T2 L14: PK3 - Drug metabolism

• What is the Phase I of drug metabolism?


  breakdown processes:

  • oxidation via p450 cytochrome enzyme complex
  • reduction
  • hydrolysis by esterases

  drug is broken down into 3 compartments:

  • active (pro-drug)
  • inactive
  • toxic
• What is the Phase II of drug metabolism?

  drug solubility by conjugation:

  • glucuronidation
  • acetylation
  • sulfation
  • methylation

  then elimination in urine / bile
• What are the 2 phases of drug metabolism?



  Phase I: drug breakdown (oxidation via P450 cytochrome)

  Phase II: solubilisation (packaging to become more excretable)

  
• What is a prodrug?


  a drug or compound that is metabolised into a pharmacologically active drug.

  examples:

  • Enalapril to Enalaprilat
  • Codeine into Morphine
  • Levodopa to Dopamine
• What are cytochrome p450 inhibitors?


  rapidly block action of cytochrome p450 enzyme (within days)

  drugs reliant on that system cannot be metabolised and levels will rise toxic levels in system

  should NOT be given together

  eg ciproflaxin, amiodarone, Ritonavir / Cobicistat, alcohol (acute), grapefruit juice
• Why are Ritonavir / Cobicistat given alongisde antivirals in HIV treatment?


  they are cytochrome p450 inhibitors

  enhance treatment
• What are cytochrome p450 inducers?


  induce production of enzyme

  slow process (weeks/months)

  eg alcohol (chronic), carbamazepine, rifampicin
• What is the 'therapeutic index'?


  Ratio of concentration associated with toxicity (MTC) vs concentration associated with efficacy (MEC).
• What are extensive (normal) metabolisers in terms of genetics?


  individual with two active 'normal' alleles
• What are intermediate metabolisers in terms of genetics?


  individuals with one normal and one abnormal allele
• What are poor metabolisers in terms of genetics?

  two abnormal alleles
• What are ultra-rapid metabolisers in terms of genetics?


  duplication of two normal alleles
• What is the effects of CYP2D6 polymorphism with ultra-rapid metaboliser?


  exaggerated response to codeine

  opiate toxicity even at low dose
• What is the effect of CYP2D6 polymorphism with poor metaboliser?


  inadequate pain relief by codeine
• What ethnicity / race has highest prevalence of CYP2D6 ultra-metabolisers?

  african / ethiopian (29%)
• How is the activity of N-acetyltransferase genetically determined?


  fast acetylators at increased risk of: Isoniazid hepatotoxicity

  slow acetylators at increased risk of:

  • Isoniazid neuropathy
  • drug-induced lupus with Hydralazine
• What are the main factors that are affected in both phases of drug metabolism?


  Phase I: cytochrome p450

  Phase II: N-acetyltransferase
• How is the relationship between rate of drug metabolism and drug concentration in non-saturable metabolism (first order kinetics)?

  
  

  proportional

  
• How is the relationship between rate of drug metabolism and drug concentration in saturable metabolism (zero-order kinetics)?


  Independent

  
• What is Cytochrome p450 inhibition?


  rapid process that leads to higher serum drug concentrations
• What is Cytochrome p450 induction?


  slower process that leads to lower serum drug concentrations