Pharmacokinetics
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Pharmacokinetics

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Dr.Adel

Dr.Adel

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Pharmacokinetics Pharmacokinetics Presentation Transcript

  • Pharmacokinetics In Anaesthesia
  • Pharmacokinetics
    • -The study of drug disposition or movement in the body involving change of its conc with time
    • Or what the body does to the drug including absorption, distribution ,metabolism, excretion.
    • + study of mathematical relationship to develop models to interpret rate of change of Cp
  • Routes of adminstration
    • Oral route : convenient but unreliable ?
    • Oral bioavailability 1 st pass metabolism
    • Sublingual : higher bioavailability
    • Parenteral : intramuscular
    • intravenous 100% bioavailability
    • larger vol ,irritant drug
    • but needs skill
    • toxic and anaphylaxis
  • Absorption
    • Most drugs are either weak acids or bases
    • In the stomach acidic drugs mostly unionised
    • What is pka ?
    • Ph – Pka = log ionised/ unionised fraction for an acid
    • The reverse in basic drugs
    • -Local anaesthetic drugs are example of weak bases
    • How it act?
    • LA are less effective at acidic medium (infection)
    • pka lip sol prot bind%
    • Lidocaine 7.8 110 64
    • Bupivacaine 8.1 560 95
    • -onset depends on pka
    • -potency lipid solubility
    • -duration and toxicity degree of protein binding
  • Distribution
    • Once in the plasma
    • -Protein binding to either albumin or alpha1 glycoprotein. The free fraction is the pharmacological active part
    • -Lipid soluble drugs extensively distributed to the vessel rich group eg thiopentone
  • Volume of distribution
    • The amount of fluid that would be required to contain the drug in the body at the same conc as in plasma
    • It is not a real but a theoretical volume
    • Dose given/conc of the drug at time zero on the graph
    • VD approximate 5L means highly bind to PP
    • E.g. warfarin, plasma expander dextran
    • -VD approx ECF vol means lipid insoluble e.g muscle relaxants
    • -VD approx TBW means lipid soluble like phenytoin
    • -VD greater thanTBW not only penetrate cells but also bind to tissue protein like morphine,digoxin
  • VD
    • Small VD means ionised drug or bind toPP
    • Fentanyl VD 350 L ?
    • Large VD means you need large loading dose to achieve effective serum level
    • Also means tendency to accumulate as tissue stores exhausted then any dose can cause toxic serum level
  • Metabolism
    • Lipid soluble drugs converted to water soluble in 2 phases in the liver
    • Phase I oxidation, reduction, hydrolysis byCp450 enzyme to less lipophyllic structure
    • -affected by enzyme inducer and inhibitors
    • Phase II conjugation to water soluble excreted by kidney, capacity limited step
    • -the rule is metabolite inactive but exceptions are there e.g. diazepam, codiene, ketamine
  • EXCRETION
    • -Clearance is different from excretion
    • -if it exceeds RBF this means extrarenal clearance
    • As biliary, pulmonary, milk, saliva and tears
    • -if the fraction of a drug excreted unchanged small this means extensively metabolised so dose to be adjusted in patients with liver impairment
    • -basic drugs requires acidic urine to be excreted and vice versa
  • Mathematic models
    • First order kinetics -ve exponential curve
    • T1/2 is independent on the amount of drug but the amount eleminated each half life is proportional to amount present
    • Mathematically by 5 half lives 97% of the drug will be eliminated
    • Most drugs undergo 1 st order kinetics
    • Zero order kinetics or saturation kinetics seen in ethanol poisoning, phenytoin overdose
  • Compartment Models
    • Math models designed to describe how drug conc in plasma changes with time
    • It gives us idea about VD ,t1/2 and characteristics of elimination process
    • One compartment model :theoretical assumption
    • What are informations we can get by plotting Cp versus time in one comprtment model?
    • -CP at time zero
    • -VD = bolus/CP at time zero
    • -T1/2
    • -elimination constant rate kel
    • -total body clearance =VD by kel
  • Two compartment model
    • The fall of CP occurs in 2 distinct phases
    • -rapid decline or distribution phase
    • -slower or elimination phase
    • A typical biexponential process
    • -in the same way rate constant for both phases can be detrmined by extrapolation on the graph
  •  
  • Context sensitive half life
    • The time taken for Cp to fall by 50% after an infusion designed to maintain steady state level has been stopped .
    • -in 3 compartment model at steady state both peripheral comp are in equilibrium with C comp thus after stopping infusion the only way for cp to fall is elimination ie the slower process
    • -remifent isCSHLT insensitive while fent and thiop are sensitive
  • Hypnotic infusion
  • Context sensitive ½ time
  • Narcotic infusion
  • CSHT
  • Practical application
    • By knowing VD ,T1/2 one can calculate both dose required and dosing interval to attain serum therapeutic level
    • Monitoring serum level of toxic druge like amikacin, gentamycin
    • Drugs given by continuous infusion
    • Loading dose =CPss .VD
    • infusion rate =Cpss .clearance (kel x VD)
    • BET or 3 step infusion scheme for propfol infusion to have CPss of 35 mg/L
    • Choice of anesthetic drugs for day case surgery with small VD ,short t1/2 and high plasma clearance i.e propofol+alf is better than thiopentone+fent
    • Modify drug dose in elderly with altered VD protein binding and clearance
    • Design of TCI systems fed by CSHT.
  • Target controlled infusion TCI