Block 1 Lecture 5 -- Incretins, DPP4-I, etc. Flashcards Preview

PHS 933 > Block 1 Lecture 5 -- Incretins, DPP4-I, etc. > Flashcards

Flashcards in Block 1 Lecture 5 -- Incretins, DPP4-I, etc. Deck (71):
1

What is an incretin?

a hormone released from the intestines acting on beta cells

2

What are the 2 incretins

GIP, GLP1

3

GIP

glucose-dependent insulinotropic polypeptide

4

GLP-1

glucagon-like peptide-1

5

What are ADRs of GLP-1 receptor agonists?

1) n/v (decreases with time)
2) weight loss (can be desired)

6

What are C/I's for GLP-1 receptor agonists?

f/h of thyroid cancer

7

Describe the structure of GLP-1.

peptide from preproglucagon precursor

8

half-life of GLP-1?

5 minutes

9

How is GLP-1 metabolized?

inactivated by DPP-4

10

What is DPP-4?

Dipeptidyl peptidase IV

11

What are the GLP-1 based therapies?

1) Exenatide (Byetta)
2) Liraglutaide (Victoza)
3) Albiglutide (Tanzeum)
4) Dulaglutide (Trulicity)

12

Describe the structure of Exenatide.

peptide from salivary gland of gila monster with 53% homology (more potent, not metabolized by DPP-4)

13

Describe the structure of Liraglutide.

97% homology to GLP-1 (more potent).
-- AA subs + FA group
-- avoids DPP-4
-- binds albumin SubQ

14

Describe the structure of Albiglutide.

recombinant GLP-1 dimer fused to albumin
-- AA subs to avoid DPP-4

15

Describe the structure of Dulaglutide.

2 disulfide-linked recombinant GLP-1 analogs fused to human Ig
-- AA subs to avoid DPP-4

16

When are GLP-1 receptor agonists used?

for T2DM...
1) as add-on therapy with metformin, sulfonylurea, TZD
2) as monotherapy after tx failure -- not first line after diet/exercise

17

Other important notes for Exenatide:

-- 6-12% of pts develop Abs
-- C/I if ClCr less than 30

18

How is exenatide supplied?

1) IR: bid before meals
2) ER microsphere: q week

19

What is the half-life of IR exenatide?

3 hours

20

What is the half-life of ER exenatide?

2 weeks

21

How is liraglutide supplied?

only 1: subq once daily without regard to meals

22

What is the only incretin analog without thyroid tumor risk?

IR exenatide

23

What is the half-life of albiglutide's formulation?

5 days

24

How is albiglutide supplied?

only 1: subq q week
-- drug powder + diluent are separate

25

Other important considerations for albiglutide:

1) wait 5-10 mins after mixing powder + diluent
2) anti-drug Ab response in rodents avoided determining thyroid tumor potential

26

How is dulaglutide supplied?

only 1 -- 1 dose q week

27

What is the half-life of dulaglutide's formulation?

5 days

28

What DPP-4 inhibitors are on the market?

1) Sitagliptin (januvia)
2) saxagliptin (onglyza)
3) alogliptin (Nesina)
4) linagliptin (tradjenta)

29

What is DPP-4?

a protease on the surface of endothelial cells and circulating in blood that inactivates GLP-1 and GIP

30

What is alpha-glucosidase?

GI enzyme that breaks down...
-- complex starches
-- oligosaccharides
-- disaccharides

31

What alpha-glucosidase inhibitors are on the market?

1) acarbose (Precose)
2) miglitol (Glyset)

32

What is the MoA of alpha-glucosidase inhibitors?

1) inhibits sucrose --> glucose + fructose
2) delays monosaccharide absorption from small intestine to blunt rise in postprandial glucose

33

What are the ADRs of alpha-glucosidase inhibitors?

flatulence, cramping, diarrhea

34

How to treat a hypoglycemic patient as a result of combo therapy with acarbose?

GIVE GLUCOSE=DEXTROSE (not sucrose)

35

Describe ADME for acarbose.

not absorbed

36

How is miglitol different from acarbose in terms of PK?

1) miglitol is absorbed
2) miglitol is excreted by the kidneys
-- reduce in severe renal failure

37

How are alpha-glucosidase inhibitors adminstered?

orally before meals
(titrate dose to balance glucose with ADRs)

38

When are alpha-glucosidase inhibitors used?

often in recently-diagnosed pts with mild hyperglycemia
-- monotherapy
-- in combo with sulfonylureas

39

What is amylin?

a peptide produced in beta cells that is secreted with insulin

40

What is another name for amylin?

amyloid polypeptide

41

What are the amylin analogs on the market?

Pramlintide (SymlinPen)

42

Describe the structure of Pramlintide.

synthetic amylin analog with AA modifications
-- increases SubQF
-- prevents aggregation

43

What are the effects of amylin/amylin analogs?

bind amylin receptors in brain to...
1) decrease glucagon release
2) delay gastric emptying
3) increase satiety

44

When is Pramlintide used?

for T1/T2DM injected immediately before eating as adjunct to insulin

45

What should you do if an insulin-treated diabetic as also started on pramlintide?

reduce prandial insulin dose by 50% and re-titrate

46

What is bromocriptine?

a semi-synthetic ergot alkaloid derivative that acts in the brain as a DA receptor agonist

47

How does bromocriptine treat hyperglycemia?

not known...
1) may increase DA signaling to decrease cortisol and SNS outflow
2) may reset circadian rhythms altered by obesity

48

For what diseases is bromocriptine usually used?

parkinsons

49

What are the available SGLT2 inhibitors?

canagliflozin (Invokana)
dapagliflozin (Farxiga)
empagliflozin (Jardiance)

50

What is SGLT2?

Sodium-Glucose Co-Transporter 2
-- main site of filtered glucose reabsorption in the kidney

51

What is the MoA for SGLT2 inhibitors?

inhibiting SGLT increases urinary glucose excretion to reduce plasma [glucose]

52

When should SGLT2 inhibitors be avoided?

severe renal impairment
(they have reduced efficacy)

53

What is a major ADR of SGLT2 inhibitors?

UTIs

54

How are DPP-4 inhibitors administered?

once daily without regard to meals

55

What are ADRs of DPP-4 inhibitors?

they are rare...
-- major advantage over GLP-1 receptor agonists

56

What is the MoA of DPP-4 inhibitors?

increase [GIP] and [GLP-1]
-- increase insulin secretion
-- decrease [glucagon]
-- improve fasting and postprandial hyperglycemia

57

What are disadvantages of DPP-4 inhibitors compared to GLP-1 receptor agonists?

1) less effective at insulin production, first-phase response, and glucagon output
2) no effect on satiety, body weight, gastric emptying

58

With what drugs do DPP-4 inhibitors have additive effects?

1) metformin
2) TZDs
3) sulfonylureas
4) insulin

59

With what drugs are DPP-4 inhibitors combined?

1) metformin
2) pioglitazone

60

Why is GIP not a good drug candidate?

-- it increases glucagon release
-- no glucose lowering activity although it is minorly insulinotropic

61

How are incretins secreted?

from gut in response to quantity of nutrients ingested

62

What is the function of incretins?

mediate stimulation of insulin secretion
-- gets it going before peak [glucose]
-- needs basal [glucose] for stimulation

63

Why don't GLP-1 receptor agonists cause hypoglycemia?

incretins require at least a 70mg/dL basal level of insulin for stimulation

64

What are the effects of GLP-1?

1) glucose-dependent insulinotrophy
2) beta-cell proliferation
3) inhibits of glucagon secretion if high [glucose]
4) inhibits gastric motility
5) promotes satiety

65

What is the purpose of reducing gastric motility?

reducing postprandial glucose spike

66

How does GLP-1 promote satiety?

hits some receptors in the brain

67

What should be done if pt started incretin analog in addition to sulfonylurea therapy?

need lower dose of sulfonylureas

68

How do GLP-1 and GIP have effects on the beta cell?

own beta-cell receptor
-- activates adenylyl cyclase to increase cAMP
-- activates PKA
-- PKA amplifies Ca-mediated secretion

69

What is the main MoA for GLP-1's insulinotropic effects?

1) transcription of proinsulin gene for increased insulin synthesis
2) stimulation of secretion (GPCR)

70

What is the basis for GLP-1 receptor agonists' black box warning?

ER forms caused thyroid tumors in rats/mice, although no human evidence

71

What are the restrictions on GLP-1 receptor agonists?

REMS