Hypoglycemic Agents Flashcards
Describe the production of insulin from mRNA to final product and the relevance of the C peptide.
Insulin is produced as a prepro hormone. In the golgi apparatus the proinsulin is cleaved into insulin. The cleavage byproduct is C-peptide, which can be used to measure insulin production.
Describe the different forms of insulin.
Insulin can occur as a monomer, dimer, or hexamer. The hexamer is complexed with two Zn atoms. The storage form is closer to hexamer, while the active form is a monomer.
Describe how glucose, alpha-2, and beta-2 receptors effect insulin secretion.
Glucose enters pancreatic islet beta cells through the GLUT 2 transporter. It is phosphorylated to G6P by glucokinase, and used to create ATP. The production of ATP causes inactivation of the ATP-sensitive potassium channel, leading to activation of voltage-gated calcium channels and release of intracellular calcium. Secretory granules fuse with cellular membranes. Alpha-2 inhibits teh secretion of insulin, while beta-2 stimulates insulin secretion.
Describe the phases of insulin secretion with constant glucose infusion with respect to individuals who are healthy, with DM1, and with DM2.
Healthy - Spike with initial infusion, and a lower spike with continued infusion
DM 1 - no spikes
DM 2 - no initial spike
How does insulin induce transport of glucose into cells?
Insulin receptor activation causes PI3K-mediated fusion of vesicle containing membrane bound GLUT4 transporters with cellular membranes. Can also increase synthesis of GLUT1 and GLUT 4 transporters
List the rapidly-acting insulin preparations and why they have this property
Lispro, aspart, glulisine
Two amino acids are switched to prevent aggregation of insulin monomers
List the short-acting insulin preparations
regular insulin
List the intermediate insulin preparation and how it acheives this
NPH is insulin complexed with a protamine and Zn.
Describe the two ultra-long-acting insulin preparations and how they work.
Glargine - complexed with Zn and altered so it precipitates in neutral subcutaneous tissue
Detemir - complexed with a fatty acid side chain so it associates with albumin
Describe the four different insulin regimens discussed in the DSA
- Conventional - twice daily Regular/NPH mixtures
- Intensive Therapy - RAI/NPH followed by regular insulin and NPH separately
- Intensive Therapy - Regular bolus insulin before meals with BID or QID long-actining insulin
- Continuous subcutaneous insulin infusion
Describe split-mixed insulin regimens
Insulin is administered in preparations of R/NPH before breakfast and dinner or bedtime. Typically, the doses will be a larger portion of NPH than regular insulin
What is the Dawn Phenomenon
Both normal and diabetic patients have an increased requirement for insulin in the morning due to hyperglycemia induced by evening cortisol.
What are the possible adverse reactions of insulin therapy?
Hypoglycemia, lipoatrophy, and lipohypertrophy
How should you correct DKA
Normal saline infusion along with insulin therapy
Describe the treatment approach of DM2 with respect to 1st line, and alternate therapies.
Initial therapy - lifestyle modifications and metformin
Most individuals fail monotherapy and must utilize a combination therapy.
Describe the effects of metformin on metabolism of glucose, weight, blood sugar, and cholesterol
Metformin reduces hepatic gluconeogenesis and increases peripheral uptake of glucose, while decreasing intestinal absorption. It does not cause weight gain or HYPOGLYCEMIA. Reduces LDL, cholesterol, and triglycerides.
What are the ADRs and CIs of metformin?
ADR - metallic taste and anorexia
CI - renal and hepatic failure along with those predisposed to lactic acidosis (cardiac failure and hypoxic lung disease)
Describe the multiple MOAs of sulfonylureas?
Sulfonylureas induce the release of insulin by blocking ATP-sensitive K+ channels. They also cause increased expression of insulin receptors and glucose transporters while inhibiting hepatic gluconeogenesis.
Insulin levels will eventually return to baseline, but blood glucose will be maintained.
What are the second generation sulfonylureas?
Glimepiride, Glipizide, glyburide
What are the uses of sulfonylureas?
Sulfonylureas are typically used in situation where patients fail to normalize blood glucose with metformin. They are used in combination therapy. Ideal patients are over 30 years old with some beta-cell function and a blood sugar below 300.
Note: Replacing one sulfonylurea for another is ineffective in achieving a response.
What are the adverse effects of sulfonylureas?
Hypoglycemia (especially renal/hepatic function impaired), aplastic anemia, agranulocytosis, and cholestatic jaundice.
What are non-sulfonylurea secretagogues? Give two examples.
Meglitinides. Repaglinide and Nateglinide.
Describe the MOA and administration of Meglitinides.
These drugs bind the ATP-sensitive potassium channel receptor at a different site than sulfonylureas. They can be taken orally before meals, but must be skipped if the meal is skipped.
What are the ADRs of CIs of meglitinides?
Comparable to sulfonylureas
What are a1-glucosidase inhibitors? Describe their MOA, ADRs, and CIs?
MOA - These oligosaccharides bind and block brush border enzymes inhibiting post-prandial spike in glucose
ADR - GI disturbance leading to poor patient compliance
CIs - IBD, partial bowel obstruction, colonic ulcers, DKA, or cirrhosis
What is a prototype thiazolidinedione?
Pioglitazone
Describe the MOA of TZDs?
TZD’s bind transcription factors increasing the sensitivity of target tissues to insulin
What are the ADRs of TZDs?
Weight gain, edema, mild anemia, and possible MI (long-term)
What are the therapeutic uses of amylin analogs (pramlintide)?
Used in patients on large amounts of insulin who experience large glucose swings.
What are the ADRs of pramlintide?
GI disturbances, hypoglycemia, dizziness, lethargy, and additional daily injections
What are the MOAs of GLP-1 analogs (Exenatide)?
Increase glucose-dependent release of insulin
Prevent glucagon release
Suppress appetite
What are the therapeutic uses of exenatide?
Use with metformin and/or sulfonylurea
What are the ADRs of GLP-1 analogs?
GI disturbances and additional daily injections
What are DPP-4 inhibitors?
These inhibit the breakdown of GIP and GLP-1.
What are the ADRs of DPP-4 inhibitors?
Anaphylazis, Stevens-Johnson Syndrome, Hepatic Failure
What is the MOA and ADR of SGLT-2 inhibitors?
MOA - Block the resorption of glucose in the kidneys
ADR - increased risk of genital mycotic infections and UTIs
