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PHS 933 > Block 1 Lecture 3 -- Diabetes III > Flashcards

Block 1 Lecture 3 -- Diabetes III Flashcards

1
Q

What meglitinide analogs are available on the market?

A

1) repaglinide (Prandin)

2) nateglinide (Starlix)

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2
Q

describe absorption of meglitinide analogs.

A

30 minute onset; peak effect in 1 hour

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3
Q

how should meglitinide analogs be administered?

A

take 5 min before a meal multiple times a day

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4
Q

what is the half-life of meglitinide analogs?

A

1 hour

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5
Q

What is the MoA of meglitinide analogs?

A

Same as sulfonylureas except quicker and weaker affinity for sulfonylurea receptor

    • much more highly selective for beta KATP, not CV
    • partially restore initial insulin release
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6
Q

When are meglitinide analogs most effective?

A

for isolated postprandial hyperglycemia

    • less effective for fasting hyperglycemia
    • combined with metformin (not sulfonylureas)
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7
Q

What is an advantage of meglitinide analogs over other secretagogues?

A

fewer episodes of hypoglycemia

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8
Q

What are the first generation sulfonylureas?

A

1) tolbutamide (Oranase)
2) tolazamide (Tolinase)
3) chlorpropamide (Diabinese)

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9
Q

Why are 1st gen sulfonylureas no longer used?

A

long t1/2 = hypoglycemia, interactions

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10
Q

What are the 2nd gen sulfonylureas?

A

1) glyburide (Micronase, Diabeta)
2) micronized glyburide tablets (Glynase PresTab)
3) Glipizide (Glucotrol, XL)
4) Glimepiride (Amaryl)

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11
Q

Describe elimination of sulfonylureas

A

major hepatic, partial renal

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12
Q

What are contraindications for sulfonylureas?

A

1) T1DM
2) pregnancy
3) severe hepatic/renal dysfunction

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13
Q

What things interact with sulfonylureas?

A

1) excessive EtOH
- - enhance action
2) sulfonamides, clofibrate, ASA
- - protein displacement
3) nonselective beta-blockers
- - mask hypoglycemia
4) diuretics, beta blockers
- - hyperglycemic agents

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14
Q

How does EtOH interact with sulfonylureas?

A

enhanced action

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15
Q

How do sulfonamides, clofibrate interact with sulfonylureas?

A

displace protein bound (99%) sulfonylureas

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16
Q

How do nonselective beta-blockers interact with sulfonylureas?

A

mask hypoglycemia Sxs

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17
Q

How do diuretics, beta-blockers interact with sulfonylureas?

A

hyperglycemic agents

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18
Q

What factors of other drugs should trigger an interaction warning?

A

1) metabolism
2) excretion
3) protein displacement

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19
Q

What is the MoA of sulfonylureas?

A

bind sulfonylurea receptor (SUR) on beta cells’s ATP-sensitivie K+ channel to inhibit outward flow of K+ and cause depolarization
– does not increase biosynthesis

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20
Q

What occurs over time with prolonged admin of sulfonylureas?

A

1) decreased hepatic gluconeogenesis

2) increased insulin sensitivity via receptor expression/signaling

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21
Q

What happens with administration greater than 1 year?

A

1) downregulation of SURs on beta-cells
- - fasting [insulin] declines to pre-tx levels
2) FPG levels are maintained, though, due to decreased gluconeogenesis

22
Q

What happens with long-term administration of sulfonylureas?

A

progressive beta-cell failure –> hyperglycemia after 1 year

    • not due to drug metabolism
    • other drugs may reduce failure
23
Q

Describe comparative efficacy of sulfonylureas

A

less long-term efficacy vs. metformin/glitazones

24
Q

What are ADRs of sulfonylureas?

A

1) hypoglycemia

2) weight gain

25
Q

What effect do sulfonylureas have on first-phase insulin secretion?

A

none…they do not correct this

26
Q

treatment for IGT/pre-diabetes?

A

diet

27
Q

general tx for 0-5 years of T2DM?

A

diet + metformin

28
Q

general tx for 5-15 years of T2DM?

A

combo therapy

29
Q

general tx for 15+ years of T2DM?

A

insulin inj.

30
Q

Agents in the biguanide class:

A

1) metformin (Glucophage)

- - of historical note: phenformin

31
Q

What ADRs of metformin?

A

1) n/v/d, cramps in 20% of pts

2) BLACK BOX: lactic acidosis

32
Q

How to deal with GI ADRs of metformin

A

titrate of weeks

will decrease with time

33
Q

Why does metformin cause lactic acidosis?

A

inhibition of gluconeogenesis interferes with hepatic lactate metabolism

34
Q

MoA of metformin:

A

increases activity of AMP-dependent PK (AMPK)
– increases AMP: inhibits gluconeogenic enzymes, decreases cholesterol synthesis, increases FA oxidation, increases glucose uptake

35
Q

Why is phenformin no longer on market?

A

caused more severe lactic acidosis

36
Q

When is lactic acidosis most likely to occur?

A

1) renal failure (decreased clearance of lactate and metformin)
2) alcoholism (NAD depletion so LDH can’t work)
3) tissue anoxia (cardiopulmonary dysfunction)

37
Q

When should metformin’s dose be adjusted?

A

when CrCl less than 50

38
Q

What does IV iodinated contrast media cause?

A

decreased renal fx

39
Q

Effects of metformin:

A

1) decreased gluconeogenesis
2) increased skeletal muscle glucose uptake
3) decreased intestinal glucose absorption

40
Q

What are metformin’s advantages over sulfonylureas?

A

1) no increase in insulin (less hypoglycemia)
2) effective for 2-5 yrs
3) positive TG, cholesterol changes
4) no weight gain
5) delays progression

41
Q

How is metformin excreted?

A

unchanged renally

    • secreted via OCT2
    • adjust if concomitant cationic drug
42
Q

What is OCT2?

A

Organic cation transporter 2

43
Q

What is protein-binding quality of metformin?

A

none in plasma

44
Q

Dosing of glyburide:

A

24hr duration = QD or BID

45
Q

Duration of micronized glyburide:

A

12 hrs

46
Q

Duration and t1/2 + dosing of glimepiride:

A 
t1/2 = 10 hr
duration = 24 hr (QD dosing)
47
Q

t1/2 and duration of glipizide

A

3 hr; duration = 12 hr

48
Q

How is glipizide supplied?

A

conventional and XL

49
Q

compare F among 2nd gen sulfonylureas:

A

1) glyburide: poor/variable
2) micronized glyburide: quick/consistent
3) glipizide: rapid/consistent
4) glimepiride: quick/consistent

50
Q

How does glimepiride compare to glyburide?

A

equivalent clinically…
glimepiride = lower insulin/C-peptide
glimepiride = increased glucose uptake

51
Q

What sulfonylureas should be used with caution in renal impairment (hypoglycemia)?

A

glyburide and glimepiride

52
Q

Which sulfonylureas should be adjusted in hepatic impairment?

A

all

PHS 933 (14 decks)

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