April 20, 2016 - Pharmacology of OHA's

Question 1

Alpha-Glucosidase Inhibitors

Answer 1

Acts on the GI tract

Act as competitive inhibitors of intestinal brush border alpha-glucosidases. These are potent inhibitors of glucoamylase, alpha-amylase, and sucrase.

This delays carbohydrate absorption and reduces the post-prandial glycemic excursion by 30-50%.

However, the carbohydrates go into your large bowel where they are fermented by bacteria and create a lot of flatulence, diarrhea, and bloating.

Question 2

Metformin

Answer 2

Biguanide class

Acts on adipose tissue, muscle tissue, and liver.

Reduces hepatic glucose output and improves insulin resistance (although the cellular mechanisms are unclear)

First-line treatment for DM2

Take with food to avoid GI upset (the main side effect)

Question 3

Thiazolidinediones (TZDs)

Answer 3

Acts on adipose tissue, muscle tissue, and liver.

Acts as a transcription agonist which increases the activation of genes involved in lipid and carbohydrate metabolism, which increases insulin sensitivity.

Lowers HbA1C by 1.0-1.5%

Adverse effects are fluid retention, edema, and weight gain (especially not good for diabetics), and higher risk of MI and death. They also cost a lot of money.

Question 4

Insulin Secretagogues

Answer 4

Acts on the pancreas.

Include sulphonylureas, meglitinides, and incretins.

Reduce HbA1C by 1.0-1.5%

Question 5

Incretins

Answer 5

Are GLP-1 agonists and DPP-IV inhibitors.

GLP-1 stimulates insulin when glucose is eaten orally, and DPP-IV breaks down GLP-1 afterwards (so inhibiting it allows GLP-1 to work longer).

Oral glucose provokes higher insulin response with equivalent dose given IV due to the release of gut hormones (princiapply GLP-1). This “incretin effect” is reduced in patients with DM2.

The nice thing about these secretagogues is that insulin is secreted in a glucose-dependant manner which reduces the risk of hypoglycemia.

Adverse effects include nausea and vomiting, acute pancreatitis, UTRI, and the long-term safety data is not known. Also expensive.

Question 6

SGLT2 Inhibitors

Answer 6

Sodium-GLucose coTransporter 2

Acts on the kidneys

The new kid on the block. SGLTs are glucose transporters that drive glucose reabsorption in the renal tubule. SGLT2 is only in the kidney and is reponsible for renal glucose reabsorption. By inhibiting these transporters, the drug acts as a “glucoretic” and the patient will pee out glucose (250-400 calories per day).

Lowers HbA1C by 0.5-0.75%, weight loss, lowers blood pressure (through volume depletion), raises HDL (but also raises LDL), and is an oral tablet. Also demonstrates a mortality benefit in a high-risk population.

Side effects include genitourinary infections, hypotension, and a modest raise in LDL.

Question 7

Progression of DM2

Answer 7

1. Lifestyle intervention
2. OHA
3. OHA 1 + 2
4. OHA 1 + 2 + 3
5. Insulin