Pharmacology of Injectables for Type 1 Diabetes Mellitus Exam 2

Question 1

What are the constituents of insulin?

Answer 1

• 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

Question 2

Synthesis of insulin

Answer 2

Pro-insulin is processed in the Golgi apparatus of beta cells into insulin and the C-peptide

Question 3

Storage of insulin

Answer 3

• stored in granules of βcells
• stored crystals containing 2 atoms of zinc and 6 molecules of insulin.
• Insulin naturally self-aggregates into hexamers

Question 4

Secretion of of insulin

Answer 4

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

Question 5

What are thing that can trigger an increase in insulin secretion?

Answer 5

• Meal
• Sympathetic activation
• Insulin secretagogues

Question 6

What are thing that can trigger a decrease in insulin secretion?

Answer 6

• Insulin
• Leptin
• High glucose
• Low FFA
• Diazoxide
• Phenytoin
• Vinblastine
• Colchicine

Question 7

Degradation of of insulin

Answer 7

• Endogenous insulin: 40% by kidneys, 60% by liver

- Exdogenous insulin: 60% by kidneys, 40% by liver

Question 8

What is the half life of insulin in the blood?

Answer 8

3-6 min (<10 min)

Question 9

How does insulin activate glucose transporters to move to surface of membrane?

Answer 9

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

Question 10

What are the pathways that the IRS can trigger?

Answer 10

• Phosphatidylinoaitol-3 kinase pathway

- MAP kinase pathway

Question 11

What are the classifications of insulin?

Answer 11

• rapid acting (contain zinc)
• short acting (contain zinc)
• intermediate acting (contain protamine; cloudy)
• long acting

Question 12

What are the rapid acting insulin?

Answer 12

• Insulin lispro (Humalog, Admelog)
• Insulin aspart (Novolog, Fiasp)
• Insulin glulisine (Apidra)

Question 13

Insulin lispro

Answer 13

• 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

Question 14

Insulin aspart

Answer 14

• less tendency to aggregate -> disassociate into monomers

Question 15

What are the short acting insulin?

Answer 15

Regular insulin (Humulin R, Novolin R)

Question 16

Regular insulin

Answer 16

• 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.

Question 17

What are the intermediate acting insulin?

Answer 17

Insulin (Humulin N, Novolin N)

Question 18

Insulin

Answer 18

• 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

Question 19

What are the long acting insulin?

Answer 19

• Insulin Glargine (Lantus, Toujeo, Basaglar)
• Insulin Detemir (Levemir)
• Insulin Degludec (Tresiba)

Question 20

Insulin Glargine

Answer 20

• 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

Question 21

Insulin Detemir

Answer 21

• ↑ 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

Question 22

Insulin Degludec

Answer 22

• half life: > 24 hours

- duration: > 42 hours

Question 23

What are the Insulin Delivery Systems?

Answer 23

• Standard s.c. injection
• Portable Pen injectors
• Continuous subcutaneous insulin infusion device
• Inhalation delivery device

Question 24

Afrezza

Answer 24

inhalation insulin powder

Question 25

What is the non-insulin hormone amylin analog?

Answer 25

Pramlintide

Question 26

Pramlintide MOA

Answer 26

• pramlintide is similar in structure to amylin analog
• helps the pt utilize glucose;
• delays gastric emptying
• decreases postprandial glucagon secretion
• improves satiety

Question 27

How is amylin released?

Answer 27

from the beta cells with insulin

Question 28

Pramlintide pearls

Answer 28

• administered s.c.

- cannot be mixed with insulin in syringe