Pharmacology Of Diabetes

Question 1

Metformin primary mechanisms of action

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

Drug target for metformin

Answer 2

5′-AMP-activated protein kinase (AMPK)

The primary site of metformin action is the hepatocyte mitochondria

Question 3

Side effects of metformin

Answer 3

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 4

Extra info metformin

Answer 4

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)

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

Question 5

Dipeptidyl peptidase 4 inhibitors

Answer 5

Sitagliptin

Question 6

Mechanism of action of DPP-4

Answer 6

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 7

Drug target of DPP-4

Answer 7

vascular endothelium

Question 8

Side effects of DPP-4

Answer 8

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 9

Extra info of DPP4

Answer 9

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

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

In 2020 – Sitagliptin was the 49th most commonly prescribed drug in West London area

Question 10

Sulphonylurea

Answer 10

Gliclazide

Question 11

Mechanism of action of Sulphonylurea

Answer 11

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 12

Drug target for Sulphonylurea

Answer 12

ATP-sensitive potassium channel

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

Question 13

Side effect of Sulphonylurea

Answer 13

Weight gain is a likely side effect
Hypoglycaemia (2nd most common)

Question 14

Extra info on Sulphonylurea

Answer 14

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

Weight gain is mitigated by the concurrent administration with metformin.

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

In 2020 – Gliclazide was the 15th most commonly prescribed drug in West London area

Question 15

SGLT-2 inhibitors

Answer 15

Dapaglifozin

Question 16

Mechanism of action of SGLT-2

Answer 16

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

Question 17

Site of action of SGLT-2

Answer 17

SGLT2

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

Question 18

Side effects of SGLT-2

Answer 18

Uro-genital infections due to increased glucose load (5% of patients)
Slight decrease in bone formation

Can worsen diabetic ketoacidosis (stop immediately)

Question 19

Extra info of SGLT-2

Answer 19

SGLT2 inhibitors cause weight loss and a reduction in BP

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

In 2020 – Dapaglifozin was the 127th most commonly prescribed drug in West London area

Question 20

Therapeutic objectives

Answer 20

Weight loss to reduce insulin resistance and cardiovascular disease

Reduce blood pressure to reduce cardiovascular disease

Improve lipid profile to reduce cardiovascular disease

Reduce blood glucose to reduce microvascular and macro vascular disease

Question 21

Metformin pharmacokinetics

Answer 21

Pka is 12.4 so will be changed in even the most alkaline tissue

Question 22

Diabetic keto acidosis

Answer 22

Patient who take SGLTS-early warning signs may be slower ,pt checks glucose and its normal-get acidosis