Pharma - Diabetes

Question 1

What is Metformin’s primary mechanism of action?

Answer 1

→ metformin activates AMPK in hepatocyte mitochondria
→ this inhibits ATP production
→ blocks gluconeogenesis + subsequent glucose output
→ also blocks adenylate cyclase which promotes fat oxidation
→ both help to restore insulin sensitivity

Question 2

What is Metformin’s drug target?

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 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

Why does Metformin cause side effects in the GI tract?

Answer 4

→ highly polar and requires organic cation transporter-1 (OCT-1) to access tissues
→ explains why it can accumulate in the liver (therapeutic effect) + in GI tract (side effects)

Question 5

When is Metformin most effective?

Answer 5

→ most effective in the presence of endogenous insulin

→ so is most effective with some residual functioning pancreatic islet cells

Question 6

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



Answer 6

Sitagliptin

Question 7

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

Answer 7

→ Work by inhibiting the action of DPP-4

→ enzyme is present in vascular endothelium and can metabolise incretins in the plasma

Question 8

What is the purpose of incretins?

Answer 8

→ Incretins (e.g. GLP-1) are secreted by enteroendocrine cells + help stimulate the production of insulin when it is needed (e.g. after eating) + 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 site of action + drug target for a DDP-4 inhibitor?

Answer 9

→ DDP-4 = drug target

→ vascular endothelium

Question 10

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

Answer 10

→ Upper respiratory tract infections (5% of patients)
→ Flu-like symptoms e.g. headache, runny nose, sore throat
→ Serious allergic reactions (less common)
→ avoid in patients with pancreatitis

Question 11

What side effects don’t arise as a result of DDP-4 inhibitors?

Answer 11

weight gain

Question 12

When are DDP-4’s most effective?

Answer 12

→ when there are some residual pancreatic cell activity present
→ because they mainly cause increased insulin secretion

Question 13

What is an example of a sulphonylurea?

Answer 13

Gliclazide

Question 14

What is the main mechanism of action of sulphonylurea?

Answer 14

→ Inhibit the ATP-sensitive potassium (KATP) channel on the pancreatic beta cell. → 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 and site of action of sulphonylurea?

Answer 15

→ ATP-sensitive potassium channel

→ primary site of SUs inhibitor action = pancreatic beta cell

Question 16

What are the main side effects of sulphonylurea?

Answer 16

→ weight gain is a likely side effect

→ hypoglycaemia is 2nd most common

Question 17

When is sulphonylurea most effective? Why?

Answer 17

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

Question 18

How is weight gain mitigated when using sulphonylureas?

Answer 18

concurrent administration of metformin

Question 19

What is an example of a SGLT2 inhibitor?

Answer 19

Dapaglifozin

Question 20

What is an SGLT2 inhibitor?

Answer 20

sodium-glucose co-transporter inhibitor

Question 21

What is the primary mechanism of action for SGLT2 inhibitors?

Answer 21

→ inhibits sodium-glucose co-transporter 2 in the renal proximal convoluted tubule
→ reduces glucose reabsorption + increases urinary glucose excretion.

Question 22

What is the drug target + site of action for SGLT2 inhibitors?

Answer 22

→ SGLT2 (sodium glucose co-transporter 2)

→ in the proximal convoluted tube

Question 23

What are the side effects of SGLT2 inhibitors?

Answer 23

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

Question 24

What are the additional positives of SGLT2 inhibitors?

Answer 24

can cause weight loss + reduction in BP

Question 25

When are SGLT2 inhibitors the least effective?

Answer 25

→ less effective in patients with renal impairment

→ depends on normal renal function

Question 26

A 72 year old woman, Mrs Wallace, attends a GP routine health check.

BMI = 31
BP = 144/92
Mother died of diabetes
no polyuria, polydipsia or weight loss
HbA1c = 65 mmol/mol
LDLs = 5.18 mmol/L
HDLs = 0.8 mmol/L
triglycerides = 6.53 mmol/L.  Urinalysis = glycosuria but no ketones

What is the patient’s problem?

Answer 26

→ High Hb1ac

→ High Blood pressure

→ dyslipidemia

→ obesity

→ Possible metabolic syndrome?

Question 27

A 72 year old woman, Mrs Wallace, attends a GP routine health check.

BMI = 31
BP = 144/92
Mother died of diabetes
no polyuria, polydipsia or weight loss
HbA1c = 65 mmol/mol
LDLs = 5.18 mmol/L
HDLs = 0.8 mmol/L
triglycerides = 6.53 mmol/L.  Urinalysis = glycosuria but no ketones

What is the therapeutic objective for this patient?

Answer 27

→ Lose weight – reduces insulin resistance and reduces cardiovascular disease.
→ Reduce blood pressure – reduces cardiovascular disease.
→ Improve lipid profile – reduces cardiovascular disease.
→ Reduce blood glucose – reduces microvascular and macrovascular complications of diabetes.

Question 28

A 72 year old woman, Mrs Wallace, attends a GP routine health check.

BMI = 31
BP = 144/92
Mother died of diabetes
no polyuria, polydipsia or weight loss
HbA1c = 65 mmol/mol
LDLs = 5.18 mmol/L
HDLs = 0.8 mmol/L
triglycerides = 6.53 mmol/L.  Urinalysis = glycosuria but no ketones

Derived from the NICE guidance for treatment, what would you prescribe for Mrs Wallace?

Answer 28

→ 500 mg/day, oral metformin

→ give her advice on lifestyle changes, e.g. dietary changes and exercise

Question 29

Consider the molecular structure of metformin. How do you think the molecular structure of metformin would influence it’s absorption into the blood and distribution to body tissues?

Answer 29

→ charged ion, can’t penetrate the phospholipid membrane so it’s poorly absorbed and can’t be distributed to a lot of body tissues
→ uses an organic cation transporter 1 (OCT1), can only penetrate the body tissues with that transporter

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

→ Small Bowel OCT-1 = allows metformin to be absorbed orally
→ Hepatocyte OCT-1 allows it to be distributed to the site of action
→ Proximal Tubule OCT-1 = helps withe the excretion of metformin

Question 31

Mrs Wallace is provided with lifestyle advice and several months later is started on standard release metformin (500mg/day;oral). Despite this treatment approach, 6 months later Mrs Wallace is attending a regular GP appointment and her HBA1c has only fallen to 62mmol/mol. She has a recurrent 2-year history of UTIs. What would you do next?

Answer 31

→ consider dual therapy, metformin + another drug
→ no SGLT2 inhibitors due to the side effect of urogenital infections + recurrent history
→ no sulphonylurea due to risk of weight gain when she’s already trying to lose weight
→ DPP-4 inhibitors vs. pioglitazone
→ pioglitazone is cheaper

Question 32

What are the main side effects of pioglitazone?

Answer 32

→ weight gain
→ pedal oedema
→ bone loss
→ precipitation of congestive heart failure

Question 33

What is pioglitazone?

Answer 33

→ Thiazolidinediones
→ synthetic ligands for peroxisome proliferator-activated receptors (PPARs)
→ alter the transcription of genes influencing carbohydrate + lipid metabolism
→ results in changed amounts of protein synthesis + metabolic changes

Question 34

What is the primary mechanism of action of pioglitazone?

Answer 34

→ improving insulin sensitivity through its action at PPAR gamma 1 and PPAR gamma 2, and affects lipid metabolism through action at PPAR alpha
→ increases in glucose transporters 1 and 4, lowered free fatty acids, enhanced insulin signalling, reduced tumour necrosis factor alpha (TNF alpha) and remodelling of adipose tissue

Question 35

Mrs Wallace has a stabilized Hb1Ac of 57 mmol/mol. Her drug treatment for her diabetes remains unchanged – metformin and pioglitazone. However, during this time, Mrs Wallace has developed chronic kidney disease.
Mrs Wallace’s most recent serum creatinine estimated her GFR at 37. The table 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 35

→ GFR between 30-45 = if already taking metformin, consider 50% dose decrease