2 How 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
3 What 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.
4 Outline Review of Concepts Therapeutic drug Monitoring Clearance, K, Half-Life, Volume of DistributionTherapeutic drug MonitoringPharmacokinetic Drug InteractionsCasesDiscussion/Questions
5 Pharmacokinetics (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
6 Pharmacokinetics (PK) and pharmacodynamics (PD) Plasma SiteConcen oftration ActionDoseEffectsPKPD
7 Pharmacokinetics 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.
8 Pharmacokinetics 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.
9 Basic 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 !
10 Volume of Distribution, Clearance and Elimination Rate Constant Volume 100 LClearance10 L/hr
11 Volume of Distribution, Clearance and Elimination Rate Constant Volume 100 L (Vi)V2Cardiac andSkeletal MuscleClearance10 L/hr
12 Volume of Distribution = Cardiac andSkeletal MuscleVolume 100 L (Vi)VClearance10 L/hrVolume of Distribution =Dose_______Plasma Concentration
13 Volume 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
14 Volume 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) ?
15 CL = 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
16 CL = kVIf V increases then k must decrease as CL is constant
17 Important 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
18 Volume 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.
19 Volume of Distribution An abstract conceptGives information on HOW the drug is distributed in the bodyUsed to calculate a loading dose
21 Question 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
22 Answer: 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.
23 ClearanceAbility 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
24 Maintenance 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
25 Question 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.
26 Answer 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
27 Half-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.
28 Intravenous 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
31 Steady-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.
32 Accumulation to Steady State 100 mg given every half-life …200194187.5175150100…971009487.57550
34 What is Steady State (SS) ? Why is it important ? Rate in = Rate OutReached in 4 – 5 half-lives (linear kinetics)Important when interpreting drug concentrations in TDM or assessing clinical response
36 Therapeutic 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
37 Drug 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
38 Why 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
39 Potential 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