2How to use this powerpoint presentation This supplements the other course materialYou can view it on line or download it to your computer and view it without being connected to the internet.Work through the presentation at the start of the course and note any issue which are not clear.Read up on areas that you are not familiar with and revisit the presentation from time to time.Try the powerpoint based exercises
3What is clinical pharmacokinetics ? Study of the time course of a drug’s movement through the body.Understanding of what the body does to (or with) the drug.Application of Therapeutic Drug Monitoring (TDM) and individualisation of drug therapy.
4Outline Review of Concepts Therapeutic drug Monitoring Clearance, K, Half-Life, Volume of DistributionTherapeutic drug MonitoringPharmacokinetic Drug InteractionsCasesDiscussion/Questions
5Pharmacokinetics (PK) & pharmacodynamics (PD) PK - What the body does to the drug?Absorption; distribution, metabolism, excretion (ADME)PD - What the drug does to the body?Drug concentration at the site of action or in the plasma is related to a magnitude of effect
6Pharmacokinetics (PK) and pharmacodynamics (PD) Plasma SiteConcen oftration ActionDoseEffectsPKPD
7Pharmacokinetics vs Pharmacodynamics…concept Fluoxetine increases plasma concentrations of amitriptyline. This is a pharmacokinetic drug interaction.Fluoxetine inhibits the metabolism of amitriptyline and increases the plasma concentration of amitriptytline.
8Pharmacokinetics vs Pharmacodynamics…concept If fluoxetine is given with tramadol serotonin syndrom can result. This is a pharmacodynamic drug interaction.Fluoxetine and tramadol both increase availability of serotonin leading to the possibility of “serotonin overload” This happens without a change in the concentration of either drug.
9Basic ParametersIn the next few slides the basic concepts and paramaters will be described and explained.In pharmacokinetics the body is represented as a single or multiple compartments in to which the drug is distributed.Some of the parameters are therefore a little abstract as we know the body is much more complicated !
10Volume of Distribution, Clearance and Elimination Rate Constant Volume 100 LClearance10 L/hr
11Volume of Distribution, Clearance and Elimination Rate Constant Volume 100 L (Vi)V2Cardiac andSkeletal MuscleClearance10 L/hr
12Volume of Distribution = Cardiac andSkeletal MuscleVolume 100 L (Vi)VClearance10 L/hrVolume of Distribution =Dose_______Plasma Concentration
13Volume of blood cleared of drug per unit time Cardiac andSkeletal MuscleVolume 100 L (Vi)VClearance10 L/hrClearance =Volume of blood cleared of drug per unit time
14Volume 100 L (Vi) Clearance = 10 L/hr Volume of Distribution = 100 L Cardiac andSkeletal MuscleVolume 100 L (Vi)VClearance10 L/hrClearance = 10 L/hrVolume of Distribution = 100 LWhat is the Elimination Rate Constant (k) ?
15CL = kVk = 10 Lhr -1 = 0.1 hr -1100 L10 % of the “Volume” is cleared (of drug) per hourk = Fraction of drug in the body removed per hour
16CL = kVIf V increases then k must decrease as CL is constant
17Important ConceptsVD is a theoretical Volume and determines the loading doseClearance is a constant and determines the maintenance doseCL = kVDCL and VD are independent variablesk is a dependent variable
18Volume of Distribution Apparent volume of distribution is the theoretical volume that would have to be available for drug to disperse in if the concentration everywhere in the body were the same as that in the plasma or serum, the place where drug concentration sampling generally occurs.
19Volume of Distribution An abstract conceptGives information on HOW the drug is distributed in the bodyUsed to calculate a loading dose
21Question What Is the is the loading dose required fro drug A if; Target concentration is 10 mg/LVD is 0.75 L/kgPatients weight is 75 kgAnswer is on the next slide
22Answer: Loading Dose of Drug A Dose = Target Concentration x VDVD = 0.75 L/kg x 75 kg = LTarget Conc. = 10 mg/LDose = 10 mg/L x L= 565 mgThis would probably be rounded to 560 or even 500 mg.
23ClearanceAbility of organs of elimination (e.g. kidney, liver to “clear” drug from the bloodstreamVolume of fluid which is completely cleared of drug per unit timeUnits are in L/hr or L/hr/kgPharmacokinetic term used in determination of maintenance doses
24Maintenance Dose Calculation Maintenance Dose = CL x CpSSavCpSSav is the target average steady state drug concentrationThe units of CL are in L/hr or L/hr/kgMaintenance dose will be in mg/hr so for total daily dose will need multiplying by 24
25Question What maintenance dose is required for drug A if; Target average SS concentration is 10 mg/LCL of drug A is L/kg/hrPatient weighs 75 kgAnswer on next slide.
26Answer Maintenance Dose = CL x CpSSav CL = L/hr/kg x 75 = L/hrDose = L/hr x 10 mg/L = mg/hrSo will need x 24 mg per day = 270 mg
27Half-Life and kHalf-life is the time taken for the drug concentration to fall to half its original valueThe elimination rate constant (k) is the fraction of drug in the body which is removed per unit time.
28Intravenous Bolus Injection dC/dt œ C = -k.C = -(CL/V).C Drug ConcentrationTimeC1Exponential decaydC/dt C= -k.CC2Intravenous Bolus InjectionExponential Decay:dC/dt œ C = -k.C = -(CL/V).CIntegrating:C(t) = C(0).e-kt
31Steady-StateSteady-state occurs after a drug has been given for approximately five elimination half-lives.At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.
32Accumulation to Steady State 100 mg given every half-life …200194187.5175150100…971009487.57550
36Therapeutic Index Therapeutic index = toxic dose/effective dose This is a measure of a drug’s safetyA large number = a wide margin of safetyA small number = a small margin of safety
37Drug Concentrations May Be Useful When There Is: An established relationship between concentration and response or toxicityA sensitive and specific assayAn assay that is relatively easy to performA narrow therapeutic rangeA need to enhance response/prevent toxicity
38Why Measure Drug Concentrations? Lack of therapeutic responseToxic effects evidentPotential for non-complianceVariability in relationship of dose and concentrationTherapeutic/toxic actions not easily quantified by clinical endpoints
39Potential for Error When Using TDM Assuming patient is at steady-stateAssuming patient is actually taking the drug as prescribedAssuming patient is receiving drug as prescribedNot knowing when the drug concentration was measured in relation to dose administrationAssuming the patient is static and that changes in condition don’t affect clearanceNot considering drug interactions