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 function is needed

Question 5

What does metformin use to access it’s target?

Answer 5

• highly polar - charged even in the most alkaline tissue
• requires organic cation transporter-1 (OCT-1)

Question 6

Where is OCT-1 expressed in the body?

Answer 6

• enterocytes in small bowel which allow metformin to be absorbed
• hepatocytes in the liver which allow it to be distributed to sites of action
• proximal tubules in the kidney which allow it to be excreted

Question 7

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

Answer 7

sitagliptin

Question 8

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

Answer 8

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

Question 9

What are Incretins?

Answer 9

(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 10

What is the drug target of DPP-4 inhibitors?

Answer 10

DPP-4 (in vascular endothelium)

Question 11

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

Answer 11

• Upper respiratory infections (5% of patients)
• Flu like symptoms (headache, runny nose, sore throat)
• Serious allergic reactions
• AVOID in patients with PANCREATITIS
• doesn’t cause weight gain

Question 12

When are DPP-4 inhibitors effective?

Answer 12

• when some residual beta cell function is present
• work by augumenting insulin

Question 13

What is the primary mechanism of action of Sulphonylurea?

Answer 13

• 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 14

What is the drug target of Sulphonylurea?

Answer 14

ATP-sensitive potassium channel in the pancreatic beta cell

Question 15

What are the main side effects of taking Sulphonylureas?

Answer 15

• weight gain
• hypogylcaemia

Question 16

When are Sulphonylureas effective?

Answer 16

• when some residual beta cell function is present
• work by augumenting insulin

Question 17

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

Answer 17

mitigation of weight gain

Question 18

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

Answer 18

hypoglycaemia, especially when other glucose-lowering drugs are prescribed

Question 19

What is an example of Sulphonylureas?

Answer 19

Gliclazide

Question 20

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

Answer 20

Dapaglifozin

Question 21

What is the mechanism of action of SGLT2 inhibitors?

Answer 21

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

Question 22

What is the drug target of SGLT2 inhibitors?

Answer 22

SGLT2 in the proximal convoluted tubule

Question 23

What are the common side effects of taking SGLT2 inhibitors?

Answer 23

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

Question 24

When are SGLT2 inhibitors most effective?

Answer 24

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

Question 25

Why might patients on SGLT-2 inhibitors not know that they are in diabetic ketoacidosis?

Answer 25

• DKA can occur at normal glucose levels
• early warning sign of rising glucose is slow or compeletely lost

Question 26

What is the risks associated with Pioglitazone?

Answer 26

• greater risk of CVD (heart failure)

Question 27

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

Answer 27

• lifestyle
• more effective in reducing fasting glucose and blood glucose than metformin
• review should be undertaken

Question 28

What are the three lines of treatment for type 2 diabetes after lifestyle intervention?

Answer 28

1. HbA1c 48mmol/mol = metformin
2. First intensification of HbA1c 58mmol/mol = dual therapy of metformin and one other drug
3. Second intensification = triple therapy or insulin based treatment

Question 29

What is the goal HbA1c level after a diabetes intensification of 58mmol/mol

Answer 29

53mmol/mol

Question 30

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

Answer 30

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

Question 31

How do you change treatment for diabetes patients who develop CKD?

Answer 31

Question 32

What are patients with CKD on metformin at risk of?

Answer 32

Lactic acidosis