Pharmacology of Diabetes

Question 1

What is the primary effect of Metformin?

Answer 1

Metformin activates AMPK in hepatocyte mitochondria. This inhibits ATP production. This blocks gluconeogenesis and subsequent glucose output. It also blocks adenylate cyclase which promotes fat oxidation. Both help to restore insulin sensitivity.

Question 2

What does AMPK stand for?

Answer 2

5′-AMP-activated protein kinase

Question 3

What is the Primary site for Metformin?

Answer 3

The primary site of metformin action is the hepatocyte mitochondria

Question 4

What are the main side effects of Metformin?

Answer 4

GI side effects (20-30% of patients)

e.g. Abdominal pain, decreased appetite, diarrhoea, vomiting)



Question 5

What Increases Metformin’s side effects?

Answer 5

When very high doses are given. A slow increase in dose may improve tolerability.

Question 6

Why can Metformin accumulate in the Liver and GI tract?

Answer 6

Metformin is highly polar and requires organic cation transporter-1 (OCT-1) to access tissues. This explains why it can accumulate in the liver (therapeutic effect) and gastrointestinal tract (side effects)

Question 7

When is Metformin most effective?

Answer 7

Metformin is most effective in the presence of endogenous insulin, so is most effective with some residual functioning pancreatic islet cells

Question 8

What type of drug is Sitagliptin?

Answer 8

Dipeptidyl-peptidase 4 (DPP-4) inhibitors



Question 9

What is the primary effect of Sitagliptin?

Answer 9

Work by inhibiting the action of DPP-4. This enzyme is present in vascular endothelium and can metabolize incretins in the plasma.

Question 10

What are Incretins?

Answer 10

Incretins (e.g. GLP-1) are secreted by enteroendocrine cells and help stimulate the production of insulin when it is needed (e.g. after eating) and reduce the production of glucagon by the liver when it is not needed (e.g. during digestion). Incretins also slow down digestion and decrease appetite.



Question 11

What is the primary target of Sitagliptin?

Answer 11

DPP4, vascular endothelium

Question 12

What are the main side effects of Sitagliptin?

Answer 12

Upper respiratory tract infections (5% of patients) Flu-like symptoms e.g. headache, runny nose, sore throat

Less common but serious:

Serious allergic reactions/ avoid in patients with pancreatitis



Question 13

What is a benefit of using Sitagliptin?

Answer 13

Compared to other anti-diabetic drugs (although not metformin) these drugs do not appear to cause weight gain.

Question 14

What makes Sitagliptin more effective?

Answer 14

DPP-4 I’s act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present.

Question 15

What type of drug is Gliclazide?

Answer 15

Sulphonylurea

Question 16

What is the primary effect of Gliclazide?

Answer 16

Inhibit the ATP-sensitive potassium (KATP) channel on the pancreatic beta cell. This channel controls beta cell membrane potential. Inhibition causes depolarization, which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis.



Question 17

What is the primary target of Gliclazide?

Answer 17

ATP-sensitive potassium channel



The primary site of SUs inhibitor action is the pancreatic beta cell



Question 18

What are the main side effects of Gliclazide?

Answer 18

Weight gain is a likely side effect

Hypoglycaemia (2nd most common)



Question 19

How can you mitigate weight gain risk when using Gliclazide?

Answer 19

Weight gain is mitigated by the concurrent administration with metformin.



Question 20

What must be discussed with the patient prior to Gliclazide prescription?

Answer 20

The risk of hypoglycaemia associated with sulfonylureas should be discussed with the patient, especially when concomitant glucose-lowering drugs are prescribed.

Question 21

What type of drug is Dapaglifozin?

Answer 21

Sodium-glucose co-transporter (SGLT2) inhibitors



Question 22

What is the primary effect of Dapaglifozin?

Answer 22

Reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.



Question 23

What is the primary target of Dapaglifozin?

Answer 23

SGLT2



The primary site of SGLT2 inhibitor action is the proximal convoluted tubule

Question 24

What are the main side effects of Dapaglifozin?

Answer 24

Uro-genital infections due to increased glucose load (5% of patients)

Slight decrease in bone formation



Can worsen diabetic ketoacidosis (stop immediately)

Question 25

What are some possible positive side effects of SGLT2 inhibitors?

Answer 25

SGLT2 inhibitors cause weight loss and a reduction in BP



Question 26

In which type of patients are SGLT2 inhibitors less effective in?

Answer 26

SGLT2i action depends on normal renal fucntion so they are less effective in patients with renal impairment