Drugs Used in Diabetes .pdf

1 Drugs Used in Diabetes DR T. CHIDUMAYO, MD, PHARMACOLOGY  2 Intended Learning Outcomes List the Drug classes and examples of drugs used in List management of Diabete...

1 Drugs Used in Diabetes DR T. CHIDUMAYO, MD, PHARMACOLOGY  2 Intended Learning Outcomes List the Drug classes and examples of drugs used in List management of Diabetes Describe Describe the mechanisms of actions of drugs used in management of Diabetes Understand the clinical indications adverse effects and Understand contraindications of drugs used in management of Diabetes  3 Insulins characterized by onset and duration of action Prototype: insulin R (regular) Others: insulin aspart, insulin lispro, insulin glulisine Insulins Intermediate-Acting Insulin Prototype: Neutral Protamine Hagedorn (NPH) insulin Others: insulin Lente Long-Acting Insulin Prototype: insulin ultralente Others: insulin protamine zinc, insulin glargine, insulin detemir  4 Controls the uptake, use, and storage of cellular nutrients Promotes uptake of glucose by cells MOA Insulin mobilizes glucose transporters (GLUT-4) on the surface of muscle (Mechanism and adipose tissue of Action) Increases glycogen deposition in liver and muscles Inhibits gluconeogenesis in liver  5 Uptake of amino acids promoting protein synthesis Functions of Synthesis of triglycerides and inhibition of lipolysis in insulin cont. adipose tissue Binds to insulin-like growth factor receptor (IGF-1) for growth-promoting effects 6  7 Frequently delivered parenterally, typically subcutaneously An inhaled formulation available Interindividual variability in the Pharmacokinetics pharmacokinetics: variability and unpredictability in the time to peak hypoglycemic effect Lente insulins absorb more slowly because of crystal size 8  9 Indication: Diabetes mellitus (type 1 and type 2) Side Effects Indication Hypoglycemia and SEs Lipodystrophy: localized atrophy of subcutaneous fat (lipoatrophy) or enlargement of fat deposits (lipohypertrophy) Lipoatrophy: immune response, lipohypertrophy : generation of fat cells Edema: Na + retention  10 NPH insulin is regular insulin treated with protamine and zinc at a neutral pH (7.2) Protamine zinc insulin provides NPH Insulin slow, even absorption subcutaneously Protamine as a reversal agent for heparin Biguanides 11  12 Reduce blood glucose without stimulating insulin secretion Biguanides Prototype Metformin  13 Reduce blood glucose without stimulating insulin secretion Prototype Metformin Biguanides Reduced gluconeogenesis Adenosine monophosphate (AMP) kinase inhibits enzymes involved in gluconeogenesis AMP kinase plays a role in energy homeostasis  14 Increased action of insulin in muscle and fat through AMP kinase Delays glucose absorption from GI tract MOA cont: Direct stimulation of glycolysis in tissue with Biguanides increased glucose removal from blood Reduced plasma glucagon Glucagon increases glucose levels by breaking down glycogen  15 Metformin is excreted in urine unchanged Renal clearance through tubular secretion Pharmacology Indication of Metformin Type 2 diabetes mellitus Contraindication Metabolic acidosis  16 Abdominal pain, nausea, diarrhea Reduced absorption of vitamin B12 and folate: but risk of Side Effects reduced vitamin B12Hypoglycemia: low risk of hypoglycemia Serious Lactic acidosis (rare): patients with renal impairment 17 Sulfonylureas 18  19 Oral agents that lower blood glucose by increasing insulin secretion (insulin secretagogues) First-Generation Agents Prototype: Tolbutamide Sulfonylureas Others: Chlorpropamide, tolazamide, acetohexamide Second-Generation Agents Prototype: Glyburide Others: Glipizide, gliclazide, glimepiride  20 SU mechanism of action Bind to beta-cell sulfonylurea Inward rectifier ATP-sensitive potassium channel Binding opens a voltage-gated calcium channel, receptor (SUR-1) leading to calcium influx and insulin release Reduce serum glucagon levels Reduce in glucagon release from pancreatic alpha cells 21  22 Elimination half-lives of first- generation agents vary Half-lives of second-generation agents are short (3 to 5 hours) Pharmacokinetics Biologic half-lives, the amount of time for of SU which they are effective, is longer than their elimination half-lives All sulfonylureas are metabolized by the liver and excreted in urine Dose adjustments in hepatic impairment to avoid hypoglycemia  23 Indication: Diabetes mellitus (type 2) Hypoglycemia: Hypoglycemia from over secretion of insulin Glyburide may impair the body’s ability to prevent Indication & endogenous insulin secretion during hypoglycemia Side Effects Flushing: more common with older agents like chlorpropamide Weight gain: Increased insulin activity in adipose tissue Less frequent with the second-generation sulfonylureas Hematologic toxicities: Anemias and thrombocytopenias mainly with chlorpropamide Sodium-glucose transport proteins-2 (SGLT2) inhibitors 24  25 SGLT MOA Sodium-dependent glucose co-transporters (SGLT) : found in mucosa of small intestine and proximal tubules of the nephrons SGLT1 and SGLT2 nephrons have both SGLT2 and SGLT1. SGLT2 is 1:1 sodium: glucose ratio (98% glucose reabsorption) SGLT2 inhibition reduce transcellular epithelial glucose reabsorption independent of glucose-dependent insulin secretion by the pancreatic β cells  26 SGLT2 Examples  Prototype Dapagliflozin: inhibits of SGLT2-mediated reabsorption of glucose in the kidney.  Comparable glycemic efficacy with glipizide  increased incidence of breast and bladder cancers and hepatotoxicity.  Remogliflozin and Sergliflozin (SGLT2 inhibitors) increased urinary glucose excretion in a dose-dependent manner without stimulating insulin secretion  No hypoglycemia, and body weight gain  27 Adverse effects: SGLT2 inhibitors Fatigue, increased urine output, increased hematocrit Mycotic genital or urinary tract infections Hypoglycemia (rare)  28 α -Glucosidase Inhibitors (AGIs)  29 α-Glucosidase Inhibitors (AGIs) Reduce blood glucose by inhibiting breakdown of carbohydrates to glucose in the gut Prototype: Acarbose Others: Miglitol, Voglibose  30 Glucosidases (GSs) Only such as maltase, monosaccha MOA cleave complex rides can be absorbed carbohydrates to (Mechanism into the glucose bloodstream of Action) AGIs are carbohydrate analogues : α- that bind reversibly with much greater affinity than carbohydrates Glucosidase to these GS enzymes Inhibitors (AGIs) Competitive inhibition of the GSs delays absorption of carbohydrates along the gastrointestinal (GI) tract  31 Reduce spike in blood sugar after a meal MOA α- AGIs differ slightly in the target Glucosidase enzymes they inhibit Inhibitors Acarbose also has a small effect on α- cont. amylase Miglitol inhibits isomaltase and β- glucosidases; β-glucosidases cleave β-linked sugars such as lactose  32 Acarbose acts locally Metabolism occurs by intestinal bacteria and digestive enzymes Pharmacokinetics Indications Diabetes mellitus (type 2): Predominantly postprandial hyperglycemia New-onset diabetes with mild hyperglycemia  33 Contraindicating: Irritable bowel syndrome (IBS) and Inflammatory bowel disease: GI side effects exacerbate the symptoms of IBS Side Effects: Contraindications : α-Glucosidase Flatulence, bloating, abdominal Inhibitors discomfort, diarrhea Reduced with time because of up-regulation of α- glucosidase enzymes in the distal small intestine Hypoglycemia: only with concomitant administration of sulfonylureas Hypoglycemia managed with glucose and not sucrose 34  35 Incretins  36 Prototypes: Dipeptidyl Peptidase (DPP)–4 Inhibitors ( “Gliptins”) sitagliptin Others: saxagliptin, vildagliptin Incretin Mimetics Prototype: exenatide Incretins MOA (Mechanism of Action) Patients with type 2 diabetes mellitus have insulin resistance and an inappropriate increase in glucagon release Incretin hormones e.g, glucagon-like peptide-1 (GLP-1) and glucose- dependent insulinotropic polypeptide (GIP) lower blood glucose  37 MOA cont. GLP-1 and GIP stimulate insulin release from pancreatic beta cells. GLP-1 lowers glucagon secretion from alpha cells, reduces appetite, slows gastric emptying, and regulates beta-cell growth Agents that overcome actions DPP-4 enzyme inactivates enhance effects of incretins Incretin mimetics are GLP-1 analogues that are not degraded by DPP-4 and thus act as GLP-1 agonists The gliptins work by inhibiting the DPP-4 enzyme, which prevents the breakdown of incretins 38  39 Exenatide is administered by subcutaneous injection Circulating half-life of 60 to 90 minutes Gliptins is oral Pharmacokinetics Indication: Diabetes mellitus (type 2) Side Effects: Hypersensitivity reactions Increased incidence of infection with Sitagliptin  40 Meglitinides  41 Oral agents that lower blood glucose by increasing insulin secretion Prototype: repaglinide Meglitinides Others: nateglinide MOA (Mechanism of Action) Insulin secretagogues Bind to beta cell sulfonylurea receptor (SUR- 1)  42 Binding leads to calcium influx and insulin release MOA cont. Rely on functioning beta cells to achieve pharmacologic effect Not useful in type 1 diabetes mellitus 43  44 Rapidly and completely absorbed. Peak plasma concentrations in less than 1 hour Meglitinides Pharmacokinetics Metabolized in liver, with short elimination half-life of 1 to 2 hours Dose adjustments in impaired liver function  45 Administered just before meals for postprandial hyperglycemia Meglitinides Pharmacoki Food increases absorption of nateglinide but minimal impact netics cont. on repaglinide absorption Indication: Diabetes mellitus (type 2)  46 Gemfibrozil (a fibrate) reduces the metabolism of repaglinide, hence severe episodes of hypoglycemia Side Effects: Contraindications and side effects Hypoglycemia: Although less common than with the sulfonylureas Weight gain greater with meglitinides than metformin  47 Thiazolidinediones  48 Oral agents that lower blood glucose by increasing sensitivity of cells to insulin Prototype: rosiglitazone Others: pioglitazone Thiazolidinediones MOA (Mechanism Of Action) TZDs are peroxisome proliferator–activated receptor– gamma (PPAR-γ) agonists The PPAR-γ receptors are a complex family of receptors found in the cell nucleus in muscle, fat, and liver Regulate expression of genes responsible for lipid and protein metabolism, insulin signal transduction, adipocyte and other tissue differentiation  49 Thiazolidinediones MOA cont. Decrease insulin resistance Promote expression and translocation of glucose transporters in muscle and adipose tissue This increases glucose uptake into muscle and adipose tissue Reduce hepatic production of glucose Activation of the PPAR-γ receptor inhibits cytokine production and increased adiponectin production Adiponectin stimulates glucose uptake in muscle, protects against atherosclerosis  50 Thiazolidinediones Pharmacology Peak plasma levels 1 -2 hours after administration Both rosiglitazone and pioglitazone are metabolized by hepatic CYP450 enzymes Indication: Diabetes mellitus (type 2) Contraindicated in heart failure  51 Weight gain: Redistribution of adipocytes from visceral to subcutaneous regions Edema: Up-regulating tubular transporters for sodium and reducing glomerular filtration rate (GFR) Cardiovascular: Heart failure Thiazolidinediones Side Effects Myocardial ischemia reported with rosiglitazone Fractures: TZDs impair osteoblasts Not used in pregnancy 52  53  Bardal, Stan; Bardal, Stan; Waechter, Jason; References Waechter, Jason; Martin, Doug; Martin, Doug. Applied Pharmacology. Elsevier Health Sciences. Kindle Edition.