Drug treatment of type 2 diabetes Flashcards
Insulin effects on hepatic cells
Decreases gluconeogenesis, glycogenolysis, ketogenesis
Insulin effects in muscle cells
Increases GLUT-4 translocation to the membrane
Increases glucose uptake, glucose oxidation, glycogen synthesis, amino acid uptake, protein synthesis
Decreases glycogenolysis and amino acid release
Insulin effects in adipocytes
Increase glucose uptake, increase triglyceride synthesis
Decrease FFA and glycerol release
Net effect of insulin
To cause hypoglycaemia and increase fuel storage in muscle, fat tissue and liver
Sulfonylureas
e.g. gliclazide, glipizide, glimepriride
All orally active
All bound to plasma protein
Primary mechanism of action of sulfonylureas
Stimulates endogenous insulin release
Binding site on ATP sensitive K-channel to inhibit the opening of the channel similar to ATP
Secondary mechanism of action of sulfonylureas
Evidence these drugs:
- sensitise B-cells to glucose
- decrease lipolysis
- decrease clearance of insulin by the liver
Therapeutic uses of sulfonylureas
Useful in type-2 DM only
- over 40 years old
- DM duration less than 10 years
- daily insulin less than 40 units
Can be used in combination with other anti-diabetic drugs
Major side effect: hypoglycaemia
Biguanide drugs
Oral antihyperglycaemic agents
Differ from sulfonylureas and meglitinides both chemically and in mechanism of action
Do not stimulate insulin release or cause hypoglycaemia
Appear to increase glucose uptake in muscle and decrease glucose production by liver
Biguanide drugs mechanism of action
Suppression of hepatic glucose production through gluconeogenesis through AMP - AMPK dependent and independent pathways
AMPK increases expression of nuclear transcription factor SHP
SHP inhibits expression of hepatic gluconeogenesis genes (PEPCK) and G-6-Pase
Biguanides action
Increase insulin sensitivity
- possibly through improved binding to insulin receptors
Enhances peripheral glucose uptake
- increased GLUT 4 translocation through AMPK
- heart muscle metabolic changes by p38 MAPCK and PKC dependent mechanisms and independent of AMPK
Increases fatty acid oxidation via decreased insulin induced suppression of fatty acid oxidation
Decreases glucose absorption from GI tract
Properties of metformin
Orally active
Does not bind plasma proteins
Excreted unchanged in urine
- half life 1.3-4.5 hours
Often combined in single pill with other anti-diabetic medications
Also used for polycystic ovary syndrome
Adverse effects and toxicity of biguanides
Metormin produces lactic acidaemia only rarely
- more frequent in patients with renal impairment
Nausea, abdominal discomfort, diarrhoea, metallic taste, anorexia
Vitamin B12 and folate absorption decreased with chronic metformin
MI or septicaemia mandate immediate stoppage
Metformin contraindications
Hepatic disease
Past history of lactic acidosis
Cardiac failure
Chronic hypoxic lung disease
Glitazones e.g.
Thiazolidinediones
Glitazones
Troglitazone was first approved for use in NIDDM; off the market now due to hepatic failures
Rosiglitazone now off the market due to CVS damage
Pioglitazone now only one remaining approved
Activate peroxisome proliferator activated receptor gamma (PPARy)
Glitazone pharmacodynamics
In presence of endogenous or exogenous insulin, gliatozones will:
- decrease gluconeogenesis, glucose output and triglyceride production in liver
- increase glucose uptake and utilisation in skeletal muscle
- increase glucose uptake and decrease fatty acid output in adipose tissue
- cause differentiation of adipocytes
Glitazone pharmacokinetics
Pioglitazone: taken once or twice daily orally
- plasma levels peak about 3 hours
- plasma half life is 3-7 hours; active metabolites
- liver metabolism and excreted in faeces (2/3) and urine (1/3)
Adverse effects and drug interactions of gliatazones
Fluid retention (promotes amiloride sensitive sodium ion reabsorption in renal collecting ducts) causing oedema, mild anaemia
Dose related weight gain
Safety in pregnancy and lactation not determined
Do not cause lactic acidosis, even in patients with renal impairment
Liver damage may require regular blood tests
Pioglitazone adverse effects and drug interactions
Subject to interactions due to liver metabolism
May lower oral contraceptive levels containing ethinyl estradiol and norethindrone
Glucagon like peptide 1 analogs
Facilitate glucose control by
- augmenting pancreas response
- suppresses pancreatic release of glucagon helping stop the liver overproducing glucose
- slows down gastric emptying
- reduces appetite and promote satiety via hypothalamic receptors
- reduces liver fat content
Side effects of glucagon like peptide 1 analogs
Mainly GI in nature
Acid or sour stomach
Belching
Diarrhoea
Heartburn
Exenatide
High plasma concentration
Strong effects on receptors
Injectables only
New oral formulation in clinical trials
Dipeptidyl peptidase 4 inhibitors
Class of oral hypoglycaemic agents
Mechanism of action is via increased levels of incretins GLP1 and GIP
Increased incretins
- inhibit glucagon release
- increase glucose induced insulin secretion
- decrease gastric emptying
- reduce hepatic glucose production
- improved peripheral glucose utilisation
Types of DPP-4 inhibitors
Vildagliptin (reversible)
Sitagliptin (reversible)
Saxagliptin (covalently bound)
DPP-4 inhibitor features
Orally active
Few side effects
Modest elevations of incretins
Weight neutral, no GI side effects
DPP-4 inhibitors and cancer
Enzyme known to be involved in suppression of certain malignancies as it functions as a tumour suppressor
Not yet seen with drugs in long term preclinical studies
SGLTs
SGLT1 found in small intestine and proximal straight tubule of the nephron
SGLT2 found in proximal convoluted tubule
100% of glucose has to be reabsorbed along the nephron, 90% by SGLT2
Blocking this transporter causes blood glucose to be eliminated through the kidney
SGLT2 inhibitors
Dapagliflozin- approved for use in Europe April 2012
- IC50 for SGLT2 is less than 1/1000 of the IC50 for SGLT1
Canagliflozin- approved by FDA 10th Jan 2013 to treat type 2 diabetes in adults
Effects of SGLT2 inhibitors
Inhibition of renal tubular Na+ glucose cotransporter –> reversal of hyperglycaemia –> reversal of glucotoxicity
Increase insulin sensitivity in muscle
- increase GLUT4 translocation
- increase insulin signalling
Increase insulin sensitivity in liver
- decrease G-6-Pase
Decrease gluconeogenesis
- decrease Cori cycle
- decrease PEP carboxykinase
Increase beta cell function
Side effects of SGLT inhibitors
Rapid weight loss (due to glycosuria)
Tiredness
Osmotic diuretic so dehydration
Can worsen UTI and thrush
