Insulin and Antidiabetic Drugs PDF 2020-2021

Insulin and Oral Hypoglycemic Drugs By:Siti Nur Rasyidah Md Ramli Types of Diabetes  Diabetes Mellitus Type 1 Insulin Dependent Diabetes Mellitus (IDDM) caused by destruction of pancreatic β cells  Diabetes Mellitus Type 2 Non-insulin Dependent Diabetes mellitus (NIDDM)cause by...

Insulin and Oral Hypoglycemic Drugs By:Siti Nur Rasyidah Md Ramli Types of Diabetes  Diabetes Mellitus Type 1 Insulin Dependent Diabetes Mellitus (IDDM) caused by destruction of pancreatic β cells  Diabetes Mellitus Type 2 Non-insulin Dependent Diabetes mellitus (NIDDM)cause by insulin resistance Type I diabetes is related to loss of insulin- secreting cells in the pancreas. Type II diabetes is related to target cell resistance to the action of insulin.  Type I vs Type II Diabetes Type I Type II High Plasma Glucose High-very high Low-Absent Insulin Levels High-normal 1-20 years Age at Onset 12+ years Yes Islet Antibodies No No Obesity Yes (60-90%) Yes (diabetic coma) Ketosis Variable 10% Prevalence 90% Usually Ineffective Oral Hypoglycemics Effective Required Insulin Therapy may be required Consequences of Diabetes Acute Hyperglycemia ketoacidosis diabetic coma (hyperglycemia or hypoglycemia) Chronic Complications of Diabetes Retinopathy Coronary and Most common cause cerebrovascular of blindness in Disease people of working 2–4 fold increased risk age of coronary heart disease and stroke; 75% Nephropathy have hypertension 16% of all new patients needing renal replacement therapy Foot Problems 15% of people with diabetes develop Erectile Dysfunction foot ulcers; 5–15% of May affect up to 50% of people with diabetic men with long- foot ulcers need standing diabetes amputations Regulation of Insulin Secretion from the Pancreas Glucose Ca2+ GLUT-2 Depolarization K+ Glucose Ca2+ ATP Glucokinase Insulin Glucose-6-Phosphate Insulin Insulin  Insulin is a type of peptide hormone  Reduces amount of glucose in blood  Produced by beta cells (islets of Langerhans) Insulin - Mechanism of Action Normal Insulin Function: Fuel Storage Glucose Storage Gluconeogenesis TG Glucose and FFA Uptake Insulin Insulin Insulin Glucose Uptake Muscle Pancreas Gluconeogenic amino acid release to liver  Endogenous Insulin Other hormones that raise blood glucose levels include:  Cortisol  Glucagon  Growth hormone  Epinephrine  Estrogen  Progesterone Treatment of Type 1 Diabetes Insulin replacement  COMMONLY USED INSULIN PREPARATIONS Type Onset Peak Duration Usage (hr) (hr) (hr) Rapid Lispro (human analog) Lys to 0.2-0.5 0.5-2 3-4 Meals/acute hyperglycemia Pro in B chain Good for acute diabetic ketoacidosis Aspart 0.2-0.5 0.5-2 3-4 Glulisine 0.2-0.5 0.5-2 3-4 Short acting Regular (human) 0.25-1 1-3 5-8 Meals/acute hyperglycemia Intermediate NPH (human) 1.5-2 6-12 18-24 Basal Insulin and overnight coverage Long-Acting Glargine (human analog) 1-2 24 Basal Insulin and Gly to Asn in A chain, 2 extra overnight coverage- good Arg in B chain 24 hr insulin coverage Detimir 2-4 11-14  Insulin Delivery Systems Inhaled Exubera Major Adverse Effect of Insulin Therapy: Insulin in the Absence of Carbohydrate can Lead to Severe Hypoglycemia 1. First detected at a plasma glucose level of 60 to 80 mg/dl (3.3 to 4.4 mM). - Sweating, hunger, paresthesia (numbness) , palpitations, tremor, and anxiety, -principally of autonomic origin 2. At < 60 mg/dl - Difficulty in concentrating, confusion, weakness, drowsiness, a feeling of warmth, dizziness, blurred vision, and loss of consciousness - Neuroglycopenic symptom: occur at lower plasma glucose levels than do autonomic symptoms. Treatment of Type 2 Diabetes Type 2 Diabetes Mellitus Inhibitors of Intestinal Glucose Absorption: Acarbose (Precose) and Miglitol (Glyset) Acts as an -glucosidase inhibitor: prevent cleavage of disaccharides to monosaccharides in the intestine Delay's carbohydrate absorption and reduced postprandial plasma glucose. No effect on lipid profiles Tends not to cause weight gain GI side effects include flatulence (80%), diarrhea (27%) and nausea (8%). Titrating the dose of drug slowly reduces GI side effects. Additive effect when used in combination with sulfonylureas and metformin Sulfonylureas: Mechanism of Action  For many years, the sulfonylureas were the only class of antidiabetic drugs approved as oral agents in the United States.  Sulfonylureas increase the secretion of insulin from the pancreatic b cells in response to glucose and other stimuli,  thereby lowering blood glucose levels by increasing plasma insulin concentrations.  Secondary effects of sulfonylurea therapy may include improvement in hepatic and peripheral insulin sensitivity. Sulfonylureas: Mechanism of Action - Sulfonylureas GLUT2 Na+ K+ Na+ KIR K+ K+ Vm K+ - Pancreatic Ca2+ Voltage-gated ß cell Ca2+ channel ↑ Ca2+ Insulin granules Sulfonylureas: Mechanism of Action SULFONYLUREAS  Oral administration and bind to plasma proteins  Actions can be enhanced by alcohol ~50% of new onset Type II diabetic can reach appropriate glycemic control  First Generation: less potent but longer half lives  Acetohexamide rapidly metabolized, but active metabolite 4-7 hrs  Chlorpropamide (24-48 hours)  Tolazamide (4-7 hrs)  Tolbutamide (4-7 hrs) SULFONYLUREAS  2nd Generation: 100x more potent, but shorter half-life (3-5 hrs)  Glyburide (glibenclamide) (may cause hypoglycemia)  Glimeperide  Glipizide Insulin Secretagogue: Repaglinide and Nateglinide  Chemically Unrelated to Sulfonylureas but same mechanism of action  Rapid absorption with half-life of 1 hour. Can be taken right before meal Less likely to cause hypoglycemia  Metabolized by liver.  Caution in patients with insufficiency. Repaglinide approved for mild to moderate liver failure Nateglinide for moderate liver failure. Biguanides: Insulin Sensitizers  In medieval Europe, a plant locally known as Goat’s Rue (Galega officinalis) was used to treat symptoms of diabetes. The plant contained the compound guanidine.  In the 1950’s, the biguanide Phenformin was introduced for treating type 2 diabetes in the U.S.. It was withdrawn from the market due to cases of fatal lactic acidosis. Metformin: Mechanism of Action  Metformin is the only agent in the biguanide class of antidiabetics available in the United States for the treatment of type 2 diabetes.  Metformin does not stimulate insulin secretion. it inhibits glucose production by hepatocytes and stimulates glucose uptake by skeletal muscle, in both instances via activation of AMP-activated protein kinase (AMPK). Metformin’s activation of AMPK results in reduced acetyl-CoA carboxylase activity, increased fatty acid oxidation, and decreased expression of lipogenic enzymes. DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:1294-1301. Zhou G et al. J Clin Invest. 2001;108:1167-1174. Metformin: Mechanism 2nd Generation of Biguanide Action METFORMIN  Major mechanism of action:  AMP-dependent kinase. Inhibits conversion of acetyl CoA to malonyl CoA, by acetyl- CoA carboxylase, the rate-limiting step in lipogenesis. Net result is a faster rate of fatty acetyl-CoA influx into the mitochondria where it undergoes oxidation to ketone bodies  Increases expression or activity of glycolytic enzymes and GLUT-4, decreases activity of gluconeogenic enzymes  Net: hepatic glucose production and  glucose uptake in muscle and adipose. METFORMIN  Can reduce plasma glucose levels by 25% and decrease hemoglobin A1c by 1-2%. Also lowers plasma triglyceride levels  Does not lead to hypoglycemia when used alone i.e., is anti-hyperglycemic  Adherence to prescribing guidelines is crucial to minimize risk of metabolic acidosis CONTRAINDICATIONS of metformin  Parenteral radiographic contrast administration: may cause acute renal failure and lactic acidosis in patients on metformin. Must withhold metformin just prior to and for 48 hours after the completion of the procedure.  Metabolic acidosis, lactic acidosis and diabetic ketoacidosis  Metformin is substantially eliminated by the kidney and is absolutely contraindicated for use in patients with renal failure or renal impairment (creatinine ≥1.5 in men, or ≥ 1.4 in women). Thiazolidinediones: Pioglitazone, Rosiglitazone  Activate nuclear receptors: peroxisome proliferator-activator receptors (PPAR-g).  Increases gene expression in muscle, liver and fat to increase insulin sensitivity.  Seem to have additional beneficial effects on blood vessels to reduce hypertension and atherosclerosis  Can be used as monotherapy or in combination with metformin or sulfonylureas PPARg: Sites of Metabolic Action  PPARg ligands have direct effects on adipose tissue and probably on skeletal muscle, pancreas, and liver.  An indirect effect of PPARg that occurs via adipose tissue is alteration of various cytokines, notably decreased tumor necrosis factor-a and increased adiponectin.  Decreased serum concentrations of free fatty acids (FFA) results from increased fat synthesis and decreased lipolysis in adipose tissue. PPARg: Sites of Metabolic Action Insulin Sensitivity Insulin Sensitivity  Glucose output Thiazolidinediones: Pioglitazone  Some metabolites pharmacologically active  Excreted primarily in the feces  Half-life: plasma half-life is 3 to 7 hours 16 to 24 hours for metabolites  Extensively (>99%) bound to albumin  No evidence of drug-induced hepatotoxicity Should not be used in patients who experienced jaundice while taking troglitazone Can worsen or cause heart failure. Also cause edema, decrease hematocrit Thiazolidinediones: Rosiglitazone (Avandia)  Some evidence of drug-induced hepatotoxicity Rosiglitazone linked to fatal ischemic heart disease Don’t use in class 3 or 4 failure. Can worsen or cause heart failure. Also cause edema, decrease hematocrit Thiazolidinediones: Rosiglitazone (Avandia)  Some evidence of drug-induced hepatotoxicity Rosiglitazone linked to fatal ischemic heart disease Don’t use in class 3 or 4 failure. Can worsen or cause heart failure. Also cause edema, decrease hematocrit NEW CLASSES OF HYPOGLYCEMICS DRUGS  New classes of hypoglycemics drugs  Amylin: 37-aa peptide produced by β cells and co-secreted with insulin. Inhibits glucagon secretion, delays gastric emptying and suppress appetite.  Pramlintide: Modified amylin peptide used with insulin to prevent postparandial hyperglycemia.Must be injected.  New classes of hypoglycemics drugs  Incretin: Glucagon-like peptide (GLP-1 released from the gut to augment glucose-dependent insulin secretion from pancreas). same effects as amylin plus increases Beta cell number Incretin is rapidly broken down by dipeptidyl peptidase-4 enzyme (DPP-4)  Exenatide; Incretin mimetic (injected)  Sitagliptin: DPP-4 inhibitorb (oral)  Vildagliptin: DPP-4 inhibitor (oral)