Endocrine Drugs 11 to 20
Describe the pharmacokinetics of metformin?
Well absorbed, not protein bound, not metabolised, elimination t1/2: 1.5-3 hours, excreted by kidney as unchanged compound
What are the side effects of metformin?
Gastrointestinal most common 20%, decreased absorption Vit B12, lactic acidosis esp with renal
disease, ETOH, chronic cardiopulmonary disease
With regard to sulphonylureas, what is the mechanism of action of glipizide?
Prompt: It's a sulphonylurea.
Increase insulin release from the pancreas bind to receptor associated with ATP sensitive K channel, inhibits efflux of K ions, results in depolarization and opens ca channel, influx of Ca causes release of preformed insulin
Reduction of serum glucagon levels
Closure of potassium channels in extrapancreatic tissues
Notes: Patients more prone to hypo than with biguanides eg metformin
What are the effects of hydrocortisone?
Mediated by glucocorticoid receptors
Physiologic + permissive effects
Catabolic and anti-anabolic effects
Anti-inflammatory + immunosuppressive effects
Other effects: CNS, pituitary axis, psychiatric, renal, neonatal lung
Pass: Bolded and one other
Extra. Prompt: Describe the anti-inflammatory and immunosuppressant effects of hydrocortisone.
Suppress inflammatory mediators (cytokines + chemokines, as well as PGs + leukotrienes)
Inhibit tissue macrophages + APCs Suppress mast cell degranulation
Reduce antibody production (in large doses)
What are the effects of chronic steroid use?
Metabolic effects (moon face, fat redistribution, striae, weight gain, myopathy, muscle wasting, thin skin, bruising, hyperglycaemia, osteoporosis, diabetes, aseptic necrosis, wound healing impaired
Other effects (peptic ulcers, psychosis, depression, cataracts, glaucoma, salt retention, hypertension)
Adrenal suppression (> 2 weeks dosage)
Pass: Bolded and 3 others
Describe the pharmacokinetics of metformin.
- Well absorbed, not protein bound, not metabolised, elimination half-life 1.5 to 3 hours
- Excreted by kidney as unchanged compound
- Bold and one other to pass
Outline some common side effects of metformin.
- GI most common (20%) – limits compliance with this drug
- High anion gap metabolic acidosis (lactic acidosis) especially in patients with co-existent renal disease, ethanol, chronic cardiopulmonary disease
- Bold to pass
Contrast the mechanism of action of metformin (biguanide) and glipizide (sulfonylurea).
- Increases insulin release from pancreas (patients more prone to hypoglycaemia with glipizide compared with metformin)
- Decreases serum glucagon levels
- Mechanism unclear but:
- May reduce hepatic gluconeogenesis
- Not dependent on functioning pancreatic Beta cells – so doesn’t influence insulin release from pancreas
- May directly stimulate glycolysis in tissues with increased glucose removal from blood
- Decreases glucose absorption in the gut
- Bold to pass
Describe the mechanism of action of corticosteroids at a cellular level.
- Most of known effects via widely distributed glucocorticoid receptors
- Present in blood in bound form on Corticosteroid Binding Globulin (CBG)
- Enters cell as free molecule
- Intracellular receptor bound to stabilising proteins (most important heat shock protein 90, Hsp90)
- Complex binds molecule of cortisol then actively transported into nucleus where binds to Glucocorticoid Receptor Elements (GRE) on the gene
- Interacts with DNA and nuclear proteins regulating transcription. Resulting mRNA exported to cytoplasm for protein production for final hormone response.
- Bold to pass
How can corticosteroids be classified?
PROMPT – How do they differ in their action?
- Length of action (hydrocortisone short to medium-acting, dexamethasone or betamethasone long-acting)
- Anti-inflammatory activity (Potency: hydrocortisone 1, prednisolone 5, dexamethasone 30)
- Mineralocorticoid activity i.e. salt retaining (fludrocortisones 250 times that of hydrocortisone)
- Topical vs non topical
- Bold to pass
What are the side effects of corticosteroid use?
PROMPT – What about long term effects?
- Short term (<2 weeks)
- Behaviour changes
- Acute peptic ulcer
- Acute pancreatitis
- Long term
- Cushing’s syndrome (moon facies, fat redistribution, fine hair growth, acne) secondary to hormonal actions. (Rate of development function of dose and genetic background).
- Hyperglycaemia, diabetes
- Osteoporosis, aseptic necrosis
- Psychiatric (hypomania, acute psychosis, depression)
- Sodium, fluid retention, potassium loss
- Adrenal suppression/Addisonian crisis
- Poor wound healing
- Bold and 4 others
What are the complications of insulin administration?
- Hypoglycaemic unawareness
- Insulin allergy (usually due to non-insulin contaminants)
- Immune insulin resistance
- Lipodystrophy at injection sites
- Bold + 1 to pass