Antidiabetic drugs for type II Flashcards
Normal insulin release
-1st phase peak
-2nd phase peak
insulin release in Type II diabetics
-one short peak over longer period of time
-insulin resistance + reduced insulin secretion
Actions of antidiabetic drugs
-Insulin secretion
-Glucagon secretion
-Appetite control
-Neurotransmitter dysfunction
-Glucose reabsorption
-Glucose uptake and utilization
-lipotoxicity
-hepatic glucose output
-GI
-come back to slide 63
Agents that enhance insulin secretion
-Sulfonylureas
-Meglitinides (shorter duration)
Sulfonylurea drugs
-Tolbutamide
-Tolazaamide
-Chlorpropamide
-Glyburide
-Glipizide
-Glimepiride
Meglitinide drugs
-Nateglinide
-Repaglinide
Sulfonylurea MOA
-must have B cells
-inc release of insulin
-may restore first phace
-inc B-cell sensitivity to glucose and inc glucose stimulated insulin release
Sulfonylurea mech
-binds sulfonylurea receptors on B cells mimics atp (binds ATP binder on K channel)
-inactivates K channel
-dec cell polarization (depolarization)
-activate Ca channels
-inc Ca and activity of microfilaments =
-inc exocytosis of insulin containing granules
Sulfonylurea in high glucose setting
-GLUT 2 take glucose in B cell
-metabolized to ATP
-inc ATP activates sulfonylurea receptor = close K channels
Insulin release in low glucose setting
-dec glucose intake and metabolism
-more ADP keeps K channel open
-Ca stays closed
-insulin granules stay inside
1st gen sulfonylureas
-Tolbutamide* (lowest potency, shortest duration)(6-12h)
-Tolazamide (12-14h)
-Chlorpropamide* (higher potency and duration)(24-72h)
2nd gen sulfonyureas
-Glipizide (12-24)
-Glyburide
-Glimepiride
-way more potent and 24h
-used more than 1st gen
-lower doses than 1st gen
Structures of sulfonylureas vs meglitinides
-prob no sulfa
Repaglinide (prandin)
-meglitinide
-similar MOA to sulfonylurea agents
-quick onset, short duration
-tablet taken before each meal
-shorter t1/2 than sulfonylureas
Nateglinide
-meglitinide
-very specific for KATP blocking
-in pancreas vs CV tissue
-shorter t1/2 = lower risk of hypoglycemia
-synergistic w metformin
Adverse effects of sulfonylureas
-prolonged hypoglycemia (long half-life)
-Glyburide worse than glipizide, glimepiride
-misdiagnosed as stroke that leads to permanent neurological damage and death
-risk of CV events?
-GI probs
-weight gain and inc number of secondary failures
Drug interactions that may enhance sulfonylureas
-increase risk of hypoglycemia
-displace sulfonylureas from plasma protein binding
-may also dec the metabolism of sulfonylureas by liver
-salicylates
-phenylbutazone*
-sulfonamides*
-clofibrate*
Drugs with hypoglycemic effects
-alcohol excessive intake
-high dose salicylates
Drugs which cause hyperglycemia that will oppose therapy
-oral contraceptives
-epinephrine
-thiazide diuretics
-corticosteroids
-thyroid
Agents that enhance incretin effect
-GLP-1R agonists
-GLP1 and GIP dual agonist
-DPP-IV inhibitors
-Amylin analogs
GLP-1R agonist drugs
-Exenatide
-Liraglutide
-Lixenatide
-Dulaglutide
-Semaglutide
GLP1 and GIP dual agonist drug
-Tirzepatide
DDP-IV inhibitor drugs
-Saxagliptin
-Sitagliptin
-Linagliptin
-Alogliptin
Amylin Analog drug
-Pramlintide
Incretin effect
-oral glucose stimulates a larger insulin response than IV glucose
-something in the Gi tract must be increasing insulin response
-stimulating B-cell after meal
-cAMP pathway and ERK1/2 pathway
-GLP, GIP, DPP-IV
GIP
-glucose-dependent insulinotropic peptide
-duodenal cells
GLP-1
-glucagon like peptide 1
-glucose dependent
GLP-1 MOA
-secreted from L cells in intestine after food eaten
-stimulates insulin secretion
-dec glucagon secretion
-slow gas emptying
-reduce food intake
-inc B cell mass and maintain function
-improve insulin sensitivity
-enhance glucose disposal
-STIMULATED INSULIN SECRETION IS GLUCOSE DEPENDENT
GLP-1 receptor signaling
-Gs to cAMP or Gq to Ca = glucose stimulates insulin secretion
-GBy to P13K and Ca and cAMP = glucose stimulated ERK1/2 phosphorylation = gene transcription and B cell proliferation
Incretin effect in type II diabetics
-diminished
-insulin doesn’t respond as well to nutrient
GLP-1 tx of type 2
-provide long lasting GLP-1 analog OR
-prevent degradation of endogenous GLP-1 OR
-positive modulators for GLP-1 receptor
Benefits of GLP-1s
-reduce HYPERglycemia w low risk of HYPOglycemia
-weight loss
-inc beta cell mass (maybe)
Exenatide (Byetta)
-GLP-1 for type 2
-39aa peptide from Gila monster saliva
-activates GLP1 receptor
-enhance 1st phase secretion
-longer t1/2 than GLP-1
Exenatide counseling
-longer t1/2 = twice daily or once a week injections
-co admin w metformin, TzDs, or sulfonylureas
Exenatide side effects
-N/V, pancreatitis
-risk thyroid C-cell tumors
-DO NOT USE in pt w family hx of thyroid cancer
Liraglutide
-Victoza
-hGLP-1 aa7-37
-DPP can recognize and inactivate it still
-fatty acid chain added
-13 hour t1/2
-subQ daily
-can co admin w metformin, TzDs, sulfonylureas