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therapeutics 2 > exam 2: antidiabetic drugs > Flashcards

exam 2: antidiabetic drugs Flashcards

1
Q

agents that enhance insulin secretion

A
  • sulfonylureas
  • meglitinides
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2
Q

sulfonylureas
products

A
  • tolbutamide
  • tolazamide
  • chlorpropamide
  • glyburide
  • glipizide
  • glimepiride
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3
Q

sulfonylureas
mechanism of action

A
  1. binds to sulfonylurea receptors
  2. inactivates K+ channel
  3. decreased cell polarization
  4. activates voltage sensitive Ca2+ channels
  5. increase intracellular Ca2+ and activity of microfilaments
  6. increased exocytosis of insulin containing granules
  • must have functioning beta cells
  • increased release of insulin
  • may restore beta cell sensitivity to glucose and increase glucose stimulated insulin release
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4
Q

tolbutamide

A

1st generation sulfonylurea
(Orinase)
- potency: 1
- duration: 6-12h

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5
Q

tolazamide

A

1st generation sulfonylurea
(Tolinase)
- potency: 5
- duration: 12-14h

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6
Q

chlorpropamide

A

1st generation sulfonylurea
(Diabinese)
- potency: 6
- duration 24-72h

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7
Q

glipizide

A

2nd generation sulfonylurea
(Glucotrol)
- potency: 100
- duration: 12-24h

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8
Q

glyburide

A

2nd generation sulfonylurea
(DiaBeta)
- potency: 150
- duration: 24h

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9
Q

glimepiride

A

2nd generation sulfonylurea
(Amaryl)
- potency: 150
- duration: 24h

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10
Q

sulfonylureas
drug interactions that increase risk of hypoglycemia

A

displacement of sulfonylureas from plasma protein binding
- salicylates
- phenylbutazone
- sulfonamides
- clofibrate
- alcohol

phenylbutazone, sulfonamides, and clofibrate may also decrease metabolism of sulfonylureas by liver

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11
Q

sulfonylureas
adverse effects

A
  • lasting and prolonged hypoglycemia due to long half life -> has been misdiagnosed as stroke and led to permanent neurological damage and death in elderly
  • risk of CV events
  • GI problems
  • weight gain
  • increased numbers of secondary failures
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12
Q

sulfonylureas
drug interactions that cause hyperglycemia

A

opposes action of sulfonylureas and insulin therapy
- oral contraceptives
- corticosteroids
- epinephrine
- thyroid medications
- thiazide diuretics

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13
Q

meglitinides
products

A
  • repaglinide
  • nateglinide
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14
Q

repaglinide

A

meglitinide
(Prandin)
- non-sulfonylurea hypoglycemic agent
- mechanism of action similar to sulfonylureas
- quick onset, short duration
- PO preprandial

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15
Q

nateglinide

A

meglitinide
(Starlix)
- non-sulfonylurea KATP channel blocker
- pancreas and CV tissue
- shorter half life than repaglinide
- less risk of hypoglycemia
- synergistic with metformin

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16
Q

agents that enhance the incretin effect

A
  • GLP-1R agonists
  • GLP-1 and GIP dual agonist
  • DPP-IV inhibitors
  • amylin analogs
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17
Q

incretin effect

A

oral glucose stimulates a larger insulin response than IV glucose
- GIP secreted from duodenal K cells and GLP-1 secreted from ileal L cells
- cAMP pathway: postprandial blood glucose elevation leads to increase in insulin secretion
- ERK1/2 pathway: pancreatic b-cell stimulation leads to increase in beta-cell proliferation and protection from apoptosis

*diminished in T2DM

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18
Q

GLP-1R agonists
products

A
  • exenatide
  • liraglutide
  • lixenatide
  • dulaglutide
  • semaglutide
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19
Q

exenatide

A

GLP-1R agonist
(Exendin 4; Byetta)
- 39aa peptide
- enhances first phase secretion
- SC twice daily or once weekly
- co-administered with metformin, thiazolidinediones, or sulfonylureas

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20
Q

liraglutide

A

GLP-1R agonist
(Victoza)
- hGLP-1 aa7-37
- SC daily
- can be co-administered with metformin, thiazolidinediones, or sulfonylureas

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21
Q

dulaglutide

A

GLP-1R agonist
(Trulicity)
- peptides slowly released from IgG Fc domain by reduction of disulfide bonds in linker region
- SC once weekly

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22
Q

lixisenatide

A

GLP-1R agonist
(Adlyxin)
- 44aa peptide
- SC daily

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23
Q

semaglutide

A

GLP-1R agonist
(Ozempic)
- 31aa peptide
- extensively bound to serum albumin
- SC once weekly

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24
Q

GLP-1R agonists
adverse effects

A
  • nausea/vomiting
  • pancreatitis
  • risk of thyroid c-cell tumors
  • contraindicated in patients with a family history of medullary thyroid cancer
  • not contraindicated in liraglutide; monitor calcitonin levels
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25
Q

PO semaglutide

A

GLP-1R agonist
(Rybelsus)
- oral bioavailability: 0.4-1%
- absorbed from stomach
- PO once daily

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26
Q

basal insulin/GLP-1R agonist combinations

A

Soliqua
- 100U glargine + 33mcg lixisenatide/mL
- max daily dose: 60U/20mcg

Xultophy
- 100U degludec + 3.6mg liraglutide/mL
- max daily dose: 50U/1.8mg

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27
Q

GLP-1 and GIP dual agonist
products

A

tirzepatide

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28
Q

tirzepatide

A

GLP-1 and GIP dual agonist
(Mounjaro)
- full GIP receptor agonist
- biased GLP-1 receptor
- preferential coupling to cAMP over beta-arrestin
- reduces internalization (desensitization) of GLP-1 receptor to maintain GLP-1 effect
- purported to reduce A1c and body weight more effectively than GLP-1R agonists
- SC weekly

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29
Q

DDP-IV inhibitors
mechanism of action

A

inhibits incretin proteolysis
- enhances actions of endogenous GLP-1

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30
Q

DDP-IV inhibitors
products

A
  • sitagliptin
  • saxagliptin
  • linagliptin
  • alogliptin
31
Q

DDP-IV inhibitors
characteristics

A
  • reduces hyperglycemia and HbgA1c
  • low risk of hypoglycemia
  • considered weight neutral
  • may be co-administered with metformin and thiazolidinediones
  • PO once daily
32
Q

sitagliptin

A

DDP-IV inhibitor
(Januvia)
- not extensively metabolized
- excreted in urine (kidney)

33
Q

saxagliptin

A

DDP-IV inhibitor
(Onglyza)
- CYP3A4/5 substrate
- major metabolite is active
- excreted in urine (kidney)

34
Q

linagliptin

A

DDP-IV inhibitor
(Tradjenta)
- not extensively metabolized
- excreted in feces (liver)

35
Q

alogliptin

A

DDP-IV inhibitor
(Nesina)
- not extensively metabolized
- excreted in urine (kidney)

36
Q

DDP-IV inhibitors
adverse effects

A
  • nausea/vomiting
  • constipation
  • headache
  • severe skin reactions
  • pancreatitis
  • joint pain
  • heart failure
  • reduced white blood cell counts, which may lead to infections
  • potential increased risk of cancers
37
Q

amylin analogs
products

A

pramlintide

38
Q

pramlintide

A

amylin analog
(Symlin)
- 37aa peptide normally co-secreted with insulin
- slows gastric emptying, decreases food intake, inhibits glucagon secretion
- blunts postprandial rise in blood glucose
- used in conjuction with insulin
- SC injection
- useful in both T1DM and T2DM

39
Q

agents that reduce glucose absorption or increase glucose excretion

A
  • a-glucosidase inhibitors
  • SGLT2 inhibitors
40
Q

a-glucosidase inhibitors
mechanism of action

A

decreases absorption of carbohydrate from intestine via inhibition of gut a-glucosidases (sucrase, maltase, glucoamylase)
- PO with meals

41
Q

a-glucosidase inhibitors
adverse effects

A

GI: diarrhea, nausea, flatulence

42
Q

a-glucosidase inhibitors
products

A
  • acarbose
  • miglitol
43
Q

acarbose

A

a-glucosidase inhibitor
(Precose)
- minimally absorbed
- risk of liver damage at doses >100mg TID

44
Q

miglitol

A

a-glucosidase inhibitor
(Glyset)
- completely absorbed

45
Q

SGLT2 inhibitors
mechanism of action

A
  • decreases threshold for glucose excretion in urine
  • reduces blood glucose levels
  • decreases A1c as monotherapy and with metformin & sulfonylureas
  • significant weight loss observed with monotherapy
46
Q

SGLT2 inhibitors
characteristics

A
  • indicated for T2DM as an adjunct to diet and exercise
  • not used in T1DM due to increased risk of ketoacidosis
47
Q

SGLT2 inhibitors
adverse effects

A
  • increased risk of genital/UT infections
  • increased urine flow/volume depletion/hypotension
  • increased risk of diabetic ketoacidosis
  • contraindicated in pts with renal impairment (eGPF < 30mL/min/1.73m2)
  • increased risk of lower limb amputation
48
Q

SGLT2 inhibitors
products

A
  • canagliflozin
  • empagliflozin
  • dapagliflozin
  • ertugliflozin
  • bexagliflozin
49
Q

canagliflozin

A

SGLT2 inhibitor
(Invokana)
100, 300mg daily

50
Q

empagliflozin

A

SGLT2 inhibitor
(Jardiance)
10, 25mg daily

51
Q

dapagliflozin

A

SGLT2 inhibitor
(Farxiga)
5, 10mg daily

52
Q

ertugliflozin

A

SGLT2 inhibitor
(Steglatro)
5, 10mg daily

53
Q

bexagliflozin

A

SGLT2 inhibitor
(Benzavvy)
20mg daily

54
Q

agents that reduce insulin resistance/lipotoxicity

A
  • biguanides
  • thiazoladediones
55
Q

insulin resistance

A

decreased responsiveness to insulin
- OGTT with prolonged elevation of plasma glucose with normal or elevated insulin levels

56
Q

insulin resistance causes

A
  • polymorphisms in insulin signaling pathway proteins
  • obesity, especially accumulation of fat in abdominal cavity
  • inactivity
57
Q

insulin resistance in skeletal muscle

A

impaired glucose uptake

58
Q

insulin resistance in adipose tissue

A
  • impaired glucose uptake
  • impaired inhibition of lipolysis
  • mobilization of fatty acids to other tissues
59
Q

insulin resistance in liver

A

impaired inhibition of glucose output via gluconeogenesis or glycogenolysis

60
Q

role of fatty acids in obesity-induced insulin resistance

A
  • free fatty acid levels increased in obese people
  • acute increased FFA levels causes insulin resistance
  • acute decreased plasma FFA levels reduces chronic insulin resistance

*predominant effect is on insulin-stimulated glucose transport

61
Q

biguanides
products

A

metformin

62
Q

metformin

A

biguanide
(Glucophage)
- antihyperglycemic agent
- decreases blood glucose concentrations in T2DM without concentration falling below normal
- lower risk for lactic acidosis
- rarely causes hypoglycemia or weight gain
- 500-850mg BID/TID before meals
- may be used in combination with sulfonylureas

63
Q

biguanides
mechanism of action

A

activator of AMP-activated kinase (AMPK)
- increases efficiency or sensitivity to insulin in liver, fat, muscle cells
- decreased gluconeogenesis in liver
- increased glycolysis and glucose uptake in muscle and fat cells

64
Q

metformin action in skeletal muscle

A
  • AMP accumulates during exercise and activates AMPK
  • AMPK phosphorylates TBC1D1/4, which promotes GTPase activity of Rab
  • Rab dissociates from GLUT4, allowing translocation
65
Q

metformin
adverse effects

A
  • contraindicated in disorders that increase tendency toward lactic acidosis
  • decreased vitamin B12 absorption
  • decreased serum triglycerides and LDL levels
  • reduces risk of adverse CV events
  • nausea/vomiting/diarrhea
66
Q

thiazolidinediones
mechanism of action

A

activators of peroxisome proliferator-activated receptor gamma (PPARg)
- decreases insulin resistance or improves target cell response to insulin
- decreases differentiation of mesenchymal stem cells into osteoblasts
- mainly targets adipocytes

67
Q

thiazolidinediones in adipocytes

A
  • enhances adipocyte differentiation
  • enhances FFA uptake into SC fat
  • reduces serum FFA
  • shifts lipids into fat cells from non-fat cells
68
Q

thiazolidinediones in liver

A
  • enhances glucose uptake
  • reduces hepatic glucose production
69
Q

thiazolidinediones in skeletal muscle

A

enhances glucose uptake

70
Q

thiazolidinediones
products

A
  • rosiglitazone
  • pioglitazone
71
Q

rosiglitazone

A

thiazolidinedione
(Avandia)
- 4-8mg once daily

72
Q

piogliazone

A

thiazolidinedione
(Actos)
- 15-30mg once daily
- associated with increased risk of bladder cancer

73
Q

thiazolidinediones
adverse effects

A
  • restricted prescribing due to CV toxicities
  • some hepatotoxicity (check liver function)
  • contraindicated in NYHA class III or IV heart failure
74
Q

factors regulated by activation of PPARg

A

resistin
- elevated in T2DM
- mRNA levels decrease

adiponectin
- decreased in T2DM
- mRNA levels increase

TNFa
- increased in T2DM
- mRNA levels decrease

therapeutics 2 (8 decks)

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