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

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

1
Q

What is an incretin?

A

a hormone released from the intestines acting on beta cells

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2
Q

What are the 2 incretins

A

GIP, GLP1

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3
Q

GIP

A

glucose-dependent insulinotropic polypeptide

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4
Q

GLP-1

A

glucagon-like peptide-1

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5
Q

What are ADRs of GLP-1 receptor agonists?

A

1) n/v (decreases with time)

2) weight loss (can be desired)

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6
Q

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

A

f/h of thyroid cancer

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7
Q

Describe the structure of GLP-1.

A

peptide from preproglucagon precursor

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8
Q

half-life of GLP-1?

A

5 minutes

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9
Q

How is GLP-1 metabolized?

A

inactivated by DPP-4

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10
Q

What is DPP-4?

A

Dipeptidyl peptidase IV

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11
Q

What are the GLP-1 based therapies?

A

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

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12
Q

Describe the structure of Exenatide.

A

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

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13
Q

Describe the structure of Liraglutide.

A

97% homology to GLP-1 (more potent).

    • AA subs + FA group
    • avoids DPP-4
    • binds albumin SubQ
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14
Q

Describe the structure of Albiglutide.

A

recombinant GLP-1 dimer fused to albumin

– AA subs to avoid DPP-4

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15
Q

Describe the structure of Dulaglutide.

A

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

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16
Q

When are GLP-1 receptor agonists used?

A

for T2DM…

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

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17
Q

Other important notes for Exenatide:

A
    • 6-12% of pts develop Abs

- - C/I if ClCr less than 30

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18
Q

How is exenatide supplied?

A

1) IR: bid before meals

2) ER microsphere: q week

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19
Q

What is the half-life of IR exenatide?

A

3 hours

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20
Q

What is the half-life of ER exenatide?

A

2 weeks

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21
Q

How is liraglutide supplied?

A

only 1: subq once daily without regard to meals

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22
Q

What is the only incretin analog without thyroid tumor risk?

A

IR exenatide

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23
Q

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

A

5 days

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24
Q

How is albiglutide supplied?

A

only 1: subq q week

– drug powder + diluent are separate

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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

PHS 933 (14 decks)

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