Block 1 Lecture 4 -- Thiazolidinediones Flashcards Preview

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Flashcards in Block 1 Lecture 4 -- Thiazolidinediones Deck (32):
1

What was the first TZD?

troglitazone

2

What are the currently available TZDs?

rosiglitazone
pioglitazone

3

Why is troglitazone no longer available?

development of rare, idiosyncratic liver toxicity that progressed from hepatic failure to death

4

When was troglitazone removed?

2000

5

What is PPAR-gamma?

peroxisome proliferator-activated receptor-gamma
-- nuclear hormone receptor (transcription factor)

6

What are the endogenous ligands of PPAR-gamma?

oxidized fatty acids

7

Where is PPAR-gamma mainly expressed?

adipose

8

How were TZDs discovered?

during screening for lipid-lowering agents

9

What is the function of PPAR-gamma?

regulate glucose- and lipid-metabolism genes

10

What is PPAR-gamma's effect on insulin resistance?

1) decreased lipolysis --> decreased FFA release
-- fat cell differentiation
-- liver/muscle TG --> SubQ
2) decreased [TNF-alpha] release

11

What is PPAR-gamma's effect on muscle?

increased [GLUT-4]
-- indirect effect...not exposed to high concentrations of FFAs

12

How is pioglitazone different from rosiglitazone?

pioglitazone cross-reacts with PPAR-alpha

13

What are the effects of PPAR-alpha agonism (pioglitazone)?

-- slight decrease in plasma TG
-- slight increase in HDL
-- minor decrease in CV endpoints

14

What is the MoA of TZDs?

synthetic ligands of PPAR-gamma
-- reduce insulin resistance (via lipolysis & TNF; and via GLUT-4 in muscle)

15

What conclusions have been made about rosiglitazone's CV ADRs?

1) no beneficial CV effects
2) no increased risk of MI if combined with metformin or sulfonylurea (vs. metformin OR sulfonylurea)

heart failure, stroke, etc. not addressed

16

What are the ADRs of TZDs?

1) fluid retention, weight gain
2) increased heart failure risk

17

Why don't TZDs produce hypoglycemia?

lower [glucose] only in presence of insulin by improved sensitivity

18

What are contraindications of TZDs?

moderate-severe (NYHA Class III/IV) heart failure

19

Describe the onset of TZDs.

slow onset
-- 1-3 months until max effect
-- longer-lasting effects (years) compared to sulfonylureas

20

Describe the absorption of TZDs.

well-absorbed without regard to food

21

Describe the metabolism of TZDs.

hepatic (CYP2C8)
-- does not affect kinetics of other drugs

22

Why do TZDs carry a heart failure risk?

plasma volume expansion, edema (not macrovascular/atherosclerotic)

23

What restrictions are on TZDs?

none (REMS removed)

24

What does REMS stand for?

Risk Evaluation and Mitigation Strategy

25

Is there a box warning for TZDs?

yes -- heart failure
liver toxicity no longer a boxed warning

26

Quantify the risk for TZDs and heart failure.

chronic use = 2x increase; most often when combined with insulin

27

Why do TZDs cause fluid volume expansion?

PPAR-gamma in kidney has these effects

28

When are TZDs used?

after secondary failure (for patients not controlled by other agents)
-- NOT FIRST LINE

29

Describe the effectiveness of TZDs.

effective in majority of new patients
effective when combined with metformin, sulfonylureas, insulin

30

What testing is recommended for TZDs?

routine liver enzyme tests (recommended by FDA)

31

Why is liver toxicity no longer a labeled warning?

no evidence of liver toxicity with either agent

32

What is the indication for TZDs?

t2dm