Principles of Pharmacokinetics
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1 Principles of Pharmacokinetics Ákos Csomós MD, PhD Professor, Head of Department Medical Centre, Hungarian Defence Force, Budapest
2 Pharmacokinetics: Very basics How the organ affects the drug: 1) Absorption 2) Distribution 3) Metabolism 4) Elimination Pharmacodynamics: How the drug affects the organ: Direct effect (inhalational anaesthetics) Receptor effect (H 2 antagonists) Enzymes (neostigmine)
3 Pharmacokinetics
4 Absorption of drugs Diffusion (for most drugs), which depends on: Solubility Tissue permeability (in relation to ph) Surface area Regional blood supply GI system: Motility, enzyme effect First pass metabolism Lungs (inhalational agents): Cardiac output and respiratory minute volume 1.
5 Lipid solubility pk: ionisation of drug low pk = stronger acid Total body ph Protein binding Distribution of drugs Reduces the proportion and availability of free drug Volume of distribution and clearance is inversely proportional to protein binding Regional blood distribution Redistribution from blood: Compartment models Albumin binding: thiopentone, warfarin, salycilates 2.
6 One compartment model V d Dose Elimination
7 What is volume of distribution (V d )? It is the volume of water, in which the drug is distributed for the measured plasma concentration. Drug distribution in plasma only: V d = blood volume Drug distribution in total body: V d = total body water Average volumes (for 70 kg): V d = dose concentration Digoxin Propranolol Lidocaine Aspirin Warfarin 500 l 250 l 120 l 12 l 9 l
8 Durg metabolism (=kinetics) ZERO ORDER the metabolism is constant (=the same amount) is metabolized in a given time, independently of plasma concentration (Cp) FIRST ORDER the metabolism depends on the plasma concentration (=the same proportion) is metabolized in a given time 3.
9 Elimination curves 3. ZERO ORDER FIRST ORDER
10 Three compartment model
11 Definition of different compartments V1 CENTRAL COMPARTMENT (Vc): into which the drug is injected, e.g. blood, lungs, cerebrospinal fluid (~brain) V2 PERIPHERAL COMPARTMENT (vessel-rich, fast redistribution): e.g. muscle tissue, extracellular space V3 PERIPHERAL COMPARTMENT (vessel-poor, slow): e.g. fat tissue IMPORTANT! These are theoretical volumes, can NOT be attributed to any anatomical or physiological structures.
12 Three compartment model
13 Analogue of a three compartment model
14 Original DIPRIFUSOR compartment model Launched: December 1999 (!)
15 Original DIPRIFUSOR compartment model Each values were calculated by a computer simulation program: Volume of V1: 228 ml/kg Distribution constants between compartments: k12 = /min k21 = /min k13 = /min k31 = /min Elimination constant from V1: /min Age was NOT used by this model ( ) MARSH model
16 Changes of propofol plasma concentration in a three compartment model
17 10 minutes vs. 3 hours infusion No equilibration V1 = V2 = V3 Reduction in plasma level is determined by redistribution Reduction in plasma level is determined by elimination
18 Half-time (T 1/2 ) The time required for a given concentration value to be reduced to its half. The reduction is exponential, which is best described by the time constant (τ): 1τ = 63 %, 2τ = 86,5 %, 3τ = 95 %, 4τ = 99,75%. T 1/2 = Redistribution half-time vs. elimination half time? None of these expresses the drug kinetics in practice. k 4.
19 Context-sensitive half time (CSHT) Context-sensitive half time (CSHT): the time required to half the plasma concentration after stopping an intravenous infusion of a drug. The context is the volume of infusion. After steady-state condition reached, the half time will become context insensitive. 2 hours 6 hours 9 hours Propofol 20 min 30 min 50 min Alfentanil 40 min 70 min 80 min Fentanyl 40 min 4 hrs 5 hrs
20 ASA I. healthy volunteers were given infusion of alfentanil (n=15) and remifentanil (n=15) for 3 hours. Context-sensitive half times (50% reduction): Alfentanil: 47.3 ±12 min. Remifentanil: 3.2 ±0.9 min. Terminal elimination half times: Alfentanil: 76.5 ±12.6 min. Remifentanil: 11.8 ±5.1 min.
21 CSHT vs. elimination half time
22 CSHT vs. elimination half time Remifentanil
23 Distribution of 10 minutes infusion Redistribution to V3 is minimal. There is no steady state condition. After stopping the infusion, redistribution is higher in proportion than elimination. CSHT value is closer to redistribution half-time. NB: elimination is only from the central compartment.
24 Distribution of 3 hours infusion More drug reaches the peripheral (V3) compartment; distibution is equalized to steady state condition: V1 = V2 = V3. There is no redistribution after stopping the infusion, the reduction in plasma level is determined by elimination. CSHT value is closer to elimination half-time. NB: elimination is only from the central compartment.
25 Pharmacokinetics of commonly used iv. anaesthetics, comparing 10 min and 3 hours infusion CSHT (min) V d (litre/kg) Redistr. T 1/2 (min) Elimin. T 1/2 Clearance (ml/min/kg) Remifentanil 3 / / 0.4 0,5 / 1,5 8 / 20 min 40 / 60 Alfentanil 10 / / / 3 1 / 2 hrs 3 / 8 Sufentanil 14 / 20 / 11 Fentanyl 12 / 70 3 / 5 1 / 2 3 / 5 hrs 10 / 20 Propofol 5 / 21 2 / 10 1 / 4 4 / 7 hrs 20 / 30 Thiopentone 4 / / / 7 5 / 18 hrs 3-4
26 Pharmacokinetics of TIVA vs. TCI
27 Differences expressed by measuring units Total Intravenous Anaesthesia (TIVA): Propofol administration: mg/hour Target Controlled Infusion (TCI): Propofol administration: µg/ml
28 Why do we need TCI?
29 TCI target concentration and speed of administration Propofol blood concentration 1. TCI start 2. Target: 6 µg/ml 3. Target: 4 µg/ml 4. Target: 6 µg/ml 5. TCI stop Propofol speed of admin.
30 Differences between propofol TCI models MARSH 70 kg patient SCHNIDER 70 kg patient V l/kg 15.9 l 4.27 l 4.27 l V l/kg 32.4 l x (age-53) litre 24 l V l/kg l 238 l 238 l Marsh model calculates higher V1 volume. Schnider model uses constant V1 volume. Considerable difference exist in bolus administration!
31 How much do you weigh?
32 What body weight would you use? There are two patients, both 170 cm tall; one weights 160 kg, the other is 80 kg. Would you give twice as much propofol? There are two patients, both weight 100 kg; however, there is 50 cm difference in body height. Would you give the same amount of propofol?
33 Which body weight should be used for TIVA/TCI? Determining the appropriate body weight is crucial in TIVA/TCI (for Vd). Most pharmacokinetic studies were done in healthy patients: there are no data in obesity, liver disease and elderly. Even remifentanil has been reported to overdose in obese (Egan, 1998) Solution? There is a maximum body weight in each TCI pump, above which it does not work.
34 Tall need more than obese LBM: Ideal body weight: 170 cm, 80 kg: kg kg 170 cm, 160 kg: kg kg 200 cm, 100 kg: 78 kg kg 150 cm, 100 kg: kg kg Calculations: LBM (male) = 1.1 x bodyweight 128 x (bodyweigh/height) 2 IBW (male) = x (body height 152.4)
35 TTPE and k eo
36 TTPE TTPE = Time To Peak Effect = Time required for the plasma and effect site concentration curves to cross each other. Independent of bolus dose.
37 Time to peak effect (TTPE)
38 k eo in a three compartment model The effect site is considered to have no volume, so the rate constant for movement into and out of this compartment is the same (K1e=Keo).
39 How did they calculate the propofol k eo value? MARSH model used AEP monitor to determine the effect of propofol; k eo = Modified MARSH model (Struys) use different k eo value = 1.2. SCHNIDER model used EEG monitor; k eo = There is no consensus on which one is better
40 Decrement time
41 Decrement time Definition: the required time to reach a given lower plasma concentration. It is calculated by the TCI model; helps in estimating the awakening time of the patient. Awakening plasma concentration (=decrement concentration) is set by the user; normally 1-2 µg/ml
42 What is shown in a TCI pump display?
43 Thanks for your attention!
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