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Clinical Pharmacology > 5.2 Diabetes Mellitus > Flashcards

5.2 Diabetes Mellitus Flashcards

1
Q

What stimulates insulin secretion?

A

In response to:
Increase glucose
Incretin (GLP-1, GIP)
PS activity (M3)

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2
Q

What is he plasma half life of insulin?

A

5 minutes

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3
Q

What inhibits insulin release?

A

Decrease plasma glucose levels
Cortisol
Sympathetic activity at alpha2 receptors

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4
Q

What is the role of insulin?

A

Inhibition of gluconeogenesis and glycogenolysis
Increasing glycogen stores
Promote uptake of glucose into tissues

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5
Q

Describe the pattern of secretion of insulin

A
  • secreted into the blood even during fasting to prevent receptor downregulation
  • biphasic pattern of insulin release due to rate and extent of plasma glucose concentration following a meal
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6
Q

What are common signs and symptoms of T1DM?

A 
Polydipsia 
Polyuria
Weight loss
Fatigue/lethargy
Blurred vision
Hyperglycaemia
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7
Q

What test result are indicative of T1DM?

A

Fasting glucose of more than 6.9mmol/L
Random plasma glucose greater than 11mmol/L
Plasma or urine ketones in presence of hyperglycaemia.
HbA1c of greater than 48mmol/mol

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8
Q

What does HbA1c represent?

A

The percentage of RBC with a sugar coated ( glycated haemoglobin). Reflects the average blood sugar over the last 10-12 weeks mmol/mol

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9
Q

What is the biochemical triad of diabetic ketoacidosis?

A

Hyperglycaemia
Ketonaemia
Acidosis

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10
Q

When should diabetic ketoacidosis be suspected?

A

Blood glucose of great than 11mmol/L
AND
polydipsia, polyuria, abdominal pain, V+D, lethargy, confusion, visual disturbance, acetonic breath, symptoms of shock

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11
Q

What are the precipitating factors for diabetic ketoacidosis?

A

Infection, trauma, non-adherence to insulin treatment, DDIs

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12
Q

How is DK treated?

A

I.V. Infusion of fluids with Potassium and then

I.V. Infusion of soluble insulin.

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13
Q

When might a patient be in DK and euglycaemic?

A

When T1DM haven’t eaten for a long time

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14
Q

What are the different types of therapeutic insulin’s used?

A

Porcine
Bovine
Human insulin (recombinant DNA or enzymatic modification of porcine)

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15
Q

Why must insulin be given parenterally?

A

As insulin is a protein and will be digested in the gut so oral administration not suitable

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16
Q

How is insulin usually administered?

A
  • Subcutaneous injection into adipose

- I.V. Injection used in emergency

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17
Q

What methods are used to reduce the absorption of insulin?

A
  • Protamine and/or zinc complex with natural (bovine/porcine) insulins – used less now
  • Soluble (neutral) insulin forms hexamers – delaying absorption from site of injection. [plasma] greatest after 2-3 hr – dosing 15-30 min prior to meals often prescribed
  • Insulin analogues – recombinant modifications – a few amino acid changes – changes PK not PD
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18
Q

Why is it important to rotate site of administration of insulin?

A

Reduce lipodystrophy

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19
Q

What devices are commonly used in insulin administration?

A

Syringes
Pens
Pumps
Inhalers

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20
Q

What are the adverse effects of insulin?

A

Hypoglycaemia

Lipodystrophy

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21
Q

What are the contraindications of insulin?

A

Renal impairment - hypoglycaemia risk

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22
Q

What are the important drug interactions of insulin?

A

Does of insulin needs increasing with systemic steroids.

Caution with other hypoglycaemic agents

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23
Q

What is basal bolus dosing?

A

A common dosing schedule for young active T1DM patients. Provides some flexibility. Take 2 insulin medications, 1. Rapid acting bolus 30mins before each meal e.g. aspart 2. Long acting basal once a day e.g. glargine

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24
Q

What is diabulimia?

A

When a T1DM stops or reduces their insulin to control their weight

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25
Q

Why is insulin administered s.c and not P.o?

A

As it is a peptide hormone that would be digested in the gut.

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26
Q

What is the difference between [glucose] and HbA1c? What information do they provide?

A 
[glucose] = plasma glucose concentration at that moment in time. Measured in mmol/L
HbA1c = glycated haemoglobin, reflects average blood sugar level over last 10-12 weeks mmol/mol
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27
Q

Would you need to increase or decrease insulin dosing in a patient with renal impairment?

A

In renal impairment the dosing of insulin should be reduced as insulin in excreted through the renal system. Normal dosing could result in hypoglycaemia as the insulin remains for longer

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28
Q

Why does insulin need to be modified or analogues used? How does this change PK properties?

A

Modified to produce 2 different kinds of insulin analogues. Fast acting bolus (aspart) and slow acting basal (glargine)
Changes the absorption

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29
Q

What is the causation of T2DM?

A

Insulin into cells reduced due to cellular resistance associated with obesity.

30
Q

How is T2DM managed?

A 
Education
Weight loss - surgery
Initially non-insulin therapies. 
Insulin in poorly managed or later stage disease
Treat co-morbidities
31
Q

Give an example of a biguanide?

A

Metformin

32
Q

What is the mechanism of action of metformin?

A

Decreased hepatic glucose production by inhibiting gluconeogenesis. Some gluconeogenesis remains so risk of hypoglycaemia reduced.
Suppress appetite, limit weight gain.

33
Q

What are the adverse affects of biguanides?

A

GI upset - nausea, vomiting, diarrhoea

34
Q

What are the contraindications of metformin?

A

Excreted unchanged by kidneys - stop if EGFR is <30mL/min (CKD stage 4/5)
Alcohol intoxication

35
Q

What are important drug interactions of biguanides?

A

ACEi, diuretics, NSAIDs - drugs that may impair renal function
Loop and thiazide like diuretics that increase glucose reabsorption so can reduce metformin action

36
Q

Give an example of sulfonylureas

A

Gliclazide

37
Q

How does gliclazide work?

A

Stimulates pancreatic insulin secretion by blocking ATP-dependant K+ channels
Decreased K+ in the cell causes membrane depolarisation causing calcium influx.
Need residual pancreatic function to work (no use for T1DM)

38
Q

What are the indications for gliclazide?

A

Used in combination with other agents (metformin) for the treatment of T2DM
Flirt line option if metformin contraindicated

39
Q

What are the adverse effects of sulfonylureas?

A

mild GI upset – nausea, vomiting, diarrhoea, hypoglycaemia (works at low [glucose])
Weight gain through anabolic effects of insulin

40
Q

What are the contraindications of gliclazide?

A

Hepatic and renal disease - caution as at risk of hypoglycaemia

41
Q

What are the important drug interaction of gliclazide?

A

Other hypoglycaemic agents

Loop diuretics and thiazide like can increase glucose so reduce action of sulfonylureas

42
Q

Give examples of thiazolidinediones?

A

Pioglitazones

Rosiglitazone

43
Q

What is the mechanism of action of glitazones?

A

Insulin sensitisation in muscle and adipose, ↓hepatic glucose output by activation of PPAR-γ → gene transcription

44
Q

Why do glitazones take a long time to cause benefit?

A

As mechanism of decreasing hepatic glucose output is via gene transcription. This takes time and can take 6-8 weeks to show any benefit

45
Q

What are the side effects of glitazones?

A

GI upset, fluid retention, fracture risk, bladder cancer, weight gain

46
Q

What are the warnings and contraindications of glitazones?

A

Heart failure because of fluid retention

47
Q

Give examples of SGLT-2 inhibitors

A

Dapagliflozin

Canagliflozin

48
Q

What is the mechanism of action of gliflozins?

A

Competitive reversible binding at the SGLT-2 in the PCT
Decreases glucose reabsorption at the kidneys and increases urinary glucose excretion. Causes modest weight loss and the hypoglycaemic risk is low.

49
Q

What are the indications of gliflozins?

A

Adjunct to insulin in TIDM (high BMI)

TIIDM as add on therapy

50
Q

What are the side effects of gliflozins?

A

UTI and genital infection

Thirst and polyuria

51
Q

What a re the contraindications of gliflozins?

A

DKA in T2DM

Hypotension

52
Q

What are the drug interactions with gliflozins?

A

Antihypertensives

Other hypoglycaemic agents

53
Q

What are the physiological effects of GLP-1?

A 
Pancreas - increase insulin biosynthesis and secretion, decrease glucagon secretion 
Brain - increased satiety 
Liver- decreased glucose production 
Muscle - increased glucose uptake
Stomach - decreased gastric emptying
54
Q

Give examples of Dipeptidyl peptidase -4 inhibitors

A

Sitagliptin

Saxagliptin

55
Q

What is the mechanism of action of gliptins?

A 
Prevent incretin (GLP-1) degradation - increases plasma incretin concentrations. Glucose dependant so postprandial action. Do not stimulate insulin secretion at normal blood glucose - lower hypoglycaemic risk.
Suppress appetite (weight neutral)
56
Q

What are the side effects of gliptins ?

A

GI upset, small pancreatitis risk

57
Q

What are the contraindications of gliptins?

A

Pregnancy

History of pancreatitis

58
Q

What are the important drug interactions of gliptins?

A

Other hypoglycaemic drugs

Loop and thiazide like diuretics

59
Q

Give examples of glucagon-like peptide-1 receptor agonists?

A

Exenatide
Liraglutide
Aka incretin mimetics

60
Q

Describe the mechanism of action of Exenatide

A

↑glucose dependant synthesis of insulin secretion from β-cells
activate GLP-1 receptor – resistant to degradation by DPP-4

61
Q

Why are GLP-1 receptor agonists given subcutaneously?

A

As they are peptides and would be digested if given orally.

62
Q

When are GLP-1 receptor agonists indicated?

A

NICE suggest add-on if triple therapy ineffective

63
Q

What are the side effects of GLP-1 receptor agonists ?

A

GI upset, decreased appetite with weight loss

64
Q

When are GLP-1 receptor agonists contraindicated?

A

Renal impairment

65
Q

Wh must extended release metformin tablets be swallowed whole?

A

As usually it is the capsule coating that is causing the modification and slows the absorption. Breaking the capsule would mean the dose was absorbed quicker than desired.

66
Q

Metformin can come in combination tablet options. What are the advantages and disadvantages of these options?

A

Advantages : improved adherence

Disadvantages: difficult to modify doses

67
Q

Why is there particular caution for metformin in patients with impaired renal function?

A

As metformin is excreted without being metabolised. If the glomerular filtration rate is impaired then metformin wont be excreted as quickly.

68
Q

Why do sulfonylureas tend to promote weight gain?

A

Gliclazide stimulate insulin release by blocking the ATP-dependant K+ channels. As more insulin released, this promotes anabolic reactions and weight gain.

69
Q

Why do incretin mimetics have a low risk of hypoglycaemia compared to other hypoglycaemic agents?

A

Incretin mimetics are GLP-1 receptor agonists and increase the synthesis of insulin dependant on levels of glucose.

70
Q

Why is the duration of action of glitazones such as pioglitazone not related to the T1/2?

A

As glitazones act via the PPAR-gamma gene causing gene transcription that results in increase insulin sensitisation in muscle and adipose tissue. Gene transcription can take take and benefit from drug can take 6-8 weeks.

71
Q

For most patients what is the first hypoglycaemic agent that would be prescribed?

A

Metformin

Clinical Pharmacology (26 decks)

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