Absorption
Bioavailability
Fraction of drug dose reaching systemic circulation compared with the same dose given IV
Bioavailability for an IV dose assumed to be 100%.
Measurement
Ratio of the areas under the concentration/time curves for a dose given IV and PO. Both curves must continue until reach x-axis and plasma conc is zero
Factors that influence bioavailability
Absorption
- Physicochemical
- Enteric coating, liquid, water or lipid soluble, acids or bases, reactions with other drugs etc
- Patient factors
- Stasis, malabsorption
- Route of admin – transdermal, mucous membranes etc
- 1st pass metabolism – oral and rectal drugs absorbed into portal circulation where undergo metab by hepatic enzymes
- GTN hydrolysed by enzymes in gut epithelium
- Extraction ratio is fraction of drug removed from blood by liver
- Depends on hepatic blood flow, uptake and enzyme activity
Distribution
Volume of distribution
Equal to the amount of water in which an injected dose would have to be diluted in order to give the measured plasma concentration
Vd = dose / plasma conc (before any metabolism or elimination has occurred)
Depends on
- Size
- Protein binding (if small not restricted by protein binding)
- Ionization
- Lipid solubility
ECF 15L
Enters cells 42L (TBW)
Tissue binding >TBW
NMDRs limited to tissues with capillary fenestrae (muscle) as large, charged (ionized) and poorly lipid soluble
Clearance
Volume of plasma completely cleared of drug per unit time
Cl = Rel / plasma conc
Eg for kidney
Cl = urine conc x flow (Rel) / plasma conc
Half life
Time taken for plasma conc to fall to half its initial value
50, 25, 12.5, 6.25, 3.125
t1/2 = 0.693 x Vd / Cl
Therefore halving the clearance or doubling the Vd doubles the half life.
Time constant
Time at which process would have been complete if the initial rate of change had continued
37, 13.5, 5
t1/2 = 0.69 Tc
Loading dose, intervals and infusions
LD = Vd x required plasma conc
Infusion rate must equal Rel for constant Cp
If no LD steady state reached after 5T1/2 or 3 Tc
Multicompartment models
Compartments formed by different tissues that share pharmacokinetic properties eg vessel – rich, medium, poor
Elimination only from central compartment and goes on throughout
Vd is the sum of compartment volumes at steady state
Transfer between compartments is exponential
Drug moves from central to peripheral and back again
Terminal elimination T½ is the T½ of the final exponential washout
Context sensitive T½
Plasma conc influenced more by redistribution than elimination unless infusion has gone on for a very long time
The time it takes for the plasma conc to fall to ½ its initial value after stopping an infusion designed to maintain a constant plasma concentration
Depends on the duration of the infusion due to differing amounts of peripheral loading
Will eventually = elimination T½ if infusion lasts long enough
Steady state when input equals elimination
Remi 5mins
Alfentanil flattens out at 50mins after 3h
Propofol 20mins after 2h