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BRS2 Pharmacology and Therapeutics > Pharmacology of Diabetes - Core Drugs & Case Study > Flashcards

Pharmacology of Diabetes - Core Drugs & Case Study Flashcards

1
Q

What are the 4 main classes of drugs that are most commonly prescribed in the West London area for the treatment of diabetes?

A
  1. Metformin
  2. Dipeptidyl-peptidase 4 (DPP-4) inhibitors
  3. Sulphonylureas
  4. Sodium-glucose co-transporter (SGLT2) inhibitors
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2
Q

In 2020, Metformin was the 4th most commonly prescribed drug in the West London area.

What is the primary mechanism of action of Metformin?

A

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

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3
Q

What is the drug target for Metformin?

A

5’-AMP-activated protein kinase (AMPK)

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4
Q

What are the main side effects of Metformin?

A

GI side effects

E.G.

  • Abdominal pain
  • Decreased appetite
  • Diarrhoea
  • Vomiting
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5
Q

What proportion of patients experience GI side effects when on Metformin?

A

20-30%

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6
Q

Give an example of GI side effects that a patient who is on Metformin could experience.

A

E.G.

  • Abdominal pain
  • Decreased appetite
  • Diarrhoea
  • Vomiting
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7
Q

GI side effects can be experienced by patients who are on Metformin.

  1. When is this particularly evident?
  2. How may tolerability be improved?
A
  1. Particularly evident when very high doses are given

2. A slow increase in dose may improve tolerability

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8
Q

What does Metformin require to access tissues?

A

Requires organic cation transporter-1 (OCT-1) to access tissues

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9
Q

Why does Metformin require organic cation transporter-1 to access tissues?

A

Metformin is highly polar

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10
Q

Why can Metformin accumulate in the liver and GI tract?

A

Metformin is highly polar and so requires organic cation transporter-1 (OCT-1) to access tissues

—-> can accumulate in liver (therapeutic effect) and GI tract (side effects)

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11
Q

When is Metformin most effective? Why?

A

Most effective when there is residual functioning pancreatic islet cells

Because metformin is most effective when there is still some endogenous insulin

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12
Q

Sitagliptin is an example of what class of diabetes drug?

A

DPP-4 (dipeptidyl-peptidase 4) inhibitors

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

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13
Q

What is the primary effect of DPP-4 inhibitors?

A

Inhibit action of DPP-4 enzyme (found in vascular endothelium) which can metabolise incretins in the plasma

—> increased plasma incretin levels

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14
Q

What is the primary site of DPP-4 inhibitor action?

A

Vascular endothelium

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15
Q

What kind of cells secrete incretins?

A

Enteroendocrine cells

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16
Q

What are the 3 main functions of incretins?

A
  1. Help stimulate insulin production when it is needed (e.g. when eating)
  2. Reduce glucagon production by the liver when it is not needed (e.g. during digestion)
  3. Slow down digestion and decrease appetite
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17
Q

What is the function of DPP-4?

A

This enzyme can metabolise incretins in the plasma

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18
Q

What are some possible side effects of DPP4-inhibitors?

A

Upper respiratory tract infections

Flu-like symptoms, E.G.

  • Headache
  • Runny nose
  • Sore throat

Less common but serious:
- Serious allergic reactions/avoid in patients with pancreatitis

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19
Q

What proportion of patients experience upper respiratory tract infections as a side effect of taking DPP-4 inhibitors?

A

5%

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20
Q

Patients with what condition should avoid using DPP-4 inhibitors?

A

Pancreatitis

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21
Q

What common side effect do DPP4i drugs not appear to cause, compared to other anti-diabetic drugs (although not metformin)?

A

Weight gain

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22
Q

Why do DDP-4 I’s require some residual pancreatic beta cell activity to be effective?

A

Because they mainly act by increasing insulin secretion

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23
Q

Gliclazide is a common example of what class of diabetes drug?

A

Sulphonyureas

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

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24
Q

What is the primary effect of Sulphonylureas?

A

Inhibit ATP-sensitive potassium (KATP) channel on the pancreatic beta cells

These channels control beta cell membrane potential

Inhibition causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis

25
Q

What does the KATP channel control?

A

Controls beta cell membrane potential

26
Q

What does inhibition of the KATP channel of pancreatic beta cells result in?

A

Inhibition causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis

27
Q

What is the drug target for Sulphonylureas?

A

ATP-sensitive potassium (KATP) channels

28
Q

What is the primary site of action of Sulphonylureas?

A

Pancreatic beta cell

29
Q

What are the 2 most common side effects one might experience when taking Sulphonylureas?

A
  1. Weight gain

2. Hypoglycaemia

30
Q

Why do Sulphonyureas require some residual pancreatic beta-cell activity to be effective?

A

Because they mainly act by increasing insulin secretion

31
Q

Weight gain is a common side effect of taking Sulphonylureas to treat diabetes.

How can this be mitigated?

A

By concurrent administration with metformin

32
Q

How should you navigate the risk of hypoglycaemia when prescribing Sulphonylureas to treat diabetes?

A
  • Discuss risk with patient

- Especially when concomitant glucose-lowering drugs are prescribed

33
Q

Dapaglifozin is a common example of what class of diabetes drug?

A

Sodium-glucose co-transporter (SGLT2) inhibitors

2020 - Dapaglifozin was 127th most commonly prescribed drug in West London area

34
Q

What is the primary mechanism of action of SGLT2 inhibitors?

A

Reversibly inhibits SGLT2 in renal proximal convoluted tubule

To reduce glucose reabsorption + increase urinary glucose excretion

35
Q

What is the drug target for SGLT2 inhibitors?

A

SGLT2

36
Q

What is the primary site of SGLT2 inhibitor action?

A

Proximal convoluted tubule

37
Q

What are some possible side effects of taking SGLT2 inhibitors?

A

Urogenital infections - due to increased glucose load

38
Q

Why can urogential infections occur in patients taking SGLT2 inhibitors to treat diabetes?

A

Due to increased glucose load

39
Q

What should happen in the case of diabetic ketoacidosis worsened by SGLT2 inhibitor action?

A

Stop immediately

40
Q

Why are SGLT2 inhibitors less effective in patients with renal impairment?

A

Because SGLT2i action depends on normal renal function

41
Q

What proportion of patients taking SGLT2 inhibitors to treat diabetes might experience urogenital infections?

A

5%

42
Q

What is the seven step process for deciding and implementing drug treatment for a patient?

  1. Identify the patient’s problem
  2. …
A
  1. Identify the patient’s problem
  2. Specify the therapeutic objective
  3. Select a drug on the basis of comparative efficacy, safety, cost + 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)
43
Q

Case - Mrs Wallace

Age - 72yo
Sex - F
Reason for GP appointment - routine health check

Brief History:
Mother - died of diabetes
Reports no polyuria, polydipsia or weight loss

Investigations:
BMI - 31
BP - 144/92mmHg

Follow up appointment - Bloods:
HbA1c - 65mmol/mol
LDL-cholesterol - 5.18 mmol/L
HDL-cholesterol - 0.8mmol/L
BP - 148/91HHmg

Further appointment - confirmed elevated HbA1c

What is the patient’s problem?

A

High HbA1c (Diabetes = > 48mmol/L)
High Blood Pressure
Dyslipidaemia
Obesity

Metabolic syndrome?

44
Q

Case - Mrs Wallace

Age - 72yo
Sex - F
Reason for GP appointment - routine health check

Brief History:
Mother - died of diabetes
Reports no polyuria, polydipsia or weight loss

Investigations:
BMI - 31
BP - 144/92mmHg

Follow up appointment - Bloods:
HbA1c - 65mmol/mol
LDL-cholesterol - 5.18 mmol/L
HDL-cholesterol - 0.8mmol/L
BP - 148/91HHmg

Further appointment - confirmed elevated HbA1c

What is the patient’s problem?

A

High HbA1c (Diabetes = > 48mmol/L)
High Blood Pressure
Dyslipidaemia
Obesity

Metabolic syndrome?

45
Q

Case - Mrs Wallace

Age - 72yo
Sex - F
Reason for GP appointment - routine health check

Brief History:
Mother - died of diabetes
Reports no polyuria, polydipsia or weight loss

Investigations:
BMI - 31
BP - 144/92mmHg

Follow up appointment - Bloods:
HbA1c - 65mmol/mol
LDL-cholesterol - 5.18 mmol/L
HDL-cholesterol - 0.8mmol/L
BP - 148/91HHmg

Further appointment - confirmed elevated HbA1c

What is the most likely diagnosis?

A

T2DM - hyperglycaemia, no osmotic syndrome, risk factors

High HbA1c (Diabetes = > 48mmol/L)
High Blood Pressure
Dyslipidaemia
Obesity

Metabolic syndrome?

46
Q

Case - Mrs Wallace

Age - 72yo
Sex - F
Reason for GP appointment - routine health check

Brief History:
Mother - died of diabetes
Reports no polyuria, polydipsia or weight loss

Investigations:
BMI - 31
BP - 144/92mmHg

Follow up appointment - Bloods:
HbA1c - 65mmol/mol
LDL-cholesterol - 5.18 mmol/L
HDL-cholesterol - 0.8mmol/L
BP - 148/91HHmg

Further appointment - confirmed elevated HbA1c

What is the therapeutic objective for this patient?

A

Lose weight - reduces insulin resistance + reduces risk of CVD

Reduce BP - reduces risk of CVD

Improve lipid profile - reduces risk of CVD

Reduce blood glucose - reduces risk of microvascular + macrovascular complications of diabetes

47
Q

Case - Mrs Wallace

Age - 72yo
Sex - F
Reason for GP appointment - routine health check

Brief History:
Mother - died of diabetes
Reports no polyuria, polydipsia or weight loss

Investigations:
BMI - 31
BP - 144/92mmHg

Follow up appointment - Bloods:
HbA1c - 65mmol/mol
LDL-cholesterol - 5.18 mmol/L
HDL-cholesterol - 0.8mmol/L
BP - 148/91HHmg

Further appointment - confirmed elevated HbA1c

We are focusing on the treatment of T2DM. Using the algorithm found on this link: https://www.nice.org.uk/guidance/ng28/resources/algorithm-for-blood-glucose-lowering-therapy-in-adults-with-type-2-diabetes-pdf-2185604173

What would you prescribe for Mrs Wallace?

A
  1. Lifestyle intervention: Promote physical activity + diet/nutrition changes first
  2. See how that affects high HbA1c and other issues over a few weeks
  3. Review
  4. If no significant change in HbA1c following lifestyle intervention, or if more help is needed, consider metformin
48
Q

Consider the molecular structure of metformin:

C4H11N5 (look up image online)

Metformin pKa = 12.4

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

A

Metformin is charged and highly polar

pKa = 12.4 - so even in most alkaline tissue (bile pH = 9), metformin will be charged

It can be dissolved in water/aqueous environment but won’t dissolve well in lipids. It will be difficult for metformin to diffuse into body tissues and cells for absorption.

Will have to use alternative transport mechanisms - using organic cation transporter 1 (OCT-1)

49
Q

Where is OCT-1 expressed?

A

Hepatocytes (liver)
Enterocytes (small bowel)
Proximal tubules (kidney)

50
Q

Organic cation transporter 1 (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?

A

Small bowel OCT-1 allows metformin to be absorbed

Hepatocyte OCT-1 allows it to be distributed to the site of action

Proximal tubule OCT-1 helps excretion

51
Q

Case - Mrs Wallace

Age - 72yo
Sex - F
Reason for GP appointment - routine health check

Brief History:
Mother - died of diabetes
Reports no polyuria, polydipsia or weight loss

Investigations:
BMI - 31
BP - 144/92mmHg

Follow up appointment - Bloods:
HbA1c - 65mmol/mol
LDL-cholesterol - 5.18 mmol/L
HDL-cholesterol - 0.8mmol/L
BP - 148/91HHmg

Further appointment - confirmed elevated HbA1c

Interventions:

  • Provided with lifestyle advice
  • Standard release metformin (500mg/day;oral)

6 months later

  • HbA1c only fallen to 62mmol/mol
  • History of recurrent UTIs

What would you do next?

A
  • Do another lifestyle review

Patient might have stuck with treatment however there is a chance that they didn’t

  • If no difference, alter medication
52
Q

Case - Mrs Wallace

Age - 72yo
Sex - F
Reason for GP appointment - routine health check

Brief History:
Mother - died of diabetes
Reports no polyuria, polydipsia or weight loss

Investigations:
BMI - 31
BP - 144/92mmHg

Follow up appointment - Bloods:
HbA1c - 65mmol/mol
LDL-cholesterol - 5.18 mmol/L
HDL-cholesterol - 0.8mmol/L
BP - 148/91HHmg

Further appointment - confirmed elevated HbA1c

Interventions:

  • Provided with lifestyle advice
  • Standard release metformin (500mg/day;oral)

6 months later

  • HbA1c only fallen to 62mmol/mol
  • History of recurrent UTIs

Drug Options & SEs

  • DDP-4 inhibitor: URTIs
  • Pioglitazone: Heart failure
  • Sulphonylurea: Weight gain
  • SGLT2 inhibitor: Urogenital infections

https://www.nice.org.uk/guidance/ng28/resources/algorithm-for-blood-glucose-lowering-therapy-in-adults-with-type-2-diabetes-pdf-2185604173

What is the best choice drug for this patient?

A

Consider drug:

  1. Efficacy
  2. Side effects
  3. Cost
  4. Efficacy:

These drugs have similar efficacy

  1. Side effects:

Patient has high BMI and a history of recurrent UTIs —> no sulphonylurea or SGLT2 inhibitor

  1. Cost:

Pioglitazone ~ 30x cheaper than DPP-4 inhibitor

Choice = Pioglitazone + metformin

53
Q

What type of drug target does metformin have?

A

Enzyme

54
Q

What type of drug target do DPP-4 inhibitors have?

A

Enzyme

55
Q

What type of drug target do sulphonylureas have?

A

Ion channels

56
Q

What type of drug target do SGLT2 inhibitors have?

A

Transport protein

57
Q

Case - Mrs Wallace

Age - 72yo
Sex - F
Reason for GP appointment - routine health check

Brief History:
Mother - died of diabetes
Reports no polyuria, polydipsia or weight loss

Investigations:
BMI - 31
BP - 144/92mmHg

Follow up appointment - Bloods:
HbA1c - 65mmol/mol
LDL-cholesterol - 5.18 mmol/L
HDL-cholesterol - 0.8mmol/L
BP - 148/91HHmg

Further appointment - confirmed elevated HbA1c

Interventions:

  • Provided with lifestyle advice
  • Standard release metformin (500mg/day;oral)

6 months later

  • HbA1c only fallen to 62mmol/mol
  • History of recurrent UTIs

Further interventions
- Metformin + pioglitazone

During this time, Mrs Wallace has developed chronic kidney disease.

90% of a standard dose of oral metformin is excreted unchanged via the kidney.

Regulations state that, with this eGFR level, metformin dose should be decreased by 50%.

Why should dosage be decreased and why do you think renal impairment could cause problems for diabetic patients on metformin?

A

Most oral metformin is excreted unchanged via the kidney

In CKD, metformin will not be excreted properly via kidney and will accumulate, leading to increased serum metformin levels and excessive metformin action and response

Decrease dosage to stabilise this

58
Q

Case - Mrs Wallace

Age - 72yo
Sex - F
Reason for GP appointment - routine health check

Brief History:
Mother - died of diabetes
Reports no polyuria, polydipsia or weight loss

Investigations:
BMI - 31
BP - 144/92mmHg

Follow up appointment - Bloods:
HbA1c - 65mmol/mol
LDL-cholesterol - 5.18 mmol/L
HDL-cholesterol - 0.8mmol/L
BP - 148/91HHmg

Further appointment - confirmed elevated HbA1c

Interventions:

  • Provided with lifestyle advice
  • Standard release metformin (500mg/day;oral)

6 months later

  • HbA1c only fallen to 62mmol/mol
  • History of recurrent UTIs

Further interventions
- Metformin + pioglitazone

Mrs Wallace is struggling with the GI side effects of metformin.

What recommendations could be made to help with this?

A
  • Taking metformin after food, not before
  • Switch to a better tolerated preparation, e.g. sustained release metformin is absorbed slowly so there are fewer GI side effects (H/E is more expensive)

BRS2 Pharmacology and Therapeutics (6 decks)

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