DM Hypoglycemics Flashcards
What are Insulin Sensitizers
Biguanides
Thiazolidinediones
Name a Biguanide
Metformin
MOA of Metformin
Lower hepatic glucose production
Raise density of insulin receptors at tissues
Lower intestinal glucose absorption
Improve muscular glucose absorption
Uses of Metformin
Does not affect insulin secretion
Take with meals or after meals to lower GI ADR
ADR of Metformin
GI issues - diarrhoea, vomiting, indigestion.
Raise risk of Vit B12 malabsorption and hence Vit B12 deficiency and can worsen symptoms of neuropathy
Use with caution in patients with renal problems
Names of Thiazolidinediones
Pioglitazone
Rosiglitazone
MOA of Thiazolidinediones
Raise insulin-dependent glucose disposal and lower insulin resistance in periphery and liver
Exact mechanism unclear.
Primary MOA is to activate nuclear transcription factor PPAR-gamma.
PPAR ligands regulate glucose metabolism, adipogenesis, improve insulin sensitivity at adipose tissues, liver and skeletal muscles.
Stimulation of receptors can raise production of GLUT 1 and GLUT 4, enhancing tissue sensitivity to insulin.
Uses of Thiazolidinediones
High glucose-lowering efficacy
Does not affect insulin secretion
ADR of Thiazolidinediones
Weight gain, peripheral edema, higher risk of HF (fluid retention) and bone fractures
Pioglitazone induce CYP450 activity and reduce serum concentrations of CYP450 metabolized drugs
What are examples of Insulin Secretagogues
Sulfonylurea
Meglitinides
MOA of Sulfonylurea
Stimulate insulin release from beta cells in pancreatic islets
Target b-cell ATP-sensitive K channel, which plays major role in controlling b-cell membrane potential
Bind to SU receptor proteins, subunits of K-ATP channels.
Drug binding inhibits K-ATP channel mediated K+ efflux, triggering Ca-dependent exocytosis of insulin granules from pancreatic b-cells
Efficacy of Sulfonylurea
Take 0.5h before food for better absorption
ADR of Sulfonylurea
Can cause weight gain (1-4kg) due to lipogenic effect of insulin
Risk for hypoglycaemia, highest in Glibenclamide. Especially in elderly and renal or hepatic impairment
Contraindicated for Sulfa Allergy
Names of Sulfonyurea
Glipizide
Glicazide
Glibenclamide
Glimepiride
Names of Meglitinides
Nateglinide
Repaglinide
MOA of Meglitinides
Bind and close ATP-dependent K channels on pancreatic beta cells in glucose-dependent manner stimulating insulin release.
This is mediated through unique binding site on SUR1 of beta cell that differs from sulfonylureas’ site of action.
Efficacy of Meglitinides
Taken before meals to control post-prandial glucose levels - due to rapid onset and short DOA
ADR of Meglitinides
Use with caution in hepatic impairment patients.
Example of a a-Glucosidase inhibitors
Acarbose
MOA of acarbose
a-glucosidase hydrolyzes oligosaccharides to glucose and other sugars
Reversibly inhibit membrane-bound a-glucosidase in intestinal brush borders, slowing down rise in glucose levels after a meal.
ADR of acarbose
Higher glucose load in colon causes gaseous distension and flatulence
Stomachache, occasional diarrhoea, belching
Banned for patients with GI issues such as IBD, severe renal or hepatic disease.
Examples of Incretin-based therapy drugs
Dipeptidyl Peptidase 4 Inhibitors
Glucagon-like Peptide-1 Receptor Agonist
Names of DPP-4 inhibitors
Sitagliptin
Vildagliptin
Linagliptin
MOA of DPP-4 inhibitors
DPP-4 is an enzyme that degrades the incretin hormones (stimulated with meals) GLP-1 and GIP.
DPP-4 inhibitors prolong action of endogenous incretins
This stimulates pancreatic B-cells to raise glucose-stimulated insulin release
Suppress a-cell mediated glucagon release and hepatic glucose production.
Uses of DPP-4 inhibitors
Intermediate glucose-lowering efficacy
Neutral effect on weight
Minimal risk of hypoglycaemia”
ADR of DPP-4 inhibitors
GI issues - Diarrhoea, nausea, stomachache
Flu-like symptoms - headache, runny nose, sore throat
Skin reactions
Use with caution in patients with history of pancreatitis”
Names of GLP-1 Receptor Agonist
Exenatide
Liraglutide
Semaglutide
MOA of GLP-1 Receptor Agonists
Activate GLP-1 receptor in pancreatic beta cells.
Raise insulin release in presence of elevated glucose
This insulin secretion subsides as blood glucose concentrations fall and approach euglycaemia.
Uses of GLP-1 Receptor Agonist
Reduces appetite and helps weight loss (esp liraglutide)
Cardiorenal effects - Cardioprotective, with evidence of fall in major CVS events, composite kidney outcome driven by macroalbuminuria
ADR of GLP-1 Receptor Agonist
GI issues - nausea, vomiting, diarrhoea
Name examples of SGLT2 Inhibitors
Empagliflozin
Canagliflozin
Dapagliflozin
MOA of SGLT2 Inhibitors
SGLT2 is a low-affinity, high-capacity glucose transporter. Responsible for 90% of reabsorption of filtered glucose from tubular lumen.
Reduces renal tubular glucose reabsorption without stimulating insulin release.
Lowers renal threshold for glucose
Raise urinary glucose excretion.
Uses of SGLT2 Inhibitors
Reduce major CVS events
Reduce overall CV death
Reduce risk of hospitalization for HF
Reduce risk of kidney outcomes
Favourable effects on lipids and weight too
ADR of SGLT2 Inhibitors
UTI and increased urination
Female genital mycotic infections
Higher risk of lower limb amputation (Canagliflozin)
Diabetic ketoacidosis, esp euglycaemic DKA
