T2 L15: PK 4 - Drug excretion

• What is drug clearance?


  The sum of all the drug-eliminating processes, principallydetermined by hepatic metabolism and renal excretion

  can also be defined as the theoretical volume of fluid from which a drug is completely removed in a given period of time
• Ciprofloxacin is a cytochrome p450 inhibitor. If a patient takes warfarin alongside it, they will present with bruising.
• Clarithromycin is a cytochrome p450 inhibitor. If a patient takes statins alongside it, they will present with muscle aches and pains.
• What are the two ways of drug excretion?


  excretion without metabolism (unchanged)

  metabolised then excreted
• What are the components of renal excretion and what do they do?


  glomerulus - glomerular filtration

  Proximal convulated tubule - secretion

  distal convulated tubule - reabsorption

  
• What are some other excretory methods?


  bile (faeces)

  sweat

  exhaled air

  saliva

  breast milk
• What are some causes of low drug clearance?


  normal variation

  renal impairment

  liver impairment

  enzyme inhibition

  genetic poor metaboliser

  neonate (infant - child under 28 days)

  old age
• What are some causes of high drug clearance?


  normal variation

  increased renal blood flow

  genetic hypermetabolism

  enzyme induction
• What is the clinical presentation of digoxin toxicity?


  Nausea, vomiting, visual disturbances, arrhythmias
• A 59-year-old man presented to the ED with a 2 day history of palpitations, nausea, vomiting and visual disturbances. He had been on digoxin for AF for the past 12 years. He had a recent episode of acute gastroenteritis.

  Blood results:

  • Cr 245 (79-118)
  • Ur 18 ( 2.5-6.7)
  • eGFR 23 (>60)

  What is the cause of his presentation?

  blood results show acute kidney injury

  gastroenteritis causes diarrhoea and vomiting

  causing fluid loss

  which harms the kidney

  blood tests show acute kidney injury

  kidney cannot excrete digoxin, causing build up

  above symptoms due to digoxin toxicity
• What is the 'therapeutic index'?


  Therapeutic Index = Ratio of toxicity concentration (MTC) vs efficacy concentration(MEC)

  drugs with wide therapeutic margin are usually safer

  
• What kind of therapeutic margin does Digoxin have and what are the implications?


  Narrow. Implications: Increased risk of toxicity with small changes in dose.

  
• What is 'half-life' and what information does it provide?


  Time for the concentration of drug in plasma to halve

  Provides information on:

  • Time course of drug elimination
  • Time course of drug accumulation
  • Choice of dose interval
• How many half lives does it take for a drug to be completely washed out of the system?

  5
• What is 'dynamic equilibrium' in relation to pharmacokinetics?


  steady state

  amount of drug going in is the same as drug going out

  
• What is the 'loading dose'?

  Initial dose.
• Generally, if a drug has a big volume of distribution, it will require a big loading dose.
• Why is warfarin given with a big loading dose?

  as soon as in circulation, warfarin attaches to protein

  if not enough warfarin, all will attach to protein and none will take effect
• Loading dose to satisfy the proteins, then excess dose to actually take effect.
• How is the loading dose curve in oral administration?


  determined by volume distribution

  concentration fluctuates

  
• How is the loading dose curve in IV administration?


  determined by volume of distribution

  flat

  
• What is the relationship between half life, volume of distribution (Vd) and clearance (CL)?

  longer the half life, longer the Vd, lower CL

  clearance and half life inversely proportional

  volume of distribution and half life directly proportional

  
• What are loading dose, maintenance dose and dose interval determined by?

  loading dose → volume of distribution

  maintenance dose → clearance

  dose interval → half life
• A 76-year-old woman is admitted with septicaemia from the urinary tract infection and the plan is to treat with IV gentamicin once daily.

  Blood results show acute kidney injury:

  Cr 322 (reference range 79-118)

  Ur 26 (reference range 2.5-6.7)

  eGFR 13 (reference >60)

  How will this affect the dosing of gentamicin?

  administer in longer intervals

  give gentamicin dose, then observe levels daily

  until it's safe to give next dose