Drug 4

• drug metabolism


  chemical transformation of a drug into products within body (mainly CYP450 enzymes)
• drug excretion


  physical process that leads to irreversible removal of drug from body
• drug elimination


  removal of drug through metabolic and excretion
• drug elimination proportions


  75% metabolism 25% excretion
• routes of drug excretion

  urine (kidneys), faeces (bile), sweat, breast milk, hair, expired air
• drug clearance


  efficiency of drug elimination, ratio of elimination rate to conc of drug in plasma
• what does drug clearance tell

  the volume of plasma that would be cleared of drug per unit of time
• fu


  fraction of drug unbound in the plasma
• total renal clearance =

  glomerular filtration + active secretion - reabsorption
• fe 


  fraction of administered drug excreted unchanged in the urine (renal clearance)
• dose adjustments for impaired renal and hepatic functions

  renal - eGFR hepatic - child-pugh score
• hydrophilic drugs Fe


  high
• lipophilic drugs Fe


  low
• first order kinetics


  change in amount of drug in body by a constant fraction per unit time (hyperbola graph, log plasma conc is linear)
• zero order kinetics


  change in amount of drug in body by a constant amount per unit of time (linear)
• what order kinetics do most drugs follow

  first order (constant half life), change to zero order as drug conc increase and elimination mechanisms saturated
• steady state conc


  conc of drug in plasma reached when rate of drug absorption is equal to rate of drug elimination following repeated dosing
• how long dose it take to reach steady state conc

  4-5 half lives, then maintenance dose to keep in therapeutic range
• how to achieve clinical response from drug quickly

  loading dose (Vd) x target plasma conc followed by maintenance dose
• total body clearance calculation (NCA)

  dose (mg) x F / AUC
• how much CO do kidneys receive

  25%
• how much renal plasma flow filtered through glomerular capillaries

  20%
• what can pass through glomerular capillaries


  small, free (not plasma protein bound) drugs can pass through into filtrate
• why does GFR (120ml/min) decline

  aging or disease
• renal clearance by glomerular filtration calculation

  fu x GFR
• how calculate eGFR


  measure how well creatine is cleared to indicate renal function, if impaired high blood creatine
• passive reabsorption in renal excretion

  most glomerular filtrate returns to circulation via peritubular capillaries, only 1% becomes urine, water reabsorbed so drug conc increase and diffuse back across conc gradient to capillaries
• what drugs can passively reabsorb

  ionised drugs, can't cross lipid membrane is why the urine pH is important
• how is salicylate (aspirin metabolite) overdose treated

  i.v give sodium bicarbonate to increase urine pH = ionisation of acid = less reabsorption
• active secretion


  drugs excreted from peritubular capillaries to tubular lumen (proximal), mediated by transporters
• 2 x SLC transporters that active secrete from capillary into urine

  OAT 1 and OAT 3 (have overlapping substrate specificity)
• factors that influence renal excretion

  drug conc in plasma, plasma protein binding, urine pH, renal blood flow, impaired renal function, molecular size and weight, transporters
• probenecid 


  an OAT1/3 inhibitor, PK enhancer. Given with drugs to stop active secretion into urine, stays in plasma and prolong action
• what drugs are excreted into bile

  glucuronides