Block 1 Lecture 3 -- Diabetes III Flashcards by Drew Spargo

What meglitinide analogs are available on the market?

1) repaglinide (Prandin)

2) nateglinide (Starlix)

How well did you know this?

Not at all

Perfectly

describe absorption of meglitinide analogs.

30 minute onset; peak effect in 1 hour

How well did you know this?

Not at all

Perfectly

how should meglitinide analogs be administered?

take 5 min before a meal multiple times a day

How well did you know this?

Not at all

Perfectly

what is the half-life of meglitinide analogs?

1 hour

How well did you know this?

Not at all

Perfectly

What is the MoA of meglitinide analogs?

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

How well did you know this?

Not at all

Perfectly

When are meglitinide analogs most effective?

for isolated postprandial hyperglycemia

- less effective for fasting hyperglycemia
- combined with metformin (not sulfonylureas)

How well did you know this?

Not at all

Perfectly

What is an advantage of meglitinide analogs over other secretagogues?

fewer episodes of hypoglycemia

How well did you know this?

Not at all

Perfectly

What are the first generation sulfonylureas?

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

How well did you know this?

Not at all

Perfectly

Why are 1st gen sulfonylureas no longer used?

long t1/2 = hypoglycemia, interactions

How well did you know this?

Not at all

Perfectly

What are the 2nd gen sulfonylureas?

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

How well did you know this?

Not at all

Perfectly

Describe elimination of sulfonylureas

major hepatic, partial renal

How well did you know this?

Not at all

Perfectly

What are contraindications for sulfonylureas?

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

How well did you know this?

Not at all

Perfectly

What things interact with sulfonylureas?

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

How well did you know this?

Not at all

Perfectly

How does EtOH interact with sulfonylureas?

enhanced action

How well did you know this?

Not at all

Perfectly

How do sulfonamides, clofibrate interact with sulfonylureas?

displace protein bound (99%) sulfonylureas

How well did you know this?

Not at all

Perfectly

How do nonselective beta-blockers interact with sulfonylureas?

mask hypoglycemia Sxs

How well did you know this?

Not at all

Perfectly

How do diuretics, beta-blockers interact with sulfonylureas?

hyperglycemic agents

How well did you know this?

Not at all

Perfectly

What factors of other drugs should trigger an interaction warning?

1) metabolism
2) excretion
3) protein displacement

How well did you know this?

Not at all

Perfectly

What is the MoA of sulfonylureas?

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

How well did you know this?

Not at all

Perfectly

What occurs over time with prolonged admin of sulfonylureas?

1) decreased hepatic gluconeogenesis

2) increased insulin sensitivity via receptor expression/signaling

How well did you know this?

Not at all

Perfectly

What happens with administration greater than 1 year?

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

What happens with long-term administration of sulfonylureas?

progressive beta-cell failure –> hyperglycemia after 1 year

- not due to drug metabolism
- other drugs may reduce failure

Describe comparative efficacy of sulfonylureas

less long-term efficacy vs. metformin/glitazones

What are ADRs of sulfonylureas?

1) hypoglycemia

2) weight gain

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

none...they do not correct this

treatment for IGT/pre-diabetes?

diet

general tx for 0-5 years of T2DM?

diet + metformin

general tx for 5-15 years of T2DM?

combo therapy

general tx for 15+ years of T2DM?

insulin inj.

Agents in the biguanide class:

1) metformin (Glucophage) | - - of historical note: phenformin

What ADRs of metformin?

1) n/v/d, cramps in 20% of pts | 2) BLACK BOX: lactic acidosis

How to deal with GI ADRs of metformin

titrate of weeks | will decrease with time

Why does metformin cause lactic acidosis?

inhibition of gluconeogenesis interferes with hepatic lactate metabolism

MoA of metformin:

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

Why is phenformin no longer on market?

caused more severe lactic acidosis

When is lactic acidosis most likely to occur?

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

When should metformin's dose be adjusted?

when CrCl less than 50

What does IV iodinated contrast media cause?

decreased renal fx

Effects of metformin:

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

What are metformin's advantages over sulfonylureas?

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

How is metformin excreted?

unchanged renally - - secreted via OCT2 - - adjust if concomitant cationic drug

What is OCT2?

Organic cation transporter 2

What is protein-binding quality of metformin?

none in plasma

Dosing of glyburide:

24hr duration = QD or BID

Duration of micronized glyburide:

12 hrs

Duration and t1/2 + dosing of glimepiride:

``` t1/2 = 10 hr duration = 24 hr (QD dosing) ```

t1/2 and duration of glipizide

3 hr; duration = 12 hr

How is glipizide supplied?

conventional and XL

compare F among 2nd gen sulfonylureas:

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

How does glimepiride compare to glyburide?

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

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

glyburide and glimepiride

Which sulfonylureas should be adjusted in hepatic impairment?

all