Konorev: Drugs for Diabetes Flashcards
What is Diabetes mellitus?
a group of common metabolic disorders resulting in hyperglycemia
- deficiency of insulin
- inability of body to respond to insulin
- increased level of counter-regulatory hormones that oppose insulin action
Diagnostic criteria for DM?
-increased plasma glucose levels
Type 1 DM
-insulin dependent
Type 2 DM
-no insulin dependent
What does insulin normally do?
lowers blood glucose
What are things that raise blood glucose levels?
- T3/4
- Glucagon
- Epinephrine
- Glucocorticoids
What is insulin’s effect on plasma K+ levels?
decreases them
-when ATP is generated in the cell due to glucose metabolism after insulin lets it in, that ATP blocks the K+ efflux channel
What does PKA do?
- generated after GPCR=Gs ligands are activated (B2-AR agonists or GLP-1 receptor agonists)
- it opens up the Ca2+ channel so that can rush in and promote the exocytosis of insulin
What opposes the creation of PKA?
- GPCR-Gi ligands:
- Somatostatin
- alpha2-AR agonists
What is the VDCC
-L-type Ca2+ channel
What drugs are used in diabetes?
- insulins
- amylin analog
- insulin secretagogues
- Biguanides
- Thiazolidinediones
- Sodium-glucose co-transporter 2 (SGLT2) inhibitors
- Inhibitors of a-glycosidases
What are the insulin secretagogues?
- Sulfonylureas
- Meglitinides
- GLP-1 agonists
- Dipeptidyl Peptidase-4 (DPP-4) inhibitors
what is most important when treating Diabetes?
tight glycemic control
Rapid acting insulins (3)
- Aspart
- Lispro
- Gluisine
Short acting insulin
-regular insulin
Intermediate acting insulin
NPH: neutral Protamine Hagerdorn
Long acting insulin
- Detemir
- Glargine
Standard delivery of insulins
Subcutaneous injection using disposable nedles and syringes
What is that really cool new technology thing he talked about?
- a bi hormonal bionic pancreas
- secretes insulin and glucagon
- registers HR
What is Amylin?
a pancreatic hormone synthesized by B-cells
MOA of amylin
- inhibits glucagon secretion
- enhances insulin sensitivity
- decreased gastric emptying (slows the rate of intestinal glucose absorption)
- causes satiety
What does satiety mean?
feeling full
What is the amylin analog drug?
Pramlintide
-these amylins are usd with insulin to control postprandial hyperglycemia
What are the Incretins?
a group of FI hormones that stimulate a decrease in blood glucose levels
-Glucagon-like peptide-1 (GLP-1)
What is GLP-1?
- synthesized by intestinal L-cells
- promotes: B cell proliferation, insulin gene expression, glucose-dependent insulin secretion
- inhibits glucagon secretion
- also causes satiety, inhibits gastric emptying
What is the one thing that’s wrong with GLP-1?
it has a very short half-life
- 1-2 minutes
- not an effective drug
What are the incretin mimetics?
- long-acting GLP-1 receptor agonists
- Dipeptidyl peptidase-4 (DPP-4) inhibitors
- remember, it stimulates insulin release and inhibits glucagon release
- does a great job of lowering blood glucose
Long-acting GLP-1 receptor agonists
- Exenatide
- Liraglutide
What does the GLP-1 receptor agonists do? MOA?
- Gs protein receptor
- makes PKA…. upregulates insulin gene transcription and potentiates the Ca2+ influx so we can secrete it
- Glucose enters cell and makes ATP… blocks K+ efflux channels
DPP-4 inhibitors
- Sitagliptin
- Linagliptin
- Saxagliptin
- Alogliptin
MOA of DPP-4 inhibitors
- they stop DPP-4 which is a serine protease that degrades GLP-1 and other incretins
- keeps that good GLP-1 intact
What are the K(ATP) channel blockers?
Sulfonylureas: first and second gen
Non-sulfonylureas(meglitinides)
Sulfonylureas
- First Gen: Chlorpropamide, Tolbutamide, Tolazamide
- Second gen: Glipizide, Glyburide, Glimepiride
non- sulfonylureas (meglitinides)
- Nateglinide
- Repaglinide
MOA of Katp channel blockers
- Bind to SUR- sulfonylurea receptor
- blocking K+ current through Kir6.2, inwardly rectifying potassium channel
Biguanides
Metformin
MOA of metformin
- Activation of AMP-dependent Protein Kinase
- but then it shows metformin blocking a mitochondria
- decreases glucoeogenesis
- decreases glucose and insulin if elevated
Thiazolidinediones
- Pioglitazone
- Tosiglitazone
Thiazolidinediones MOA
- ligands of peroxisome proliferator-activated receptor-gamma (PPARg)
- PPARg is a nuclear receptor expressed primarily in fat, muscle, liver tissue, and endothelium
- inhibits NFKB, AP-1, and STAT
What are the Sodium-glucose co transporter 2 inhibitors (Gliflozins)?
- Canagliflozin
- Dapagliglozin
- Empagliglozin
What does SGLT2 do?
- normally, it lets glucose get completely reabsorbed in the kidney
- now, we can excrete some of it in the urine which is nice if you’re diabetic
Alpha glycosidase inhibitors
- Acarbose
- Miglitol
MOA of alpha glycosidase inhibitors
- only monosaccharides are absorbed from GI into the blood
- competitive inhibition of a-glycosidases, a family of enzymes on the intestinal epithelium defer digestion and thus absorption of ingested starch and disaccharides
- lower postprandial hyperglycemia to create an insulin-sparing effect
