DA4Final Exam Hypoglycemic
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How can ADRs develop from insulin administration?
- Too large a dose administered
- Mismatch between dose and food intake
- increased insulin-independent glucose use (exercise)
- addiditive effects with other physiologic hormones on insulin sensitivity (adrenal insufficiency)
What are the body responses to low glucose?
- increase of counter regulatory hormones (NE, Epi, GH, glucagon)
- sweating, hunger, palpitations, paresthiesias, tremor, anxiety due to autonomic stimulation
- Neuroglycopenic symptoms- confusion, drowsiness, blurred vision, loss of consciousness (below 30mg/dL)
What are the ADRs associated with insulin administration?
- Allergy and resistance: w/recombinant if aggregated or denatured
- Lipoatrophy: site of insulin injection
- Insulin edema: severe hyperglycemia/ketoacidosis
Name the Four classes of Hypoglycemic Agents:
- Insulin Sensitizers (Thiazolidinediones)
Effects of Sulfonylureas:
- Stimulate release of insulin from B-islet cells
- promote reduction of blood glucose levels
- decreased liver clearance of insulin
- Acutely: increase insulin levels
- Chronically: levels return to pre-treatment levels with better response of target tissues to insulin
MOA of Sulfonylureas:
- bind to the SUR1/Kir6.2 proteins on beta-islet cells
- Blocks Inward-Rectifier K ion channel (Kir6.x)
- depolorizing the cell allowing Ca++influx
Name the (2) 1st Generation and (2) 2nd Generation Sulfonylureas and the major indication:
- 1st Gen: Tolbutamide and Chlorpropamide
- 2nd Gen: Glyburide and Glipizide
- NIDDM: non-insulin dependent diabetes mellitus
Name the two Secretagogues classes with agents and the MOA:
- Meglitinide- repaglinide
- Phenylalanine derivative- nateglinide
- Block ATP-sensitive K channels, not at SUR
Which class of hypoglycemic agent is Metform and it's MOA:
- Biguanide-Decreases hepatic glucose production and enhances insulin action in muscle and adipos tissue
- hepatic effect is mediated by activation of AMP-activated protein kinase (AMPK). Which does the following:
- Inhibits HMG-CoA reductase
- Inhibits AcCoA carboxylase
- Increased SIRT1 (silent information regulator two-1)
- Reduces plasma Triglycerideds by ~20%
What is the side effect of metformin and why does it happen?
- Produces lactic acidosis
- decreases lactate uptake by hepatocytes due to decrease in gluconeogeneis
What is the major class of insulin sensitizers? What do they bind to get the effect? Name the three drugs with the current status.
- Class: Thiazolidinedione PPAR agonist
- Peroxisone Proliferator-Activated Receptor-gama (PPARy) which are nuclear transcription factors
- Troglitazone- withdrawn due to severe liver toxicity
- Rosiglitazone- Restricted use by FDA
- Pioglitazone- Black Box Warning (Avandia)
What agents activate PPARgama and what are some of the results?
- Increase transcription factor expression and translocation of GLUT transporter portein
- Decreased inflammation (Reduction COX2, IL1, TNF)
- Adipocyte differentiation- increased lipid storage which
- reduces FFA and allows muscle to respond normally to insulin
- induces expression of adiponectin by adipocytes
SE and Toxicity issues associated with Insulin Sensitizers
- SE: weight gain, edema and plasma volume expansion
- Toxicity: liver toxicity
What are the two alpha-Glucosidase Inhibitors and what is the MOA? Effects?
- Acarbose and Miglitol
- targets alpha-Glucosidase on the intestianl brush border to reduce intestinal absorption of starch, dextrin, and disaccharides
- Does not stimulate insulin secretion
- 3--50% reduction of HbA1c levels
What are the two major incretins with the drugs?
- Glucagon-Like Peptide-1 (GLP-1): Exendin-4, Liraglutide
- Gastric Inhibitory Peptide (GIP):
What are the effects of GLP-1? Where is it derived from? MOA?
- GLP1- stimulates insulin-released in type 2
- GLP1- natural peptide produced from intestinal L-cells that take proglucagon, cleaved Proconvertase 1/3 to produce a peptide that binds beta islet cell receptors to enhance insulin release, GLP1 is stimulated with food intake
- Degraded rapidly by Dipeptidyl Peptidase IV
- Increases expression of GLUT2 by pancreatic beta cell through cAMP-CREB/PKA/Rap/RAF/MEK/ERK
What is the agent derived from the Gila Monster with relevant information?
- GLP1 agonist from saliva
- Reduces HbA1c levels by 1-1.3% in Type 2 diabeties
- Mono or Combo therapy
- t1/2: 2-3 hours
Which agent only reguires 1x daily dosing? Why? Which class?
- has a C16 fatty acyl group allows binding to albumin or other plasma proteins
- GLP1 receptor agonist
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