Steroidal and non-steroidal biochemistry

• what are steroids?

  - hormones derived from mevalonic acid

  - enzyme that produces mevalonic acid (HMG-CoA reductase) is drug target for statins

  - several different steroid hormone classes are derived from cholesterol by modification of steroid ring structure and SC of cholesterol

  - different steroids bind to specific steroid receptors (usually in nucleus) allowing transcription of various genes

  
• squalene epoxide - lanosterol - cholesterol - pregenolone - progestagens - 1. GCs 2. MCs 3. androgens - oestrogens

  
• what is the steroid structure?

  - basic 4 ring structure (6:6:6:5) with sidechains (SCs)

  - beta-hydroxy configuration

  - hydroxy or ketone at C-11 gives anti-inflammatory activity

  
• what are the 2 stress GC hormones?

  cortisone and cortisol
• what are the 2 synthetic GC derivatives?

  - prednisolone and methylprednisolone

  - prednisolone is produced from prednisone (keto-derivative) by drug metabolism
• what are GC hormones for?

  - promote gluconeogensesis and decrease inflammation by suppressing immune system

  - excess can result in Cushing's syndrome whilst sudden withdrawal can result in adrenal insufficiency
• what are NSAIDS?


  - anti-inflammatory drugs that decrease the production of leukotrienes and thromboxanes

  - inhibit COX-1 and -2 which control the synthesis of these

  - most inhibit both but selective to COX-2 inhibitors can cause serious CV side effects
• what is the difference between COX1 and COX2?

  COX-1

  - Is made constitutively in most tissues

  - Is required for normal gastric tissue, platelet aggregation and renal homeostasis

  
  

  COX-2

  - Is inducible in response to products of immune and inflammatory cells

  - required in joints and endothelial cells

  - PG's produced mediate the pain, heat, redness, and swelling of inflammation and fever of infection

  
• what is aspirin?


  - irreversible and selective COX-1 inhibitor

  - disappears rapidly from blood but has extended duration of action

  - effect potentiated by caffeine

  - long-term low dose use decreases blood clotting (CVD secondary prevention)

  - not recommended for use in children (<16yrs) due to risk of Reye's syndrome (type of encephalopathy)

  
• what is ibuprofen (and related drugs)?

  - e.g. ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen

  - reversible inhibitors of COX 1 and 2

  - analgesic, anti-inflammatory and antipyretic activity due to COX 2 inhibition

  - only S-enantiomer is active

  - some risk of ulcers

  
• what is diclofenac?


  - dichloro-phenyl-acetic acid

  - stronger inhibitor of COX-2

  - use inceases risk of CV complications but decreases ulcer risk

  - duration of action is 6-8 hours due to accumulation in synovial fluid