PK – Concentrations

Master answer

FACTORS

Factors may be pharmacokinetic, Pharmacodynamic or Patient factors

1) Pharmacokinetic factors

• Absorption:
  • enables an appreciation of bioavailability and variation in di­fferent routes
  • heparin is an example, there is reduced absorption SC due to endothelial protein binding
• Distribution :
  • highly lipid soluble drugs generally have a high volume of distribution
    • plasma levels will therefore appear markedly decreased when compared to dose
  • Protein Binding:
    • Total plasma levels may not be reflective of active drug level
    • E.g: Phenytoin and hypoalbuminemia (Low total, but enough free unbound drug)
  • the pKa may be relevant as the amount ionised may be more important in determining
    • eff­ect rather than the total plasma level (ability to cross membranes)
  • Effect site concentration may not be adequate inspite of plasma concentration
    • (E.g Vancomycin in Ventriculitis, where high plasma levels are no guarantee of bactericidal CSF levels)
• Metabolism:
  • drugs may have saturable metabolic pathways such that even at high doses the drug will
  • be cleared at a fixed rate (phenytoin)
  • co-administration of drugs may upregulate metabolic catalysts (e.g. CYP450s) increasing
  • metabolism, or compete for substrate/catalyst decreasing metabolism
• Excretion:
  • drugs that are excreted renally may have much higher plasma concentration if there is impairment or oliguria.
• Measurement related factors:
  • Measurement Assay used
  • Timing of sample collection
    • In relation to dosing: Peak, trough, etc
    • In relation to steady state concentration: Caution when interpreting before 3-5 half lives

2) Pharmacodynamic factors

• Relationship of plasma concentration to clinical drug effect:
  • E.g. There is no relationship in the case of Levetiracetam
• Active Metabolites
  • Plasma concentration may not correlate to clinical effect in the presence of Active metabolites
• Drug action receptor sensitivity
  • action at the sensor (e.g. competitive antagonist vs non-competitive antagonist)
• Appreciation of reference values for plasma concentration levels
  • To check therapeutic eff­ect
    • antimicrobials -minimal inhibitory concentration levels
  • To monitor side e­ffects
    • local anaesthetic agents -CNS:CVS ratios

3) Patient factors

• Age (decreased sedative concentrations required in elderly)
• Lean body mass vs toal body mass (lipid soluble versus small V_D drugs)
• Renal and hepatic function (may prolong and elevate plasma concentrations)
• Pharmacogenetic factors
  • abnormalities in CYP450 (e.g. variable codeine metabolism)
  • abnormal plasma esterases – suxamethonium metabolism
• Individual variability in Drug Response

CLINICAL RELEVANCE

• Drug plasma concentrations are relevant when certain criteria are met:
  • demonstrated relationship between drug concentration and therapeutic or toxic eff­ect (digoxin)
  • narrow therapeutic window (carbamazepine)
  • variability in plasma level such that response cannot be predicted from dose alone (warfarin)
  • drug produces eff­ects, intended or unwanted, that are difficult to monitor (heparin)
  • Convenient to collect, Fast and Accurate results
  • Good benefit to cost

JC 2019

Answer by JC