Drugs and Their Targets in T2DM Flashcards
Mechanisms of actions of T2DM therapies?
- Increase secretion of insulin (insulin DEPENDENT action):
• Sulphonylureas
• Incretin mimetics (AKA megaglitinides)
• DDP-4 inhibitors - Decreasing insulin resistance and reducing hepatic glucose output (insulin DEPENDENT action):
• Biguanides
• Thiazolidinediones (AKA glitazones) - Slowing glucose absorption from GI tract (insulin INDEPENDENT action):
• α-glucosidase inhibitors - Enhancing glucose excretion by the kidney (insulin INDEPENDENT action):
• SGLT2 (sodium glucose type-2) inhibitors
What is cellular energy status linked to?
Linked to insulin secretion in the pancreatic β-cell
Mechanism of insulin secretion?
- Elevation of BG conc.
- Increased diffusion of glutamate into the β-cell by facilitated transport (GLUT2)
- Phosphorylation of glucose by glucokinase
- Glycolysis of glucose-6-phosphate in mitochondria yielding ATP
- Increased ATP/ATP ratio within cell closes ATP-sensitive K+ channels (KATP) channels causing membrane depolarisation
- Opening of voltage-activated Ca2+ channels increases intracellular Ca2+ (triggers insulin secretion)
Structure of the KATP channel?
Octomeric complex of:
• 4 potassium inward rectifier 6.2 subunits (Kir6.2)
• 4 sulphonylurea receptor 1 subunits (SUR1)
Tetramer of Kir6.2 subunits form a potassium selective ion channel
Regular of the KATP channel?
SUR1 subunits regulate potassium channel activity
ATP binding to each of the Kir6.2 subunits CLOSES the channel causing depolarisation of the β-cell and insulin release (when extracellular glucose is high)
ADP-Mg2+ binding to the SUR1 subunits OPENS the channel maintain the resting potential of the β-cell and inhibits insulin secretion (when extracellular glucose is low)
Mechanism of action of sulphonylureas (SUs)?
Used in T2DM
- Seem to act by displacing binding of ADP-Mg2+ from the SUR1 subunit
- Bind to SUR1 and CLOSE the channel; this causes depolarisation and insulin release INDEPENDENT of plasma glucose conc.
This means that insulin release is essentially uncoupled from glucose conc. which explains why these drugs can cause hypoglycaemia
Examples of sulfonylureas?
First generation:
• Tolbutamide
Second generation:
• Glibenclamide (AKA glyburide)
• Glipizide
Which of the SUs are longer-acting?
Glibenclamide and Glipazide are more potent and longer-acting; this is likely to have no significant clinical advantage and may in fact cause hypoglycaemia more easily
At risk patients with SUs?
Risk of hypoglycaemia due to excessive insulin secretion; there is a greater risk with:
• Longer-acting agents
• In the elderly
• In patients with reduced hepatic/renal function
Which drugs can SUs be combined with?
Metformin
Thiazolidinediones
Adverse effects of SUs?
Undesirable weight gain
Mechanism of action of Glinides?
Similar to SUs as they bind to SUR1 (at a separate site) to close the KATP channel
Triggers insulin release
Examples of Glinides?
Repaglinide
Nateglinide
Advantage of Glinides over SUs?
Rapid onset/offset kinetics and so are less likely to cause hypoglycaemic
Administration of Glinides?
Active orally and are taken before meals to reduce post-prandial rise in BG
They can be used in conjunction:
• Metformin
• Thiazolidinediones
Describe the incretin effect
Ingestion of food stimulates release of the following from enteroendocrine cells in the SI:
• Glucagon-like 1 (GLP-1) from L-cells in the ileum and colon
• Glucose dependent insulinotropic peptide (GIP) from K-cells in the jejunum/duodenum
These enter the portal blood and cause decreased BG by:
• GLP-1 and GIP enhance (INCREMENT) insulin release from pancreatic β-cells and decrease gastric emptying; there is enhanced glucose uptake and utilisation
• GLP-1 decreases glucagon release from pancreatic α-cells; there is decreased glucose production
Mechanism of action of incretin analogues?
Mimic action of GLP-1 but are longer lasting
Binds to GPCR GLP-1 receptors, which increase intracellular cAMP conc.
Increase insulin secretion, suppresses glucagon secretion, slows gastric emptying and reduces appetite
Examples of incretin analogues?
Exenatide
Liraglutide (longer-acting agent)
Benefits of incretin analogues?
Modest weight loss
Reduce hepatic fat accumulation
Adverse effects of incretin analogues?
Nausea
Hypoglycaemic
Pancreatits (very rarely)
Administration of Liraglutide?
Once daily subcutaneous injection
Function of DPP-4 enzyme?
AKA dipeptidyl peptidase-4 (DPP-4)
Rapidly terminates actions of GLP-1 and GIP
Mechanism of action of DPP-4 inhibitors (AKA Gliptins)
Competitively inhibit DPP-4 and thus prolong the actions of GLP-1 and GIP
Examples of Gliptins?
Sitagliptin
Saxigliptin
Vildagliptin
Administration of Gliptins?
Usually combined with thiazolidinediones or metformin; can be used as a monotherapy
Sitagliptin is orally administered once daily and is mostly well tolerated
Benefits of Gliptins?
No hypoglycaemic (when used as a MONOTHERAPY)
Weight-neutral
What is α-Glucosidase inhibitor?
Dietary carbohydrates require digestion to monosaccharides to be absorbed in the SI
It is a brush-border enzyme that breaks down starch and disaccharides to absorbable glucose
Mechanism of action of α-Glucosidase inhibitors?
Delay absorption of glucose and so reduce post-prandial increase in BG
Uses of α-Glucosidase inhibitors?
Used in T2DM patients who are inadequately controlled by lifestyle measures or other drugs
Example of α-Glucosidase inhibitors?
Acarbose (only clinically relevant one)
Adverse effects of α-Glucosidase inhibitors?
Occur in the GI tract as the undigested carbohydrates are welcomed by the colonic bacteria: • Flatulence • Loose stools and diarrhoea • Abdominal pain • Bloating
Benefit of α-Glucosidase inhibitors?
NO RISK OF HYPOGLYCAEMIA
Examples of Biguanides?
METFORMIN - 1st line agent for T2DM (with normal hepatic and renal function)
Mechanism of action of Metformin?
Reduce hepatic gluconeogenesis (by stimulating AMP-activated protein kinase (AMPK))
Increases glucose uptake and utilisation by skeletal muscle (increases insulin signalling)
Reduces carbohydrate absorption
Increases fatty acid oxidation
Benefits of Metformin?
Suitable for oral administration
Prevent hyperglycaemic but does NOT cause hypoglycaemic
Cause WEIGHT LOSS (unlike insulin and agents that promote insulin release)
Can be combined with, e.g: insulin, TZDs, SUs
Adverse effects of Metformin?
GI upsets (diarrhoea, nausea and anorexia)
Rarely, LACTIC ACIDOSIS (avoid routine use in patients with hepatic/renal disease)
Main effect of TZDs?
Enhance the action of insulin at target tissues but do not directly affect insulin secretion
They reduce amount of insulin required to maintain a given BG
Mechanism of action of TZDs (AKA Glitazones)
Exogenous agonists of PPARγ, which is mostly in adipose tissue, that assoc. with retinoid-receptor X (RXR)
Activated PPARγ-RXR complex acts as a transcription factor and binds to DNA to promote gene expression of proteins inv. with insulin signalling:
• Lipoprotein lipase
• Fatty acid transport protein
• GLUT4 (this is regulated by insulin)
Benefits of TZDs?
Promote fatty acid uptake and storage in adipocytes, rather than in skeletal muscle and liver
Reduced hepatic glucose output
Adverse effects of TZDs?
Weight gain
Fluid retention
Some of the drugs in this class can cause serious hepatotoxicity (they are not used anymore)
• Ciglitazone
• Troglitazone
Increased incidence of bone fractures
Only TZDs still in use?
Pioglitazone
Combination therapy with TZDs?
May be combined with either metformin or an SU, to achieve control of BG
Mechanism of action of SGLT2 (Sodium-Glucose co-transporter 2) inhibitors?
Selectively block reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to cause GLYCOURIA; this decreases BG
Benefits of SGLT2 inhibitors?
Little risk of hypoglycaemia
Calorific loss, i.e: glucose voided, and water accompanying glucose, i.e: osmotic diuresis, contributes to weight loss
Example of SGLT2 inhibitors?
Dapagliflozin
Adverse effects of SGLT2 inhibitors?
Glycosuria increases risk of thrush and other urinary infections, etc
