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PR3152 > Pharmacology - Diabetes Mellitus > Flashcards

Pharmacology - Diabetes Mellitus Flashcards

1
Q

What is the mechanism of action of metformin?

A

→ Reduces gluconeogenesis in the liver by activating AMP-activated protein kinase
→ May also enhance tissue sensitivity to insulin – ↑tissue glucose uptake

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2
Q

What is the bioavailability of metformin?

A

40-60% by PO

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3
Q

What is the duration of action of metformin?

A

8-12h

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4
Q

How long does it take for the onset of clinical effect of metformin?

A

Days
Max effects take up to 2 week

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5
Q

How much plasma protein binding does metformin exhibit?

A

minimal

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6
Q

What is the half-life of metformin?

A

3h

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7
Q

How is metformin eliminated?

A

90% excreted unchanged in urine

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8
Q

Does metformin require dose adjustments?

A

Yes, for renal impairment

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9
Q

What is the initiation dose for metformin IR?

A

500-850mg oD

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10
Q

What is the max dose for metformin IR?

A

2500-2550mg daily

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11
Q

How should metformin IR be titrated upwards?

A

Can titrate upwards in 500-850mg intervals Q1-2 weeks divided OD-TDS

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12
Q

What is the initiation dose for metformin XR?

A

500mg OD

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13
Q

How should metformin XR be titrated upwards?

A

Can titrate upwards in 500mg intervals weekly

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14
Q

What is the max dose for metformin XR?

A

2000mg divided into OD or BDX
If >2000mg needed, switch to IR

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15
Q

What are the adverse effects of metformin?

A

→ Anorexia – bec it ↓appetite, but may reduce it TOO MUCH
→ GI disturbances – diarrhoea (weight loss), vomiting, indigestion
→ Metallic taste
→ ↑ risk of vit B12 malabsorption – B12 deficiency in long-term
→ Use w caution in patients w renal impairment – cannot excrete fast enough, accumulates in kidneys
→ Use in caution in patients at risk of lactic acidosis – esp in patients w hepatic, cardiovascular issues

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16
Q

What are the contraindications for metformin?

A

→ GFR < 30ml/min
→ Hypoxic states or at risk for hypoxemia – ↑ risk for lactic acidosis
eg Sepsis, respiratory failure, liver impairment, alcoholism, ≥80yo, HF, acute decompensated HF

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17
Q

What DDIs are there with metformin?

A

→ Alcohol – increases risk for lactic acidosis
→ Iodinated contrast material – stop for ≥48h after admin, restart when renal function is stable
→ Inhibitors/Inducers of OCT

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18
Q

When should metformin be taken?

A

Can be taken regardless of meals

If GI Sx, take with or immediately after meal

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19
Q

What is the mechanism of action of pioglitazone?

A

→ PPARgamma agonist – promotes glucose uptake into skeletal muscle and adipose tissue
→ Does not affect insulin secretion but increases insulin sensitivity

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20
Q

How long does it take for the effects of pioglitazone to show up?

A

1 month for max effect

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21
Q

How is pioglitazone eliminated?

A

liver

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22
Q

Can pioglitazone be used in liver impairment?

A

Yes, but use w caution (monitor LFTs)

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23
Q

What are the adverse reactions associated with pioglitazone?

A

→ Hepatoxicity – monitor liver function test before initiating and periodically thereafter
→ Fluid retention – monitor for HF after initiation/dose adj (Use w caution in NYHA Class I or II)
→ ↑ Fracture risk (more in women)
→ Dose-related weight gain
→ Risk of bladder cancer
→ Increased risk of hypoglycemia if also on insulin

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24
Q

What are the contraindications for pioglitazone?

A

→ Active liver disease
→ Symptomatic or Hx of HF (esp NYHA Class III-IV)
→ Active or Hx of bladder cancer

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25
Q

What is the mechanism of action of glipizide?

A

→ ↑ pancreatic insulin release by binding to SU receptor protein subunits of the KATP channel
→ Binding to SU receptor protein inhibits the KATP channel mediated K+ efflux, which triggers the Ca2+ influx into cell, resulting in insulin release
→ Due to its action being based on the β cell, β cells must be functioning in order to see effects

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26
Q

Can glipizide be used in pregnancy?

A

No

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27
Q

What is the bioavailability of glipizide?

A

> 95%

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28
Q

How long does it take for the onset of action of glipizide?

A

1/2 h

29
Q

What is the duration of action of glipizide?

A

12-24h

30
Q

How much does glipizide bind to plasma proteins?

A

> 99%

31
Q

How long is the half-life of glipizide?

A

4h

32
Q

How is glipizide eliminated?

A

90% hydroxylated by liver
Parent and metabolites excreted in urine qand feces

33
Q

What are the adverse effects associated with glipizide?

A

Hypoglycemia (esp in elderly), weight gain (~2-5kg)

34
Q

What are the DDIs with glipizide?

A

→ Disulfiram-like reaction with alcohol (1-2 glasses still okay, skip dose that day if drinking more)
→ CYP2C9 inhibitors (eg amiodarone, 5-FU, fluoxetine)

35
Q

List 3 DPP4 inhibitors.

A

Sitagliptin, Vildagliptin, Linagliptin

36
Q

What is the mechanism of action of the DPP4 inhibitors?

A

→ DPP-4 degrades the incretins (GLP-1, GIP)
→ DPP-4i reversibly, competitively inhibits DPP-4
→ ↓ enzymatic degradation of GLP-1
→ Prolongs action of endogenous incretins
→ Stimulates β cells to secrete insulin
→ Suppresses α cell-mediated glucagon release and hepatic glucose production
→ DPP-4i thus helps to decrease blood glucose level (ONLY FOR T2DM)

37
Q

What is the bioavailability of sitagliptin?

A

~87%

38
Q

How long is the half-life of sitagliptin?

A

10-12h

39
Q

How is sitagliptin eliminated?

A

Low liver metabolism - 80% excreted unchanged in urine, the rest is excreted in faeces

40
Q

How should sitagliptin be dosed in an otherwise healthy patient?

A

100mg OD

41
Q

How should sitagliptin be dose-adjusted?

A

30≤eGFR<45: 50mg OD
eGFR<30: 25mg OD

42
Q

What DDIs does sitagliptin have?

A

Digoxin

43
Q

What are the adverse effects of DPP4i?

A

→ GI Disturbances
→ Flu-like symptoms (headache, runny nose, sore throat)
→ Skin reactions – blister-like lesions (see doctor immediately)
→ Use with caution in patients w a history of pancreatitis (reduced therapeutic benefits)

44
Q

What is the mechanism of action of GLP-1 agonists?

A

→ Activates GLP-1 receptor on β cells – stimulates adenylate cyclase → ↑cAMP → stimulates PKA → ↑ insulin secretion and ↓ glucagon release
→ Insulin secretion subsides along with the blood glucose concentration dropping
→ Is also able to delay gastric emptying and reduces appetite – weight loss

45
Q

List 2 GLP-1 agonists.

A

Liraglutide, Dulaglutide, Semaglutide

46
Q

How are GLP-1 agonists administered?

A

SC
(except semaglutide that can be administered PO as well)

47
Q

What is the bioavailability of liraglutide?

A

55%

48
Q

How does liraglutide bind to plasma proteins?

A

C16 fatty acid binds to the plasma protein

49
Q

What is the half-life of liraglutide?

A

13h

50
Q

How is liraglutide excreted?

A

Endogenously metabolised as a polipeptide

51
Q

Do GLP-1 agonists need renal adjustment?

A

No

52
Q

How should Liraglutide be dosed?

A

SC injection once weekly regardless of meals
Start at 0.6mg, then titrate to 1.2mg after 1 week. Max of 1.8mg for DM

53
Q

How should Dulaglutide be dosed?

A

SC injection once weekly regardless of meals
Start at 0.75mg, then titrate to 1.5mg after 4 weeks. Max of 4.5mg, titrate in 1.5mg intervals with at least 4 weeks b/w

54
Q

What are the adverse effects associated with GLP-1 agonists?

A

→ N/V – improves when body adjusts to treatment
→ Diarrhoea/constipation
→ Headache/tiredness

55
Q

What groups of patients should not be given GLP-1 agonists?

A

patients w pancreatitis Hx or family Hx of thyroid cancer

56
Q

What is the mechanism of action of SGLT2i?

A

→ Inhibits SGLT2 in the proximal convoluted tubule to reduce the reabsorption of glucose
→ Therefore reduces renal threshold for glucose, which increases urinary glucose excretion

57
Q

What is the bioavailability of Empagliflozin?

A

60-80%

58
Q

How long is the half life of Empagliflozin?

A

12h

59
Q

How much plasma protein binding does Empagliflozin exhibit?

A

~90%

60
Q

How is Empagliflozin eliminated

A

Undergoes minimal metabolism in the liver by glucuronidation
~40% excreted unchanged in faeces, ~20% excreted unchanged in urine

61
Q

How should empagliflozin be dosed?

A

10mg OM w or w/o food
Can increase to 25mg OM if needed
Discontinue if eGFR <45ml/min

62
Q

How should dapagliflozin be dosed?

A

5mg OM w or w/o food
Can increase to 10mg OM if needed
Discontinue if eGFR <45ml/min

63
Q

What are the adverse effects associated with SGLT2i?

A

→ Hypotension - can check bp 1st then cut down antihypertensive and start SGLT-2 - at TCU check BP again to see if need to inc antihypertensive again
→ UTI, female genital fungal infection: ensure hygiene in the genital area (esp Fournier’s gangrene in males – necrotizing fasciitis of the perineum)
→ Increased urination
→ ↑DKA risk – thirst, increased urination, inc RR, dry skin and mouth, flushing, fruity-smelling breath, headache, muscle stiffness or aches, tiredness, N/V, stomach pain
→ Canagliflozin specific: lower limb amputation, hyperkalaemia, fractures

64
Q

What is the mechanism of action of acarbose?

A

Competitively inhibit brush border α-glucosidase enzymes in the small intestine (required for breakdown of complex carbohydrates to absorb them), which delays glucose absorption and ↓PPG

65
Q

How is acarbose dosed?

A

Initiation: 25mg BD-TDS with each meal
Can increase by 25mg/day every 2-4 weeks
Max dose for ≤60kg patient: 150mg/day
Max dose for >60kg patient: 300mg/day
Use not recommended for CrCl <25

66
Q

How is acarbose eliminated?

A

Eliminated by faeces as unabsorbed drug (drug goes directly to the small intestine, whatever doesn’t get used continues along the GIT)

67
Q

What are the adverse events associated with acarbose?

A

→ GI: flatulence, abdominal pain, diarrhoea
→ Increased LFTs – risk increases at doses >100mg TDS

68
Q

What are the contraindications with acarbose?

A

→ GI diseases (obstruction, irritable bowel disease)
→ Liver cirrhosis

69
Q

What is the mechanism of action of insulin?

A

Regulates carbohydrates, fats and amino acids
- Glucose: facilitates uptake of glucose in muscle and adipose tissue and inhibits hepatic glucose output (facilitates glycogenolysis, inhibits gluconeogenesis)
- Fat: enhances fat storage (lipogenesis) and inhibits the mobilisation of fat for energy in adipose tissue (lipolysis and free fatty acid oxidation).
- Protein: increases protein synthesis and inhibits proteolysis in muscle tissue

PR3152 (5 decks)

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