More Diabetes (Pharmacology) Flashcards
What are the treatments for type1 and type 2 diabetes?
Type I (IDDM): Insulin Type 2 (NIDDM): - Biguanides - Sulphonylureas - Meglitinides - Thiazolidinediones (Glitazones) - Incretins - Dipeptidyl peptidase 4 (DPP4) inhibitors - Alpha-Glucosidase inhibitors - Insulin
Where are biguanides (eg. Metformin) absorbed?
Are they bound to plasma protein?
Are they broken down in the body?
Small intestine
not bound to plasma protein
excreted unchanged in urine
How does metformin (a biguanide) decrease blood glucose?
- decreased hepatic glucose production
- potentiates insulin action on muscle and adipose tissue
- stimulation of glycolysis in tissues, stimulates glucose uptake
- decreases carbohydrate absorption
- stimulates lactate production
- inhibit expression of genes involved in gluconeogenesis
What effect does metformin have on lipids?
- decreases LDL and VLDL
Why is it thought that metformin may influence gene expression?
It lowers the risk of some cancers?
What is it important to note that metformin does not affect?
do not affect release of: insulin glucagon growth hormone (GH) cortisol somatostatin
What 3 side effects associated with some other diabetes drugs does metformin not cause?
hypoglycaemia
stimulation of appetite
weight gain
What are the side effects of metformin?
diarrhoea
nausea
metallic taste
rare - lactate acidosis
What effect does metformin have on the absorption of ate and vitamin B12?
decreases intestinal absorption of folate and vitamin B12
When is Metformin implemented in type 2 diabetes and in combination with what?
What effect does it have on microvascular complications?
Drug of choice in obese patients who fail with diet alone
Given with sulphonylureas, thiazolidenediones and/or insulin
Reduces microvascular complications
What makes metformin pills difficult to take?
Their size
What is the half-life of metformin?
3 hours
What are the 5 drugs in the second generation of sulphonlyureas? (5 G’s)
Glibenclamide Gliclazide Glimepiride Glipizide Gliquidone
What are the 2 drugs in the first generation of sulphonlyureas?
tolbutamide - devoid of antibacterial activity chlorpropamide chlorpropamide
Where to sulphonylureas bind?
Bind to sulphynylurea binding site which is associated with the K-ATP gate
Work from outside the cell
What are the acute effects of sulphylnylureas?
Increase insulin release
Increase plasma insulin concentration
Decrease hepatic clearance of insulin
What are the effects on effeicacy of chronic use of sulphylnylureas?
No acute increase in insulin release BUT decreased plasma glucose concentration still remains
Chronic hyperglycaemia per se decreases insulin release
Down regulation of sulphonylurea receptor
What is a significance consequence of sulphynylureas being largely protein bound (90-99%)?
drug interactions:
NSAIDs, MAO inhibitors, some antibiotics etc
In what way is sulphynylurea activity affected in the elderly and those with renal disease?
excreted in urine, enhanced effect in elderly & renal disease
How do first and second generation sulphynylureas differ in terms of half life, potency and drug interactions?
1st generation long:
half life (>24 hours)
2nd generation:
short half life (7-10 hours)
100x more potent
last for 16-24 hours - can take once daily
less interactions (using smaller concentrations)
What are the adverse effects of sulphynylureas?
Main adverse effect is hypoglycaemia
Neuroglycopenia - lack of glucose supply top brain
Confusion and coma
How are the adverse effects of sulphynylureas dealt with?
Take oral glucose
If severe give iv glucose, glucagon, adrenaline
Name 2 MEGLITINIDES.
How do these differ from sulphynylureas in terms if half life, release, potency and risk of hypoglycaemia ?
Repaglinide (1998) Nateglinide (2000) T1/2: 1 hour - more rapid (cf. 7-10 hours) less sustained release less potent than sulphonylureas less hypoglycaemia
When are MEGLITINIDES taken?
Just before meals
Not a mono therapy
How do Close K+ATP meglitinides act on beta cells?
Close K+ATP channels on B-cells
Share 2 binding sites with sulphonylureas but have their own distinct binding site
More selective for B cell than cardiac/vascular K+ ATP channels
Phew many THIAZOLIDENEDIONES (GLITAZONES) are clinically available and what are they?
1
Pioglitazone - Actos® (introduced 1999)
What are the two THIAZOLIDENEDIONES that were withdrawn from the market? Why?
Troglitazone -1997-2000 - liver toxicity
Rosiglitazone - Avandia® - 1999-2010 - cardiovascular problems
What are THIAZOLIDENEDIONES (GLITAZONES)?
Which tissues do they act on?
Ligands for transcription factors
Selective agonists for PPARgamma (nuclear Peroxisome Proliferator- Activated Receptor gamma) PPARgamma combines with RXR (retinoid X receptor)
found in adipose tissue, muscle and liver
How does Pioglitazone (THIAZOLIDENEDIONES (GLITAZONES)) work/what does it do?
Activates insulin responsive genes that control carbohydrate and lipid metabolism
Needs insulin to be effective
Reduces insulin resistance in peripheral tissues
Reduces glucose production by liver
Increases glucose uptake in muscle and adipose tissue potentiates actions of insulin
increase adipocyte number & lipogensis
What type if drug is Pioglitazone?
A THIAZOLIDENEDIONE (GLITAZONE)
What is the half life of Pioglitazone?
How is it carried in the body?
How long does it take for its maximum effect in the body to develop?
T1/2 7 hours - T1/2 24 hours active metabolite
Bound
6-12 weeks
Is Pioglitazone a montherapy?
No, Give with metformin, insulin or other hypoglycaemic drugs
What are the side effects of Pioglitazone?
weight gain (1-4kg) due to increased differentiation of adipocytes, fluid retention by stimulating amiloride sensitive Na+ absorption
What are incretins?
What 2 incretins in the human body do you know about and where are they produced?
INCRETIN - 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 is Exendin-4?
What is Exenatide?
Exendin-4 isolated from saliva of Glia monster 50% homology with GLP1
Exenatide - synthetic version of exendin-4 - Byetta FDA approved 2005
What are the effects of Exenatide (a synthetic incretins)?
Acts on incretin receptor (GLP-1 receptor) Stimulates insulin release Suppresses glucagon secretion Reduces appetite and body weight Slows gastric emptying Stimulated beta cell number
Is Exenatide (a synthetic incretins) active orally?
No, peptides - not orally active
What are Serine protease dipeptidyl peptidase 4 (DPP4) inhibitors and how do they work?
Name some
Serine protease dipeptidyl peptidase 4 (DPP4) breakdown incretins
inhibitors: Sitagliptin,Vildagliptin (Galvus), Saxagliptin (Onglyza), Sitagliptin + metformin (Janumet, USA) Vildagliptin + metformin (Eucreas, UK)
How do Serine protease dipeptidyl peptidase 4 (DPP4) inhibitors affect weight?
Do they cause hypoglycaemia
Side effects?
no effect on weight, no hypoglycaemia
Possible side effect: increase in incidence of some cancers - incretins may be agents involved in cell growth etc.
What are alpha-GLUCOSIDASE INHIBITORS?
Name 2
Inhibits intestinal brush border alpha-glucosidase
acarbose (1995) ) & miglitol (2000)
What effect do alpha-glucosidase inhibitors have?
What type of diabetes are they effective in?
Inhibits carbohydrate breakdown and reduce postprandial increase in blood glucose levels
effective in Type I (IDDM) and Type 2 (NIDDM)
Are alpha-glucosidase inhibitors well absorbed?
Do they cause hypoglycaemia?
Side effects?
Poorly adsorbed
Does not cause hypoglycaemia
Side effects: flatulence and diarrhoea
What are amyloid analogues?
AMYLIN ANALOGUES
Amylin (37aa) main component of pancreatic amyloid related to calcitonin/CGRP
What are the effects of amylin?
Decreases gastric emptying
Inhibits glucagon release
Promotes satiety
but - Related to Beta-amyloid and can form aggregates
What is Pramlintide?
In what type of diabetes is it effective?
What are its effects?
- analogue of human amylin with Pro replacement as in rat amylin, does not aggregate
- Adjunct for both Type I (IDDM) and Type 2 (NIDDM)
- Decreases gastric emptying
Inhibits glucagon release
Promotes satiety
Future developments in diabetes drugs?
Improved insulin delivery nasal inhalation
Afresa® inhaler submitted 2009, re-submitted July, 2010
patches
liposomes
insulin pumps with glucose sensors insulin in biodegradable microspheres
Islet transplants
Sodium glucose transporter 2 inhibitor - In kidney - can block reabsorption of glucose by 10-20pc:
canagliflozin, dapagliflozin, ipragliflozin
alpha2 - antagonists alpha2 receptors block insulin release
Beta 3 - agonists increase lipolysis/thermogenesis in brown adipose tissue
treatments for obesity?
monoamine uptake inhibitor sibutramine (withdrawan) cannabinoid CB1antagonist rimonabant (withdrawn) lipase inhibitor orlistat Approved FDA 5HT2C agonist lorcaserin(APD-356) Qsymia phentermine/topiramate In development Neuropeptide Y (NPY) agonists PYY3-36 ghrelin antagonists ghrelin vaccine melanocortin receptor (MC4R) agonists melanin-concentrating hormone antagonists
