FRCA Notes

Effects of Altered Physiological States on Pharmacokinetics

Absorption

  • For orally administered drugs
    • Prolonged GI transit time and delayed gastric emptying = slower absorption
    • Less acidic gastric pH
    • However increased proportion absorbed due to longer contact time with mucosal surfaces
  • Rapid transdermal absorption as thin stratum corneum

Distribution

  • The new-born is relatively overhydrated and loses volume over hours/days via diuresis
  • Both the absolute proportion of water (80%) and relative size of extracellular compartments are higher
  • Increased dose of water soluble drugs required to prevent lower tissue levels
  • Reduced plasma protein binding vs. adults therefore more free drug
  • pH of neonatal blood is lower and this will alter unionised/ionised fractions of drugs
  • The composition and acid-base value of blood affects plasma protein binding
  • Lower body fat
  • Increased BBB permeability

Metabolism

  • The majority of enzymes don't reach maturity until many months old
    • There are reduced plasma cholinesterase levels and reduced CYP450 enzyme activity
    • Therefore reduced Phase 1 metabolism

Excretion

  • Nephron numbers and function isn't mature for many months
  • The CrCl per unit bodyweight is <10% of an adult's
  • Overall reduced excretion

Absorption

  • Reduced gastric emptying (clinically insignificant) due to age-related autonomic changes

Distribution

  • Reduced muscle mass by proportion
    • Affects volume of distribution
    • Increases sensitivity to remifentanil that is metabolised by muscle esterases
  • Decreased albumin level
  • Decreased total body water

Metabolism

  • Reduced hepatic blood flow
  • Reduced activity of hepatic enzymes
  • Therefore reduced 1st pass metabolism of drugs = increased bioavailable fraction

Excretion

  • Reduced creatinine clearance with age

Absorption

  • Reduced gastric emptying in labour can reduce PO bioavailability
  • Delayed gastric emptying leads to increased absorption of drugs from stomach, reduced absorption from intestines
  • May be increased first pass metabolism due to higher hepatic clearance

Distribution

  • Higher TBW, plasma volume and body fat - increases volume of distribution
  • Lower albumin and a1-acid glycoprotein = increased free fraction of certain drugs

Metabolism

  • Higher hepatic blood flow = greater clearance of some drugs
  • There may be increased enterohepatic circulation of drugs
  • Acquired pseudocholinesterase deficiency = prolonged effect of suxamethonium
  • Placental enzymes may metabolise certain drugs/endogenous compounds e.g. placental lactogen degrades insulin

Excretion

  • Greater GFR = higher clearance of some drugs

Absorption

  • Largely unchanged due to preserved gastrointestinal function
  • Increased cardiac output, body surface area and gut blood flow do not manifest as clinically significant

Distribution

  • Increased volume of distribution for both hydrophilic and lipophilic drugs due to increases in both total body water and fat mass
  • Increased protein binding due to higher levels of plasma proteins; may reduce free drug fraction

Metabolism

  • Cardiac output is higher, as is hepatic and renal blood flow, so drug delivery to organs of metabolism is increased
  • This increases clearance and metabolism of flow-limited drugs with a high extraction ratio e.g. propofol, ketamine and morphine
  • There is increased Phase II metabolism, which can reduce the clinical effectiveness of drugs cleared by this route e.g. lorazepam

  • Conversely metabolic pathways may be hindered by coalescing comorbidities such as fatty liver disease, chronic kidney disease, smoking or the effects of therapeutic drugs
  • Obesity in-and-of itself does not cause consistent effects on hepatic metabolism

Excretion

  • Increased cardiac output increases GFR and therefore renal clearance
  • Clearance correlates with lean body weight and therefore is increased as LBW increases in obesity
  • Methods for calculating clearance may be inaccurate and over/under-estimated

  • Changes in pharmacokinetics arise as a result of:
    • Organ dysfunction
    • Acute phase response
    • Drug interactions
    • Therapeutic interventions

Absorption

  • Significantly reduced bioavailability of drugs other via the IV route due to:
    • GI villous atrophy
    • Poor perfusion of GI tract ± skin
    • GI motility dysfunction (surgery, hypoperfusion, use of opioids)

Distribution

  • pH changes alter ratio of unionised/ionised fraction
  • Fluid shifts i.e. increased interstitial fluid increases volume of distribution for hydrophilic drugs
  • Reduced plasma proteins

Metabolism

  • Reduced hepatic blood flow
  • Reduced protein binding
  • Reduced hepatic enzyme activity (secondary to the effects of cytokines and acute phase proteins)

Excretion

  • Renal impairment is common ± effect of RRT