pharmacology of diabetes

Question 1

Primary mechanism of action of action of metformin

Answer 1

Primary effect – 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

Primary mechanism of action of action of DPP-4 inhibitors

Answer 2

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

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 3

Primary mechanism of action of action of sulphonylureas

Answer 3

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

Question 4

Primary mechanism of action of action of SGLT-2 inhibitors

Answer 4

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

Question 5

Ex of SGLT-2 inhibitors

Answer 5

dapagliflozin

Question 6

Ex of sulphonyurea

Answer 6

gliclazide

Question 7

example of DPP-4 inhibitor

Answer 7

sitagliptin

Question 8

Drug target of metformin

Answer 8

AMPK

hepatocyte mitochondria

Question 9

DDP-4 inhibitor drug target

Answer 9

DDP-4 in vascular endothelium

Question 10

sulphonylurea drug target

Answer 10

ATP sensitive potassium channels in pancreatic beta cells

Question 11

SGLT-2 inhibitor target

Answer 11

SGLT-2 in PCT

Question 12

side effects of metformin

Answer 12

GI side effects (20-30% of patients)

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



Particularly evident when very high doses are given. A slow increase in dose may improve tolerability.



Question 13

What does metformin need to access tissues and why and what are the consequences of that

Answer 13

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 14

When is metformin most effective

Answer 14

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

Question 15

Side effects of DPP-4 inhibitors

Answer 15

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 16

weight effect of DPP-4 inhibitors

Answer 16

appears not to have weight gain

Question 17

When are DPP-4 inhibitors affective only

Answer 17

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 18

Side effect of sulphonylureas

Answer 18

weight gain likely

Question 19

What should be discussed with patients on sulphonylureas

Answer 19

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

Question 20

Sulphonylureas are only effective when

Answer 20

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

Question 21

How can weight gain on sulphonyureas be mitigated

Answer 21

Weight gain is mitigated by the concurrent administration with metformin.

Question 22

Side effect of SGLT-2 inhibitors

Answer 22

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

Slight decrease in bone formation



Can worsen diabetic ketoacidosis (stop immediately)

Question 23

SGLT 2 inhibitors effect on weight and BP

Answer 23

decrease both

Question 24

SGLT2i only work when

Answer 24

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

Question 25

1st line for first presentation of T2DM treatment

Answer 25

lifestyle intervention

Question 26

If HbA1c rises to 48 mmol/mol on lifestyle intervention what do you do

Answer 26

give metformin

to support them to get target of 48

Question 27

If HbA1c rises to 58 mmol/mol after metformin and lifestyle advice

Answer 27

1st intensification 
- give dual therapy with metformin one of the following: 
DDP-4 inhibitors (eg sitagliptin) 
sulphonylureas (eg gliclazide) 
SGLT-2i (dapagliflozin) 
pioglitazone

Question 28

If HbA1c rises to 58 mmol/mol after metformin and lifestyle advice, what level should they be supported to achieve

Answer 28

53

Question 29

if HbA1c rises to 58 mmol/mol after double based therapy@

Answer 29

insulin or triple therapy:

1) metformin, DPP4i and SU
2) metformin, pioglitazone, SU
3) metformin, pioglitazone or an SU and a SGLT-2i

Question 30

The expression of the organic cation transporter 1 (OCT-1) is highest in the following tissues: Liver hepatocytes (highest expression), the small intestinal enterocytes and the renal proximal tubules. Why do you think this is relevant to the pharmacokinetics of orally administered metformin?

Answer 30

Means that metformin would be absorbed in small intestine by transporters in enterocytes

Would then encounter hepatocytes, and the site of action for metformin is the mitochondria of hepatocytes and so it’s good for absorption that OCT1 is present more in the liver

Proximal tubule OCT 1 helps excretion

This all means it is orally available

Question 31

10 years later and Mrs Wallace has a stabilized Hb1Ac of 62mmol/mol. Her drug treatment for her diabetes remains unchanged – metformin and sitagliptin. However, during this time, Mrs Wallace has developed chronic kidney disease. NOTE - It is CLINICALLY very important that you monitor kidney function in any patient on metformin with signs of renal impairment. Mrs Wallace’s most recent serum creatinine estimated her GFR at 37. The table below describes how metformin administration should be changed based on underlying kidney function (eGFR). How should you change the treatment strategy for Mrs Wallace and why do you think renal impairment could cause problems for diabetic patients on metformin?

Answer 31

Consider halving dose as reduced renal function means less metformin is excreted so more is retained in the blood so there is a risk of hypoglycaemia