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Pharmacology – Diabetes Drugs

Pharmacology – Diabetes Drugs

Drug Drug Class Mechanism of Action Indications Adverse Effects Contraindications Alpha Cells Glucagon Natural Pancreatic Hormone ------Beta Cells ------Pre-Pro- --> Pro-Inslin via PEPTIDASE Pro-Insulin --> Insulin + C Peptide ------Uses Tyrosine Kinase Recptor STEPS: 1. Glucose Enters Beta Cells. 2. Glucose Indirectly Inhibits ATP-Sensitive K+ Channel 3. Depolarization of the Membrane Triggers Ca2+ Mediated Overall Effect: Exocytosis of Insulin Storing Granules. Favor Storage of Fuel 4. Binds + Activates Tyrosine Kinase Receptor ------(Binds to Alpha, Phosphorylates Beta) Promotes K+ Uptake 5. Promoted Uptake of Glucose by Up-Regulating GLUT-1 + GLUT-4 Inhibits Gluconeogenesis Promotes Cellular K+ Uptake: Insulin Natural Pancreatic Hormone 6. Alters the Phosphorlaytion State of Key Metabolic Enzymes 7. Induces Transcription of Several Genes Increases Glycolysis Hypokalemia (Inhibits Gluconeogenesis) Inhibits Glycogenolysis ------Stimulates Glycogenesis Phases: Increases Synthesis of Triglycerides First Phase: Increases Protein Synthesis Glucose Induced a Brief Pulse of Insulin Output (within 2 minutes) Second Phase: Delayed but More Sustained Insulin Release ------Insulin Release Can be Caused By: 1. Glucose 2. GIT Hormones (GIP, CCK) (ORAL) 3. Adrenergic A2: Decreases Insulin Release (Pre-Dominant) 4. Adrenergic B2/Vagal: Increases Insulin Release (Less Dominant) Delta Cells Somatostatin Natural Pancreatic Hormone ------Pancreatic F (PP) Cells Natural Pancreatic Hormone Polypeptide ------

Drug Drug Class Mechanism of Action Indications Adverse Effects Contraindications Bovine Insulin: Mad Cow Disease --> Removed from US Bovine Insulin Beef Pancreas Same as Human Insulin Diabetes Mellitus Porcine Insulin: Allergy Concerns --> Removed from US Porcine Insulin Pork Pancreas Lipodystrophy Drug Reactions: Hypoglycemia: ------Counter Regulatory Sympathetic Stimulation: B-Blockers: Sweating, Anxiety, Palpitation, Tremor Prolong Hypoglycemia by Inhibiting Neuroglucopenic Symptoms: Compensatory Mechanisms Deprivation of Brain Glucose Also Masks Hypoglycemia Warning Signs Dizziness, Headache, Behavioral Changes, Visual (Sweating, Tremor) Disturbances, Fatigue, Weakness, Muscular Incoordination ------Ultimately COMA Thiazides, Furosemide, Corticosteroids: ------Raise Blood Sugar Gestational Diabetes Advantages: Treatment for Hypoglycemia: Glucose Reduce Insulin Effectiveness In Surgery/Infection Diminished Antibody: ------Human Insulin Recombinant DNA Technology Less Change of Insulin Resistance Somogyi Phenomenon: Alcohol: Cannot Be Ingested Less Allergic Reactions A contested explanation of phenomena of elevated blood Preciptates Hypoglycemia by Depleting Will be Digested by Less Lipodystrophy sugar in the morning. Hepatic Glycogen Proteolytic Enzymes A rebounding high blood sugar that is a response to low ------blood sugar Insulin Resistance: ------Acute: Local Reactions (Lipodystrophy) Develops Rapidly Allergic Reactions (Protamine, Zinc) Short-Term Problem Local/Systemic Urticaria (Trauma, Stress, Etc.) Weight Gain (Insulin is Anabolic) Chronic: Edema Antibodies are Formed Against Hypokalemia Bovine/Porcine Insulin. Switch Patient to Human Insulin Diabetes Mellitus Onset Within 15 Minutes (Type I -- Sometimes Type II) Rapid-Acting Insulin Agonist Duration: <5 Hours Diabetic Ketoacidosis (Diabetic Coma) Same as Above Same as Above Only Given SC Hyperosmolar (Non-Ketonic Hyperglycemic) Coma Diabetes Mellitus Onset Within 30 Minutes (Type I -- Sometimes Type II) (Crystalline Zinc Short-Acting Insulin Agonist Duration: 5-8 Hours Diabetic Ketoacidosis (Diabetic Coma) Same as Above Same as Above Insulin/Soluble Insulin) Given SC, IV, IM Hyperosmolar Semilente Insulin (Non-Ketonic Hyperglycemic) Coma Diabetes Mellitus Neutral Protamine (Type I -- Sometimes Type II) Hagedorn Insulin Intermediate-Acting Insulin Duration: 24 Hours Diabetic Ketoacidosis (Diabetic Coma) Same as Above Same as Above (NPH Insulin) Agonist Hyperosmolar (Non-Ketonic Hyperglycemic) Coma Utralente Diabetes Mellitus (Type I -- Sometimes Type II) Long (Slow)-Acting Insulin Agonist Duration: 30 Hours Diabetic Ketoacidosis (Diabetic Coma) Same as Above Same as Above Protamine-Zinc Hyperosmolar Insulin (Non-Ketonic Hyperglycemic) Coma

Symptoms Management Management: ------Regular Insulin IV (Bolus + Infusion) Life Threatening Medical Emergency After Patient Becomes Fully Generally Seen in Type I Diabetes Conscious: Causes: Maintainence with SC Injection Infection (Most Common) ------Trauma IV Fluids: Stroke (To Correct Dehydration from Pancreatitis Osmotic Diuresis) Stressful Conditions Normal Saline (.9 NaCl) Diabetic Inadequate Doses of Insulin Later, 5% Glucose in 1/2 N Saline Ketoacidosis ------Symptoms: KCl: Nausea/Vomiting Acidosis Causes Hypokalemia Abdominal Pain Insulin Therapy Causes Hypokalemia Kussmaul Breathing (Deep, Slow) ------Change in Mental Status NaHCO3: If Blood pH <7.1 Elevated Blood/Urine Ketones ------Glucose Blood pH <7.3, Low Bicarb Phosphate: Controversial ------Antibiotics: Respiratory Infection Prevention (Pneumonia) Same as Ketoacidosis BUT… Faster Fluid Replacement is Needed and NaHCO3 is NOT Required Hyperosmolar Life Threatening Medical Emergency ------Hyperglycemic Generally Seen in Type II Diabetes Prophylactic Heparin Therapy: Syndrome Patients are Prone to Thrombosis (Hyperviscosity and Sluggish Circulation)

Drug Drug Class Mechanism of Action Indications Adverse Effects Contraindications More With 1st Gen than 2nd Gen: Hypoglycemia Nausea/Vomiting Weight Gain Hyperglycemia in Type II Diabetes Promote Insulin Release from Pancreatic B-Cells Cholestatic Jaundice (If Diet and Exercise Fails) Close K+ Channels in B-Cell Membrane --> Depolarization Introlerance to Alcohol (Disulfiram-Like Reaction) ------> Ca2+ Influx --> Insulin Release (Chlorpromamide) 1st Gen: Well-Absorbed Orally Type I Diabetes: ------Cross Placenta: Fetal Hypoglycemia Given 30- Minutes Prior to Meal Sulfonylureas Require SOME Islet Reduce Serum Glucagon Level ------ 90%-99% Bound to Plasma Protein Function to Produce Effect Oral Hypoglycemic Agent: ------Drug Interactions: (Can be Displaced) ------ Insulin Secretagogue Short-Acting: Displace from Protein Binding: Hypoglycemia Metabolized by Liver Patients with Renal/Liver Disease ------Tolbutamide (Safest for Elderly) Phenylbutazone Salicylates Sulfonamides Secreted in Urine ------2nd Gen: Intermediate Acting: Inhibit Metabolism/Excretion: Hypoglycemia ------Pregnancy (Insulin Only) Acetohexatide Tolazamide Glipizide Glyburide Phenylbutazone Salicylates Sulfonamides WARFARIN Glyburide Elderly: Tolbutamide Long-Acting: Synergize With/Prolong Action: Hypoglycemia Glimiperide Dangerous: Chlorporpamide Chlorpropamide Salicylates Propranolol Lithium Alcohol Renal Patients: Glipizide/Tolbutamine Induce Metabolism: Hyperglycemia Phenobarbital Phenytoin Rifampin Chronic Alcoholism Oppose Action/Suppress Insulin Release: Hyperglycemia Corticosteroids Diazoxide Thiazide Birth Control Rapid Onset Shorter Duration than Sulfonylureas Analog ------() Safe for Patients with Oral Hypoglycemic Agent: Block ATP-Dependent K+ Channels Hypoglycemia Hepatic Insufficiency D-Phenylalanine Renal Insufficiency Insulin Secretagogue (Same Mechanism as Sulfonylureas) Weight Gain (Metabolized in the Liver) Derivative ------() Effective in Early Insulin Release (After Meals) --> Post-Prandial Glucose Regulators

Drug Drug Class Mechanism of Action Indications Adverse Effects Contraindications Improve Target Cell Reponse to Insulin WITHOUT Increasing Pancreatic Insulin Secretion Gi Disturbances: ------Metallic Taste : Anorexia First-Line Drug Prescribed for Type II DM Nausea/Vomiting Renal/Hepatic Disease Increases AMP-Dependent Protein Kinase DIARRHEA Oral Hypoglycemic Agent: Type II Diabetes History of Lactic Acidosis Biguinides Decreases Hepatic Gluconeogenesis Abdominal Pain Insulin Sensitizer Type II Diabetes Alcoholism Metformin Decreases Intestinal Absorption of Glucose ------Anti-Hyperglycemic Agent Polycystic Ovary Syndrome Cardiac Failue Increases Peripheral Insulin Sensitivity Lactic Acidosis: Chronic Hypoxic Lung Disease Benefits: Especially in Patients with Kidney Disease/Alcoholics Modest Weight Loss ------Does NOT Cause Hypoglycemia Vitamine B12 Deficiency: Has Lipid-Lowering Acitivity Long-Term Impairment of Vitamin B12 Absorption Increases HDL, Decreases LDL Increase Tissue Sensitivity to Insulin Reduce A1C by 1-1.5% ------Hepatotoxicity Bind to Peroxisome Proliferator Activated Receptor Edema Thiaxolidinediones Gamma (PPARy) Oral Hypoglycemic Agent: Weight Gain Liver Disease Patients Glitazones Results in Increase in Insulin Sensitivity by Increasing Require Insulin to be Present Insulin Sensitizer Cardiovascular Toxicities: Pregnancy (Insulin Only) GLUT-4 Glucose Transporters Increased Risk of MI and CHF and Enhancing Glucose/Lipid Metabolism Increased Risk of Bladder Cancer (Pioglitazone) Benefits: Decrease Lipid Levels (Decrease TG, Increase HDL) Does Not Increase Pancreatic Insulin Secretion

Drug Drug Class Mechanism of Action Indications Adverse Effects Contraindications Inhibitor of Glucose Absorption from GIT ------Chronic Intestinal Diseases Inhibits A-Glucosidase on the Intestinal Brush Border, Hypoglycemia (If Given With Sulfonylureas) Inflammatory Bowel Disease Oral Hypoglycemic Agent: Type II DM which Converts Complex Carbohydrates to Simple Sugars ------Colonic Ulceration A-Glucosidase Inhibitor (Adjuncts) for Absorption. Flatulence, Diarrhea, Bloating, Abdominal Pain Intestinal Obstruction Net Result: Renal Insufficiency Decrease Post-Prandial Hyperclygemia (After Meals) Drug Drug Class Mechanism of Action Indications Adverse Effects Contraindications Glucagon-Like Peptide Type II DM Patients Mimics Enhancement of Glucose-Dependent Insulin Not Controlled with Oral Hypoglycemic Agent: Secretion Sulfonylureas/Metformin GI Disturbances (Nausea, Vomiting, Diarrhea) Regular Insulin Incretin-Based Suppresses Glucagon Secretion (Lizard Saliva) ------Pancreatitis Rapidly-Acting Insulin GLP-1 Analog Reduces Food Intake Give SC Injection 1 Hour Before Meal Slows Gastric Emptying Controls Postprandial Levels ------Glucagon-Like Peptide Type II DM Patients Mimics Enhancement of Glucose-Dependent Insulin Not Controlled with Oral Hypoglycemic Agent: Secretion Sulfonylureas/Metformin GI Disturbances (Nausea, Vomiting, Diarrhea) Regular Insulin Incretin-Based Suppresses Glucagon Secretion ------Pancreatitis Rapidly-Acting Insulin GLP-1 Receptor Agonist Reduces Food Intake Give SC Injection 1 Hour Before Meal Slows Gastric Emptying Controls Fasting Glucose Levels ------Suppresses Glucagon Release Type I DM Synthetic Analog Delays Gastric Emptying Type II DM GI Disturbances (Nausea, Vomiting, Anorexia) Pramlinitide Insulin Anti-Hyperglycemic Reduces Food Intake ------Hypoglycemia Decreases Hepatic Glucose Production Give SC Injection by Itself (No Insulin) Type II DM Oral Hypoglycemic Agent: Inhibitor of Dipeptidyl Peptidase-4 Enzyme: Used Alone or Combined with The Benefit is LOWER SIDE EFFECTS Incretin-Based Enzyme Degrades Incretin (GLP-1-Like Molecules) Metformine/Anti-Hyperglycemic Pancreatitis DPP-4 Inhibitor Agents

Drug Drug Class Mechanism of Action Indications Adverse Effects Contraindications Inhibits Sodium-Glucose Co-Transporter 2: A Membrane Protein in the Kidney that Transports Filtered Glucose Oral Hypoglycemic Agent Reduces Fasting + Prandial Glucose from the Proximal Tububle into the Epithelial Cells SGLT2 Inhibitor Reduces A1C Net Result: Decrease in Renal Glucose Reabsorption

Drug Drug Class Mechanism of Action Indications Adverse Effects Contraindications Prevents Retinopathy Inhibits Aldose Reductase Enzyme: Zopolrestat Prevents Neuropathy Aldose Reductase Inhibitor Normally Present in the Eye Converts Glucose into Fidarestat Prevents Cataracts Sorbitol All Associated with Diabetes

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