem 23
Long-acting insulin • Lower isoelectric point leading to formation of a precipitate at the injection site • slower onset and a flat, prolonged hypoglycemic effect with no peak • Insulin detemir has a fatty acid side chain that enhances association to albumin 25-04-2017 Dr.T.S.Mohamed Saleem 24
Pharmacokinetics and fate • Human insulin is produced by recombinant DNA technology • Modification of the amino acid sequence of human insulin produces insulins with different pharmacokinetic properties. • Insulin preparations vary primarily in their onset and duration of activity. • Dose, injection site, blood supply, temperature, and physical activity can also affect the onset and duration of various insulin preparations. • Because insulin is a polypeptide generally administered by subcutaneous injection. • Continuous subcutaneous insulin infusion (also called the insulin pump) is another method of insulin delivery. 25-04-2017 Dr.T.S.Mohamed Saleem 25
Adverse reactions to insulin • Hypoglycemia • Weight gain, • Local injection site reactions • Lipodystrophy • Diabetics with renal insufficiency may require a decrease in insulin dose. 25-04-2017 Dr.T.S.Mohamed Saleem 26
25-04-2017 Dr.T.S.Mohamed Saleem 27
Drug classification • Insulin secretagogues • sulfonylureas, meglitinides, D-phenylalanine derivatives • biguanides, • thiazolidinediones, • α-glucosidase inhibitors, • incretin-based therapies, • an amylin analog, • a bile acidbinding sequestrant 25-04-2017 Dr.T.S.Mohamed Saleem 28
SULFONYLUREAS 25-04-2017 Dr.T.S.Mohamed Saleem 29
Mechanism of action • Increase insulin release from the pancreas • A reduction of serum glucagon levels • Closure of potassium channels in extrapancreatic tissue 25-04-2017 Dr.T.S.Mohamed Saleem 30
Insulin Release from Pancreatic Beta Cells Sulfonylureas bind to a 140-kDa high-affinity sulfonylurea receptor inhibits the efflux of potassium ions depolarization. opens a voltage-gated calcium channel calcium influx the release of preformed insulin. 25-04-2017 Dr.T.S.Mohamed Saleem 31
Pharmacokinetics and fate • Given orally • Bind to serum proteins, • Metabolized by the liver • Excreted in the urine and feces • The duration of action ranges from 12 to 24 hours 25-04-2017 Dr.T.S.Mohamed Saleem 32
• Tolbutamide • Well absorbed but rapidly metabolized in the liver. • Its duration of effect is relatively short, with an elimination half-life of 4–5 hours • Dicumarol, phenylbutazone, some sulfonamides that inhibit the metabolism of tolbutamide. 25-04-2017 Dr.T.S.Mohamed Saleem 33
• Chlorpropamide • half-life of 32 hours • Slowly metabolized in the liver • 20–30% is excreted unchanged in the urine. • contraindicated in patients with hepatic or renal insufficiency. • Dosages higher than 500 mg daily increase the risk of jaundice. • The average maintenance dosage is 250 mg daily, • ADR • Prolonged hypoglycemic reactions • hyperemic flush after alcohol ingestion • Dilutional hyponatremia. • Hematologic toxicity (transient leukopenia, thrombocytopenia) occurs in less than 1% of patients. 25-04-2017 Dr.T.S.Mohamed Saleem 34
• Tolazamide • shorter duration of action. • more slowly absorbed. • Its half-life is about 7 hours. • Metabolized to several compounds that retain hypoglycemic effects. • If more than 500 mg/d are required the dose should be divided and given twice daily. 25-04-2017 Dr.T.S.Mohamed Saleem 35
• Glyburide • Metabolized in the liver into products • Very low hypoglycemic activity. • starting dosage is 2.5 mg/d or less, • maintenance dosage is 5–10 mg/d • ADR • hypoglycemia • Flushing • slightly enhances free water clearance • contraindicated in the presence of hepatic impairment and in patients with renal insufficiency. 25-04-2017 Dr.T.S.Mohamed Saleem 36
• Glipizide • Shortest half-life (2–4 hours) • ingested 30 minutes before breakfast • starting dosage is 5 mg/d, with up to 15 mg/d • 90% of glipizide is metabolized • 10% is excreted unchanged in the urine • Contraindicated in patients with significant hepatic or renal impairment, who would be at high risk for hypoglycemia. 25-04-2017 Dr.T.S.Mohamed Saleem 37
• Glimepiride • approved for once-daily use as monotherapy or in combination with insulin. • 1 mg has been shown to be effective, and the recommended maximal daily dose is 8 mg. • Long duration of effect with a half-life of 5 hours, • Completely metabolized by the liver to metabolites with weak or no activity. 25-04-2017 Dr.T.S.Mohamed Saleem 38
Other insulin secretagogues 25-04-2017 Dr.T.S.Mohamed Saleem 39
Repaglinide • The first member of the meglitinide group • Mechanism of action is similar to sulfonylureas • Two binding sites in common with the sulfonylureas and one unique binding site. 25-04-2017 Dr.T.S.Mohamed Saleem 40
Pharmacokinetics • Very fast onset of action • Peak effect within 1 h • Duration of action is 4–7 hours • Metabolism by CYP3A4 • Indicated for use in controlling postprandial glucose excursions. • Doses of 0.25–4 mg (maximum 16 mg/d); • Hypoglycemia is a risk • C/I in renal and hepatic impairment. 25-04-2017 Dr.T.S.Mohamed Saleem 41
Nateglinide • a D-phenylalanine derivative • Stimulates very rapid and transient release of insulin from beta cells through closure of the ATP-sensitive K + channel. • Partially restores initial insulin release in response to an intravenous glucose tolerance test • Special role in the treatment of individuals with isolated postprandial hyperglycemia, but it has minimal effect on overnight or fasting glucose levels. 25-04-2017 Dr.T.S.Mohamed Saleem 42
Pharmacokinetics • Ingested just before meals. • It is absorbed within 20 minutes with a time to peak concentration of less than 1 hour • Metabolized in the liver by CYP2C9 and CYP3A4 with a half-life of about 1 hour. • The overall duration of action is about 4 hours. • nateglinide has the advantage of being safe in those with very reduced renal function. 25-04-2017 Dr.T.S.Mohamed Saleem 43
BIGUANIDES • Metformin • Insulin sensitizer. • It increases glucose uptake and use by target tissues, • decreasing insulin resistance. 25-04-2017 Dr.T.S.Mohamed Saleem 44
Mechanism of action Metformin Activate AMP activated protein kinase (AMPA-PK) Reduce hepatic glucose production Lower blood glucose level 25-04-2017 Dr.T.S.Mohamed Saleem 45
Actions • impairment of renal gluconeogenesis, • slowing of glucose absorption from the gastrointestinal tract, • increased glucose to lactate conversion by enterocytes, • direct stimulation of glycolysis in tissues, • increased glucose removal from blood, • Reduction of plasma glucagon levels. 25-04-2017 Dr.T.S.Mohamed Saleem 46
ADME • Orally well absorbed • Half-life of 1.5–3 hours • Excreted by the kidneys • Impair the hepatic metabolism of lactic acid. • Increase the risk of lactic acidosis • The dosage of metformin is from 500 mg to a maximum of 2.55 g daily, with the lowest effective dose being recommended. 25-04-2017 Dr.T.S.Mohamed Saleem 47
ADR • Gastrointestinal (20%) • anorexia, nausea, vomiting, abdominal discomfort, and diarrhea • which occur in up to 20% of patients. • Vitamin B12 deficiency • Renal failure – lactic acidosis 25-04-2017 Dr.T.S.Mohamed Saleem 48
THIAZOLIDINEDIONES • Pioglitazone and rosiglitazone • Decrease insulin resistance. • Ligands of peroxisome proliferator-activated receptor gamma (PPAR-f), • Found in muscle, fat, and liver. • Modulate the expression of the genes involved in • lipid and glucose metabolism, • insulin signal transduction, • adipocyte and other tissue differentiation. 25-04-2017 Dr.T.S.Mohamed Saleem 49
Mechanism of actions Thiazolidinediones Activates peroxisome proliferator– activated receptor-γ (PPARγ) Regulates the transcription of several insulin responsive genes increased insulin sensitivity 25-04-2017 Dr.T.S.Mohamed Saleem 50
ADME • Pioglitazone • Well absorbed orally • Absorption is decreased with concomitant use of bile acid sequestrants. • Metabolized by CYP2C8 and CYP3A4 • starting dose is 15–30 mg/d, and the maximum is 45 mg/d. 25-04-2017 Dr.T.S.Mohamed Saleem 51
ADME • Rosiglitazone • rapidly absorbed and highly protein-bound. • It is metabolized predominantly by CYP2C8 and to a lesser extent by CYP2C9. • It is administered once or twice daily; • 2–8 mg is the usual total dose. 25-04-2017 Dr.T.S.Mohamed Saleem 52
ADR • Liver toxicity • Weight gain • osteopenia and increased fracture risk • increase the risk of bladder cancer 25-04-2017 Dr.T.S.Mohamed Saleem 53
α-Glucosidase inhibitors • Acarbose • miglitol 25-04-2017 Dr.T.S.Mohamed Saleem 54
Mechanism of action 25-04-2017 Dr.T.S.Mohamed Saleem 55
ADME • Acarbose is poorly absorbed. • It is metabolized primarily by intestinal bacteria, • Excreted into the urine. • Miglitol is very well absorbed • No systemic effects. • It is excreted unchanged by the kidney. 25-04-2017 Dr.T.S.Mohamed Saleem 56
ADR • Flatulence, • diarrhea, • Abdominal cramping 25-04-2017 Dr.T.S.Mohamed Saleem 57
Amylin analogue • Pramlintide • Synthetic amylin anlaogue • Injectable hypoglycemic agents • Approved for preprandial use in type I and II diabetes 25-04-2017 Dr.T.S.Mohamed Saleem 58
Actions • Suppress the release of glucagon • Delay gastric emptying • central nervous system mediated anorectic effects 25-04-2017 Dr.T.S.Mohamed Saleem 59
Pharmacokinetics • Rapid absorption after S.C injection • Most preferable site is abdomen and thigh • Arm administration is less reliable • Reach peak plasma concentration with in 20 min • Duration of action up to 120 min • Metabolized and excreted via kidney route • Even in less creatinine clearance no change in bioavailability efficacy 25-04-2017 Dr.T.S.Mohamed Saleem 60
Dose and administration • Inject just before meal • Type I - 15-60 mcg S.C • Typer II – 60-120 mcg S.C • Meal time insulin administration should be reduced 50% because of hypoglycemic risk 25-04-2017 Dr.T.S.Mohamed Saleem 61
ADR • Hypoglycemia • Gastrointestinal symptoms • Nausea, • Vomiting • Anorexia 25-04-2017 Dr.T.S.Mohamed Saleem 62
GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS • Exenatide • Liraglutide 25-04-2017 Dr.T.S.Mohamed Saleem 63
Action • Restore GLP-1 activity • Potentiate glucose mediate insulin secretion • Suppress postprandial glucagon release • Slow gastric emptying • Central mediated loss of appitite 25-04-2017 Dr.T.S.Mohamed Saleem 64
Exenatide • A derivative of the exendin-4 peptide in Gila monster venom • First incretin therapy available in market • 53% homology with native GLP-1, • Glycine substitution to reduce degradation by dipeptidyl peptidase-4 (DPP-4) • Recommended for suboptimal glycemic control 25-04-2017 Dr.T.S.Mohamed Saleem 65
Exenatide cont….. • Availabe injection formulation • Equal absorption from arm, abdomen and thigh • Reach peak conc with in 2 h • Duration of action is 10 h • Dose adjustment is required in case of CrCl less than 30 mL/min 25-04-2017 Dr.T.S.Mohamed Saleem 66
ADR • Nausea • Vomiting • Diarrohoea • Necrotizing and hemorrhogic pancreatitis 25-04-2017 Dr.T.S.Mohamed Saleem 67
Liraglutide • Long-acting synthetic GLP-1 analog with 97% homology to native GLP-1 • Peak levels are obtained in 8–12 hours • Elimination half-life is about 13 hours • Prolonged half-life that permits once-daily dosing. 25-04-2017 Dr.T.S.Mohamed Saleem 68
Action • Liraglutide interacts with the GLP-1 receptor • Increase insulin release • Decrease glucagon 25-04-2017 Dr.T.S.Mohamed Saleem 69
ADR • Headache • Nausea • Diarrhea • Antibody formation • Urticaria • Pancreatitis • Risk of endocrine cancer (FDA black box warning) 25-04-2017 Dr.T.S.Mohamed Saleem 70
DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS • Sitagliptin • Saxagliptin • Linagliptin 25-04-2017 Dr.T.S.Mohamed Saleem 71
Mechanism of action Incretin hormones Dipeptidyl peptidase – 1 degradation 25-04-2017 Dr.T.S.Mohamed Saleem 72 Sitagliptin Sexagliptin Linagliptin • Increase circulating levels of native GLP-1 • Glucose-dependent insulinotropic polypeptide (GIP), • Increasing glucose-mediated insulin secretion • Decreasing glucagon levels. Inhibition of enzyme
Sitagliptin • Orally well absorbed • Bioavailability 85% • Reach PPC with in 1-4 h • Half life is 12 h • Oral dose is 100 mg • Metabolized via CYP3A4 • Excreted via urine by tubular secretion 25-04-2017 Dr.T.S.Mohamed Saleem 73
ADR • Nasopharyngitis • Upper respiratory infections • Headaches • Hypoglycemia • Post marketing report • Acute pancreatitis • Hypersensitivity reactions 25-04-2017 Dr.T.S.Mohamed Saleem 74
Sexagliptin • Orally well absorbed • Dose is 2.5 to 5 mg daily • Less protein binding • Reach peak plasma conc within 2 h • Undergo metabilosm by CYP3A4/5 to form active molecule • Peak plasma conc of metabolite is 4 h • Both are excreted via urine 25-04-2017 Dr.T.S.Mohamed Saleem 75
ADR • Increased rate of infections • Upper respiratory tract and urinary tract • Headaches, peripheral edema • hypoglycemia • Hypersensitivity reactions • urticaria, facial edema 25-04-2017 Dr.T.S.Mohamed Saleem 76
ANY QUESTIONS 25-04-2017 Dr.T.S.Mohamed Saleem 77