Pharmacokinetics in liver disease, neonates, elderly

Question 1

Effects of hepatic impairment on pharmacokinetic profile of drug

Answer 1

• Decreased protein syntehsis -> decreased plasma protein levels, reduced protein binding. Note albumin levels are reduced in any acute illness as albumin is not an acute phase protein
• Phase I and phase II metabolism reduced (phase I usually affected first)
• Ascites -> increased volume of distribution
• Portocaval shunts -> increased bioavailability by reducing hepatic clearance of drugs

Question 2

Opiods and benzodiazepines in hepatic encephalopathy

Answer 2

Failure to clear ammonia -> hepatic encephalopathy

May be precipitated by opiates and benzodiazepines, which patients with severe liver failure are v susceptible to

Note peri-operatively, if regional technique contraindicated due to coagulopathy, careful titration of IV opiates may be required

Question 3

Neonatal pharmacokinetics: fluid compartments and distribution

Answer 3

• Volume and nature of pharmacokinetic compartments is different
• Newborn is relatively overhydrated, loses volume through diuresis in hours-days after birth. Absolute proportion of water is higher, and** relative amount in the extracellular compartment is also increased**
• Plasma protein binding is different for two reasons: Plasma protein levels are lower than in adult, and neonatal blood pH tends to be lower - alters relative proportions of ionised/unionised drug

Question 4

Neonatal pharmacokinetics: metabolism and excretion

Answer 4

Majority of enzymes do not reach maturity for several months
* Plasma cholinesterase levels are reduced
* Activity of cytochrome P450 family of enzymes is markedly reduced

Nephron numbers and function do not reach maturity for several months:
* Reduced rate of excretion via renal tract: creatinine clearance <10% of the adult rate per unit body weight

Note there may be wide variation between individuals of same post-conceptual age

Question 5

Pharmacokinetics in the elderly

Distribution, hepatic/renal excretion, example of remifentanil

Answer 5

• Altered volume of distribution: relative reduction in muscle mass and consequent increase in proportion of fat
• Reduction in activity of hepatic enzymes with increasing age: relative decrease in hepatic drug clearance
• Creatinine clearance reduces steadily with age
• Disease processes may alter pharmacokinetics, and polypharmacy may produce drug interactions

Note: remifnetanil is significantly metabolised by muscle esterases: metabolism may be reduced in elderly, i.e. more sensitive to remifentanil