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Year 2 - BRS > 1.2 - Pharmacology of diabetes (core drugs) > Flashcards

1.2 - Pharmacology of diabetes (core drugs) Flashcards

1
Q

What are the four classes of diabetes drugs?

A
  • metformin
  • dipeptidyl-peptidase 4 (DPP-4) inhibitor
  • sulphonylurea
  • sodium-glucose co-transporter (SGLT2) inhibitor
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2
Q

What is the primary mechanism of action of metformin?

A
  • 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 restore insulin sensitivity
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3
Q

What is the drug target of metformin?

A

5’-AMP-activated protein kinase (AMPK - enzyme) in hepatocyte mitochondria

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4
Q

What is the primary site of action of metformin?

A

Hepatocyte mitochondria

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5
Q

What is the overall action of metformin?

A

Decreased gluconeogenesis

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6
Q

What are the main side effects of metformin?

A
  • GI side effects (20-30%) patients, evident when very high doses given (slow increase in dose may improve tolerability)
  • abdominal pain
  • decreased appetite
  • diarrhoea
  • vomiting
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7
Q

What is the polarity of metformin like and how does it access tissues?

A
  • highly polar
  • requires organic cation transporter-1 (OCT-1) to access tissues
  • this explains why it can accumulate in the liver (therapeutic effects) and GI tract (side effects)
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8
Q

When is metformin most effective?

A

In the presence of endogenous insulin (so when there is some residual functioning of pancreatic islet cells)

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9
Q

What is an example of a DPP-4 inhibitor?

A

Sitagliptin

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10
Q

What is the primary mechanism of action of a DPP-4 inhibitor?

A
  • inhibits action of DPP-4 which is present in vascular endothelium and can metabolise incretins in plasma
  • incretins (e.g. GLP-1) are secreted by enteroendocrine cells and help stimulate insulin production after eating and reduce glucagon production by liver when not needed e.g. during digestion
  • incretins also slow down digestion and decrease appetite
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11
Q

What is the drug target and primary site of action of DPP-4 inhibitors?

A

DPP-4 in vascular endothelium

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12
Q

What is the overall effect of a DPP-4 inhibitor?

A

Increased plasma incretin levels

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13
Q

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

A
  • upper respiratory tract infections (5%)
  • flu-like symptoms e.g. headache, runny nose, sore throat
  • less common but serious allergic reactions
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14
Q

Which patients should you avoid giving DPP-4 inhibitor to?

A

Avoid in patients with pancreatitis

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15
Q

What is an advantage of DPP-4 inhibitors compared to other diabetic drugs?

A

Do not cause weight gain

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16
Q

When are DPP-4 inhibitors effective?

A

Act mainly by augmenting insulin secretion so are only effective when some residual pancreatic beta cell activity is present

17
Q

What is an example of a sulphonylurea?

A

Gliclazide

18
Q

What is the primary mechanism of action of sulphonylureas?

A
  • inhibit ATP-sensitive K+ channel (KATP) on pancreatic beta cell
  • this channel controls beta cell membrane potential
  • inhibition causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis
19
Q

What is the drug target and primary site of action of sulphonylureas?

A

ATP-sensitive potassium channel on pancreatic beta cell

20
Q

What is the overall effect of sulphonylureas?

A

Insulin secretion

21
Q

What are the main side effects of sulphonylureas?

A
  • weight gain is likely
  • hypoglycaemia (2nd most common)
22
Q

When are sulphonylureas effective?

A

Act by augmenting insulin secretion so only effective when there is residual pancreatic beta cell activity

23
Q

How can weight gain by sulphonylureas be mitigated?

A

By also giving metformin

24
Q

What do we need to inform patients about if they are on sulphonylureas?

A

Patients need to be informed about hypoglycaemia risk, especially if they are on other glucose-lowering drugs

25
Q

What is an example of a SGLT-2 inhibitor?

A

Dapaglifozin

26
Q

What is the primary mechanism of action of SGLT-2 inhibitors?

A

Reversibly inhibits SGLT-2 in renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion

27
Q

What is the drug target and primary site of action of SGLT-2 inhibitors?

A

SGLT-2 in renal PCT

28
Q

What is the overall effect of SGLT-2 inhibitors?

A

Decreased glucose reabsorption

29
Q

What are the main side effects of SGLT-2 inhibitors?

A
  • urogenital infections due to increased glucose load (5% of patients)
  • slight decrease in bone formation
  • can worsen diabetic ketoacidosis (stop immediately)
30
Q

What can SGLT-2 inhibitors also cause/be used for?

A

Weight loss and reduction in BP

31
Q

What is the action of SGLT-2 inhibitors dependent on?

A

Drug action depends on normal renal function so are less effective in renal impairment patients

32
Q

How does the molecular structure of metformin influence it’s absorption into the blood and distribution to body tissues?

A
  • metformin pKa = 12.4, so even in the most alkaline tissue (bile pH 9), metformin will be charged/ionised
  • metformin is very polar - transported by organic cation transporter 1 (OCT1) - expressed in hepatocytes (liver), enterocytes (small bowel) and proximal tubules (kidney)
    • SB OCT1 allows it to be absorbed
    • hepatocyte OCT1 allows it to be distributed to the site
    • proximal tubule OCT1 helps excretion
33
Q

What are side effects of metformin, DPP-4 inhibitors, pioglitazone, sulphonylurea, and SGLT-2 inhibitors?

A
  • metformin: GI e.g. diarrhoea
  • DPP-4 inhibitor: upper RTI
  • pioglitazone: heart failure
  • sulphonylurea: weight gain
  • SGLT-2 inhibitor: urogenital infections
34
Q

How does diabetic ketoacidosis develop?

A
  • not enough insulin: insulin not taken or insulin resistance increased e.g. infection
  • glucose does not enter cells
  • immediately: plasma glucose rises –> polyuria and dehydration –> patient feels awful and presents to hospital
  • slowly: liver cells make ketones (starving in the midst of plenty) –> acidosis –> patient feels awful and presents to hospital
35
Q

How can SGLTs affect diabetic ketoacidosis?

A
  • early warning sign of rising glucose may be slower and even lost completely
  • worse, normal glucose falsely reassures: “I don’t feel great but my glucose is normal, so it can’t be DKA, I’m probably just tired, no need for more insulin”
  • normal circumstances where patients NOT on SGLTs: “Glucose is high, something must be going on, I’ll take some insulin and go to the doctor”
  • take home message for SGLTs - DKA can occur with normal glucose

Year 2 - BRS (84 decks)

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