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CP6 Clinical Pharmacology
Principles of Pharmacokinetics
Vd = amount of drug in the body/ plasma drug concentration
Cl = rate of elimination of drug/plasma drug concentration
Half-life (t1/2) = 0.7xVd/Cl
Pharmacokinetics Toronto Notes 2019 Pharmacokinetic Calculation
• definition:thequantitativedescriptionoftheratesofthevariousstepsofdrugdisposition(i.e.how drugs move through the body)
• thepharmacokineticprinciplesofADME(absorption,distribution,metabolism,andelimination)can be graphically represented on a concentration vs. time graph
Time Course of Drug Action
• manykineticparametersaremeasuredusingIVdosing,suchthatabsorptionisimmediateand distribution for most drugs is rapid; thus elimination is the main process being measured
• the concentration axis is converted to a log10 concentration to allow for easier mathematical calculations
• drugssuchaswarfarincanexhibithysteresis(forasingledrugconcentration,theremaybetwodifferent response levels)
Half-Life
• definition:timetakenfortheserumdrugleveltofall50%duringelimination
• drugswithfirstorderkineticsrequirefivehalf-livestoreachsteadystatewithrepeateddosingorfor
complete drug elimination once dosing is stopped
Steady State
• drugconcentrationremainsconstantwhenamountofdrugenteringthesystemiseliminatedfromthe system
• druglevelsintherapeuticdrugmonitoringareofgreatestutilitywhenthesteadystatehasbeenreached
• specialsituations
■ use a loading dose for drugs with a long half-life and when there is clinical need to rapidly achieve therapeutic levels (e.g. amiodarone, digoxin, phenytoin)
■ use continuous infusion for drugs with a very short half-life and when there is need for a long-term effect and multiple or frequently repeated doses are too inconvenient (e.g. nitroprusside, insulin, unfractionated heparin, naloxone)
Clearance
• aquantitativemeasurementofthebodyfluidvolumefromwhichasubstanceisremovedperunittime • Cl=rateofeliminationofdrug÷plasmadrugconcentration
• mustconsiderClfromaspecificpartofthebodyandtotalbodyCl
Elimination Kinetics
• first-orderkinetics(mostcommontype)
■ constant fraction of drug eliminated per unit time
■ some drugs can follow first-order kinetics until elimination is saturated (usually at large doses) at
which point the Cl is less than would be predicted for a given concentration
■ shows linear relationship when plotted to a log (concentration) vs. time graph
• zero-orderkinetics(lesscommon,associatedwithoverdose,e.g.alcohol)
■ constant amount of drug eliminated per unit time, regardless of concentration; concept of half-life
does not apply
■ the concentration axis is converted to a log (concentration) to allow for easier mathematical
calculations
• non-linearkinetics(muchlesscommon)
■ unlike first-order kinetics which assumes no change in PK parameter with drug dose, non-linear kinetics is considered dose-dependent
■ saturation of various ADME processes creates non-linear kinetics
■ the complexity of dosing drugs with non-linear kinetics has resulted in creation of drug-specific
nomograms to aid clinicians in dosing, with these drugs often being the target of therapeutic drug monitoring
◆ examples: phenytoin, theophylline
Loading and Maintenance Doses
• loadingdosesareusedwhenimmediateeffectisneededwithparenteraladministrationbeingthemost common way of giving a large dose to “fill up” the volume of distribution
• maintenancedosesaregivenafteraloadingdoseORdrugregimencanbeginwithmaintenancedoses ■ steady state levels are achieved after ~5 half lives
■ can be given as either a continuous infusion (rare) or more commonly as intermittent oral doses
1
1. Absorption Phase 2 2. Peak Absorption 3. Post-Absorption
Distribution Phase 3 4. Elimination Phase (half-life based on
this)
4
Time to Peak Absorption
Figure 2. Time course of drug action
For most drugs it takes 5 half-lives to reach steady state with repeated dosing or to eliminate a drug once dosing is stopped
Steady state of a drug with t1/2 of 3 h. It takes about 15 h (5 x t1/2) to reach steady state.
Steady State at 5 t1/2
0 3 6 9 12 15 18 Time (h)
Figure 3. Steady state of a drug displaying first-order kinetics
Dosing interval = 6 h t1/2 = 3 h
C(t)=-kt+C0 dC/dt = -kt0 = -k
100 75 50 25
First order Zero order Non-linear order
Figure 4. First order, zero order, and non-linear kinetics
In first order kinetics (solid line), a constant fraction of the drug is eliminated per unit time; in zero order kinetics (dashed line), a constant amount of the drug is eliminated per unit time
-kt C(t)=C0e
dC/dt = -kt1
0 2 4 6 8 10 Time (h)
Drug Concentration
Drug Concentration Plasma Drug Concentration