Block 1 Lecture 3 -- Diabetes III Flashcards
What meglitinide analogs are available on the market?
1) repaglinide (Prandin)
2) nateglinide (Starlix)
describe absorption of meglitinide analogs.
30 minute onset; peak effect in 1 hour
how should meglitinide analogs be administered?
take 5 min before a meal multiple times a day
what is the half-life of meglitinide analogs?
1 hour
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
When are meglitinide analogs most effective?
for isolated postprandial hyperglycemia
- less effective for fasting hyperglycemia
- combined with metformin (not sulfonylureas)
What is an advantage of meglitinide analogs over other secretagogues?
fewer episodes of hypoglycemia
What are the first generation sulfonylureas?
1) tolbutamide (Oranase)
2) tolazamide (Tolinase)
3) chlorpropamide (Diabinese)
Why are 1st gen sulfonylureas no longer used?
long t1/2 = hypoglycemia, interactions
What are the 2nd gen sulfonylureas?
1) glyburide (Micronase, Diabeta)
2) micronized glyburide tablets (Glynase PresTab)
3) Glipizide (Glucotrol, XL)
4) Glimepiride (Amaryl)
Describe elimination of sulfonylureas
major hepatic, partial renal
What are contraindications for sulfonylureas?
1) T1DM
2) pregnancy
3) severe hepatic/renal dysfunction
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 does EtOH interact with sulfonylureas?
enhanced action
How do sulfonamides, clofibrate interact with sulfonylureas?
displace protein bound (99%) sulfonylureas
How do nonselective beta-blockers interact with sulfonylureas?
mask hypoglycemia Sxs
How do diuretics, beta-blockers interact with sulfonylureas?
hyperglycemic agents
What factors of other drugs should trigger an interaction warning?
1) metabolism
2) excretion
3) protein displacement
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
What occurs over time with prolonged admin of sulfonylureas?
1) decreased hepatic gluconeogenesis
2) increased insulin sensitivity via receptor expression/signaling
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
