Pharmacology of T2DM Flashcards
List the drugs used to treat T2DM
- Biguanides
- Sulphonyureas
- Thiazolidinediones
- Meglitinides
- Incretins
- Dipeptidylpeptidase 4 ( DPP4) inhibitors
- alpha-glucosidase inhibitors
- Sodium glucose transporter 2 (SGLT2) inhibitors
- Amylin analogues
- Insulin
What is an example of a biguanide
Metformin
Outline the characteristics of biguanides
- Don’t affect the release of insulin,glucagon,GH,cortisol,somatostatin
- May act through AMPK
- Increase AMP levels
- Inhibit adenylate cyclase/activate AMPK
- mTOR (mammalian target for rampamyacin)
- inhibition of glycerophosphate dehydrogenase
- decrease hepatic gluconeogenesis
Outline the pharmacology of metformin including how it decreases BG levels
-absorbed from the small intestine
-Half life=3 hours
-Not bound to plasma protein,excreted unchanged in urine
Decrease blood glucose concentration by:
-decreased hepatic glucose production
-potentiate insulin action on muscle & adipose tissue
-stimulation of glycolysis in tissues,stimulate glucose uptake
-decrease carbohydrate absorption
-stimulate lactate production
-inhibit expression of genes involved in gluconeogenesis
What are the benefits of biguanides
-Doesn’t cause hypoglycaemia
-Reduced microvascular complications
-Doesn’t stimulate appetite
-Doesn’t cause weight gain
It is therefore the drug of choice in obese patients who fail with diet alone
What are the side effects of biguanides
- diarrhoea
- nausea
- metallic taste
- rare lactate acidosis
- decreases intestinal absorption of folate& vitamin B12
What can biguanides be given with?
-sulphonylureas, thiazolidenediones, incretins, DPP4 inhibitors, SGLT2 inhibitors and/or insulin, but sulphonylureas, thiazolidenediones and insulin DO cause hypoglycaemia
Which GLUT channel is present in the beta cells of the pancreas?
GLUT2
What acute effects do sulphonylureas have?
- Increase insulin release
- Increase plasma insulin concentration
- Decrease hepatic clearance of insulin
What chronic effects do sulphonylureas have?
-No acute increase in insulin release but decreased plasma glucose conc still remains
-Chronic hyperglycaemia decreases insulin release
-Down regulation of sulphonylurea receptor
-Largely protein bound (90-99%)
drug interactions =
-NSAIDs, MAO inhibitors, some antibiotics etc
What are the characteristics of sulphonylureas?
-Excreted in urine, enhanced effect in elderly & renal disease
-1st gen= long half life< 24hours
-2nd gen=short half life(7-10hours)
100x more potent
lasts for 16-24hours
less interactions
What are the side effects of sulphonylureas
- Main adverse effect is hypoglycaemia
- Neuroglycopenia
- Confusion & coma( take oral glucose; if severe give iv glucose/glucagon/adrenaline)
Outline the characteristics of Meglitinides
- Half life= 1 hour
- More rapid, less sustained release, less potent that sulphonylureas, less hypoglycaemia
- Take just before meal
- Close K+ ATP channels on Beta cells
- Share 2 binding sites with sulphonylureas but have their own distinct binding site
- More selective for Beta cells than cardiac/vascular K+ ATP channels
- can be used as monotherapy
Give egs of Meglitinides
- Repaglinide (Prandin)
- Nateglinide( Stalix)
Give egs of thiazolidenediones(glitazones) and their associated adverse side effects
- Troglitazone; liver toxicity
- Rosiglitazone; cardiovascular problems
- Pioglitazone; risk bladder cancer
Outline the characteristics of thiazolidenediones(glitazones)
selective agonists for:
- PPARgamma (nuclear peroxisome proliferator-activated receptor gamma)
- PPARgamma combines with RXR(Retinoid X receptor)
-Found in adipose tissue,muscle & liver
- protein bound
- half life=7 hours ; active metabolite half life=24 hours
- Takes 6-12 weeks for max effect to develop
- Give with metformin or other hypoglycaemic drugs
Outline the mechanism of action of thiazolidenediones(glitazones)
- Activates insulin responsive genes that control CHO & lipid metabolism
- Needs insulin to be effective
- Reduces insulin resistance in peripheral tissues
- Reduces glucose production by liver
- Increases glucose uptake in muscle& adipose tissue potentiates actions of insulin
- Increase adipocyte number & lipogenesis
What are the side effects of thiazolidenediones(glitazones)
-weight gain (1-4kg) due to increased differentiation of adipocytes, fluid retention by stimulating amiloride sensitive Na+ absorption
What are incretins? Give examples.
- Compound stimulates insulin release
- GIP: glucose-dependent insulinotrophic peptide or gastric inhibitory peptide K cells in duodenum
- GLP1: glucagon-like peptide 1 L cells in distal ileum
What are the actions of incretins?
- Acts on incretin receptor (GLP-1 receptor)
- Stimulates insulin release
- Suppresses glucagon secretion
- Reduces appetite& body weight
- Slows gastric emptying
- Stimulated beta cell number
Give examples of incretins (GLP-1 analogues)
Byetta Bydureon Victoza(liraglutide) Lyxumia(lixisenatide) Eperzan(albiglutide) Trulicity(dulaglutide) Ozempic (semaglutide)
What are serine protease dipeptidyl peptidase 4 (DPP4) inhibitors?
- breakdown natural incretins
- Gliptins DPP4 inhibitors
What are the benefits of DPP4 inhibitors
- No effect on weight
- No hypoglycaemia
List some serine protease dipeptidyl peptidase 4 (DPP4) inhibitors
- Sitagliptin(Januvia)
- Vildagliptin(galvus)
- Saxagliptin(onglyza)
- Linagliptin(tradjenta)
What is a possible side effect of serine protease dipeptidyl peptidase 4 (DPP4) inhibitors
-increase in incidence of some cancers
What are eg’s of alpha-glucosidase inhibitors?
Acarbose & Miglitol
Outline the characteristics of alpha-glucosidase inhibitors
- Inhibits intestinal brush border alpha-glucosidase
- Reduces postprandial increase in blood glucose levels
- effective in IDDM& NIDDM (Type 1 &2)
- poorly adsorbed
What is the benefit of alpha-glucosidase inhibitors?
-Don’t cause hypoglycaemia
What are the potential side effects of alpha-glucosidase inhibitors?
faltulence & diarrhoea
What is the function of sodium glucose transporter 2 (SGLT2)inhibitors?
- inhibit glucose re-uptake in the kidney
- give up to 10% excretion of calorie intake
Give eg’s of SGLT2 inhibitors
- dapagliflozin (Forxiga)
- canaglifozin(Invokana-SGLT2 &SGLT1)
- empaglifozin (Jardiance)
Outline the characteristics of amylin analogues
- Amylin(37aa) main component of pancreatic amyloid related to calcitonin/CGRP
- Decreases gastric emptying
- Inhibits glucagon release
- Promotes satiety
- Related to Beta-amyloid & can form aggregates
What is Pramlintide; what’s the benefit of it
-analogue of human amylin with pro replacement as in rat amylin,
BENEFIT=does not aggregate
How should amylin analogues be taken?
Adjunct for both type 1 & type 2
Which medication controls appetite
- Incretins
- Amylin
Which medication reduces glucose reabsorption
-SGLT2 inhibitors
Which medications increases glucose uptake & utilization?
- Thiazolidinediones
- Metformin
Which medications reduces lipotoxicity
- Thiazolidinediones
- Salcylates
Which medications reduces hepatic glucose output
- Metformin
- Thiazolidinediones
Which medications reduce blood glucose levels via the GI tract
- Incretins
- alpha glucosidase inhibitors
- Amylin
- Bile acid sequestrant
Outline various treatments for obesity
- Monoamine uptake inhibitor
- Cannabinoid CB1antagonist
- Lipase inhibitor
- Belviq 5HT2c agonist
- Qsymia
- Contrave
- Saxenda GLP-1 agonist
