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3152 Endocrine (DM + Thyroid) > DM Older Therapeutic Drugs > Flashcards

DM Older Therapeutic Drugs Flashcards

1
Q

What are the non-pharmacologic therapeutic lifestyle changes that can be recommended in the management of diabetes?

A
  1. Quit smoking (ask, assess, advice, assist, arrange)
  2. Weight reduction (achieve and maintain 7% loss of initial BW)
    - good prognosis for newly-diagnosed, shown to incr sensitivity to insulin
  3. Exercise (150min/week, at least 3 days per week, no more than 2 consecutive days w/o exercise)
    - Moderate intensity: raise HR above baseline
    - Muscle strengthening activity at least 2 days per week
    - If older >55yo, balance and functional training
  4. Diet modification
    - Less carbohydrates (carbs cause incr TG), more proteins
    - Restrict alcohol (alcohol incr TG)
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2
Q

[METFORMIN]

What is Metformin MOA?

A

Metformin is a biguanide

It reduces gluconeogenesis in the liver and activates AMP-activated protein kinase
- AMP-activated protein kinase regulates cellular metabolism, cellular energy homeostasis, activates glucose and fatty acid uptake when cellular energy is low

=> Reduce hepatic glucose production and increase peripheral/muscle glucose uptake and utilization (incr insulin sensitivity)

=> Also enhance tissue sensitivity to insulin to increase glucose uptake into cells and tissues

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3
Q

[METFORMIN]

What is Metformin PD?

A

Onset: within days, max effect up to 2 weeks

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4
Q

[METFORMIN]

What is the absorption profile of Metformin?

A

Oral, duration of action 8-12h

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5
Q

[METFORMIN]

What is the distribution profile of Metformin?

A

Rapidly distributed, minimal plasma protein binding

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6
Q

[METFORMIN]

What is the metabolism profile of Metformin?

A

NOT metabolised in the liver

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7
Q

[METFORMIN]

What is the excretion profile of Metformin?

A

Renal elimination, 90% excreted unchanged in the urine
*Avoid/titrate dose in pt with renal insufficiency as it will accumulate

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8
Q

[METFORMIN]

Can metformin be used in pregnancy?

A

Yes, Cat B

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9
Q

[METFORMIN]

What is the dosing for Metformin?

A

3 times a day (with/after breakfast, lunch, dinner)

Metformin regular release
- three 850mg tabs/day (max 2550mg)
- three 1g tabs/day (max 3000mg)

Metformin extended release

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10
Q

[METFORMIN]

What are Metformin adverse effects?

A

Common: (*take with/after food to alleviate)
- GI disturbances (diarrhea, some weight loss, vomiting, ingestion)
- Anorexia
- Metallic taste

Long-term use:
- Decrease serum B12 concentrations (due to VitB12 malabsorption), lead to megaloblastic anemia

Rare but fatal:
- Lactic acidosis (BBW)

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11
Q

[METFORMIN]

Which group of patients should consider periodic measurement for VitB12 deficiency?

A

Those with anemia or peripheral neuropathy

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12
Q

[METFORMIN]

What are the signs and symptoms of lactic acidosis?

A

Nausea, shallow/labored breathing, mental confusion

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13
Q

[METFORMIN]

How does lactic acidosis occur?

How does metformin cause lactic acidosis?

How does hypoxic state cause lactic acidosis?

A

How lactic acidosis occurs:
Glucose gets broken down into Pyruvate for ATP
Pyruvate gets broken down to lactate and H+ when there is a lack of oxygen (via anaerobic respiration)
Lactate acidosis results from increase production or decrease clearance of lactate

Metformin:

  • Decreases the metabolism of pyruvate by inhibiting the enzyme that breaks down pyruvate, as a result, more pyruvate gets broken down to lactate, and lactate levels increase

Hypoxic state: e.g., in long-term runners

  • Lack of O2 in blood, causes anaerobic respiration, pyruvate gets broken down into lactate and H+
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14
Q

[METFORMIN]

What are the contraindications?

A
  1. Severe renal impairment <30ml/min (since it is renally excreted)
  2. Hypoxic states or at risk for hypoxemia
  • Heart failure (CVD): insufficient O2 increases risk of hypoxemia and hypoperfusion, but if stable HF, Metformin can still be used (avoid if acute HF, in hospital)
  • Liver impairment (hepatic disease): unable to clear pyruvate and lactate
  • Sepsis: severe hypotension, hypoperfusion
  • Alcoholism: malnutrition, incr risk of lactic acidosis
  • 80y and older: not absolute CI unless risk for hypoxia
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15
Q

[METFORMIN]

What are the DDIs?

A
  1. EtOH
  • alcohol increases risk of lactic acidosis
  1. Iodinated contrast material/radiological procedure
  • Contrast-induced renal impairment
  • Hold MET for at least 48h after contrast administration and restart when renal function returns to normal post-procedure
  1. Cationic drugs (e.g., dofetilide, cimetidine, digoxin)
  • Compete with MET for renal tubular secretion (high conc. of MET in body)
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16
Q

[METFORMIN]

Explain the eGFR cut offs and renal dose adjustments and monitoring in the use of Metformin

A

eGFR >= 60: monitor renal function annually

eGFR <60: monitor every 3-6 months

eGFR <45: half dose and monitor every 3 months

eGFR <30: contraindicated

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17
Q

[METFORMIN]

Explain Metformin place in therapy in terms of HbA1c lowering and any additional benefits.

A

Use:

  • 1st line in T2DM
  • Prevent and delay T2DM (prediabetics)
  • 1st line for Gestational diabetes (w insulin)

HbA1c:

  • Decrease HbA1c by 1.5%, up to 2%
  • Marked FPG, mild PPG

Weight:

  • Negligible weight gain, some weight loss

Hypoglycemia:

  • Low risk of hypoglycemia

Other benefits:

  • Minimal positive effects on lipid profiles (lower TG, TC, LDL)
  • Minimal possible reduction in CV events
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18
Q

[METFORMIN]

What is the recommended therapeutic (non-pharm + pharm) management for prediabetes, in order to prevent/delay diabetes?

Which group of patients may Metformin be used to prevent diabetes?

A
  1. Lifestyle is best
  • Achieve and maintain 7% loss of initial BW
  • Moderate intensity 150min/week
  1. Metformin
  • Esp for those with BMI >35kg/m2, age <60y, women with prior gestational DM
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19
Q

[SULFONYLUREAS]

What is the MOA of sulfonylureas

A

Sulfonylureas are insulin secretagogues that stimulate insulin release from B cells in the pancreas

  • SU targets the pancreatic B cell ATP-sensitive K+ channel and binds to the SU receptor proteins
  • This causes ATP sensitive K+ channel to close, hence inhibiting ATP-sensitive K+ channel mediated K+ efflux
  • This triggers the voltage-gated Ca2+ channels to open and secrete calcium into the cell, causing a calcium dependent exocytosis of insulin granules from the pancreatic B cells, hence insulin release

Secondary: decrease hepatic glucose output, incr insulin sensitivity

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20
Q

[SULFONYLUREAS]

Can SUs be used in T1DM?

What about in T2DM?

A

No as its MOA depends on functioning B cells in the pancreas islets that can secrete insulin

Can be used in T2DM, but as diabetes progress, B cells become less functional and hence SU will lost its effectiveness overtime

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21
Q

[SULFONYLUREAS]

How should SU be taken with regards to meal timing?

A

SU should be taken 15-30min before meal as it works on PPG (minimally on FPG), by stimulating insulin release

If meal is skipped/irregular meals, DO NOT TAKE SU => drive hypoglycemia

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22
Q

[SULFONYLUREAS]

List examples of the different generations of SU

A

1st Gen: Tolbutamide
2nd Gen: Glipizide, Gliclazide, Glibenclamide
3rd Gen: Glimepiride

23
Q

[SULFONYLUREAS]

Explain the absorption profile of Glipizide

A

Oral
F >95% (delayed with food intake, therefore take 15-30min before food)
Onset 0.5h
Duration of action 12-24h

24
Q

[SULFONYLUREAS]

Explain the distribution profile of Glipizide

A

Binds extensively ~99% to plasma proteins (primarily albumin)

25
Q

[SULFONYLUREAS]

Explain the metabolism profile of Glipizide

A

Liver (90%), phase 1 hydroxylation
Metabolites are inactive

*Concern with liver impairment, CYP450 DDIs
=> CYP2C9 inhibitors increase glipizide concentration

26
Q

[SULFONYLUREAS]

Explain the excretion profile of Glipizide

A

<10% excreted unchanged in urine and feces
Metabolites are excreted in urine and feces

*Action is prolonged in pt with renal impairment

27
Q

[SULFONYLUREAS]

Explain the choice of Glipizide as the preferred agent in pt with renal impairment

A

Glipizide

  • 90% hepatically eliminated via phase 1 hydroxylation
  • Inactive metabolite
  • Duration of action 12-24h (not long lasting)
  • Lower risk of hypoglycemia compared to the other SUs

Why avoid the rest?

  • The rest are mostly renally excreted, avoid use in renally impaired (CrCl <50ml/min), and elderly with poorer renal function => risk of hypoglycemia
28
Q

[SULFONYLUREAS]

What are the adverse effects of SU?

A
  1. Hypoglycemia (especially in elderly, reduced kidney or liver function)
  2. Weight gain (2-5kg)
  3. Blood dyscrasias (rare)
29
Q

[SULFONYLUREAS]

What are the CIs with SU?

A

Hypersensitivity to SUs

30
Q

[SULFONYLUREAS]

What are the DDIs with SU?

A
  1. Beta blockers
  • May mask signs and symptoms of hypoglycemia (reduces the sympathetic tone and mask symptoms such as rapid HR, tremors)
  1. EtOH
  • Disulfiram-like reaction (alcohol-like rxn such as nausea, vomiting, flushing, dizziness, chest and abdominal discomfort, hangover symptoms)
  1. CYP2C9 inhibitors (e.g. amiodarone, 5-FU, fluoxetine)
  • Incr conc. of Glipizide (2nd gen), Glimepiride (3rd gen)
31
Q

[SULFONYLUREAS]

Tolbutamide is 95% hepatically eliminated. Explain why it is not commonly used.

A

1st Gen SUs have higher risk of disulfiram-like reaction with EtOH (compared to 2nd or 3rd gen)

32
Q

[SULFONYLUREAS]

What is SU place in therapy in terms of HbA1c lowering and any additional benefits.

A

HbA1c:

  • Decrease HbA1c by 1.5%
  • Marked reduction in PPG, mild FPG

Weight:

  • Weight gain (2-5kg) *exercise, diet to minimize

Hypoglycemia:

  • High risk of hypoglycemia *ensure take before meals only, do not take if skip meals

Other benefits:

  • NIL
  • Cost-effective therapy at initial stages of diagnosis
33
Q

[THIAZOLIDINEDIONES]

Name 2 TZDs

A

Pioglitazone
Rosiglitazone

34
Q

[THIAZOLIDINEDIONES]

What is the MOA of TZDs?

A

TZDs are peroxisome proliferator activated receptor agonist, that promote glucose uptake into target cells (skeletal muscle/adipose)

It is an insulin sensitizer - decrease insulin resistance and increase insulin sensitivity

35
Q

[THIAZOLIDINEDIONES]

Which TZD is the only one approved for use in combi with insulin?

A

Pioglitazone

*TZDs generally precaution when use with insulin since it increases insulin sensitivity, can cause incr risk of hypoglycemia

36
Q

[THIAZOLIDINEDIONES]

Describe the PD (onset of action) of TZD

TZD can be take _____ meals

A

Takes up to a month to work

TZD can be taken regardless of meals

37
Q

[THIAZOLIDINEDIONES]

Describe the metabolism of TZD

A

Hepatic elimination

FYI:
- Rosiglitazone has DDI with CYP2C8 inhibitors/inducers
- Pioglitazone has DDI with CYP2C8 inhibitors/inducers as well as CYP3A4 inhibitors/inducers

38
Q

[THIAZOLIDINEDIONES]

TZD has a boxed warning due to increased risk of ______

*Use of TZD is restricted in Sg

A

Congestive heart failure (HF)

  • Contraindicated in NYHA Class III or IV HF
  • Close monitoring in NYHA Class I and II HF

If use TZD,
- After initiation or dose increase, observe pt for S&S of HF
- If HF S&S develops, initiate appropriate management for HF + discontinue/reduce dose of TZD

39
Q

[THIAZOLIDINEDIONES]

TZDs are not often use due to its wide adverse effect profile.

What are the adverse effects of TZD?

A
  1. Boxed warning due to incr risk of CHF
    - After initiation or dose increase, observe pt for S&S of HF
    - If HF S&S develops, initiate appropriate management for HF + discontinue/reduce dose of TZD
  2. Hepatotoxicity
    - Monitor LFTs
  3. Edema (due to incr sodium and fluid retention a/w HF)
    - caution in Class I and II
  4. Fracture risk (w long-term use)
    - Higher risk in women
  5. Weight gain
    - Associated with edema
  6. Bladder cancer (Pioglitazone)
  7. Elevated LDL (Rosiglitazone)
40
Q

[THIAZOLIDINEDIONES]

Describe the monitoring of LFTs as well as initiation and discontinuation with regards to the use of TZD

A

Hepatotoxicty

  • Do not initiate TZD if ALT >3x ULN
  • Discontinue if ALT >3x ULN
  • If ALT >1.5x ULN during therapy, repeat LFTs WEEKLY till normal
  • Discontinue if there are S&S of hepatic dysfunction regardless of ALT levels
41
Q

[THIAZOLIDINEDIONES]

What are the CIs w TZD

A
  1. NYHA Class III and IV HF
  2. Active liver disease (due to hepatotoxicity)
42
Q

[THIAZOLIDINEDIONES]

Explain Thiazolidinediones place in therapy in terms of HbA1c lowering and any additional benefits.

A

Use/Benefit:

  • Beneficial in pt with fatty liver disease (NAFLD, NASH) *provided liver is stable

HbA1c:

  • Decrease HbA1c by 0.5-1.4%
  • Moderate effects on FBG and PPG

Weight:

  • Weight gain (a/w edema)
43
Q

[THIAZOLIDINEDIONES]

What are the key monitoring parameters when use TZDs?

A
  1. LFTs
  2. S&S of HF
  3. Fracture risk with long-term use (women > men)
44
Q

[a-Glucosidase Inhibitors] - acarbose

What is the MOA of acarbose?

A

Delay glucose absorption and decrease PPG by competitively inhibiting brush border a-glucosidase enzymes (in SI) required for breakdown of complex carbohydrates

(Thus carbohydrates stay as complex in the gut)

45
Q

[a-Glucosidase Inhibitors] - acarbose

What is an off-label use of Acarbose?

A

T1DM pt who are on insulin but require additional control of PPG levels

46
Q

[a-Glucosidase Inhibitors] - acarbose

Describe the PD (onset of action) of Acarbose

A

Onset is rapid with each meal

*Take with meals

47
Q

[a-Glucosidase Inhibitors] - acarbose

Describe the elimination PK profile of Acarbose

A

Eliminated 50% via feces

48
Q

[a-Glucosidase Inhibitors] - acarbose

Can acarbose be used in pregnancy?

A

Yes, Cat B

49
Q

[a-Glucosidase Inhibitors] - acarbose

Acarbose is taken _____ meals, why?

A

Acarbose is taken WITH meals

PPG lowering is dose dependent (higher dose, higher potential for PPG lowering)

Take with meals as it works solely on PPG, if meal is skipped, skip the dose
*Similar to sulfonylureas

50
Q

[a-Glucosidase Inhibitors] - acarbose

What are the adverse effects of acarbose?

A
  1. GI: Flatulence, abdominal pain, diarrhea
    - FLATULENCE is the most common cause of discontinuation
    - Osmotic diarrhea pulls water into the gut, where the unabsorbed complexes are
  2. Increase LFT
    - Some risk of hepatotoxicity when doses exceed >100mg TDS
51
Q

[a-Glucosidase Inhibitors] - acarbose

What are the CIs with acarbose use?

A
  1. Breastfeeding (not studied)
  2. GI diseases (obstruction, IBD)
52
Q

[a-Glucosidase Inhibitors] - acarbose

What are the DDIs with acarbose use?

A
  1. Instestinal adsorbents (e.g., charcoals)
  2. Digestive enzyme preparation (e.g., yakult)

=> may decrease the effects of a-Glucosidase inhibitors

53
Q

[a-Glucosidase Inhibitors] - acarbose

What is its place in therapy in terms of HbA1c lowering and any additional benefits.

A

HbA1c:

  • Decrease HbA1c by 0.5-0.8%
  • Moderate effect on PPG only

Weight:

  • Neutral

Use:

  • May consider taking with the largest meal of the day/meal with most carbs, to control PPG

3152 Endocrine (DM + Thyroid) (11 decks)

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