Pharmacokinetics and Pharmacodynamics: Rational dosing and time
course
Pharmacokinetics and Pharmacodynamics: Rational dosing and time
courseLecture 2Pharmacokinetic factors affecting
dosingClearanceAbility to eliminate the drugVolume of distribution
(Vd)The measure of the apparent space in the body available to
contain the drugRelates the amount of drug in the body to the
concentration of the drug in blood or plasmaIt is the volume
apparently necessary to contain the amount of drug homogeneously at
the concentration found in the blood or plasma or waterHigh Vd =
higher concentration in extravascular tissue than in blood not
homogeneously distributed.Pharmacokinetic factors affecting
dosingClearanceAdditive character of clearanceElimination may occur
in the kidneys, liver, lungs, etc.Major sites are kidneys and
liverFirst order eliminationRate of drug elimination is directly
proportional to concentrationRate of elimination may be saturable,
if drug is given high enough (Vmax = maximum elimination
capacity)Zero order eliminationRate of drug elimination is constant
or independent of concentrationPharmacokinetic factors affecting
dosingClearanceZero order elimination will follow first order
elimination at low concentrations3 common drugs that follow zero
order eliminationEthanolPhenytoinAspirinPharmacokinetic factors
affecting dosingClearance and half lifeHalf-life (t) = the time
required to change the amount of drug in the body by one half
during elimination (or during constant infusion)Indicates the time
required to attain 50% of steady state or to decay 50% from steady
state conditionsSteady state = maximum drug level where there is an
equilibrium between administration and eliminationWill be achieved
after 4 half lives have elapsedUseful in determining drug dosage
regimensDrug infusion at constant rate
4 half lives is need to to achieve steady state6Pharmacokinetic
factors affecting dosingClearance and half lifeDrug accumulation =
if dosing interval is shorter than four half livesPharmacokinetic
factors affecting dosingBioavailabilityThe fraction of unchanged
drug reaching the systemic circulation, following administration by
any routeAfter administration, drugs need to be absorbed and pass
through several compartments (depending on the route of
administration)Absorption (ex. intestines, blood, body
compartments, etc)Elimination (orally administered drugs will pass
thru the liver first)Pharmacokinetic factors affecting
dosingBioavailabilityExtent of absorptionDepends on drug
characteristics (lipophylic, hydrophilic, pH, etc)If too
hydrophilic = difficult time to pass thru the cell membraneIf too
lipophilic = difficult to enter the blood plasmaSome drugs are
actively pumped back into the gut lumen (ex. P-glycoprotein
transporter)Drinking grapefruit juice will inhibit the
P-glycoprotein transporter, thus increasing drug
absorptionPharmacokinetic factors affecting
dosingBioavailabilityExtent of absorptionAbsorption rate also
follows zero-order and first-order absorptionZero order: rate of
absorption is independent of drug concentrationFirst order: rate of
absorption is proportional to drug concentration in the gut (which
is saturable)RouteBioavailability (%)CharacteristicsIV100 (by
definition)Most rapid onsetIM75-100Large volumes often feasible;
may be painfulSC75-100Smaller volumes than IM; may be painfulOral5
to
