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gihep 26: pharmacokinetics 2 - drug distribution (T 1/2 (time @ which Cmax…
gihep 26: pharmacokinetics 2 - drug distribution
T 1/2
time @ which Cmax is 1/2
IV bolus: short T1/2
gradual infusion: longer T1/2
bolus + infusion combination: gets more rapidly to steady state (therapeutic window)
Factors determining patient response to drug
pharmacodynamics
power of drug (effect on body)
specific
pharmacokinetics
motion of drug
effect of body on drug
non-specific, general
3 processes...
(i) absorption
transfer from admin site to circulation
bioavailability (F)
(ii) distribution
transfer from circulation to target
apparent vol of distribution (vd)
theoretical vol of fluid required to contain a drug print @ the same conc as plasma
low -> drug mainly in blood + water (warfarin + salicylic acid)
medium -> drug in blood, water + tissues (theophylline)
high -> drug mainly in tissues (digoxin)
= mass of drug in body/plasma conc = dose/plasma conc @ T=0
plasma conc = dose/vd
reflects size of distribution space
loading dose = vd x desired plasma conc
drugs are distributed unevenly between body fluids + tissues depending on...
blood flow
IV injections have rapid equilibration with well-perfused tissues + slower entry into less perfused tissues
capill permeability
membranes are permeable to hydrophobic drugs, but impermeable to hydrophilic drugs
BBB (tight junctions, few pores, astrocytes) prevents diffusion of many drugs
protein binding
albumin binds to acidic/neutral drugs
alpha1 glycoprotein binds to basic drugs
protein binding decreases plasma conc of free drug
bound drugs = inactive (reservoir)
altered in...
liver disease (hypoalbuminaemia)
kidney damage - uraemia (urea competes with drugs for binding)
age (less binding in foetus + neonate)
competition (e.g. aspirin + warfarin)
(iii) elimination
removal from body
metabolism + excretion
clearance (Cl), T1/2
! slow - toxic levels
large initial dose, small subsequent doses
therapeutic window
drug conc range of benefit
varies with patient
narrow - smaller + more frequent doses
drug monitoring
max benefit, min toxicity
@ intervals
