Diabetes (including Pharmacology) Flashcards
Describe the etiology/ pathogenesis of T1DM
Caused by absolute deficiency of pancreatic β-cell function due to immune mediated destruction of β-cells
Describe the pathogenesis of T2DM.
Progressive loss of adequate β cell insulin secretion on the background of insulin resistance
o Insulin resistance = glucose utilisation is impaired and hepatic glucose output ↑ despite presence of insulin -> simultaneous elevations in both glucose and blood insulin levels at early stage
o Once pancreas slows down, can have impaired insulin secretion -> somewhat similar to Type 1
State the differences between T1 and T2DM (7 differences)
1) C-peptide (byproduct from formation of insulin in pancreas) absent in T1DM, usually normal in T2DM but can be abnormal at later stages
2) Autoantibody positive in T1DM
3) T1DM has younger age of onset (usually < 30 y.o), T2DM usually > 40 y.o
4) Etiology (T1DM is autoimmune, T2DM insulin resistance)
5) Onset of symptoms is abrupt in T1, gradual in T2
6) Physical appearance usually thin for T1, usually obese for T2DM (insulin resistance often lead to obesity)
7) T1DM more prone to ketosis
What are the common signs of both hyper and hypoglycemia? (6 total)
1) Shaking
2) Dizziness
3) Hunger (Polyphagia)
4) Impaired/blurred vision
5) Drowsiness
6) Weakness/fatigue
What are the symptoms unique to hyperglycemia? (4 total)
- Extreme thirst (Polydipsia)
- Dry skin (from dehydration)
- Frequent urination (Polyuria)
- Decreased wound healing (from high blood glucose)
What are the unique symptoms of hypoglycemia?
- Tachycardia (fast heartbeat)
- Sweating
- Anxiousness
- Headaches
- Irritable
What are the various diagnostic tests available to diagnose diabetes?
HbA1c, FPG or 2hOGTT
At what HbA1c level would a person be considered diabetic?
HbA1c ≥ 7.0%
At what HbA1c level would a person be considered to have no diabetes?
HbA1c ≤ 6.0%
At what FPG level would a person be considered to have diabetes?
FPG ≥ 7.0mmol/L
At what FPG level would a person be considered to have no diabetes?
FPG ≤ 6.0mmol/L
At what 2hOGTT level would a person be considered to have diabetes?
2hOGTT ≥ 11.1mmol/L
At what 2hOGTT level would a person be considered to have no diabetes?
2hOGTT < 7.8mmol/L
Assuming that a person has a HbA1c level of 6.1-6.9%, state the number of further tests required to make a diagnosis on whether person has diabetes or not
1 test (either FPG or 2hOGTT)
State the number of abnormal results required to diagnose diabetes if HbA1c is not used
2 abnormal results
List the complications of diabetes
o Microvascular:
1) Retinopathy, blindness
2) Nephropathy, kidney failure
3) Neuropathy, amputation
* Occurs in 60-70% of patients
o Macrovascular:
1) Cardiovascular Disease
* Risk increases by 2-4 times
o Life expectancy ↓ by 5-10 years
State how HbA1c lowering affects the progression of microvascular and macrovascular complications respectively
Microvascular: The more lowered the HbA1c is, the slower the onset and progression of microvascular complications
Macrovascular: CV outcomes improve as HbA1c decreases but eventually worsens as HbA1c continues to drop
What are suitable measures to prevent diabetes in pre-diabetic patients?
o Lifestyle interventions:
- Achieve and maintain 7% loss of initial body weight
- Increase moderate intensity physical activity to at least 150 mins/week
o Metformin therapy
- Especially for those with BMI > 35 kg/m2, those aged < 60 years, and women with prior gestational diabetes mellitus (particularly high risk for progression to T2DM)
When is Metformin especially indicated in preventing/ delaying T2DM?
1) BMI > 35 kg/m2,
2) those aged < 60 years, and
3) women with prior gestational diabetes mellitus (particularly high risk for progression to T2DM)
What is the general HbA1c target for general population?
HbA1c ≤ 7.0%
In what group of patients would more stringent HbA1c target be acceptable?
Patients with:
1) Short disease duration
2) Long life expectancy
3) No significant CVD (lower the HbA1c, higher the risk of CVD)
In what group of patients would less stringent HbA1c target be acceptable?
Patients with:
1) History of severe hypoglycemia
2) Limited life expectancy
3) Advanced complications
4) Extensive comorbid conditions
5) Those whose target is difficult to attain despite intensive Self-Monitoring of Blood Glucose (SMBG), repeated counselling, and effective pharmacotherapy
What is the general FBG target for general population?
4.0-7.0 mmol/L
In practice: 5.0 -7.0 mmol/L targeted instead
What is the general PPG target for general population?
< 10 mmol/L
What is the MOA of Metformin?
- Primary: ↓ hepatic glucose production
- Secondary: ↑ peripheral/muscle glucose uptake and utilization (i.e↑ insulin sensitivity) via activation of AMPK (AMP-activated protein kinase)
What are the maximal doses of Metformin?
Maximum doses: 3 x 850mg or 3 x 1g (1 tab TDS basically)
What are the ADRs of Metformin?
- Common:
o GI side effects (vomiting, diarrhea, indigestion), Anorexia, Weight loss, Metallic taste (usually transient; take with food to alleviate) - Long term use:
o ↓ serum B12 concentrations
(May lead to anemias e.g Megaloblastic anemia; Greater risk in malnourished patients) - Rare but fatal:
o Lactic acidosis (signs: shallow/ laboured breathing, nausea, mental confusion)
Patient who was started on Metformin 1 week ago presents today with shortness of breath, nausea and mental confusion. Explain the possible pathogenesis of the patient’s symptom.
Metformin decreases metabolism of pyruvate by inhibiting certain enzymes -> ↑ pyruvate -> ↑ lactate (causing lactic acidosis)
What are the contraindications of Metformin?
1) Severe renal impairment (< 30ml/min)
2) Hypoxic states or at risk for hypoxemia
o Heart failure, sepsis (severe hypotension due to infection), liver impairment (cannot clear pyruvate), alcoholism (usually have malnutrition), ≥ 80 yo (not a hard contraindication)
What are the DDIs of Metformin?
1) Ethanol: ↑ risk for lactic acidosis
2) Iodinated contrast material/radiologic procedure -> risk of AKI (renal impairment) which will lead to ↑ metformin concentration
o Temporarily hold metformin for ≥ 48 hrs after contrast administration; restart when renal function returns to normal post procedure
3) Cationic drugs (e.g. Dofetilide, cimetidine, digoxin) may ↑ metformin by competing for renal tubular transport -> less metformin gets secreted
List the key points for Metformin use in renal impairment
o GFR < 60ml/min/m^2: Increase monitoring of renal function (every 3-6 months instead of once a year)
o GFR < 45ml/min/m^2: Halve Metformin dose
o GFR < 30ml/min/m^2: Stop Metformin
What is the place in therapy for metformin? (When is it used, benefits, disadvantages)
First-line (DOC) for T2DM and gestational diabetes
Prevention and delay of T2DM onset
Benefits:
- Good HbA1c reduction (1.5-2%)
- Weight loss
- Positive effects on lipid profile (TG, Total C, LDL)
- Positive CV effects
- Cheap
- Minimal adverse effects
What other off-label uses does Metformin have?
1) PCOS
2) Weight loss
What is the MOA of Sulfonylureas?
- Primary: stimulate insulin secretion by binding to SU receptors -> blocks K+ channel of the β cells -> membrane depolarisation -> Ca influx -> exocytosis of insulin granules in vesicles within the β cells
- Secondary: ↓ hepatic glucose output and ↑ insulin sensitivity
Which are the preferred SU(s) if patient is renally impaired?
Tolbutamide or Glipizide
List the duration of action of the various SUs.
Tolbutamide: 6-12 hours
the rest: 12-24 hours
Need to avoid co-administration of renally cleared drugs for which sulfonylureas?
Glibenclamide, Gliclazide, Glimepride
What are the ADRs of Sulfonylureas?
- Hypoglycemia (especially in elderly due to reduced kidney and/or liver function)
- Weight gain (~2-5 kg) -> happens with drugs that ↑ insulin secretion
- Blood dyscrasias (rare)
Which sulfonylurea needs to be avoided in renal impairment. State the CrCl at which its use needs to be avoided
Glibenclamide
CrCl < 50ml/min
What administration instructions would you give a patient who is going to start on Sulfonylurea?
Take 15-30mins before food. Should you skip meals, also skip your sulfonylurea dose to avoid hypoglycemia (supposed to target PPG).
Which sulfonylurea has the lowest risk of hypoglycemia?
Glipizide
What are the DDIs of Sulfonyureas?
1) β blockers may mask signs and symptoms of hypoglycemia
o Symptoms like tremors, fast heartbeat may be masked
o Only symptom that cannot be masked is sweating
2) Disulfiram like reaction with Ethanol (1st gen»2nd/3rd gen)
o “Alcohol-like” reaction -> symptoms include drunkenness, nausea, vomiting
3) CYP2C9 inhibitors (e.g. amiodarone, 5-FU, fluoxetine) may ↑ glimepiride, glipizide
o Affects those Sulfonylureas that are hepatically eliminated
What is/are the contraindication(s) of Sulfonylureas?
Hypersensitivity
How is Glipizide metabolised?
- Mainly liver (~90%) -> Undergoes Phase I Hydroxylation
What is SU’s place in therapy? (When is it typically used, What are the benefits and disadvantages)
2nd-line antidiabetic for T2DM, uncontrolled with diet and exercise OR in combination with other antidiabetics
No effect for T1DM (requires functioning beta-cells)
Benefits:
- Good HbA1c reduction (1.5%)
- Cost (at early stages of therapy)
Downsides:
- Weight gain
- Risks of hypoglycemia
- Efficacy wears off in long-term (15-20y)
What is the MOA of Thiazolidinediones (TZD)?
Peroxisome proliferator activated receptors (PPAR) agonist -> binding to and activation of PPAR promotes glucose uptake into target cells (skeletal muscle/adipose) by:
o ↓ insulin resistance; ↑ increase insulin sensitivity
- Note: No effects on insulin secretion but dependent on insulin presence for activity
Which TZD is the only one approved for use in combination with insulin?
Pioglitazone
What are the contraindications for TZDs?
1) Active liver disease (TZDs are hepatically cleared)
2) NYHA Class III or IV HF
What are the ADRs of TZDs? (6)
1) Hepatotoxicity
2) Edema (caution in NYHA Class I or II HF) -> from increased sodium and fluid retention
3) Increased risk of fractures (more likely in women)
4) Weight gain -> associated with edema
5) Increased risk of Congestive Heart Failure (HF)
6) Bladder cancer (Pioglitazone)
7) Elevated LDL (Rosiglitazone)
When should a patient on TZDs discontinue/ consider to discontinue TZD
1) ALT > 3x UNL (discontinue)
2) Signs and symptoms of hepatic dysfunction (regardless of ALT level)
3) Pt develop confirmed SnS of HF (consider dose reduction or discontinue)
Other than blood glucose levels, what else need to be monitored after starting TZDs?
- ALT level
(if ALT > 1.5 UNL during therapy, repeat LFTs weekly until normal; Discontinue if ALT >3x UNL) - Signs and symptoms of HF
TZDs should not be initiated if ALT > ___ UNL
3x
What are TZDs place in therapy? (When is it used, benefits, disadvantages)
(T2DM) Monotherapy or in combination with other antidiabetics
Benefits:
- Moderate reduction in HbA1c (0.5-1.4%)
- Some benefits in fatty liver disease
Downsides:
- Weight gain (from edema)
- Hypoglycemia
- Numerous adverse effects (including hepatotoxicity and increased risk of HF and fracture)
What is the MOA of alpha-glucosidase inhibitor?
- Delay glucose absorption and ↓ PPG by competitively inhibiting brush border α-glucosidases enzyme required for breakdown of complex carbohydrates (i.e prevents breakdown of complex sugars)
- Acts locally in GIT
Comment on the pharmacodynamics of Acarbose (e.g onset of action, dose based on what)
- Rapid onset with each meal
- PPG lowering effect is dose related (↑ dose, ↑ PPG lowering)
- Dosing is weight-based
What are the ADRs of Acarbose? (2)
- GI: flatulence, abdominal pain, osmotic diarrhea (most common cause of drug discontinuation; glucose present in water pulls water into large intestine)
- ↑ LFT (specific for acarbose; ↑ risk at dose >100 mg TDS)
