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
Liraglutide side effects
-N/V
-pancreatitis
-risk of thyroid tumors (monitor calcitonin levels)
Dulaglutide
-Trulicity
-inj SQ once/week
-more resistant to DPP-4
-IgG is carrier that keeps it together for long time and slowly released by breaking disulfide bonds
-GLP-1 peptides slowly released from IgG Fc domain by reduction of disulfide bonds in linker region
Dulaglutide side effects
-N/V
-pancreatitis
-risk of thyroid C-cell tumors
-do NOT use if fam hx of thyroid cancer
Lixisenatide
-Adlyxin
-44 aa peptide
-exanatide w polylysine tail
-GLP-1 agonist
-inj SQ daily before breakfast
-Soliqua (100 U glargine + 33 ug lixisenatide/mL) inj once daily
Lixisenatide side effects
-N/V
-pancreatitis
-risk of thyroid tumors
-AVOID if fam hx of thyroid cancer
Semaglutide
-Ozempic
-31aa peptide
-more resistant to DPP
-big fatty acid chain
-GLP-1 agonist
-inj SQ once weekly
-extensively bound to serum albumin
-t1/2 about a week
Semaglutide side effects
-N/V
-pancreatitis
-Thyroid tumor
-AVOID if fam hx of thyroid cancer
semaglutide oral
-Rybelsus
-little bit of oral bioavailability
-absorbed from stomach
-once daily 3, 7, 14 mg
-dimethylalanine, C-18 FA, hydrophillic spacer (Huge)
-Salcaprozate
insulin + GLP-1 combos
-Soliqua (glargine + lixisenatide) max 60/20
-Xultophy (degludec + liraglutide) max 50/1.8
Tirzepatide
-MOUNJARO
-full GIP agonist
-biased GLP-1 (prefer cAMP over B-arrestin)
-reduces internalization (desensitization) of GLP-1 receptor to maintain effect
-weekly Sq
-allegedly reduces A1c and body weight more effectively than just GLP-1 agonists
Dipeptidyl Peptidase (DDP) 4
-inhibiting incretin proteolysis
-enzyme degrades GLP-1
-serine and histidine?
-hangs out in capillaries
DDP inhibitors
-enhance actions of endogenous GLP-1
DDP inhibiting drugs (GLP-1 monitors)
-oral
-Sitagliptin (Januvia)
-Saxagliptin (Onglyza)
-Linagliptin (tradjenta)
-Alogliptin (Nesina)
Saxagliptin binding
-binds in active site of DDP-4
GLP-1 moderators (DDP inhibitors)
-admin PO qd
-reduce HYPERglycemia and A1c
-low risk of hypoglycemia
-weight neutral
-can coadmin w metformin, TzDs
Januvia and Nesina metabolism and excretion
-not extensively metabolized
-excreted in urine (kidney)
Tradjenta metabolism and excretion
-not extensively metabolized
-excreted in feces (liver)
Onglyza metabolism and excretion
-CYP3A4/5 substrate
-metabolite active
-excreted in urine (kidney)
side effects of DDPIV inhibitors (GLP-1 mods)
-N/V, constipation
-HA, skin reactions
-pancreatitis*
-joint pain*
-HF*
-immunosuppression
-maybe cancer
DDP-4 on immune cells
-inhibitors reduce WBC counts = infections
-potential inc risk of cancer
Pramlintide (Symlin)
-amylin analog
-peptide hormone tx
-37aa co secreted w insulin
-slows gastric emptying, decreases food intake, inhibits glucagon secretion
-blunts postprandial rise in BG
-use w insulin subQ
-type 1 and type 2 tx
Agents that reduce glucose absorption or increase glucose excretion
-a-glucosidase inhibitors
-SGLT2 inhibitors
a-glucosidase inhibitors
-Acarbose
-Miglitol
a-glucosidase inhibitor moa
-dec absorption of carbs from intestine via inhibition of gut a-glucosidases (sucrase, maltase, glucoamylase)
-acarbose minimally absorbed
-migitol completely absorbed
a-glucosidase inhibitor counseling (acarbose, miglitol)
-take orally w meals
-diarrhea, nausea, flatulence (glucose in colon getting fermented by bacteria)
-acarbose risk of liver damage at doses > 100 mg tid
Sodium Glucose coTransporter 2 inhibitors (SGLT2) MOA
-decrease threshold for glucose excretion in urine = more excretion
-reduce blood glucose levels
-dec A1C (monotherapy or with metformin or sulfonylureas)
SGLT2 inhibitor drugs
-empagliflozin (jardiance)
-canagliflozin (Invokana)
-dapagliflozin (Farxiga)
-Ertugliflozin (Steglatro)
-Bexagliflozin (Benzavvy)
-structures have glucose like molecule that gets them recognized (aromatic groups for high affinity)(irreversible?)
SLGT2 inhibitor counseling
-type 2
-DO NOT use in type 1 (ketoacidosis)
-dec A1c +/- metformin/sufonylureas
-weight loss
-inc UTI risk (glucose in urine)
-inc urine flow/hypotension
-inc risk of diabetic ketoacidosis
-DO NOT USE in pt w renal impairment (risk of lower limb amputation)
Agents that reduce insulin resistance/lipotoxicity
-Biguanides (Metformin)
-Thiazoladinediones (Pioglitazone, Rosiglitazone)
Insulin resistance
-decreased response to insulin
-OGTT w prolonged elevation of BG with normal or elevated insulin levels
Insulin resistance causes
-polymorphisms in insulin signaling pathway proteins (rare)
-Obesity (esp fat in abdominal cavity)
-inactivity
Insulin resistance effects
-muscle: impaired uptake
-Adipose: impaired uptake, impaired inhibition of lipolysis mobilization of FAs to other tissues
-liver: impaired inhibition of glucose output (gluconeogenesis or glycogenolysis)
Obesity and insulin resistance
-high FFA levels
-rising levels cause insulin resistance
-lowering of plasma FFA levels reduces chronic insulin resistance
-predominant effect is on insulin-stimulated glucose transport
Poymorphisms in insulin receptor lead to resistance
-Ser instead of Tyr phos of IR and IRS proteins (tyrosine kinase)
=inhibit signaling
-promoted by FA uptake, lipid by-products, inflammatory mediators
Insulin resistance mechanisms
-FFA activates mTOR and that phosphorylates IRS proteins by serines instead of tyrosines = degradation
-inc cytokines in obesity (TNFa) activate kinases = phosphirylate IRS proteins on serines (interferes function)
-phosphorylation happens on serines
- Too much P13K reduces PIP3 (less?) inhibits PI3K that reduces glucose transport
Obesity induced inflammation and insulin resistance
-hypertrophied adipocytes in obesity
-secrete MCP-1 to acttract macrophages
-infiltrated macrophages that differentiate to M1 = insulin resistance
Metformin (Glucophage)
-antihyperglycemic agent
-biguanide w lowest risk of lactic acidosis
-first choice in type 2 usually
-dec BG in type 2 w/o risk of hypoglycemia
Metformin (biguanide) advantage over sulfonylureas
-rarely cause hypoglycemia
-rarely cause weight gain
Metformin (glucophage) MOA
-biguanide
-activate AMPK
-inc efficiency/sensitivity to insulin in liver, fat, and muscle
-dec gluconeogenesis in liver
-inc glycolysis and glucose uptake in muscle/fat cells
-500-850 BID/TID AC to eliminate diarrhea
Metformin action in liver
-elevate AMPK at cost of ATP
-metformin inhibit production of ATP
-elevates AMP
-activates AMPK
-dec glucose production and lipid/cholesterol synthesis in liver
Metformin action in skeletal muscle
-AMP accumulates during exercise
=activation of AMPK
-AMPK phosphrylates TBC1D1/4 which promotes GTPase activity of Rab
-Rab dissociates from GLUT4 allowing translocation
Metformin counseling
-DO NOT USE in disorders w higher risk of lactic acidosis
-dec B-12 absorption
-N/V/D
-can use in combo with sulfonylureas
Metformin effects on blood lipid profile
-dec serum triglycerides
-dec serum LDL
-reduces risk of adverse CV events
Thiazolidinediones MOA
-dec insulin resistance or improve target cell response to insulin
-activators of peroxisome proliferator-activated receptor gamma (PPARy) (transcription factor)
-target adipocytes, liver, muscle
Main target of thiazolidines
-adipocytes
-enhance differentiation
-enhance FFA uptake into subQ fat
-reduce serum FFA
-shifts lipids into fat cells from non-fat cells
Thiazolidinedione effect on liver and muscle
-enhance glucose uptake in both
-reduces hepatic glucose production
Thiazolidinedione drugs
-Rosiglitazone (Avandia)
-Pioglitazone (Actos)
Thiazolidinedione counseling
-RESTRICTED PRESCRIBING bc CV toxicities
-associated w inc risk of bladder cancer
-some hepatotoxicity (check liver function)
-do not cause hypoglycemia
-FDA warning: do NOT USE in NYHA class 3-4 Heart failure
PPARy structure and function
slide 117
TZD modulation of blood glucose via adipokines
slide 118
Factors regulated by PPARy activation
-Resistin (high in type 2)
-Adiponectin (low in type 2)
-TNFa (high in type 2)
Resistin
-stimulate glucose export by liver and insulin resistance
-protein from white adipose tissue (WAT)
-mRNA levels dec in response to TZD
Adiponectin
-reduces blood glucose and insulin resistance
-protein from WAT
-mRNA levels inc w TZD
TNFa
-stimulates lipolysis in WAT
-insulin resistance in skeletal muscle
-from WAT
-mRNA levels decrease w TZDs
Drug summary
slide120-121
