DM Flashcards
What is the mechanism of action of metformin?
→ Reduces gluconeogenesis in the liver by activating AMP-activated protein kinase
→ May also enhance tissue sensitivity to insulin – ↑tissue glucose uptake
What is the duration of action of metformin?
8-12h
How long does it take for the onset of clinical effect of metformin?
Days
Max effects take up to 2 week
How much plasma protein binding does metformin exhibit?
minimal
How is metformin eliminated?
90% excreted unchanged in urine
Does metformin require dose adjustments?
Yes, for renal impairment
What is the initiation dose for metformin IR?
500-850mg oD
What is the max dose for metformin IR?
2500-2550mg daily
How should metformin IR be titrated upwards?
Can titrate upwards in 500-850mg intervals Q1-2 weeks divided OD-TDS
What is the initiation dose for metformin XR?
500mg OD
How should metformin XR be titrated upwards?
Can titrate upwards in 500mg intervals weekly
What is the max dose for metformin XR?
2000mg divided into OD or BDX
If >2000mg needed, switch to IR
What are the adverse effects of metformin?
→ 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
What are the contraindications for metformin?
→ 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
What DDIs are there with metformin?
→ Alcohol – increases risk for lactic acidosis
→ Iodinated contrast material – stop for ≥48h after admin, restart when renal function is stable
→ Inhibitors/Inducers of OCT
When should metformin be taken?
Can be taken regardless of meals
If GI Sx, take with or immediately after meal
What is the mechanism of action of pioglitazone?
→ PPARgamma agonist – promotes glucose uptake into skeletal muscle and adipose tissue
→ Does not affect insulin secretion but increases insulin sensitivity
How long does it take for the effects of pioglitazone to show up?
1 month for max effect
How is pioglitazone eliminated?
liver
Can pioglitazone be used in liver impairment?
Yes, but use w caution (monitor LFTs)
What are the adverse reactions associated with pioglitazone?
→ 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
What are the contraindications for pioglitazone?
→ Active liver disease
→ Symptomatic or Hx of HF (esp NYHA Class III-IV)
→ Active or Hx of bladder cancer
What is the mechanism of action of glipizide?
→ ↑ 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
Can glipizide be used in pregnancy?
No
How long does it take for the onset of action of glipizide?
1/2 h
What is the duration of action of glipizide?
12-24h
How much does glipizide bind to plasma proteins?
> 99%
How long is the half-life of glipizide?
4h
How is glipizide eliminated?
90% hydroxylated by liver
Parent and metabolites excreted in urine qand feces
What are the adverse effects associated with glipizide?
Hypoglycemia (esp in elderly), weight gain (~2-5kg)
What are the DDIs with glipizide?
→ Disulfiram-like reaction with alcohol (1-2 glasses still okay, skip dose that day if drinking more)
→ CYP2C9 inhibitors (eg amiodarone, 5-FU, fluoxetine)
List 3 DPP4 inhibitors.
Sitagliptin, Vildagliptin, Linagliptin
What is the mechanism of action of the DPP4 inhibitors?
→ 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)
How long is the half-life of sitagliptin?
10-12h
How is sitagliptin eliminated?
Low liver metabolism - 80% excreted unchanged in urine, the rest is excreted in faeces
How should sitagliptin be dosed in an otherwise healthy patient?
100mg OD
How should sitagliptin be dose-adjusted?
30≤eGFR<45: 50mg OD
eGFR<30: 25mg OD
What DDIs does sitagliptin have?
Digoxin
What are the adverse effects of DPP4i?
→ 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)
What is the mechanism of action of GLP-1 agonists?
→ 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
List 2 GLP-1 agonists.
Liraglutide, Dulaglutide, Semaglutide
How are GLP-1 agonists administered?
SC
(except semaglutide that can be administered PO as well)
What is the half-life of liraglutide?
13h
How is liraglutide excreted?
Endogenously metabolised as a polipeptide
Do GLP-1 agonists need renal adjustment?
No
How should Liraglutide be dosed?
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
How should Dulaglutide be dosed?
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
What are the adverse effects associated with GLP-1 agonists?
→ N/V – improves when body adjusts to treatment
→ Diarrhoea/constipation
→ Headache/tiredness
What groups of patients should not be given GLP-1 agonists?
patients w pancreatitis Hx or family Hx of thyroid cancer
What is the mechanism of action of SGLT2i?
→ Inhibits SGLT2 in the proximal convoluted tubule to reduce the reabsorption of glucose
→ Therefore reduces renal threshold for glucose, which increases urinary glucose excretion
How long is the half life of Empagliflozin?
12h
How much plasma protein binding does Empagliflozin exhibit?
~90%
How is Empagliflozin eliminated
Undergoes minimal metabolism in the liver by glucuronidation
~40% excreted unchanged in faeces, ~20% excreted unchanged in urine
How should empagliflozin be dosed?
10mg OM w or w/o food
Can increase to 25mg OM if needed
Discontinue if eGFR <45ml/min
How should dapagliflozin be dosed?
5mg OM w or w/o food
Can increase to 10mg OM if needed
Discontinue if eGFR <45ml/min
What are the adverse effects associated with SGLT2i?
→ 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
What is the mechanism of action of acarbose?
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
How is acarbose dosed?
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
How is acarbose eliminated?
Eliminated by faeces as unabsorbed drug (drug goes directly to the small intestine, whatever doesn’t get used continues along the GIT)
What are the adverse events associated with acarbose?
→ GI: flatulence, abdominal pain, diarrhoea
→ Increased LFTs – risk increases at doses >100mg TDS
What are the contraindications with acarbose?
→ GI diseases (obstruction, irritable bowel disease)
→ Liver cirrhosis
What is the mechanism of action of insulin?
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
