Pharmacology of Diabetes

Question 1

What is the primary mechanism of action of metformin?

Answer 1

• activates AMPK in hepatocyte mitochondria, inhibiting ATP production
• blocks glucneogenesis and therefore glucose output
• blocks adenylate cyclase, promoting fat oxidation
  (helps restore insulin sensitivity)

Question 2

What is the drug target of metformin?

Answer 2

5’-AMP-activated protein kinase (AMPK)

in the hepatocyte mitochondria

Question 3

What are the main side effects of metformin?

Answer 3

GI (20-30% of patients)
- abdominal pain
- decreased appetite
- diarrhoea
- vomiting
(common in very high doses, gradual increase in dose over time may increase tolerability)

Question 4

When is metformin the most effective?

Answer 4

in the presence of endogenous insulin

residual beta-cell action is needed

Question 5

What does metformin use to access it’s target?

Answer 5

• highly polar
• requires organic cation transporter-1 (OCT-1)
• therefore accumulates in liver (therapeutic effect), and the GI tract (side effects)

Question 6

What is an example of Dipeptidyl-peptidase 4 (DPP-4) inhibitors?

Answer 6

sitagliptin

Question 7

What is the primary mechanism of action of DPP-4 inhibitors?

Answer 7

• inhibit DPP-4, enzyme in vascular endothelium that metabolises incretins in the plasma

Question 8

What are Incretins?

Answer 8

(eg: GLP-1)
- secreted by enteroendocrine cells
- stimulate the production of insulin when necessary
- reduce the production of glucagon by the liver when not needed
- slow down digestion, decrease appetite

Question 9

What is the drug target of DPP-4 inhibitors?

Answer 9

DPP-4 (in vascular endothelium)

Question 10

What are the main side-effects of DPP-4 inhibitors?

Answer 10

• Upper respiratory infections (5% of patients)
• Flu like symptoms (headache, runny nose, sore throat)
• Serious allergic reactions
• AVOID in patients with PANCREATITIS
• NO weight gain associated

Question 11

When are DPP-4 inhibitors effective?

Answer 11

augmenting insulin secretion and therefore only effective when residual pancreatic beta-cell activity is present

Question 12

What is the primary mechanism of action of Sulphonylurea?

Answer 12

• inhibit the ATP-sensitive potassium channel (KATP) on the pancreatic beta cell
• KATP controls beta cell membrane potential
• Inhibition of KATP causes depolaristaion, stimulating Ca2+ influx and subsequent insulin vesicle exocytosis

Question 13

What is the drug target of Sulphonylurea?

Answer 13

ATP-sensitive potassium channel

in the pancreatic beta cell

Question 14

What are the main side effects of taking Sulphonylureas?

Answer 14

• weight gain

- hypogylcaemia

Question 15

When are Sulphonylureas effective?

Answer 15

They augment insulin secretion and therefore are only effective when residual pancreatic beta-cell activity is present.

Question 16

What is the result of concurrent administration of Sulphonylureas and Metformin?

Answer 16

mitigation of weight gain

Question 17

What is a risk that should be highlighted when Sulphonylureas are administered?

Answer 17

hypoglycaemia, especially when concomitant glucose-lowering drugs are prescribed

Question 18

What is an example of Sulphonylureas?

Answer 18

Gliclazide

Question 19

What is an example of Sodium-Glucose co-transporter (SGLT2) inhibitors?

Answer 19

Dapaglifozin

Question 20

What is the mechanism of action of SGLT2 inhibitors?

Answer 20

• reversibly inhibits sodium-glucose co-transporter 2
  (in the renal proximal convoluted tubule)
• reduces glucose reabsorption and increases urinary glucose excretion

Question 21

What is the drug target of SGLT2 inhibitors?

Answer 21

SGLT2

in the proximal convoluted tubule

Question 22

What are the common side effects of taking SGLT2 inhibitors?

Answer 22

• Uro-genital infections (5% of patients) due to increased glucose load
• slight decrease in bone formation
• can worsen diabetic ketoacidosis (immediately cease treatment)

Question 23

When are SGLT2 inhibitors most effective?

Answer 23

When renal function is normal, is less effective when renal function is impaired

Question 24

What are occasionally side effects of SGLT2 inhibitors?

Answer 24

• weight loss

- reduction in BP

Question 25

What is the risks associated with Pioglitazone?

Answer 25

• greater risk of CVD (heart failure)

Question 26

What should always be considered before prescribed drugs in type 2 diabetes?

Answer 26

Lifestyle

review should be undertaken

Question 27

What are the main things when deciding on which treatment to prescribe?

Answer 27

• identify the problem
• specify the treatment objective
• select drug based on: comparative efficacy, safety, cost and suitability