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Therapeutics II > Antidiabetic drugs for type II > Flashcards

Antidiabetic drugs for type II Flashcards

1
Q

Normal insulin release

A

-1st phase peak
-2nd phase peak

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2
Q

insulin release in Type II diabetics

A

-one short peak over longer period of time
-insulin resistance + reduced insulin secretion

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3
Q

Actions of antidiabetic drugs

A

-Insulin secretion
-Glucagon secretion
-Appetite control
-Neurotransmitter dysfunction
-Glucose reabsorption
-Glucose uptake and utilization
-lipotoxicity
-hepatic glucose output
-GI

-come back to slide 63

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4
Q

Agents that enhance insulin secretion

A

-Sulfonylureas
-Meglitinides (shorter duration)

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5
Q

Sulfonylurea drugs

A

-Tolbutamide
-Tolazaamide
-Chlorpropamide
-Glyburide
-Glipizide
-Glimepiride

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6
Q

Meglitinide drugs

A

-Nateglinide
-Repaglinide

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7
Q

Sulfonylurea MOA

A

-must have B cells
-inc release of insulin
-may restore first phace
-inc B-cell sensitivity to glucose and inc glucose stimulated insulin release

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8
Q

Sulfonylurea mech

A

-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

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9
Q

Sulfonylurea in high glucose setting

A

-GLUT 2 take glucose in B cell
-metabolized to ATP
-inc ATP activates sulfonylurea receptor = close K channels

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10
Q

Insulin release in low glucose setting

A

-dec glucose intake and metabolism
-more ADP keeps K channel open
-Ca stays closed
-insulin granules stay inside

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11
Q

1st gen sulfonylureas

A

-Tolbutamide* (lowest potency, shortest duration)(6-12h)
-Tolazamide (12-14h)
-Chlorpropamide* (higher potency and duration)(24-72h)

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12
Q

2nd gen sulfonyureas

A

-Glipizide (12-24)
-Glyburide
-Glimepiride

-way more potent and 24h
-used more than 1st gen
-lower doses than 1st gen

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13
Q

Structures of sulfonylureas vs meglitinides

A

-prob no sulfa

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14
Q

Repaglinide (prandin)

A

-meglitinide
-similar MOA to sulfonylurea agents
-quick onset, short duration
-tablet taken before each meal
-shorter t1/2 than sulfonylureas

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15
Q

Nateglinide

A

-meglitinide
-very specific for KATP blocking
-in pancreas vs CV tissue
-shorter t1/2 = lower risk of hypoglycemia
-synergistic w metformin

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16
Q

Adverse effects of sulfonylureas

A

-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

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17
Q

Drug interactions that may enhance sulfonylureas

A

-increase risk of hypoglycemia
-displace sulfonylureas from plasma protein binding
-may also dec the metabolism of sulfonylureas by liver
-salicylates
-phenylbutazone*
-sulfonamides*
-clofibrate*

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18
Q

Drugs with hypoglycemic effects

A

-alcohol excessive intake
-high dose salicylates

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18
Q

Drugs which cause hyperglycemia that will oppose therapy

A

-oral contraceptives
-epinephrine
-thiazide diuretics
-corticosteroids
-thyroid

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19
Q

Agents that enhance incretin effect

A

-GLP-1R agonists
-GLP1 and GIP dual agonist
-DPP-IV inhibitors
-Amylin analogs

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20
Q

GLP-1R agonist drugs

A

-Exenatide
-Liraglutide
-Lixenatide
-Dulaglutide
-Semaglutide

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21
Q

GLP1 and GIP dual agonist drug

A

-Tirzepatide

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22
Q

DDP-IV inhibitor drugs

A

-Saxagliptin
-Sitagliptin
-Linagliptin
-Alogliptin

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23
Q

Amylin Analog drug

A

-Pramlintide

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24
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
25
GIP
-glucose-dependent insulinotropic peptide -duodenal cells
26
GLP-1
-glucagon like peptide 1 -glucose dependent
27
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
28
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
29
Incretin effect in type II diabetics
-diminished -insulin doesn't respond as well to nutrient
30
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
31
Benefits of GLP-1s
-reduce HYPERglycemia w low risk of HYPOglycemia -weight loss -inc beta cell mass (maybe)
32
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
33
Exenatide counseling
-longer t1/2 = twice daily or once a week injections -co admin w metformin, TzDs, or sulfonylureas
34
Exenatide side effects
-N/V, pancreatitis -risk thyroid C-cell tumors -DO NOT USE in pt w family hx of thyroid cancer
35
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
36
Liraglutide side effects
-N/V -pancreatitis -risk of thyroid tumors (monitor calcitonin levels)
37
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
38
Dulaglutide side effects
-N/V -pancreatitis -risk of thyroid C-cell tumors -do NOT use if fam hx of thyroid cancer
39
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
40
Lixisenatide side effects
-N/V -pancreatitis -risk of thyroid tumors -AVOID if fam hx of thyroid cancer
41
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
42
Semaglutide side effects
-N/V -pancreatitis -Thyroid tumor -AVOID if fam hx of thyroid cancer
43
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
44
insulin + GLP-1 combos
-Soliqua (glargine + lixisenatide) max 60/20 -Xultophy (degludec + liraglutide) max 50/1.8
45
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
46
Dipeptidyl Peptidase (DDP) 4
-inhibiting incretin proteolysis -enzyme degrades GLP-1 -serine and histidine? -hangs out in capillaries
47
DDP inhibitors
-enhance actions of endogenous GLP-1
48
DDP inhibiting drugs (GLP-1 monitors)
-oral -Sitagliptin (Januvia) -Saxagliptin (Onglyza) -Linagliptin (tradjenta) -Alogliptin (Nesina)
49
Saxagliptin binding
-binds in active site of DDP-4
50
GLP-1 moderators (DDP inhibitors)
-admin PO qd -reduce HYPERglycemia and A1c -low risk of hypoglycemia -weight neutral -can coadmin w metformin, TzDs
51
Januvia and Nesina metabolism and excretion
-not extensively metabolized -excreted in urine (kidney)
52
Tradjenta metabolism and excretion
-not extensively metabolized -excreted in feces (liver)
53
Onglyza metabolism and excretion
-CYP3A4/5 substrate -metabolite active -excreted in urine (kidney)
54
side effects of DDPIV inhibitors (GLP-1 mods)
-N/V, constipation -HA, skin reactions -pancreatitis* -joint pain* -HF* -immunosuppression -maybe cancer
55
DDP-4 on immune cells
-inhibitors reduce WBC counts = infections -potential inc risk of cancer
56
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
57
Agents that reduce glucose absorption or increase glucose excretion
-a-glucosidase inhibitors -SGLT2 inhibitors
58
a-glucosidase inhibitors
-Acarbose -Miglitol
59
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
60
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
61
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)
62
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?)
63
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)
64
Agents that reduce insulin resistance/lipotoxicity
-Biguanides (Metformin) -Thiazoladinediones (Pioglitazone, Rosiglitazone)
65
Insulin resistance
-decreased response to insulin -OGTT w prolonged elevation of BG with normal or elevated insulin levels
66
Insulin resistance causes
-polymorphisms in insulin signaling pathway proteins (rare) -Obesity (esp fat in abdominal cavity) -inactivity
67
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)
68
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
69
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
70
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 2. Too much P13K reduces PIP3 (less?) inhibits PI3K that reduces glucose transport
71
Obesity induced inflammation and insulin resistance
-hypertrophied adipocytes in obesity -secrete MCP-1 to acttract macrophages -infiltrated macrophages that differentiate to M1 = insulin resistance
72
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
73
Metformin (biguanide) advantage over sulfonylureas
-rarely cause hypoglycemia -rarely cause weight gain
74
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
75
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
76
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
77
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
78
Metformin effects on blood lipid profile
-dec serum triglycerides -dec serum LDL -reduces risk of adverse CV events
79
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
80
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
81
Thiazolidinedione effect on liver and muscle
-enhance glucose uptake in both -reduces hepatic glucose production
82
Thiazolidinedione drugs
-Rosiglitazone (Avandia) -Pioglitazone (Actos)
83
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
84
PPARy structure and function
slide 117
85
TZD modulation of blood glucose via adipokines
slide 118
86
Factors regulated by PPARy activation
-Resistin (high in type 2) -Adiponectin (low in type 2) -TNFa (high in type 2)
87
Resistin
-stimulate glucose export by liver and insulin resistance -protein from white adipose tissue (WAT) -mRNA levels dec in response to TZD
88
Adiponectin
-reduces blood glucose and insulin resistance -protein from WAT -mRNA levels inc w TZD
89
TNFa
-stimulates lipolysis in WAT -insulin resistance in skeletal muscle -from WAT -mRNA levels decrease w TZDs
90
Drug summary
slide120-121

Therapeutics II (55 decks)

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