DM Pharmacology

Question 1

Biguanides
indication

Answer 1

Indication: Monotherapy with diet and exercise OR in combination with other agents/insulin for T2DM
- Off label: polycystic ovarian syndrome (PCOS).

Question 2

Biguanides
moa

Answer 2

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)

Question 3

Biguanides
(Dosages and administration)

Answer 3

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

Question 4

Biguanides
PD PK

Answer 4

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.

Question 5

Biguanides
ADR

Answer 5

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.

Question 6

Biguanides
DDI

Answer 6

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.

Question 7

Biguanides
Contra

Answer 7

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

Question 8

Biguanides
Special population

Answer 8

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.

Question 9

Biguanides
Comments

Answer 9

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.

Question 10

thiazolidinediones
(Drug Dosage Administration

Answer 10

Pioglitazone 15mg , 30mg (tablet)
Start with 15mg or 30mg OD

Increase dose by 15mg

Max 45mg OD

Question 11

thiazolidinediones
MOA

Answer 11

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

Question 12

thiazolidinediones
PD PK

Answer 12

PD
Up to one month for max effect
PK
Liver elimination

Question 13

thiazolidinediones
(ADR)

Answer 13

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.

Question 14

thiazolidinediones
(Contraindications

Answer 14

Contraindications
Active liver disease

Symptomatic or history of HF (esp class III to IV)

Active/history of bladder cancer.

Question 15

thiazolidinediones
DDI

Answer 15

DDI
CYP3A4 AND CYP2C8 inhibitors and inducers

Question 16

thiazolidinediones
(comments)

Answer 16

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)

Question 17

sulfonylureas
MOA

Answer 17

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.

Question 18

glipizide (Drug Dosage Administration PD PK )

Answer 18

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.

Question 19

sulfonylureas
DDI

Answer 19

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)

Question 19

sulfonylureas
ADR

Answer 19

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.

Question 19

Sulfonylurea
Contraindications

Answer 19

Contraindications
Hypersx due to SUs

Question 20

sulfonylurea comments

Answer 20

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.

Question 20

vildagliptin special population instructions

Answer 20

Hepatic dose adjustment:
CrCL ≥50ml/min: 50mg BD CrCL <50ml/min: 50mg daily

Use with caution if ≥75 years old.

Question 20

linagliptin special population + DDI

Answer 20

DDI
CYP3A4 inducers
Decreases linagliptin concentration.

Special populations
No renal or hepatic dose adjustment

Question 21

DPP4i MOA

Answer 21

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.

Question 21

Sitagliptin Dosage Administration PD PK DDI Special population

Answer 21

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

Question 22

doses for the dpp4i agents?

Answer 22

SITAGLIPTIN 100MG OD VILDAGLIPTIN 50MG BD (IF METFORMIN/TZD), 50MG OD (IF SU) LINAGLIPTIN 5MG OD

Question 23

DPP4i ADR

Answer 23

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

Question 24

DPP4i contra

Answer 24

Contra Pancreatitis Hypersensitivity

Question 25

DPP4i (Comments)

Answer 25

Decreases A1c by 0.5 – 0.8% (monotherapy). Limited human data for pregnancy. 2nd or 3rd combination therapy due to no benefits. Weight neutral

Question 26

alpha glucosidase inhibitor (Drug Dosage Administration PD PK

Answer 26

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.

Question 27

alpha glucosidase inhibitor ADR

Answer 27

ADR GI disturbances: Flatulence, abdominal pain, diarrhoea (most common cause of drug discontinuation)

Question 28

alpha glucosidase inhibitor DDI

Answer 28

DDI Intestinal adsorbents and digestive enzyme preparations Decrease effects of drug. Renal impairment: CrCl <25ml/min/1.73m2 DO NOT recommend.

Question 28

alpha glucosidase inhibitor contra

Answer 28

Contra GI diseases (obstruction, IBD) Liver cirrhosis

Question 29

alpha glucosidase inhibitor comments

Answer 29

Comments Decreases A1c by 0.4 - 1.4%.

Question 30

alpha glucosidase inhibitor MOA

Answer 30

(acts locally) by delaying glucose absorption and decreasing PPG by competitively inhibiting brush border alpha-glucosidase enzymes required for breakdown of complex carbohydrates.

Question 31

SGLT2i (Drug Dosage

Answer 31

vCanagliflozin (Invokana) 100mg 300mg Empagliflozin (Jardiance) 10mg 25mg Dapagliflozin (Forxiga) 5mg 10mg

Question 32

SGLT2I ADR

Answer 32

**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.

Question 32

SGLT2i Administration (for each drug)

Answer 32

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.

Question 33

SGLT2i dose adjustment

Answer 33

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.

Question 33

when to initiate SGLT2i if renal imp?

Answer 33

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

Question 34

SGLT2i contra | renal

Answer 34

cana = <30 empa and dapa = <45

Question 35

SGLT2i comments

Answer 35

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)

Question 36

Empagliflozin PK

Answer 36

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

Question 37

GLP1i MOA

Answer 37

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.

Question 37

SGLT2i MOA

Answer 37

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.

Question 38

ADR of GLP1RA

Answer 38

ADR - Headache, Nausea (common), -Vomiting (common), -Acute pancreatitis, - Acute cholecystitis, - Injection site reactions

Question 38

GLP1i (Drug Dosage Administration

Answer 38

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.

Question 38

PK of liraglutide

Answer 38

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.

Question 39

contra of GLP1RA

Answer 39

Contra - Patients with history of pancreatitis or family history of thyroid cancer.

Question 40

special population for GLP1RA

Answer 40

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)

Question 40

comments for GLP1RA

Answer 40

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

Question 40

special formulation of semaglutide Rybelsus

Answer 40

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.