Pharm for Hypoglycemia in T2DM: Cook

Question 1

Discuss the differences in sulfonylureas and meglitinides.

Answer 1

Sulfonylureas act by increasing insulin secretion by the B cells of the pancreas and by enhancing insulin’s effect on target tissue glu uptake.

Meglitinides act also by increasing insulin secretion but act on different receptors.
Short half-life. Taken before each meal to control post-prandial glucose levels. Met. by liver.
SFX: hypoglycemia and weight gain

Examples:
Repa(glinide)
Nate(glinide)
Miti(glinide)

Question 2

Explain the effects of metformin and limitations to its use.

Answer 2

Metformin decreases hepatic gluconeogenesis (glucophage)

Some pts are intolerant to it (d/n/v)

Question 3

Discuss the role of thiazolidinediones as “insulin sensitizers”

Answer 3

Bind specifically to PPARgamma.
This sensitizes cells to insulin (incr. glu uptake and oxidation by musc and adipose)
Decrease adipose tissue lipolysis and FA mobilization. Promotes FFA uptake and storage in adipose.

Examples:
Rosiglitazone [black box warning for CV issues]
Pioglitazone (only one used anymore)

Question 4

Explain the MOA of a-glucosidase inhibitors

Answer 4

Reduce intestinal absorption of starch and disaccharides by inhibiting brush border a-glucosidase.
Reducing uptake of carbs and post-prandial glu rise.
Used in combination w/ other hypoglycemic drugs and insulin.
Don’t actually work very well
Ex:
Acarbos
Miglitol

Question 5

Discuss the actions and therapeutic uses of somatostatin

Answer 5

Inhibits release of GH and TSH from ant. pituitary. Inhibits release of insulin and glucagon from pancreas.
Useful for tx of insulinomas and glucagonomas.
Short half-life
Ex: octreotide

Question 6

Explain the inhibition of insulin release by diazoxide

Answer 6

Inhibits insulin secretion, but not synthesis (builds up in B cells)
Used to tx various forms of hypoglycemia and inoperable insulinomas

Question 7

Discuss different mechanisms of incretins and incretin-related hypoglycemic drugs.

Answer 7

Incretins (GLP-1 and GIP) increase secretion of insulin.
GLP-1 increases glucose dependent insulin secretion.
GLP-1 inhibits glucagon stimulated glycogenolysis in the liver.
Slows gastric emptying. Decr. appetite. Decr. glucagon secretion.
All decreasing post-prandial blood glucose.

Ex:
Exenatide- more potent than GLP-1
-Thought to actually incr. number of B cells (in mice)

No GIP analogs bc of association w/ weight gain.

Sitagliptin phosphate (Januvia)- inhibits the inhibitor (DPP-4) of incretins
-prescribed off-label as weight loss drug, antiobesity

Both only used for T2DM. Not used as monotherapy, used w/ insulin and/or metformin.

Question 8

Describe the actions of the peptide amylin and discuss related drugs.

Answer 8

Amylin is normally secreted alongside insulin by B cells.
In pts w/ T1DM, neither insulin or amylin is produced.
Amylin analogs slow gastric emptying, promote satiety, and inhibit inappropriate secretion of glucagon.
Pramlintine is used to tx T1DM and T2DM. It reduces insulin dose requirements and reduces post-prandial glu levels.

Question 9

Discuss the mechanism for SGLT2 inhibitors and indicate the important contraindications for prescribing them.

Answer 9

Sodium-dependent glucose transporters of the second kind, as they are referred to by scientists, are found in the PCT of the nephron. They are responsible for reabsorption of glu (and Na). Normally, 100% of glu is reabsorbed. But in pts with T1DM, some gets out anyways (hence, sweet urine). It is a method of dripping blood glucose by increasing excretion (NOT SECRETION).

Also result in incr. energy expenditure trying to make more glu, since you are losing more of it in the urine.

Ex:
Cinagliflozin THINK: “let the glucose flo(w)!”
SFX: HTN, hyperK+, hypoglycemia, Incr. LDL
Contraindications:
Severe renal impairment (duh)
End stage renal dz (duh)
Pts on dialysis

Question 10

Describe the MOA of sulfonylureas

Answer 10

Sulfonylurea blocks the potassium channel in the cell membrane of Beta cells of the pancreas, inhibiting hyperpolarizing efflux of K+, thus causing the net charge across the membrane to be positive, resulting in depolarization and an influx of Ca2+ into the Beta cell that triggers the release of insulin. Thus, sulfonylurea INCREASES secretion of insulin from Beta cells.

• ALSO, enhance effects of insulin on target tissues, increasing glucose uptake by tissues. *
• This is NOT a long term solution to diabetes. Long-term, may decrease insulin metabolism by liver.

Examples:
1st Gen: Chlorpropamide (long half-life)

2nd Gens: - more potent
Glyburide most often used
Glipizide
Glimepiride

Contraindicated:
DON’T TAKE NSAIDs- severe hypoglycemia due to enhanced sulfonylurea action