Lecture 19 - Diabetes Mellitus - Oral Agents

‭Type II Diabetes‬ ‭Pathophysiology‬ ‭●‬ ‭DM2 most prominent‬ ‭○‬ ‭Decreased receptor number‬ ‭○‬ ‭Decreased affinity‬ ‭●‬ ‭Decreased insulin production → decreased insulin action → hyperglycemia‬ ‭Characteristics‬ ‭‬ C ● ‭ haracterized by insulin resistance and impaired insulin production‬ ‭●‬ ‭Etiology:‬ ‭○‬ ‭Unknown, possibly genetic‬ ‭○‬ ‭Obesity, sedentary lifestyle‬ ‭●‬ ‭Risk factors‬ ‭○‬ ‭Family history of diabetes‬ ‭○‬ ‭Obesity, HTN, HLD‬ ‭○‬ ‭History of GDM (gestational)‬ ‭Type II Oral Drugs‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭ urpose: Glycemic control‬ P ‭Biguanides‬ ‭Sulfonylureas: Stimulate insulin release‬ ‭Meglitinides: Stimulate insulin release‬ ‭Thiazolidinediones‬ ‭Alpha-glucosidase‬ ‭Dipeptidyl peptidase-4 (DPP-4) inhibitors‬ ‭Non-insulin injectable agents‬ ‭○‬ ‭May eventually need insulin‬ ‭Biguanides‬ ‭‬ P ● ‭ rototype: Metformin (Glucophage)‬ ‭●‬ ‭Drug of choice for initial DM2 therapy‬ ‭Mechanism of Action‬ ‭●‬ ‭Facilitates the action of endogenous insulin on the peripheral receptors to:‬ ‭○‬ ‭Decrease plasma glucose‬ ‭■‬ ‭Inhibit glucose production in the liver‬ ‭■‬ ‭Reduce glucose absorption in the gut‬ ‭○‬ ‭Sensitize insulin receptors in the target tissues (↑ efficacy)‬ ‭●‬ ‭No effect on beta cells of the pancreas‬ ‭○‬ ‭No change in insulin production‬ ‭○‬ ‭Less likely to cause hypoglycemia‬ ‭●‬ ‭Preferred oral agent due to safety and effectiveness‬ ‭Pharmacokinetics‬ ‭‬ N ● ‭ ot metabolized but excreted in kidneys‬ ‭●‬ ‭Increased risk for toxicity in renal impairment‬ ‭Therapeutic Uses‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭ M2: Glycemic control‬ D ‭Pre-diabetic/insulin resistance‬ ‭Polycystic ovarian syndrome (PCOS)‬ ‭Gestational diabetes‬ ‭Adverse Effects‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭ I: Decreased appetite, diarrhea, N/V, bloating‬ G ‭Weight loss‬ ‭Metallic taste‬ ‭Vitamin B12/folic acid deficiency‬ ‭○‬ ‭Decreased absorption‬ ‭ ‬ ‭Dose-dependent effects‬ ● ‭Toxicity‬ ‭‬ L ● ‭ actic acidosis occurs in renal failure‬ ‭●‬ ‭Inhibits oxidation of lactic acid to lactate‬ ‭●‬ ‭S/S: Malaise, fatigue, hyperventilation‬ ‭Drug Interactions‬ ‭●‬ ‭Alcohol: Behaves like metformin‬ ‭○‬ ‭Avoid to not exacerbate adverse effects‬ ‭Sulfonylureas‬ ‭‬ P ● ‭ rototype: Glyburide (DiaBeta, Micronase)‬ ‭●‬ ‭Other second generation drugs: Glipizide (Glucotrol)‬ ‭Mechanism of Action‬ ‭‬ S ● ‭ timulates the release of insulin from pancreatic islets‬ ‭●‬ ‭Increases sensitivity of insulin receptors on target cells‬ ‭●‬ ‭Does not work if pancreas is incapable of synthesizing insulin‬ ‭Pharmacokinetics‬ ‭‬ O ● ‭ ral dosing general once daily‬ ‭●‬ ‭Metabolize by liver; excreted by kidney‬ ‭Adverse Effects‬ ‭‬ H ● ‭ ypoglycemia: Dose-dependent, more likely in hepatic/renal dysfunction‬ ‭●‬ ‭Weight gain‬ ‭Containdications‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭ regnancy/lactation‬ P ‭Teratogenic in animal studies‬ ‭Risk of fetal/newborn hypoglycemia‬ ‭Excreted in breastmilk‬ ‭Meglitinides‬ ‭●‬ ‭Prototype: Repaglinide (Gluconorm)‬ ‭Mechanism of Action‬ ‭‬ S ● ‭ timulates the release of insulin from pancreas‬ ‭●‬ ‭Similar to sulfonylureas; no effect if cannot make insulin‬ ‭Pharmacokinetics‬ ‭‬ R ● ‭ apid absorption and elimination‬ ‭●‬ ‭Short acting:‬ ‭○‬ ‭Onset: 30-60 minutes‬ ‭○‬ ‭Duration: 2-4 hours‬ ‭Adverse Effects‬ ‭●‬ ‭Hypoglycemia: Patient must eat within 30 minutes after dosing‬ ‭Thiazolidinediones (Glitazones)‬ ‭‬ P ● ‭ rototype: Pioglitazone (Actos)‬ ‭●‬ ‭The only glitazone in the market‬ ‭Mechanism of Action‬ ‭●‬ ‭Enhance insulin action at the receptor site to reduce insulin resistance by:‬ ‭○‬ ‭Activating PPAR gamma receptors in the cell nucleus‬ ‭ ‬ ‭Leads to increased sensitivity of cell to insulin; increases glucose uptake‬ ○ ‭○‬ ‭Does not stimulate insulin synthesis‬ ‭ ‬ ‭Therapeutic use: Reduces insulin resistance in DM2‬ ● ‭○‬ ‭Usually paired with metformin (synergistic)‬ ‭Pharmacokinetics‬ ‭‬ P ● ‭ eaks 2 hours after dosing‬ ‭●‬ ‭Food can slow absorption‬ ‭●‬ ‭Metabolized by P450 in the liver‬ ‭Adverse Effects‬ ‭‬ D ● ‭ oes not cause hypoglycemia‬ ‭●‬ ‭Most common: URIs, headaches, sinusitis, myalgia‬ ‭●‬ ‭Most concerning: Heart failure secondary to renal retention of fluid‬ ‭○‬ ‭Exacerbated in HF patients because of fluid overload‬ ‭●‬ ‭Can cause ovulation in anovulatory peri-menopausal women‬ ‭○‬ ‭Risk for becoming pregnant without birth control‬ ‭●‬ ‭Increased risk for fracture in women‬ ‭Alpha-Glucosidase Inhibitors‬ ‭●‬ ‭Prototype: Acarbose (Precose/Glucobay)‬ ‭Mechanism of Action‬ ‭●‬ D ‭ elays absorption of dietary carbohydrates by blocking enzymes in the small intestine‬ ‭responsible for breaking down complex carbohydrates into monosaccharide forms‬ ‭●‬ ‭Reduces postprandial rise in blood glucose‬ ‭Pharmacokinetics‬ ‭‬ A ● ‭ cts in the intestine‬ ‭●‬ ‭Minimal systemic effects: 2% of active drug absorbed‬ ‭●‬ ‭Inactivated in intestine by bacteria/digestive enzymes‬ ‭Adverse Effects‬ ‭‬ D ● ‭ oes not cause hypoglycemia‬ ‭●‬ ‭GI effects: Flatulence, cramps, abdominal cramping, diarrhea, borborygmus‬ ‭Non-Insulin Injectable Agents‬ ‭‬ G ● ‭ lucagon-like peptide 1 (GLP-1) receptor agonists; Ozempic‬ ‭●‬ ‭Mimics hormone GLP-1, which endogenously controls glucose:‬ ‭ ‬ ‭Slows gastric emptying‬ ○ ‭○‬ ‭Triggers release of insulin‬ ‭○‬ ‭Inhibits postprandial rise of glucagon‬ ‭○‬ ‭Suppresses appetite‬ ‭ ‬ ‭Prototype: Exenatide (Byetta)‬ ● ‭Mechanism of Action‬ ‭●‬ ‭Mimics endogenous GLP-1 at its receptors to augment glucose control‬ ‭Therapeutic Effect‬ ‭●‬ ‭Improved glycemic control and weight loss in DM2‬ ‭Pharmacokinetics‬ ‭●‬ ‭Excreted unchanged in the urine‬ ‭Adverse Effects‬ ‭‬ H ● ‭ ypoglycemia when combined with sulfonylureas (Glyburide)‬ ‭●‬ ‭GI effects: N/V, diarrhea‬ ‭●‬ ‭Pancreatitis:‬ ‭○‬ ‭S/S: Persistent abdominal pain with/without vomiting‬ ‭○‬ ‭Drug should be stopped immediately‬ ‭●‬ ‭Hypersensitivity reactions reported in post-market surveillance‬ ‭○‬ ‭Angioedema, anaphylaxis‬ ‭○‬ ‭Immediately seek medical attention‬ ‭●‬ ‭FDA category C pregnancy risk‬ ‭○‬ ‭Anomalies seen in animal studies when given three times the dose‬