Pharmacology of Diabetes

Question 1

What are the main drugs prescribed for diabetes?

Answer 1

Metformin
Sitagliptin [Dipeptidyl-peptidase 4 (DPP-4) inhibitors]
Gliclazide [Sulphonylurea]
Dapaglifozin [Sodium-glucose co- transporter (SGLT2) inhibitors]

Question 2

What is the primary mechanism of action for Metformin?

Answer 2

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 3

What is the drug target for Metformin?

Answer 3

5′-AMP-activated protein kinase (AMPK)
The primary site of metformin action is the hepatocyte mitochondria

Question 4

What are the main side effects of Metformin?

Answer 4

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 5

Why can Metformin accumulate in the liver and GI tract?

Answer 5

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 6

When is metformin most effective?

Answer 6

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

Question 7

What drug class is Sitagliptin?

Answer 7

Dipeptidyl-peptidase 4 (DPP-4) inhibitors

Question 8

What is the primary mechanism of action for Sitagliptin?

Answer 8

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 9

What is the drug target of Sitagliptin?

Answer 9

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

Question 10

What are the main side effects of Sitagliptin?

Answer 10

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 11

What is a benefit of Sitagliptin?

Answer 11

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

Question 12

When is Sitagliptin most effective?

Answer 12

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 13

What is the drug class of Gliclazide?

Answer 13

Sulphonylurea

Question 14

What is the primary mechanism of action of Gliclazide?

Answer 14

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 15

What is the drug target of Gliclazide?

Answer 15

ATP-sensitive potassium channel
The primary site of SUs inhibitor action is the pancreatic beta cell

Question 16

What are the side effects of Gliclazide?

Answer 16

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

Question 17

When is Gliclazide most effective?

Answer 17

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

Question 18

How can the side effect (weight gain) of Gliclazide be mitigated?

Answer 18

Weight gain is mitigated by the concurrent administration with metformin.

Question 19

What should be discussed with the patient when prescribing Gliclazide?

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

What is the drug class of Dapaglifozin?

Answer 20

Sodium-glucose co-transporter (SGLT2) inhibitors

Question 21

What is the primary mechanism of action of Dapaglifozin?

Answer 21

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

Question 22

What is the drug target of Dapaglifozin?

Answer 22

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

Question 23

What are the side effects of Dapaglifozin?

Answer 23

Uro-genital infections due to increased glucose load- increased glucose in urine can casue overgrowth of bacteria (5% of patients)
Slight decrease in bone formation
Can worsen diabetic ketoacidosis (stop immediately)

Question 24

What are some other common effects of Dapaglifozin?

Answer 24

SGLT2 inhibitors cause weight loss and a reduction in BP

Question 25

When is Dapaglifozin not very effective?

Answer 25

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

Question 26

What is the “seven stop process” for prescribing medication?

Answer 26

1. Identify the patient’s problem
2. Specify the therapeutic objective
3. Select a drug on the basis of comparative efficacy, safety, cost and suitability
4. Discuss choice of medication with patient (and carer) and make a shared decision about treatment
5. Write a correct prescription
6. Counsel the patient on appropriate use of the medicine
7. Make appropriate arrangements for follow up (Monitor/ stop the treatment)

Question 27

How do you think the molecular structure of metformin would influence its absorption into the blood and distribution to body tissues?

Answer 27

• Metformin is a polar structure (ionised)
• More likely to be water soluble than lipid
• Ability to cross plasma membrane restricted (more likely to be trapped)
• Metformin pKa= 12.4 so even in the most alkaline tissue (bile pH 9), metformin almost always charged)

Question 28

If metformin is very polar, how does it move across body compartments?

Answer 28

• Metformin is transported by organic cation transporter 1 (OCT 1)
• OCT-1 is expressed in hepatocytes (liver), enterocytes (small bowel) and proximal tubules (kidney)

Question 29

OCT-1 is expressed in hepatocytes (liver), enterocytes (small bowel) and proximal tubules (kidney)

Why do you think this is relevant to the pharmacokinetics of orally administered metformin?

Answer 29

a) Small bowel OCT-1 allows it to be absorbed (intestine get the drug from the gut to the blood)

b) Hepatocyte OCT-1 allows i tot be distributed to the site of action (liver metabolites a lipid soluble drug and makes it water soluble- easier to excrete)

c) Proximal tubule OCT-1 helps excretion (Metformin is v. large + charged, so it passes the glomerulus, and requires the OCT-1 to “pick it up” and put it into the tubule

Question 30

What is the primary mechanism of action of pioglitazone?

Answer 30

Pioglitazone helps to control your blood sugar levels by helping your body make better use of the insulin it produces.

Question 31

What are the main side effects of pioglitazone?

Answer 31

should not be taken if patient has severe or uncontrolled heart failure

Question 31

What are the main side effects of pioglitazone?

Answer 31

should not be taken if patient has severe or uncontrolled heart failure

Question 32

What are the benefits of Pioglitazone?

Answer 32

CHEAP: 30x cheaper than DPP-4
older (we know how it works)