T2 DM drugs Flashcards
Insulin hepatic effects
Increases glycogenesis
Inhibits:
- Gluconeogenesis
- Glycogenolysis
- Ketogenesis
Insulin skeletal muscle effects
Increases:
- GLUT-4 translocation= more glucose uptake
- Glucose oxidation
- Glycogenesis
- Amino acid uptake
- Protein synthesis
Decreases:
- Glycogenolysis
- Amino acid release
Insulin adipocytes effects
Increase:
- Glucose uptake
- TG synthesis
Decreases:
- FFA release
- Glycerol release
Sulfonylurea examples
Glyburide
Glipizide- short half life
Glimepiride- long acting
Sulfonylurea drug properties
- Oral activity
- Protein bound
- Side effects
Orally active
Bound to plasma protein
Side effect: Hypoglycaemia
Sulfonylurea indication
In T2 DM when:
- Patient <40, but can now be younger.
- DM for <10 yrs
- Daily insulin <40 units.
Sulfonylurea primary mechanism of action
Stimulates endogenous insulin release from beta-cells
- Binds to ATP-sensitive K+ channel to inhibit it
- Triggers depolarisation of the cell
- Entry of Ca2+ triggers release of insulin
Sulfonylurea secondary mechanism of action
Sensitise beta-cells to glucose
Decreased lipolysis
Decreased clearance of insulin by the liver
Biguanide/ Metformin
- Metabolic mechanism
Increase glucose uptake in muscle and decrease glucose production in the liver.
In hepatocytes
- Stimulates AMP-activated protein kinase [AMPK] dependant and independant pathways.
- AMPK inhibits expression of PEPCK and Glucose-6-phosphates by increasing SHP
- PECK and Glucose-6-phosphatase drive gluconeogenesis
SHP
A nuclear transcription factor
It’s expression is increased by AMPK
- An effect of metformin
Inhibits expression of genes for PEPCK and Glucose-6-phosphatase
PEPCK
Phosphoenolypyruvate carboxykinase
Protein that drives gluconeogenesis
It’s synthesis is inhibited by SHP via AMPK pathway
Biguanides on insulin sensitivity
Increases insulin sensitivity
- Improves binding ability of insulin receptors.
Biguanides on peripheral glucose uptake.
Increases uptake
AMPK pathway
- Increases GLUT-4 translocation
AMPK-independant
- Changes heart muscle to metabolise glucose more using p38 MAPCK
- PKC-depedant
Biguanides effects on
- Adipose tissue
- GIT
Adipose [opposes insulin]
- Increases fatty acid oxidation by decreasing insulin-induced suppression of FA oxidation
GIT:
- Decreases glucose absorption
Metformin properties
- Oral activity
- Plasma proteins
- Metabolism and excretion
- Other indications
Orally active
Does not bind to plasma proteins
Not metabolised + excreted in urine
Other indications
- Polycystic ovarian syndrome
Adverse effects of biguanides
Lactic acidemia [increased glucose metabolism in muscle]
- Especially in those with renal impairment
GI symptoms [decreased glucose absorption]
- Nausea
- Abdominal discomfort
- Diarrhoea
- Metallic taste
- Decreased Vit B12/ Folate absorption [chronic]
Anorexia
Metallic taste
MI/ Septicaemia
Metformin contraindications
Hepatic disease
Lactic acidosis history
Cardiac failure
Chronic hypoxic lung disease
Thiazolindinediones [glitazones]
- Mechanism
- Action on: liver, skeletal muscle, adipose
Mechanism
- Activates peroxisome proliferator-activated receptor-gamma [PPAR-gamma]
Liver
- Decreases: gluconeogenesis, glucose output, TG production
Muscle
- Increase glucose uptake and utilisation
Adipose
- Increase glucose uptake
- Decrease FA output
- Causes differentiation of adipocytes
Peroxisome proliferator-activated receptor-gamma [PPAR-gamma]
Receptor that is activated by Glitazones
Receptor involved in the transcription of insulin-responsive genes
Regulates adipose lipid mechanism.
Use of glitazones
Can be used as monotherapy
Can be used with metformin or sulfonylureas.
Dose: one/twice daily
Glitazones
- Example
- Plasma life
- Metabolism
- Excretion
Example
- Pioglitazone
Half life
- 3-7hrs
- Active metabolites= 16-24 hrs
Metabolism
- Liver
Excretion
- Faeces [mainly]
- Urine
Glitazones
- Adverse effects
Fluid retention
- Oedema
- Mild anaemia
Weight gain
Not safe for breastfeeding and pregnancy
Requires regular blood tests if liver damaged
[due to liver metabolism]
Glitazone drug interactions
Due to metabolism in the liver
- Interacts with enzymes
Lowers oral contraceptive level
Glucagon-like peptide-1 [GLP-1] analogs
GLP-1 is an incretin released from intestinal cells
- Stimulates the release from insulin from beta cells.
- Its analogs perform a similar action
Example
- Exenatide
Exenatide
- Drug type
- Mechanism [liver, stomach, satiety]
GLP-1 analog
- Resistant to DPP-4 degradation
- Long half life
Mechanism
- Inhibits liver glucose output—> Suppresses release of glucagon in pancreas
- Slows gastric emptying= allows more time for glucose control.
- Reduces liver fat content
- Reduces appetite + increases satiety
Exenatide
- Use
Subcutaneous
- 30-60mins before last meal of the day.
DPP-4 inhibitors
- Overall function
- Examples
DPP-4 degrades incretins and inhibits insulin secretion.
- Inhibitors act to increase GLP-1 and GIP levels = increased incretins
- Increases the effects of incretins
Examples
- Vildagliptin
- Sitagliptin
- Saxagliptin [irreversible]
DPP-4 inhibitors
- Oral activity?
Orally active
SGLT-2 inhibitors
- Examples
Increases excretion of glucose via the urine
- Inhibits low affinity, high capacity SGLT-2 protein carrier
Examples
- Dapagliflozin
- Canagliflozin
SGLT-2 inhibitors
- Effects
Reverses hyperglycaemia by inhibiting glucose absorption
Increases insulin sensitivity in muscle and liver
Decreases gluconeogenesis
Improves beta cell function
Adverse side effects of SGLT-2 inhibitors
Rapid weight loss
Fatigue
Dehydration
May worsen UTI/ thrush.
First line drug for T2 DM
Metformin
