Endocrine pharma Flashcards
What are insulin dependent T2DM drugs?
Independent?
Mechanisms?
Insulin dependent
- Sulphonylureas, incretin mimetics, glinides, DPP4 inhibitors (increase secretion of insulin)
- metformin, TZDs (reduce insulin resistance)
Insulin independent
- a-glucosidase inhibitors (slow glucose absorption from GI tract)
- SGLT2 inhibitors (enhance glucose excretion by kidney)
Process of insulin secretion in pancreatic B cell? (6)
- Elevation of blood glucose concentration
- Increased diffusion of glutamate into the -cell by facilitated transport (GLUT2)
- Phosphorylation of glucose by glucokinase
- Glycolysis of glucose-6-phosphate in mitochondria yielding ATP
- Increased ATP/ADP ratio within cell closes ATP-sensitive K+ channels causing membrane depolarization
- Opening of voltage-activated Ca2+ channels increases intracellular Ca2+ that triggers insulin secretion
Mechanism of sulphonylureas?
- Bind to SUR1 receptors on KATP channel, closing the channel
- Causes depolarisation of B cell + insulin release
REMEMBER: insulin dependent but NOT glucose dependent!!!!!
What are sulphonylureas classed as?
Insulin secretogogues - they cause pancreatic B cell insulin secretion
Examples of sulphonylureas?
What is their effect?
- Tolbutamide
- Gliclazide
- Glipizide
Effect = decrease fasting and post-prandial blood glucose
How do sulphonylureas close the K+ channel?
Displace the binding of ADP-Mg from the SUR1 subunit
Duration of action of sulphonylureas?
- short-acting = tolbutamide
* long-acting = glibenclamide, gliclazide, glipizide (more potent than tolbutamide)
Disadvantages of sulphonylureas? (2)
- Hypoglycaemia (because they act independent of glucose!) - especially with long-acting agents, elderly, chronic kidney disease
- Weight gain = appetite increased, urinary loss of glucose decreased
What groups should sulphonylureas be avoided in?
- CKD
- Elderly
- Pregnancy
- Breast-feeding
Difference between glinides and sulphonylureas?
- Act similarly to the sulfonylureas, but their action is augmented by glycaemia
- Lack the sulphonyl urea moiety, – bind to SUR1 (at a distinct benzamido site) to close the KATP channel and trigger insulin release
Examples of glinides?
repaglinide + nateglinide
Mechanism glinides?
Benefit over sulphonylureas? (2)
Have rapid onset of action!! Promote insulin secretion in response to meals
- less likely to cause hypo
- safer than SUs in CKD because mainly hepatic metabolism
What drugs can glinides be used in conjunction with?
Contraindications? (3)
- Metformin + TZDs
Contraindications = severe hepatic impairment, pregnancy and breast feeding
Why is the insulin response to oral glucose greater than the response to IV glucose?
Explain? (6)
Incretin effect
- GLP-1 and GIP released from L cells in ileum and K cells in duodenum following food ingestion
- Enter portal blood
- GLP-1 = enhances insulin release + decreases glucagon release
- GIP = enhances insulin release
- Results in enhanced glucose uptake + decreased glucose production
- DECREASED blood glucose
DPP4-inhibitors also known as?
Mechanism of action?
Gliptins
* Competitively inhibit DPP-4 which normally breaks down GLP-1 and GIP
Example of gliptin?
Adminstration?
Benefits? (2)
Side effect?
Sitagliptin
- Administered once daily orally
- no hypoglycaemia + weight neutral
- Side effect = nausea
What are incretin analogues? Examples?
Mechanism of action?
Peptides that mimic the action of GLP-1 but are FAR longer lasting due to resistance to breakdown by DPP-4!!
* Extenatide + liraglutide
Mechanism = bind as agonists to GPCR GLP-1 receptors that increase intracellular cAMP concentration in pancreatic β-cells to stimulate insulin expression and release
Effects of incretin analogues?
- suppress glucagon secretion
- slow gastric emptying
- decrease appetite (hypothalamic action)
- modest weight loss
- Reduce hepatic fat accumulation
Administration incretin analogues?
Benefit?
Side effects? (2)
Subcutaneously
* does not cause hypo
Side effects = nausea + pancreatitis (very rare)
What is a-glucosidase? a-glucosidase inhibitors?
- Brush border enzyme that breaks down starch and disaccharides to glucose
- Inhibitors - delay absorption of glucose
Examples of a-glucosidase inhibitors? What are they used for?
Side effects?
- Acarbose, miglitol, voglibose
- Used in 2TDM patients inadequately controlled
Side effects = GI upset
Biguanide example?
When is it used?
Metformin!
* First line agent in T2DM EXCEPT in hepatic or renal impairment
Mechanism of action of metformin?
Effects? (3)
reduces hepatic gluoconeogenesis [by stimulating AMP-activated protein kinase (AMPK)]
- increases glucose uptake and utilization by skeletal muscle (increases insulin signalling)
- reduces carbohydrate absorption
- increases fatty acid oxidation
Advantages of metformin? (5)
Disadvantages? (2)
Advantages
- decreased microvascular complications
- can be administered orally
- prevents hyperglycaemia but does NOT cause hypoglycaemia
- causes weight loss
- can be combined with other agents (e.g. insulin, SU, TZD)
disadvantages
- GI upset
- LACTIC ACIDOSIS (rare) - in patients with hepatic or renal disease or excessive alcohol consumption
Explain mechanism of action of TZDs? (3)
- Enhance the action of insulin at target tissues, but do not directly affect insulin secretion – i.e. reduce insulin resistance
- Act as exogenous agonists of the nuclear receptor PPARy which associates with RXR
- Activated PPAR-RXR complex acts as a transcription factor that binds to DNA to promote the expression of genes involved in insulin signalling and lipid metabolism
Desirable effects of TZD’s? (4)
- promote fatty acid uptake and storage in adipocytes (rather than liver)
- reduce hepatic glucose output
- enhance peripheral glucose uptake
- do not cause hypoglycaemia
Adverse effects of TZD’s? (4)
Other name for TZDs?
Contraindications?
- weight gain
- fluid retention – TZDs promote Na+ reabsorption by the kidney
- several members of the class (e.g. ciglitazone, troglitazone) cause serious hepatotoxicity – only pioglitazone (which does not cause liver dysfunction) is now used
- increased incidence of bone fractures
Other name = glitazones
* Contraindicated in heart failure!!
Are sodium-glucose cotransportr 2 (SGLT2) inhibitors insulin dependent?
Mechanism of action?
No, insulin independent
* selectively block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to deliberately cause glucosuria
How to SGLT2 inhibitors cause weight loss?
Examples of SGLT2 inhibitors?
Calorific loss (i.e. glucose voided) and water accompanying glucose (i.e. osmotic diuresis) contributes to weight loss
e.g. dapagliflozin, canagliflozin, empagliflozin
