2157 ic3 t2dm drugs

MOA, pk properties, adverse side effects

metformin (biguanide) (MOA)

MOA:

• reduce gluconeogenesis in the liver

• enhance peripheral uptake of glucose mainly by skeletal muscles and improve insulin sensitivity.

* does not result in hyperinsulinemia or hypoglycemia (a condition where blood glucose levels drop below normal range)

metformin (biguanide) (ADME)

ABSORPTION:

• oral

  • bioavailability: 40-60%

  • duration of action: 8-12 hours

DISTRIBUTION:

• rapid

• minimal plasma protein binding

  • t1/2: 3h

METABOLISM: NA

ELIMINATION:

• excreted unchanged in urine (avoid in pt w renal insufficiency cause met will accumulate)

metformin (biguanide) (adverse effects + clinical use)

USED FOR:

• T2DM

ADVERSE EFFECTS:

• anorexia

• GI disturbances (diarrhea —> weightloss, vomiting, indigestion) [pt is advised to take the meds w food to minimise this]

• increased risk of vit B12 malabsorption —> vit B12 deficiency

• use w caution in pt w renal problems or lactic acidosis (heart prob)

metformin (biguanide) (drug interactions)

DRUG INTERACTION:

• ethanol (EtOH): increase risk of lactic acidosis

• inhibitor/inducer of organic cationic transporters (OCT)

  • OCT2 inhibitors (eg cimetidine, dolutegravir, ranolazine) may increase metformin by reuducing renal elimination

  • for these pt, we reduce the metformin dose by half if pt has to eat OCT2 inhibitor

METFORMIN-ASSOCIATED LACTIC ACIDOSIS

• Signs and symptoms (s/sx)

  • Nausea, vomiting, abdominal pain, shallow breathing, mental confusion

• Met inhibits gluconeogenesis and inhibits pyruvate carboxylase and prevent conversion of pyruvate to oxaloacetate

• Glucose gets broken down into pyruvate for ATP 

• Pyruvate gets broken down to lactate when there is a lack of oxygen (anaerobic resp)

• Lactate acidosis results from increased production or decreased clearance of lactate 

  • Metformin 

  • Hypoxic state (lack of oxygen the blood)

SULFONYLUREAS/ MEGLITINIDE ANALOGUES (GLIPIZIDE) (MOA)

MOA: 

• Principal target of sulfonylureas is the pancreatic B cell ATP-sensitive potassium channel, which plays a major role in controlling the B cell membrane potential 

• Sulphonylureas (SU) bind to subunits of the potassium channels

• Drug binding inhibits ATP dependant K channel mediated K+ efflux triggering a calcium dependant exocytosis of insulin granules from the pancreatic B cells 

  • Basically when the sulfonylurea binds to K channel, the K+ ions in the cell cant escape (decreased efflux)  → depolarisation of the cell occurs 

  • The calcium channel then opens and Ca2+ ions enter the cell 

  • The Ca2+ ions causes exocytosis of insulin granules 

• This requires functional pancreatic B cells → pts who have had diabetes for v long, their B cells are not as good and Glipizide may not work as well for them

SULFONYLUREAS/ MEGLITINIDE ANALOGUES (GLIPIZIDE) (ADME)

ABSORPTION: 

• Oral

  • Bioavail (F): 95% (delayed w food intake→ pt advised to take Glipizide 30min before food)

  • Onset of action: 30mins 

  • Duration of action: 12-24h 

DISTRIBUTION:

• Binds extensively (99%) to plasma proteins (albumin) 

METABOLISM: 

• Liver (90%) hydroxylation 

ELIMINATION: 

• Less than 10% excreted unchanged in urine and feces; metabolites excreted in urine and feces (action prolonged in pt w renal disease) [metabolites mean the new chemicals formed when the body breaks down ingested drugs] 

SULFONYLUREAS/ MEGLITINIDE ANALOGUES (GLIPIZIDE) (clinical use + adverse effects)

CLINICAL USE: 

• Management of T2DM when hyperglycemia cannot be managed with diet or exercise alone 

• Usually used monotherapy or in combination therapy with oral antidiabetic agents 

• Not used w sulfonylureas / meglitinide bc hey have the same MOA

ADVERSE EFFECTS: 

• Hypoglycemia (more common in elderly) [anything that increases insulin increases risk of hypoglycemia]

• Weight gain  

SULFONYLUREAS/ MEGLITINIDE ANALOGUES (GLIPIZIDE) (drug interactions)

DRUG INTERACTIONS: 

• B-blockers may mask s/sx of hypoglycemia, eg trembling 

• Disulfiram-like reaction with EtOH (means a sudden physical illness that happens when a person drinks alcohol while taking certain meds→ tachycardia, nausea etc)

• CYP2C9 inhibitors may increase glimepiride, glipizide 

Repaglinide (meglitinide analogue) (MOA)

MOA: 

• Acts like sulfonylureas

• Less potent than most sulfonylureas 

PD & PK:

• Onset more than or equal to 1hr (faster than SUs, but shorter in duration)

• Hypoglycemia (less likely than SU)

• Repaglinide: CYP2C8 & CYP3A4 substrate 

*require functional pancreatic B cells

Repaglinide (meglitinide analogue) (clinical use)

CLINICAL USE: 

• Management of T2DM when hyperglycemia cannot be managed by diet and exercise alone

• Not to be used w sulfonylureas 

Repaglinide (meglitinide analogue) (drug interactions)

 DRUG-DRUG INTERACTIONS (INCLUDING BUT NOT LIMITED TO): 

• Repaglinide + insulin NPH has reported to cause myocardial infarction (MI) 

• Repaglinide + fibric acid derivatives may increase hypoglycemia (contraindicated use) 

Empagliflozin (SGLT-2 inhibitor) (MOA)

MOA: 

• Inhibit sodium glucose co-transporter-2 (SGLT-2)

• Decrease reabsorption of filtered glucose 

• Decrease renal threshold for glucose 

• Increase urinary glucose excretion 

• All of the filtered glucose is reabsorbed in the proximal tubules through the sodium glucose co-transporters SGLT2 and SGLT1 

• SGLT2 inhibitors reduce glucose reabsorption in proximal tubule → glucosuria (presence of excess glucose in the urine) w low risk of hypoglycemia 

  • Leads to glucosuria, loss of calories and BP reduction

Empagliflozin (SGLT-2 inhibitor) (ADME)

ABSORPTION: 

• Oral 

  • Bioavailability (F): 60-80%

  • Cmax: 1-2 hours 

DISTRIBUTION:

• Binds extensively (90%) to plasma proteins 

  • t1/2 : 12hr 

METABOLISM: 

• Minimal liver metabolism ; glucuronidation (a liver detox process that attaches a sugar molecule to a drug that makes the chemical more soluble, the body can then remove it safely from the urine)

ELIMINATION: 

• About 50% unchanged in urine; about 41% unchanged in feces

Empagliflozin (SGLT-2 inhibitor) (clinical use + adverse effects)

CLINICAL USE: 

• Management of T2DM as sequential addition to, or dual therapy w metformin 

• Recommended for pt w T2DM who need to reduce their risk of adverse cardiorenal outcomes and /or hospitalisation for heart failure 

ADVERSE EFFECTS: 

• Urinary tract infection (UTI)

  • Avoid in pts w recurring UTI

• Increased urination 

  • Give once a day in the morning to reduce side effects (increased urination, dw to disrupt their sleep)

• Female gential mycotic (fungal) infection 

• Diabetic ketoacidosis (DKA) (including euglycemic DKA)

  • Empagiflozin decreases calories → increased metabolism of FA (aka lipolysis)→ prof of ketone bodie (eg BOHB) which are acidic → diabetes ketoacidosis occurs → usually does not happen unless pt has insulin deficiency bc insulin helps to suppress lipolysis 

  • Fournier gangrene (a life threatening infection of the tissue under the skin)

what are Incretin-based therapies  

• DPP-4 inhibitors (sitaglipin) 

• GLP-1 receptor agonists (semaglutinide) → now this is the first line for DM management 

• Dual GIP/GLP-1 receptor agonists

what are incretins

• They are a group of metabolic hormones → released after eating and in a glucose-dependant manner 

• They increase the secretion of insulin released from pancreatic B cells of Islets of Langerhans (only in the presence of hyperglycemia) 

• Two major incretin hormones secreted by the small intestine 

  • Glucose dependantinsulinotropicpolypeptide (GIP)

  • Glucagonlikepeptide-1 (GLP-1)

Sitagliptin (DPP-4 inhibitor)

Sitagliptin (DPP-4 inhibitor) (MOA)

• Dipeptidyl peptidase-4 inhibitor (DPP- 4 inhibitor)

MOA: 

• Binds and inhibits DPP-4 protein

• Decrease enzymatic degradation of endogenous incretins (GLP-1 and GIP)

• Prologs the action of endogenous incretins 

Sitagliptin (DPP-4 inhibitor) (ADME)

ABSORPTION:

• Oral 

  • F: 87%

DISTRIBUTION:

• t1/2= 10-12hr

METABOLISM:

• Minor

• Liver metabolism 

ELIMINATION: 

• 80% excreted unchanged in the liver, rest in feces 

  • Hence pt w renal impairment req dose adjustments if they wanna tale sitagliptin 

  • However there is another drug linagliptin (also a DPP-4 inhibitor) that is excreted largely unchanged in the feces and does not req dose adjustment in pt w renal impairment 

Sitagliptin (DPP-4 inhibitor) (CLINICAL USE + adverse effect)

CLINICAL USE:

• Management of t2DM

• Usually used dual or triple combination therapy with oral antidiabetic agents 

ADVERSE EFFECTS

• Flu-like symptoms (headache, runny nose, sore throat)

• Arthralgia (severe joint pain that can be disabling → pt advised to stop sitagliptin if its unbearable)

• Dermatologic reactions → bullous pemphigoid, hypersensitivity rxn)

• Acute pancreatitis 

  • Not a direct cause of DPP-4 inhibition, but rather bc of this prolonged incretin effect that can cause pancreatic b cell hyperplasia → overgrowth of cells causing blockage of exocrine duct along pancreas → digestive juices cant flow out, pressure in pancreas increases and pancreas starts digesting itself 

Semaglutide (GLP-1 agonist) [ozempic] (MOA)

• Semaglutide binds to GLP-1 receptors on pancreatic B cells 

• This activates adenylate cyclase (it turns ATP to cyclic AMP, a second messenger)

• Increase cAMP → increased pKa (protein kinase A) signalling

• Increased glucose dependant insulin secretion from B cells

• Decreased glucagon secretion 

  • Decreased gluconeogenesis 

• Decreased hepatic glucose production 

• Improved glycemic control 

Semaglutide (GLP-1 agonist) [ozempic] (ADME)

ABSORPTION:

• SC

  • Once weekly dose 

  • F: 89%

  • Multidose → one pen can be used multiple times 

• Oral 

  • Once daily dose 

  • F: 0.4%-1% (to be taken on a empty stomach followed by a 30min post dose fast with no more than 120ml of water) 

DISTRIBUTION:

• Binds extensively to plasma proteins (>99% to albumin)

  • t1/2= 1 week (extended due to plasma protein binding and slow elimination) 

METABOLISM:

• Endogenously metabolised (broken down by the body's own enzymes) in a similar manner to polypeptides without a specific organ as a major route of elimination 

ELIMINATION: 

• Little or none excreted unchanged 

Semaglutide (GLP-1 agonist) [ozempic] (clinical use+ adverse effects)

CLINICAL USE:

• Ozempic and Rybelsus used in the management of t2DM 

• May be used in combination with other antidiabetic agents and/or insulin 

  • Ozempic is preferred for pt w history of or are at risk of ASCVD (atherosclerotic disease) or pt w chronic kidney disease, or when weight loss is desired 

• Wegovy 

  • Chronic weight management 

ADVERSE EFFECTS:

• nausea/vomiting/abdominal pain (slows down gastric emptying) (improves when body adjusts to treatment)

• diarrhea/constipation 

• headache/fatigue (due to reduced calorie intake)

• Alopecia (associated w rapid weight loss) 

• Acute pancreatitis (B cell hyperplasia)

• Acute gallbladder disease 

• Worsening of preexisting diabetic retinopathy 

  • Due to rapid correction of hyperglycemia → osmotic shift in the macrovascular (main arteries and veins; large blood vessels) of retina

Semaglutide (GLP-1 agonist) [ozempic] (drug interactions + procedural risk)

DRUG INTERACTIONS:

• Delayed gastric emptying may affect the absorption of concomitant oral medications

PROCEDURAL RISK:

• May increase the risk of aspiration (increase risk of chemical pneumonitis) during procedures req general anaesthesia or deep sedation 

  • Pt gg for surgery is advised to skip a dose a week before surgery 

Tirzepatide (Long acting dual GIP and GLP-1 receptor agonist 

• Activity on the GIP similar to native GIP hormone 

• Activity on the GLP-1 receptor is lower compared to native GLP-1 hormone) (MOA)

MOA:

• Enhances insulin secretion (glucose dependant) 

• Improves insulin sensitivity 

• Reduces glucagon conc 

  • Inhibits gluconeogenesis

• Delays gastric emptying 

• Reduces appetite and food intake 

Tirzepatide (ADME)

ABSORPTION:

• SC → ONCE WEEKLY dose 

  • F: 80%

  • A SINGLE USE PEN 

D:

• Binds extensively to plasma proteins (>99% to albumin) 

  • t1/2 = 5 days (extended due to plasma protein binding and slow elimination)

M:

• Proteolytic cleavage of the peptide backbone (not impt she wont test)

E:

• Urine and feces (as metabolites) 

Tirzepatide (clinical use + adverse effects)

CLINICAL USE: 

• Mounjaro: management of t2dm as an adjunct to exercise and diet 

  • May be used in combination w other antidiabetic agents and/or insulin 

  • Prefer in overweight or obese pt where weight loss is desired 

ADVERSE EFFECTS: 

• nausea/vomiting/abdominal pain (less when body adjusts to treatment)

• diarrhea/constipation

• Dizziness / fatigue  

• Alopecia 

• Acute pancreatitis 

• Acute gallbladder disease 

• Worsening of preexisting diabetic retinopathy 

Tirzepatide (drug interactions and procedural risk)

DRUG INTERACTIONS: 

• Delayed gastric emptying may affect the absorption of concomitant oral medications 

• Oral contraceptive : decreased absorption resulting in decreased serum conc 

  • Switch to non oral contraceptive method / barrier method of contraception for 4 weeks after initiation of Tirzepatide and 4 weeks after each dose escalation of Tirzepatide → bc gastric emptying effects of GLP-1 is dose dependant 

PROCEDURAL RISK: 

• May increase the risk of aspiration during procedures that req general anesthesia and deep sedation → pt advised to stop taking the meds one week prior