Diabetes Core Drugs

Question 1

What is the primary mechanism of metformin?

Answer 1

1. Primary effect – metformin activates AMPK in hepatocyte mitochondria
2. This inhibits ATP production
3. This blocks gluconeogenesis and subsequent glucose output
4. Also blocks adenylate cyclase which promotes fat oxidation
5. Both help to restore insulin sensitivity

Question 2

What is the target of metformin and primary site of action?

Answer 2

1. 5′-AMP-activated protein kinase (AMPK)

2. Primary site of metformin action is the hepatocyte mitochondria

Question 3

What are the main side effects of metformin?

Answer 3

GI side effects (20-30% of patients)

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

Question 4

How can you reduce the side effects of metformin?

Answer 4

• Particularly evident when very high doses are given

- A slow increase in dose may improve tolerability

Question 5

What does metformin need to access tissues and why?

Answer 5

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

Question 6

When is metformin most effective?

Answer 6

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

Question 7

In 2020 in West London how commonly were these drugs prescribed?

Answer 7

• Metformin: 4th
• Sitagliptin: 49th
• Gliclazide: 15th
• Dapaglifozin: 127th

Question 8

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

Answer 8

Sitagliptin

Question 9

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

Answer 9

1. Primary effect - Work by inhibiting the action of DPP-4
2. This enzyme is present in vascular endothelium and can metabolise incretins in the plasma.
3. 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)
4. Incretins also slow down digestion and decrease appetite.

Question 10

What is the drug target of DPP4 inhibitor and primary site of action?

Answer 10

• DPP-4

- primary site of DPP-4 inhibitor action is the vascular endothelium

Question 11

What are the main side effects of DPP4 inhibitors?

Answer 11

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

Question 12

What are the. less common but serious side effects of DPP4 inhibitors?

Answer 12

Serious allergic reactions/ avoid in patients with pancreatitis

Question 13

What is better about DPP4 inhibitors than other anti-diabetic drugs but metformin do?

Answer 13

not appear to cause weight gain.

Question 14

When are DPP4 inhibitors most 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 is an example of a sulphonylurea?

Answer 15

Gliclazide

Question 16

How do sulphonylureas work?

Answer 16

1. Primary effect – Inhibit the ATP-sensitive potassium (KATP) channel on the pancreatic beta cell.
2. This channel controls beta cell membrane potential
3. Inhibition causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis

Question 17

What is the target for sulphonylureas and where is primary site of action?

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 sulphonylureas?

Answer 18

1. Weight gain is a likely side effect

2. Hypoglycaemia (2nd most common)

Question 19

When are sulphonylureas most effective?

Answer 19

The sulfonylureas act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present

Question 20

How is weight gain mitigated with sulphonylureas?

Answer 20

by the concurrent administration with metformin

Question 21

Why is the risk. of hypoglycaemia important with sulphonylureas?

Answer 21

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

Question 22

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

Answer 22

Dapaglifozin

Question 23

What is the primary mechanism action of SGLT-2 inhibitors?

Answer 23

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

Question 24

What is the drug target and primary site of action of SGLT-2 inhibitors?

Answer 24

-SGLT2

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

Question 25

What are the main side effects of SGLT-2 inhibitors?

Answer 25

1. Uro-genital infections due to increased glucose load (5% of patients)
2. Slight decrease in bone formation
3. Can worsen diabetic ketoacidosis (stop immediately)

Question 26

What do SGLT-2 inhibitors cause?

Answer 26

• weight loss

- reduction in BP

Question 27

What. does SGLT-2 inhibitor action depend on?

Answer 27

normal renal fucntion so they are less effective in patients with renal impairment