DM Pharmacology Flashcards
Biguanides
indication
Indication: Monotherapy with diet and exercise OR in combination with other agents/insulin for T2DM
- Off label: polycystic ovarian syndrome (PCOS).
Biguanides
moa
MOA:
Primary: decrease hepatic glucose production (inhibits gluconeogenesis in liver = increase AMP-activated protein kinase)
Secondary: increase peripheral/muscle glucose uptake and utilization (increase insulin sensitivity)
Biguanides
(Dosages and administration)
Metformin IR
250mg 500mg 850mg 1000mg
Start with 500-850mg OD
Increase by 500-850mg OD every 1-2 weeks in divided doses.
Max dose 2500 – 2550 mg OD.
Metformin XR
500mg 750mg 1000mg
Start with 500mg OD
Increase by 500mg weekly.
Max dose 2000mg OD. May divide dose to 1000mg BD if glycaemic control not achieved with OD dosing.
If dose >2000mg needed, switch to IR
Biguanides
PD PK
PD
Onset within days max 2 weeks
PK
A: Oral, F 40-60%, DOA: 8-12h
D: Rapidly distributed, minimal plasma protein binding. T1/2 3h
M: NA
E: Renal elimination, 90% in urine unchanged.
Biguanides
ADR
Common:
GI disturbances (diarrhoea, N/V, indigestion), anorexia, loss of appetite, metallic taste.
Usually transient and to take with food and increase dose regularly to minimise GI disturbance.
Long term:
May decrease serum B12.
Consider periodic measurement esp in those with anemia, peripheral neuropathy, or symptoms such as numbness, tingling.
Rare but fatal:
Lactic acidosis (3/100,000 patients/year)
Symptoms – N/V, abdominal pain, shallow/labored breathing, mental confusion.
Biguanides
DDI
DDI
EtOH/alcohol:
Increase risk of lactic acidosis.
Iodinated contrast material (for radiologic procedures e.g., x-rays, CT scan):
Temporarily withhold metformin for ≥48 hours after administration. Restart when renal function is stable and acceptable post procedure.
(Metformin may accumulate)
Organic cationic transporters (OCT) inhibitors/inducers e.g., cimetidine, dolutegravir, ranolazine):
May increase metformin by decreasing its renal elimination.
Biguanides
Contra
Contraindications
Severe renal impairment (GFR <30ml/min)
Hypoxic states/hypoxia risk (increased risk of lactic acidosis)
E.g.,
HF (avoid use in acute decompensated heart failure), sepsis, respiratory failure, liver impairment, alcoholism, ≥80 yo
Biguanides
Special population
May be considered for pregnancy patients with T2DM (low risk)
Require renal dose adjustment.
Metformin IR suitable for children ≥10 years; metformin XR not suitable for children.
Biguanides
Comments
Decreases A1c by 1.5%.
Negligible weight gain and hypoglycaemia.
- Good for obese patients (loss of appetite) and elderly patients (low risk of hypoglycaemia)
Possible reduction in CV with T2DM.
Prevent and delay T2DM.
OK for pregnancy.
thiazolidinediones
(Drug Dosage Administration
Pioglitazone 15mg , 30mg (tablet)
Start with 15mg or 30mg OD
Increase dose by 15mg
Max 45mg OD
thiazolidinediones
MOA
Peroxisome proliferator activated receptor gamma ( PPARgamma ) agonist to promote
glucose uptake into target cells (skeletal muscle/adipose tissue)
- ↓insulin resistance; ↑ increase insulin sensitivity
- No effects on insulin secretion
thiazolidinediones
PD PK
PD
Up to one month for max effect
PK
Liver elimination
thiazolidinediones
(ADR)
Hepatotoxicity
Monitor LFT prior to initiation and periodically thereafter.
Do not initiate therapy/discontinue if ALT > 3xUNL.
If ALT > 1.5xULN during therapy, repeat LFT weekly until normal.
Discontinue if s/sx of hepatic dysfunction regardless of ALT level.
Fluid retention
Caution use in NYHA Class I and II HF
Monitor s/sx of HF after initiation/dose adjustment.
Monitor weight gain from fluid retention.
Fracture (increased risk, esp women)
Risk of bladder cancer
Increased risk of hypoglycaemia with insulin therapy.
thiazolidinediones
(Contraindications
Contraindications
Active liver disease
Symptomatic or history of HF (esp class III to IV)
Active/history of bladder cancer.
thiazolidinediones
DDI
DDI
CYP3A4 AND CYP2C8 inhibitors and inducers
thiazolidinediones
(comments)
Decreases A1c by 0.4 - 1.4%.
**has some weight gain effects
**
Appears beneficial to patients with fatty liver disease (NAFLD and NASH)
CV effects
Potential reduction in risk of stroke
Increase risk of HF
Progression of diabetes kidney disease (neutral)
sulfonylureas
MOA
Primary: stimulate insulin secretion by blocking K+ channel of b-cells in pancreas islets (NEED BETA CELLS TO WORK).
- Targets the b-cell ATP-sensitive potassium (K ATP) channel, which controls the b-cell membrane potential.
- Binds to the SU receptor protein subunits of the K ATP channel inhibits K ATP channel mediated K+ efflux depolarisation opens voltage gated Ca channel trigger calcium dependent exocytosis of insulin granules from b-cells.
Secondary: decrease hepatic glucose output and increase insulin sensitivity.
glipizide (Drug Dosage Administration PD PK )
Glipizide
5mg 10mg (tablet)
5 mg BD (max dose 40mg/day)
Onset 12-24 hours
Inactive metabolite
A: F>95%
Onset: 1/2h
DOA: 12-24h
D: Binds extensively (99%) to plasma proteins (primarily albumin)
T1/2 4h
M: Hepatic 90%, hydroxylation
E: <10% excreted unchanged in urine + faeces. metabolites are excreted in urine + faeces.
sulfonylureas
DDI
DDI
Betablockers
May mask the signs and symptoms of hypoglycaemia.
EtOH/alcohol
Disulfiram-like reactions
(1st gen»> 2nd/3rd gen)
Flushing, tremors. Usually, 1-2 glasses a day is okay, however if patient drinks a lot, to avoid dosing.
CYP2C9 inhibitors e.g., amiodarone, 5FU, fluoxetine)
sulfonylureas
ADR
Hypoglycaemia
Use with caution in patients with irregular meal schedules.
Use with caution in elderly patients as more likely to have kidney failure titrate dose.
Weight gain (appx 2-5kg)
Exercise to minimise weight gain.
Sulfonylurea
Contraindications
Contraindications
Hypersx due to SUs
sulfonylurea comments
Decreases A1c by 1.5%.
No apparent benefits other than blood glucose lowering.
Take 15-30min before meal.
Glipizide has lowest risk of hypoglycaemia compared to other SUs.
Glipizide and tolbutamide recommended for renal impairment, however still need to watch for kidney function in glipizide as overdose can cause hypoglycaemia.
vildagliptin special population instructions
Hepatic dose adjustment:
CrCL ≥50ml/min: 50mg BD CrCL <50ml/min: 50mg daily
Use with caution if ≥75 years old.
linagliptin special population + DDI
DDI
CYP3A4 inducers
Decreases linagliptin concentration.
Special populations
No renal or hepatic dose adjustment
DPP4i
MOA
Inhibit DPP4 enzyme
- Decrease enzymatic degradation of GLP1.
- Prolong action of endogenous incretins.
- Stimulates B cell to increase glucose stimulated insulin release.
- Suppress alpha cell mediated glucaogon release and hepatic glucose production.
Sitagliptin
Dosage Administration PD PK
DDI
Special population
100mg OD
Take regardless of meals.
A: oral
F 87%
D: T1/2 10-12h
M: low liver metabolism
E: 80% excreted unchanged in urine, rest in faces.
DDI Digoxin
Increase digoxin conc (minimal).
Special population
Renal dose adjustment:
eGFR ≥ 30 to < 45 mL/min/1.73 m2: 50mg OD
eGFR < 30 mL/min/1.73 m2: 25mg OD
doses for the dpp4i agents?
SITAGLIPTIN 100MG OD
VILDAGLIPTIN 50MG BD (IF METFORMIN/TZD), 50MG OD (IF SU)
LINAGLIPTIN 5MG OD
DPP4i
ADR
ADR
Generally mild side effects
GI disturbances
Severe joint pain that can be disabling (persist even after stopping treatment)
Flu like symptoms: headache, running nose, sore throat.
Acute pancreatitis
Hypersx reaction
Bullous pemphigoid, skin rash
Start on prednisolone
DPP4i contra
Contra
Pancreatitis
Hypersensitivity
DPP4i
(Comments)
Decreases A1c by 0.5 – 0.8% (monotherapy).
Limited human data for pregnancy.
2nd or 3rd combination therapy due to no benefits.
Weight neutral
alpha glucosidase inhibitor
(Drug Dosage Administration PD PK
Acarbose
25mg 50mg 100mg (tablets)
Weight based dosing.
Start 25mg BD/TDS, take with meals.
Increase by 25mg/day every 2-4 weeks.
Max dose
150mg/day (≤60kg)
300mg/day (>60kg)
Rapid onset with each meal.
Eliminated 50% via faeces as unabsorbed drug.
alpha glucosidase inhibitor ADR
ADR
GI disturbances:
Flatulence, abdominal pain, diarrhoea (most common cause of drug discontinuation)
alpha glucosidase inhibitor DDI
DDI
Intestinal adsorbents and digestive enzyme preparations
Decrease effects of drug.
Renal impairment: CrCl <25ml/min/1.73m2 DO NOT recommend.
alpha glucosidase inhibitor contra
Contra
GI diseases (obstruction, IBD)
Liver cirrhosis
alpha glucosidase inhibitor comments
Comments
Decreases A1c by 0.4 - 1.4%.
alpha glucosidase inhibitor MOA
(acts locally) by delaying glucose absorption and decreasing PPG by competitively inhibiting brush border alpha-glucosidase enzymes required for breakdown of complex carbohydrates.
SGLT2i
(Drug Dosage
vCanagliflozin (Invokana)
100mg
300mg
Empagliflozin (Jardiance)
10mg
25mg
Dapagliflozin (Forxiga)
5mg
10mg
SGLT2I ADR
Hypotension, urinary urgency
Increases water excretion in urine.
Check BP and down titrate HTN lowering agents before starting.
**Increased risk of DKA **(esp euglycemic DKA)
Precipitated by severe stress, dehydration, undereating, alcohol use, illness stop drug.
Hypoglycaemia, renal impairment, increased LDL.
Genital mycotic infection/UTI (>5%) (higher in females).
Sugar in urine increases risk of UTI/infection.
Check history for both before starting. Counsel good toilet hygiene, changing undergarments regularly to discourage pathogen breeding.
= infection causes Fournier’s gangrene (necrotising fasciitis of the perinium)
Canagliflozin specific: lower limb amputation, hyperkalemia, fractures.
SGLT2i
Administration (for each drug)
Canagliflozin (Invokana)
100mg OD before first meal of the day
Increase to 300mg if eGFR >60ml/min and need further BG control.
Empagliflozin (Jardiance)10mg OD, taken in the morning with or without food.
Max dose 25mg OD.
Dapagliflozin (Forxiga) 5mg OD, taken in the morning with or without food.
Max dose 10mg OD.
SGLT2i dose adjustment
empa and dapa no need dose adjustment above 45 egfr
for cana, eGFR 30 to 60 ml/min: 100 mg OM
(CANA)However, if albuminuria>300mg/d, may continue 100mg OM.
when to initiate SGLT2i if renal imp?
if jUST glycemic control
<45 do not initiate
discontinue if <45 persistently
if cardiorenal also
<25 for dapa, <20 for empa DO NOT initiate
discontinue if starting dialysis
SGLT2i contra
renal
cana = <30
empa and dapa = <45
SGLT2i comments
Decreases A1c by 0.8-1.0%.
Limited human data for pregnancy.
Neutral for hypoglycaemia.
Slight weight loss benefits
ASCVD: canagliflozin and empagliflozin ONLY.
HF: shorten hospitalisation (all)
CKD: prevent/delay microalbuminuria (all)
Empagliflozin PK
A: Oral,
F 60-80%
Cmax 1-2h
D: T1/2 12h
90% plasma protein bound
M: minimal metabolism by liver (glucuronidation)
E: ~40% unchanged in faeces, ~27% unchanged in urine
GLP1i
MOA
GLP1 is an incretin, which is a naturally occurring hormone released from the GI tract. GLP-1 inhibitors act as receptor agonists/endogenous GLP1 and binds to the receptors on B cells,
Incretin=↓gastric emptying,↑glucose-dep insulin biosynth, ↓glucagon, ↑b-cell function, and ↓appetite
Activate GLP1 receptor on pancreatic b-cell= stimulates adenylate cyclase = increase cAMP = stimulate PKA = increase insulin secretion and decrease glucagon release.
Insulin secretion decreases as blood glucose concentration decreases and approaches euglycemia.
SGLT2i MOA
MOA: Inhibition of SGLT2 glucose transporters located in the proximal tubules of kidneys decrease renal threshold for glucose and hence increased renal glucose excretion AND decreased reabsorption of filtered glucose decreased blood glucose.
ADR of GLP1RA
ADR
- Headache, Nausea (common),
-Vomiting (common),
-Acute pancreatitis,
- Acute cholecystitis,
- Injection site reactions
GLP1i
(Drug Dosage Administration
1) Liraglutide (Victoza®)
Initiate at 0.6mg SC injection OD regardless of meals.
Titrate to 1.2mg after 1 week.
Max 1.8mg
2) Dulaglutide (Trulicity®)
Initiate at 0.75mg SC injection once weekly regardless of meals.
Titrate to 1.5mg after 4 weeks.
Max 3 – 4.5mg
3) Semaglutide (Ozempic®) Initiate at 0.25mg SC injection once weekly regardless of meals.
Titrate to 0.5mg after 4 weeks.
Max 1mg
4) Semaglutide (Rybelsus®)
Initiate at 3mg PO once daily 30 mins before first meal of day.
Titrate to 7mg after 30 days.
Max 14mg
Can consider dosing in the morning on empty stomach OR atleast ½ hour before other meds/food/drink WITH NO MORE THAN 120ML WATER for adequate absorption.
Can also consider taking with PPI/H2PA to reduce stomach acidity.
PK of liraglutide
A: F 55%
D: C16 fatty acid binds to plasma proteins. T1/2 13hr (extended due to plasma protein binding)
M: endogenous metabolism like polypeptides without specific organ as major route of elimination.
E: little/none excreted unchanged.
contra of GLP1RA
Contra
- Patients with history of pancreatitis or family history of thyroid cancer.
special population for GLP1RA
BLACK BOX
WARNING: Thyroid
C-cell tumors in
animals. Human
relevance unknown.
Counsel patients
regarding the risk of
medullary thyroid
carcinoma and the
symptoms of thyroid
cancers.
DO NOT USE IN PREGNANT MOTHERS (liraglutide)
comments for GLP1RA
Decreases A1c by 1-2 %.
Weight loss benefits.
Neutral hypoglycaemia
Expensive
Recommended as 1st line before insulin when greater glucose lowering is needed.
ASCVD benefits (liraglutide, duraglutide, semaglutide)
Minimal CKD benefits (some benefit in reducing macroalbuminuria in SC agents)
Neutral HF benefit
special formulation of semaglutide Rybelsus
Co-formulated with absorption enhance SNAC to protect it as it passes through the GI tract SNAC increases pH reversibly to protect drug from proteolytic degradation and enhancing its BA.
