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BRS Year 2 > Pharmacology of Diabetes > Flashcards

Pharmacology of Diabetes Flashcards

1
Q

What are the 4 most common main drug classes prescribed for diabetes?

And what is an example of each of these?

A
  1. Metformin
  2. Dipeptidyl-peptidase 4 (DPP-4) inhibitors - Sitagliptin
  3. Sulphonylurea - Gliclazide
  4. Sodium-glucose co-transporter (SGLT-2) inhibitors - Dapaglifozin
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2
Q

What is the primary mechanism of action for Metformin?

A

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.

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3
Q

What is the drug target site for Metformin?

A

5′-AMP-activated protein kinase (AMPK)

The primary site of metformin action is the hepatocyte mitochondria

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4
Q

What are the main side effects for Metformin?

A

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

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5
Q

What does metformin require to access tissues?

A

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)

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6
Q

What is the primary mechanism of action for DPP-4 inhibitors?

A

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.

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7
Q

What is the drug target site for DPP-4 inhibitors?

A

DPP-4

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

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8
Q

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

A

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

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9
Q

What makes DPP-4 inhibitors better than other anti-diabetic drugs?

A

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

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10
Q

What is the primary mechanism of action for Sulphonylurea?

A

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.

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11
Q

What is the drug target site for Sulphonylurea?

A

ATP-sensitive potassium channel

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

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12
Q

What are the main side effects for Sulphonylurea?

A

Weight gain is a likely side effect

Hypoglycaemia (2nd most common)

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13
Q

What do Sulphonylureas need to be effective?

A

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

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14
Q

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

A

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

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15
Q

What is the drug target site for SGLT-2 inhibitors?

A

SGLT2

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

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16
Q

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

A

Uro-genital infections due to increased glucose load (5% of patients)

Slight decrease in bone formation

Can worsen diabetic ketoacidosis (stop immediately)

17
Q

What are benefits of SGLT-2 inhibitors?

A

SGLT2 inhibitors cause weight loss and a reduction in BP

18
Q

72F - Routine health check.
BMI = 31, BP = 144/92mmHg, mother died of diabetes. She reports no polyuria, polydipsia or weight loss.

Her GP a routine NHS health check. During a follow up appointment, Mrs Wallace’s blood tests reveal the following: HbA1c is 65 mmol/mol, LDL-cholesterol 5.18 mmol/L, HDL-cholesterol 0.8 mmol/L, and triglycerides 6.53 mmol/L.

Urinalysis shows glycosuria but no ketones. Her blood pressure is 148/91HHmg.

A further appointment confirmed the elevated HbA1c.

What is the patient’s problem?

A

Hypertension - elevated consistently

Elevated Hb1Ac - elevated consistently

Glycosuria

High BMI - obese (>30)

Dyslipidemia:
High triglycerides - normal is less than 1.7mmol/L
Hypercholesterolemia - high cholesterol

Metabolic syndrome: All indicative of T2DM

19
Q

What is the therapeutic objective for this patient?

A
  1. Lose weight - obesity contributing to the diabetes, increasing insulin resistance
  2. Reduce BP - reduce risk of CVD
  3. Reduce BGL - reduce complications associated with prolonged elevated BGL e.g. micro and macro vascular diseases
  4. Improve lipid profile = reduce risk of CVD
20
Q

Using the algorithm below (derived from the NICE guidance for treatment) what would you prescribe for Mrs Wallace to treat her T2DM?

A

Nothing has been given to Mrs Wallace, therefore no intensifications will be given

Firstly, give Mrs Wallace a lifestyle intervention - weightloss

If patient adheres to lifestyle intervention, it is as effective as metformin

21
Q

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?

Structure: N - C(NH)2 - C - (NH) - NH3+

A

Acts like a weak base - a polar molecule with the NH3+

pKa of the drug determines how ionised it is - v. high pKa of 12.4, therefore metformin is always ionised (as the body pH goes max up to pH 9 in bile)

Cannot diffuse across membranes effectively - exists in the ionised state

Therefore, it is water soluble, travels through the stomach and is absorbed in the small intestine via transporter proteins

22
Q

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?

A

OCT-1 presence in the small intestine allows for metformin absorption into the blood via oral administration = Absorption

OCT-1 presence in the renal proximal tubules allows for excretion of the drug from the blood = excretion

Site of action = OCT-1 in the liver hepatocytes = allows for drug to access the liver = distribution

23
Q

What are pro-drugs?

A

Inactive drug

Gets converted into active state when it goes through the liver

24
Q

How much does metformin change between oral ingestion to excretion?

A

Barely metabolised by liver
Pretty much same structure ingested as is excreted

Normally drugs are ionised in the liver so it is easier to excrete, by metformin already exists in its ionised form

25
Q

Two-year history of “recurrent urinary tract infection”

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.

What would you do next?

A

Ask Mrs Wallace if she is sticking to her treatment plan?

Is she struggling to lose weight - is she adhering to the lifestyle changes?

How good is her compliance with the medication?

If both are tried and well, progress onto first intensification - dual therapy with DPP-4 inhibitor

26
Q

Why not prescribe sulphonylurea to Mrs Wallace?

Why not prescribe SGLT to Mrs Wallace?

Why DPP-4 or pioglitazone? How might you decide between these 2?

A

Sulphonylurea: side effects include promotion of weight gain (Mrs Wallace = obese)

SGLT: side effects include increased glucose loss in the urine (Mrs Wallace already has recurrent UTIs, this will make it worse)

DDP-4: side effects increase upper respiratory tract infections, 30x more expensive that pioglitazone

Pioglitazone: increased incidence of heart failure

Could use cost to decide as there is no history to whether Mrs Wallace is more sensitive to upper respiratory tract infection or heart failure

27
Q

For Metformin, what is the:

  1. Primary drug target
  2. Drug target type
  3. Location
  4. Action
A
  1. AMP activated protein kinase
  2. Enzyme
  3. Hepatocyte mitohondria
  4. Decreased gluconeogenesis
28
Q

For DPP-4, what is the:

  1. Primary drug target
  2. Drug target type
  3. Location
  4. Action
A
  1. Dipeptidyl peptidase-4 (DPP-4)
  2. Enzyme
  3. Vascular endothelium
  4. Increased plasma incretin levels
29
Q

For Sulphonylureas, what is the:

  1. Primary drug target
  2. Drug target type
  3. Location
  4. Action
A
  1. ATP-sensitive K+ channels
  2. Ion channels
  3. Pancreatic beta cells
  4. Insulin secretion
30
Q

For SGLT-2 inhibitors?, what is the:

  1. Primary drug target
  2. Drug target type
  3. Location
  4. Action
A
  1. Sodium glucose co-transporter-2
  2. Transport protein
  3. Proximal Convoluted Tubule
  4. Decreased glucose reabsorption
31
Q

10 years later - Mrs Wallace stabilized Hb1Ac = 62mmol/mol.

Her drug treatment for her diabetes remains unchanged – metformin and sitagliptin.

However, during this time, Mrs Wallace has developed chronic kidney disease.

NOTE - It is CLINICALLY very important that you monitor kidney function in any patient on metformin with signs of renal impairment.

GFR = 37 recently for Mrs Wallace.

[ >60 GFR = no adjustment need
45-60 GFR = monitor eGFR in 3-6 months
30-45 GFR = consider 50% dose decrease of Metformin
< 30 = contraindicated ]

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?

A

Treatment change for Mrs Wallace:
Reduce Metformin dosage by 50%
Take metformin with food, sustained release of metformin = absorbed more slowly so excreted more slowly = lesser exposure of gut and kidneys to metformin at a given time

Renal impairment = problematic in diabetic patients on Metformin because 90% excreted in the kidneys, so lack of excretion = build up of metformin. Metformin is unchanged, not metabolised = active form of metformin accumulates = can lead to a hypoglycaemia. Side effects build up with the metformin too

Hypoglycaemia = worry in elderly due to increased likelihood of falls and fractures

32
Q

When in metformin most effective?

A

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

33
Q

When are DP4i’s most effective?

A

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

34
Q

What do you need to discuss with patients when starting on sulfonylureas?

A

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

35
Q

What happens when sulphonylureas are given alongside metformin?

A

Weight gain is mitigated by the concurrent administration with metformin.

36
Q

What do SGLT-2 inhibitors need to work?

A

SGLT2 action depends on normal renal function so they are less effective in patients with renal impairment

BRS Year 2 (110 decks)

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