The effect of ageing on Pharmacokinetics and Pharmacodynamics

Chronological and Physiological Age

• Aging leads to a deterioration in physiological function in all systems
• A linear increase in the incidence and number of co-morbidities is seen with age
• Chronological age alone is not an accurate indicator of general health as longevity continues to rise with improving social conditions and healthcare
• Inter-individual variability in physiological age among the elderly is very large
• Both pharmacokinetics and pharmacodynamics of drugs are altered in the elderly

Pharmacodynamics

• As a rule of thumb, the response to most anaesthetic and analgesic drugs is increased in the elderly
• Sensitivity tends to increase with age even in those patients that are relatively fit

Pharmacokinetics

• The distribution and metabolism of anaesthetic and analgesic agents need to be considered
• Induction agents
  • ↑ Free-drug concentrations
    • Contracted blood volumes
  • ↓ Reduction in protein binding
• Hydrophilic drugs
  • ↓ Volume of distribution
• Lipophilic drugs
  • ↑ Volume of distribution (higher relative % body fat)
• Clearance of most drugs is decreased
  • ↓ Organ-based elimination due to diminished enzyme, renal or liver function
  • ↓ Decrease in anaesthetic clearance
  • Remifentanil metabolism is independent of organ function

Target Controlled Infusions

• Propofol TCI is less reliable at the extremes of age as most PK algorithms have not been tested in the elderly
• Over-prediction of both plasma and effect-site is common
  • Extrahepatic uptake is reduced for propofol in elderly patients, therefore more drug is available in the induction phase
  • ↓Cardiac output leads to an increase in time to the peak effect (slower onset)
• It is important to control and maintain the level of drugs with narrow therapeutic indexes
  • Hysteresis reflects the latency after administration of a bolus or the rapid infusion that gives rise to a given plasma concentration and the manifestation of an effect
  • Delay in clinical effect occurs as the site of action of the anaesthetic/analgesic drug is not the plasma
  • Drugs must pass from the plasma to the effect site which is the central nervous system
• Plasma-effect site equilibration rate constant (ke0)
  • Movement of drugs between compartments is concentration-driven
  • Rate of drug movement between the central compartment (V1) and the effect-site can be described as a first-order constant
• The T1/2 ke0 is the time required for concentration at the effect site to reach 50% of the plasma concentration
• Steady-state or equilibrium can be considered to have been reached when this value is surpassed three to four times
• The context-sensitive half-time is the time required for the plasma concentration of a drug administered by infusion to decrease by 50% after an infusion is stopped
  • Properties of the drug and duration of infusion impact the context-sensitive half-time
• Context-sensitive half-time of propofol, fentanyl and alfentanil increase over time whereas remifentanil remains the same

Age does not significantly affect the plasma concentrations of opioids or the accuracy of remifentanil TCI. PD differences account for the decrease in requirements in the elderly as age has a relatively minor effect on plasma concentrations

Three-Compartment Model in the Elderly

• After IV administration the drug is distributed to the different compartments
• Tissue uptake depends on several factors
  • Cardiac output
  • Concentration gradient
  • Lipid solubility
  • Molecular size
  • Protein binding
• V1 (Central Compartment )
  • ↓ in the elderly (25%)
    • ↓ loading dose required
  • Drug is distributed from V1 to the other compartments
    • V2 (Fast Peripheral Compartment)
    • V3 (Slow Peripheral Compartment)
  • Some drug clearance can also occur via metabolism and elimination reactions
• V2 (Fast Peripheral Compartment)
  • Drug rapidly diffuses from V1 to V2
  • Contains well-perfused tissue (e.g. muscle)
    • ↓ elderly
      • slower drug redistribution
• V3 (Slow Peripheral Compartment)
  • Drug slowly diffuses from V1 to V3
  • Contains poorly perfused tissues (bone and fat)
    • ↑ elderly
      • Stores highly lipid-soluble drugs and has a very large capacity
• The sum of the three compartments or volumes constitutes the steady-state/ equilibrium volume
• V1, V2 and V3 are each modified as a function of age (lean weight changes with age)
• ↓ V1 which results in ↑ plasma concentrations
• ↑ Pharmacodynamic response (↑ brain sensitivity) to the anaesthesia and analgesic agents
• ↑ Vd in equilibrium phase particularly with lipid-soluble drugs

Propofol

• Marsh model
  • Does not take age into account
  • Assumes that age has no impact on any parameter of TCI for propofol
  • Plasma concentrations tend to be higher than those calculated by the model
  • Can be used as long as titration up is done slowly
  • Elderly patients will require a lower target concentration which can be achieved and maintained by the Marsh model
• Schnider model
  • V1 remains fixed with age and weight
  • ↓ V2 with age
  • ↓ Transfer between V1 and V2 with age
  • 25% error is highest during the induction phase which could lead to overdosing at that stage
• Eleveld model
  • Ce50 was found to decrease with age, whilst delay was found to increase with age
  • Allometric scaling of ke0
  • It is likely the most accurate model for the elderly

Remifentanil

• Minto model
  • Well validated
  • Covariates include age, sex and lean body weight
  • Age produces a change in ke0 leading to longer equilibrium times – Older patients have lower ke0 hence the importance of slow titration

Slow titration of drugs is EXTREMELY important to provide optimal dosing in the elderly. Onset is generally slow and pharmacodynamic sensitivity is increased. BE PATIENT!