Pharmacology of Injectables for Type 1 Diabetes Mellitus Exam 2 Flashcards
What are the constituents of insulin?
- C-peptide chain
- A chain
- B chain
- becomes active when C-peptide chain is cleaved off
- A and B chain are held together by disulfide bridges
Synthesis of insulin
Pro-insulin is processed in the Golgi apparatus of beta cells into insulin and the C-peptide
Storage of insulin
- stored in granules of βcells
- stored crystals containing 2 atoms of zinc and 6 molecules of insulin.
- Insulin naturally self-aggregates into hexamers
Secretion of of insulin
glucose comes into cell via glucose transporters -> increases ATP -> shuts down ATP/K channel -> causes Ca++ channel to open -> Ca++ enters cell -> induces exocytosis of insulin granules
What are thing that can trigger an increase in insulin secretion?
- Meal
- Sympathetic activation
- Insulin secretagogues
What are thing that can trigger a decrease in insulin secretion?
- Insulin
- Leptin
- High glucose
- Low FFA
- Diazoxide
- Phenytoin
- Vinblastine
- Colchicine
Degradation of of insulin
- Endogenous insulin: 40% by kidneys, 60% by liver
- Exdogenous insulin: 60% by kidneys, 40% by liver
What is the half life of insulin in the blood?
3-6 min (<10 min)
How does insulin activate glucose transporters to move to surface of membrane?
binds to insulin receptor in the tissue in the liver, muscle cells, adipose tissue -> insulin receptor is an enzyme linked receptor -> has an extracellular portion (alpha subunit) and a transmembrane portion which has a cytosolic portion that is a tyrosine kinase -> causes another insulin to come bind in order to form a dimer -> dimerization activates the cytosolic portion -> phosphorylated -> active receptor -> now that it’s autophosphorylated, it’s ready to phosphorylate other things -> phosphorylates IRS (insulin related substance) -> triggers amplification of pathways -> after all this happens, causes the glucose transporters to move to the surface of the membrane
What are the pathways that the IRS can trigger?
- Phosphatidylinoaitol-3 kinase pathway
- MAP kinase pathway
What are the classifications of insulin?
- rapid acting (contain zinc)
- short acting (contain zinc)
- intermediate acting (contain protamine; cloudy)
- long acting
What are the rapid acting insulin?
- Insulin lispro (Humalog, Admelog)
- Insulin aspart (Novolog, Fiasp)
- Insulin glulisine (Apidra)
Insulin lispro
- First monomeric insulin in market
- To enhance its shelf-life: stabilized into hexamers by a cresol preservative
- When given s.c. -> quickly dissociates into monomers and is rapidly absorbed
- Onset: 5-15 min, & peak conc. around 1hr
Insulin aspart
- less tendency to aggregate -> disassociate into monomers
What are the short acting insulin?
Regular insulin (Humulin R, Novolin R)
Regular insulin
- Soluble crystalline zinc insulin
- Onset: 30 - 60 min post s.c. injection; peak: 2-3 hr
- Duration of action: 6-8 hr
- in the vial, aggregates into dimers which stabilize around the zinc ions to create hexamers
- Only insulin that is okay to give by i.v.
What are the intermediate acting insulin?
Insulin (Humulin N, Novolin N)
Insulin
- combined with protamine
- Once injected, proteolysis degrades the protamine and frees the insulin to be absorbed
- Onset: 2-4 hours
- Duration: 8-12 hours
- can be mixed with short / rapid acting insulin
- unpredictable PK
What are the long acting insulin?
- Insulin Glargine (Lantus, Toujeo, Basaglar)
- Insulin Detemir (Levemir)
- Insulin Degludec (Tresiba)
Insulin Glargine
- Soluble, “peakless” insulin analog
- soluble in acidic soln (in vial) but precipitates (insoluble) in pH of body after s.c. inj. -> Forms a depot that releases individual molecules of insulin into blood
- slow onset of action
- peak: 4-6 hours
- duration: 11-24 hours
- cannot mix with other agents
Insulin Detemir
- ↑ self-aggregation in the s.c. tissue and reversible albumin binding.-> Slow dissociation from albumin = long-acting properties similar to those of insulin glargine
- Dose-dependent onset: 1-2 hr
- duration > 12 hours
Insulin Degludec
- half life: > 24 hours
- duration: > 42 hours
What are the Insulin Delivery Systems?
- Standard s.c. injection
- Portable Pen injectors
- Continuous subcutaneous insulin infusion device
- Inhalation delivery device
Afrezza
inhalation insulin powder
What is the non-insulin hormone amylin analog?
Pramlintide
Pramlintide MOA
- pramlintide is similar in structure to amylin analog
- helps the pt utilize glucose;
- delays gastric emptying
- decreases postprandial glucagon secretion
- improves satiety
How is amylin released?
from the beta cells with insulin
Pramlintide pearls
- administered s.c.
- cannot be mixed with insulin in syringe
