01-07 PHARM Oral DM Agents

Question 1

Name the 4 big classes of oral DM2 drugs and their site of action.

Answer 1

1. SKM/insulin target tissues: insulin resistance
   —thiazolidinediones (pio-glitazone, Actos)
2. Gut: decreased GLP1 release
   —exenatide (Byetta)
3. Pancreas: islet cell dysfxn
   —sulfonylureas (glyburide, glipizide)
4. Liver: excess glucose release and decr storage
   —Rx: metformin

Question 2

Metformin
—MOA
—Benefits
—ADRs

Answer 2

INDICATION
—first line choice for DM2 pts w/o risk of lactic acidosis

MOA
—not fully understood, thought to result in activation of AMP activated protein kinase.

BENEFITS
—unlikely to cause weight gain or hypoglycemia

ADRs:
—1. Adverse effects are primarily G.I. (nausea, vomiting, diarrhea). minimized by taking the drug w/ food/starting w/ low dose
—2. BLACK BOX In a small percentage of cases, Metformin can cause lactic acidosis especially in pts w/ impaired hepatic or renal function, acute CHF or dehydration, and in alcoholics, since lactic acid clearance might be decreased.

Question 3

Sulfonylureas
—Indication
—Example meds
—MOA
—ADRs

Answer 3

INDICATION
—DM2; adjunct therapy w/ metformin

EXAMPLES
—glyburide, glipizide

MOA
—binds to a receptor that modulates the ATP-sensitive K+ channels in pancreatic β-cells and CLOSES them (as does ↑ [ATP]) → depolarization of the cell as K+ cannot leave → voltage-gated Ca2+ channels let Ca2+ in → more insulin released

ADRs
—Insulin-related: hypoglycemia, weight gain
—Some pts don’t respond (1° failure), others develop resistance over time (2° failure)
—Rare ADRs incl: hemato. or hepatic, CNS (dizziness, confusion), and derm (rash) effects.

Question 4

Thiazolidinediones
—Indication
—Example meds
—MOA
—ADRs

Answer 4

INDICATION
—DM2

EXAMPLES
—pioglitazone (Actos), rosiglitazone (Avandia)

MOA
—sensitize peripheral target tissues to the effects of insulin by binding to the PPAR-RXR (peroxisome proliferation-activated receptor—retinoic acid receptor) transcription factor complex in FAT CELLS and up-regulates transcription of PPAR genes

ADRs
—severe hepatotoxicity in a small but significant # of pts therefore measure LFTs
—also weight gain
—also fluid retention (be careful w/ CHF pts!)

Question 5

Exenatide
—indication
—Example meds
—MOA

Answer 5

INDICATION
—DM2

EXAMPLES
—Byetta

MOA
—Analog of GLP-1 (an incretin)

Question 6

DPP-4 Inhibitors

—FYI

Answer 6

block the enzyme that degrades GLP-1 therefore effectively increase the bioavailability of GLP-1