Pharmacology 2

pharmacokinetics

Distribution

• increasing age
  • albumin decreases
    • need less acidic drug
  • alpha-1 glycoprotein increases!
    • may need more alkaline drug

metabolism + excretion

• orders
  • zero order ‘PEAT’
    • NON-LINEAR KINETICS!
    • Phenytoin, Paracetamol
    • Ethanol (and methanol)
    • Aspirin
    • Thiopentone, theophylline
    • also clonidine!
  • 1st order
• hepatic
  • hepatic extraction ratio
    • extraction ratio = arterial concentration - venous concentration / arterial concentration
      • fraction of drug removed on each pass through the liver
    • hepatic clearance = extraction ratio x hepatic blood flow
    • Blaschke’s Triangle
      • high extraction ratio (>0.7)
        • flow dependent, binding independent elimination
          • propofol
          • propranolol
          • lidocaine
          • opioids
          • tricyclics
          • PLOT
      • low extraction ration (<0.3)
        • enzyme dependent, binding dependent
          • phenytoin
          • barbiturates
          • benzodiazepines
          • theophylline
          • warfarin
          • ‘Protein Binding Bears Thinking Wabout’
        • enzyme dependent, binding independent
          • paracetamol
            • as its hardly protein bound at all
• renal
  • urinary clearance
    • = (urine concentration x urine production rate) / plasma concentration
• numbers
  • half life
    • T1/2 = 0.693 x time constant
  • time constant (Tau)
    • time taken to reach 37% of original concentration
    • time taken to get to 1/e’th of original concentration
    • time it would take for the concentration of a drug to reach 0 if the initial rate of elimination continued
    • = T1/2 / 0.693
    • 1 / rate constant
    • FOR THE LUNG: TIME CONSTANT = COMPLIANCE x RESISTANCE!
  • Drug volume & concentration
    • VD = amount of drug given / concentration at time zero
    • loading dose = Vd x Cp (a variation of the above)
    • maintenance dose = Cp x Cl
    • K = 1 / time constant
    • K = clearance / Vd
    • Time constant = Vd / clearance
    • Bioavailability = AUC oral / AUC iv
  • infusion kinetics
    • at steady state
      • input = output
      • infusion rate (mL/min) x infusion conc (mg/mL) = clearance (mL/min) x plasma conc (mg/mL)
    • Cl = input x plasma conc

Phase 2

acetylation

• rapid
  • autosomal dominant
  • 40%
    • always a smaller proportion at the top
• slow
  • autosomal recessive
  • 60%
• drugs affected (HIS PDP)
  • Hydralzine
  • Isoniazide
  • Sulfonamides
  • Phenelzine
  • Dapsone
  • Procainamide

Or glucoronidation, sulphation, methylation, glycination

Make things water soluble for excretion in urine

Phase 1

Hydrolysis, reduction or oxidation

CYP450

• inducers
  • Carbamazepine
  • Rifampicin
  • Alcohol (chronic) + cigarettes
  • Phenytoin
  • Griseofulvin
  • Phenobarbitone
  • Sulfonyureas
• inhibitors
  • Sodium valproate
  • Isoniazide
  • Cimetidine
  • Ketoconazole + fluconazole
  • Fluoxetine
  • Alcohol (acute) + amiodarone
  • Cardiac + liver failure
  • Erythromycin + clarithromycin
  • Sulfonamides
    • thiazide diuretics
    • antibiotics
  • Ciprofloxacin + chloramphenicol
  • Omeprazole
  • Metronidazole
  • others
    • Grapefruit juice
    • HIV serum protease inhibitors
    • tamoxifen
• specifics
  • 2C9
    • NSAIDs, phenytoin, warfarin
  • 2D6
    • codeine, tramadol, oxycodone
    • 10% of UK population (30% of Chinese) have slow activity
  • 2E1
    • fluoride containing volatiles
    • and paracetamol!
  • 3A4
    • opiates, benzodiazepines