Drugs in T2DM Flashcards
What is the pathway of production of insulin within the beta cell?
Elevation of blood glucose that is transferred into the beta cell via GLUT2
Phosphorylation of glucose by glucokinase
Glycolysis of glucose-6-phosphate in mitcohondria yeilding ATP
Increased ATP/ADP ration within cell closes kATP channels causing depolarisation
Opening of voltage activated Ca2+ channels increases Ca2+ in cell triggering the release of insulin via exocytosis in storage granules
What is the structure of kATP channels?
Octomeric complex containing 4 Kir6.2 core subunits and 4 sulphonylurea receptor 1 subunitis (SUR1)
What is the action of SUR1?
Regulates potassium channel activity
How does ATP cause the closing of Kir6.2 channels?
When all 4 sites on Kir6.2 inner core are occupied by ATP the potassium channel will close causing depolarisation of the beta cell and insulin release
How does ADP-magnesium interact with the SUR1 subunits?
Opens the channel maintaining the resting potential of the beta cell and inhibits insulin secretion
What class of drugs are sulphonylureas?
Insulin secretogoues
What is the mode of action of SUs?
Cause pancreatic beta cell insulin secretion - requires functional beta cells to be effective
Displace the binding of ADP-magnesium from the SUR1 subunit closing the kATP channel and stimulatin insulin release
What are the different types of SU?
Short acting = tolbutamide
Long acting = glicazide, glipizide
What are the long term effects of SUs?
Reduce the microvascular complications of diabetes
What are the side effects of SU?
Hypoglycaemia
Weight gain
Who are hypos more likely with in patients who take SU?
Long acting agents in anyone
Elderly
Patients with reduced hepatic/renal function
CKD
In what patients are SUs CI in?
Pregnant women
Women who are breastfeeding
When are SUs utilised?
First line in patient intolerant to metformin or with weight loss
Second line with metformin
Third line with metformin and thiaolidinedione
How do SUs cause weight gain?
Anabolic effect of insulin increased
Appetite increased
Urinary loss of glucose decreased
What is the mechanism of action of glinides?
Similar to SU bu action is augmented by glycaemia
How are glinides metabolised?
Hepatic - safter than SUs in CKD
How are glinides absorbed?
Active orally Rapid onset (30-60mins)/ offset 4hr kinetics
Under what scenario are glindes prescribed?
In conjunction with metformin and thiazoldinediones
What are the incretin hormones?
GLP-1
GIP
What do GLP-1 and GIP enhance?
Insulin release from pancreatic beta cells (delay gastric emptying)
What does GLP-1 decrease?
Release of glucagon from pancreatic alpha cells
What does a reduced glucagon release result in?
Decreased hepatic gluconeogenesis
How can the incretin effect be restored in T2DM?
Reducing the breakdown of the endogenous incretins
Administering exogenous incretin analogues resistant to breakdown
What enzyme breaks down GLP-1 and GIP?
DDP-4
When are DDP-4 inhibitors used?
In comobo with a SU or metformin but can be a monotherapy
What is the main adverse effect of DPP-4 inhibitors?
Nausea
NO hypoglycaemia
Weight neutral
What are examples of incretin analogues?
Extenatide are peptides that mimic the action of GLP-1 but are far longer lasting due to resistance to breakdown by DPP-4
How do incretin hormones increase the levels of insulin?
Bind as agonists to GPCR GLP-1 receptors that increase intracellular cAMP conc in pancreatic beta cells to stimulate insulin expression and release
What are the additional effects of incretin analogues beside the release of insulin?
Suppress glucagon secretion Slow gastric emptying Decrease appetite (hypothalamic action) Weight loss Reduce hepatic fat accumulation (good for NAFLD)
How are incretin analogues administered?
SC twice daily
What are the side effects of incretin analogues?
Nausea
Pancreatitis
Where can alpha-glucosidase be found?
Brush border enzyme that breaks down starch and disaccharides to absorbable glucose
What are examples of alpha glucosisade inhibitors?
Acarbose
When should acarbose be taken?
With a meal to delay the absorption of glucose and thus reduce postprandial increase in blood glucose
What are the side effects of alphpa-glucosidase inhibitors?
Flactulence Loose stools Diarrhoea Abdominal pain Bloating
What drug is classed in the biguanide group?
Metformin
When is metformin used?
1st line drug in T2DM irrespective of obesity with normal hepatic and renal function
What is the mode of action of metformin?
Reduced hepatic gluconeogenesis by stimulating AMPK
Increases glucose uptake and utilization by skeletal muscle
Reduces carbohydrate absorption
Increases fatty acid oxidation
What will metformin do in the long term?
Reduces the microvascular complications of diabetes
How is metformin administered?
Orally BD or TDS
What desirable effects does metformin have?
Weight loss
Prevents hyperglycaemia without causing hypoglycaemia
Combined with other agents
What are the adverse effects of metformin?
GI upset - diarrhoea, nausea, anorexia
Lactic acidosis
What is the mode of action of thiaxoldinediones?
Enhance the action of insulin at target tissues - do not directly affect insulin secretion i.e. reduce insulin resistance
What transcription factor do glitazones act on?
PPAR gamma to promote the expression of genes that code for several proteins involved in insulin signalling and lipid metabolism
What are the desirable effects of glitazones?
Promote fatty acid uptake and storage in adipocytes, rather than in skeletal muscle and liver
Reduce hepatic glucose output
Enhance peripheral glucose uptake
Do NOT cause hypoglycaemia
What are the adverse effects to glitazones?
Weight gain due to the differentation of pre-adipocytes to mature adipocytes
Fluid retention - promote sodium reabsorption by the kidney causing hepatotoxicity
Increased incidence of bone fractures
SHOULD NOT BE USED IN HEART FAILURE
What is the mode of action of SGLT-2 inhibitors?
Act to selectively block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephoron to delibratley cause glucosuria
What are the desirable effects of SGLT-2 inhibitors?
Reduce hyperglycaemia with a low risk of hypoglycaemia
Calorific loss and weight loss
