Wk 10: Anti-diabetic drugs Flashcards
What is the mechanism of action of glucose when releasing insulin?
- Glucose attaches to GLUT-2 receptor on pancreatic cell surface
- Glucose metabolised by mitochondria
- Generates ATP, inactivates K = depolarisation
- Activates calcium channel, influx of calcium
- Releases insulin
What is the mechanism of action of insulin?
- Insulin binds to insulin receptor
- Receptor phosphorylated
- Activates cell signalling
- Releases glucose transporter 4 (GLUT4 )
- GLUT4 imports glucose into cell
- Lowers blood glucose
What do you add/do during insulin preparation to delay absorption?
- Zinc: zinc-insulin hexamer: Inc stability + delays abs
- Protamine: prolong release
Give examples of 3 available rapid acting insulin
- Lispro
- Aspart
- Glulisine
5-15 mins before meal
How does lispro differ from normal human insulin?
- AA proline at B28 replaced by lysine
- AA lysine at B29 replaced by proline
- Prevents dimer/hexamer formation
Short acting insulin
- 30-45 mins before meal
- IV admin: managing diabetic ketoacidosis
Give examples of insulin sensitisers
- Biguanides: Metformin
- Thiazolidinediones/glitazones: pioglitazone
What is the action of biguanides?
- Dec hepatic gluconeogenesis
- Improves insulin sensitivity
- Stimulates tissue uptake of glucose esp muscle
- Antihyperglycemic effect
When is metformin used?
First line in T2DM for overweight patients
What is the mechanism of action of metformin?
- OCT1 transports metformin into cell
- Once in liver, interacts w/ mitochondrial electron compex 1
- AMP inc, detected by AMPK
- AMPK triggers inc of conversion of NADH to NAD + inc lactate into cell
- Lactate inc, pyruvate dec, dec hepatic glucose prod
- AMPK also dec gluconeogenesis gene prod -> dec hepatic glucose prod
What is the mechanism of action of pioglitazone?
- Activation of PPARy (fat, muscle + liver cells) -> restoration of target genes:
- Dec interleukin-6
- Inc adiponectin + insulin sensitising - Inc GLUT 1 + 4 expression -> glucose uptake into peripheral tissues
Does pioglitazone require insulin?
Yes
What are the adverse effects of glitazones?
- Weight gain
- Liver dysfunction
- HF
- Bladder cancer
- Fracture risk
When is glitazones used?
3rd line therapy after metformin + sulfonylureas
Give examples of insulin secretagogues
- SU
- Meglitinides: Repaglinide
What is the mechanism of action of sulfonylurea?
- Sulfonylurea binds to SUR1 + blocks k channel causing depolarization
- Activates calcium channel causing influx in calcium
- Triggers insulin secretion
When is the use of sulfonylureas drugs ineffective?
No insulin prod:
- T1DM
- Post-pancreatectomy
What are the adverse effects of sulfonylurea?
- GI disturbance
- Hypo
- Weight gain
- Renal impairment
What is the mechanism of action of meglitinides?
Bind to SUR1 receptor on b cells stimulating insulin release
When should meglitinides be used?
- Poor renal function
- Irregular eating habits
What are the adverse effects of meglitinides?
- Hypo
- Visual disturbance
- Di + vom
Give examples of agents that mimic incretin
- DPP4 inhibitors: gliptins
- GLP-1 agonist (mimetics): exantatide
What are incretin hormones?
Hormones that release GLP-1 + GIP following food
- Activate cell
- Stim cAMP
- Stim EPAC2
- Activates pathways, secreting insulin
When should GLP-1 be used?
3rd line - in place of insulin, glitazones + DPP4 inhibitors
What are the adverse effects of GLP-1 agonists?
Acute pancreatitis
Exenatide
- Injectable
- Lowers blood glucose
- Excreted by kidney but don’t use if GFR <30
What is the role of DPP4?
Inactivates + degrades incretin hormones
What is the mode of action of gliptins?
- Competitive inhibitor of DPP-4: binds directly to DPP-4 enzyme
- Red inactivation of GLP-1 + GIP
- Prolongs GLP-1 + GIP activity to help red glucose levels
What are the unwanted effects of gliptins?
- GI
- Pancreatitis
- Dec apetite
Give an example of a drug that slow intestinal absorption of glucose
A-glucosidase inhibitor (acarbose)
- Competes w/ dietary oligosaccharides for a-glucosidase enzymes
- Postprandial peak of blood gluc red + conc more stable
What is the adverse effects of acarbose?
Diarrhoea + Flatulence
Give an example of an agent that inhibits glucose reabsorption in the kidney
SGLT2 inhibitor (glifozins)
- Competitive reversible inhibitors of SGLT2
- Red glucose absorption from tubular filtrate + inc urinary glucose
- Insulin independent
When is SGLT2 inhibitors not recommended + ineffective?
- Not recommended: GFR <60ml/min
- Ineffective: GFR <30ml/min
What are the adverse effects of SGLT2?
- Rapid weight loss
- UTI
