PharmacokineticPharmacokineticss

In AnaesthesiaIn Anaesthesia

PharmacokineticsPharmacokinetics

-The study of drug disposition or movement -The study of drug disposition or movement in the body involving change of its conc in the body involving change of its conc with timewith time

Or what the body does to the drug Or what the body does to the drug including absorption, including absorption, distribution ,metabolism, excretion.distribution ,metabolism, excretion.

+ study of mathematical relationship to + study of mathematical relationship to develop models to interpret rate of develop models to interpret rate of change of Cpchange of Cp

Routes of adminstrationRoutes of adminstration Oral route : convenient but unreliable ?Oral route : convenient but unreliable ? Oral bioavailability 1Oral bioavailability 1stst pass pass

metabolismmetabolism Sublingual : higher bioavailabilitySublingual : higher bioavailability Parenteral : intramuscularParenteral : intramuscular intravenous 100% bioavailabilityintravenous 100% bioavailability larger vol ,irritant larger vol ,irritant

drugdrug but needs skillbut needs skill toxic and toxic and

anaphylaxisanaphylaxis

AbsorptionAbsorption

Most drugs are either weak acids or basesMost drugs are either weak acids or bases In the stomach acidic drugs mostly In the stomach acidic drugs mostly

unionisedunionised What is pka ?What is pka ?

Ph – Pka = log ionised/ unionised fraction for Ph – Pka = log ionised/ unionised fraction for an acid an acid

The reverse in basic drugsThe reverse in basic drugs

-Local anaesthetic drugs are example of weak -Local anaesthetic drugs are example of weak basesbases

How it act?How it act?

LA are less effective at acidic medium LA are less effective at acidic medium (infection)(infection)

pka lip sol prot bind%pka lip sol prot bind%

Lidocaine 7.8 110 64Lidocaine 7.8 110 64

Bupivacaine 8.1 560 95Bupivacaine 8.1 560 95

-onset depends on pka-onset depends on pka

-potency lipid solubility-potency lipid solubility

-duration and toxicity degree of protein -duration and toxicity degree of protein bindingbinding

DistributionDistribution

Once in the plasmaOnce in the plasma

-Protein binding to either albumin or -Protein binding to either albumin or alpha1 glycoprotein. The free fraction alpha1 glycoprotein. The free fraction is the pharmacological active partis the pharmacological active part

-Lipid soluble drugs extensively -Lipid soluble drugs extensively distributed to the vessel rich group eg distributed to the vessel rich group eg thiopentonethiopentone

Volume of distributionVolume of distribution The amount of fluid that would be required to contain The amount of fluid that would be required to contain

the drug in the body at the same conc as in plasmathe drug in the body at the same conc as in plasma It is not a real but a theoretical volumeIt is not a real but a theoretical volume Dose given/conc of the drug at time zero on the graphDose given/conc of the drug at time zero on the graph

VD approximate 5L means highly bind to VD approximate 5L means highly bind to PPPP

E.g. warfarin, plasma expander dextranE.g. warfarin, plasma expander dextran

-VD approx ECF vol means lipid insoluble e.g -VD approx ECF vol means lipid insoluble e.g muscle relaxantsmuscle relaxants

-VD approx TBW means lipid soluble like -VD approx TBW means lipid soluble like phenytoinphenytoin

-VD greater thanTBW not only penetrate -VD greater thanTBW not only penetrate cells but also bind to tissue protein like cells but also bind to tissue protein like morphine,digoxinmorphine,digoxin

VDVD

Small VD means ionised drug or bind Small VD means ionised drug or bind toPPtoPP

Fentanyl VD 350 L ? Fentanyl VD 350 L ? Large VD means you need large Large VD means you need large

loading dose to achieve effective loading dose to achieve effective serum levelserum level

Also means tendency to accumulate Also means tendency to accumulate as tissue stores exhausted then any as tissue stores exhausted then any dose can cause toxic serum leveldose can cause toxic serum level

MetabolismMetabolism Lipid soluble drugs converted to water Lipid soluble drugs converted to water

soluble in 2 phases in the liversoluble in 2 phases in the liverPhase I oxidation, reduction, hydrolysis Phase I oxidation, reduction, hydrolysis

byCp450 enzyme to less lipophyllic byCp450 enzyme to less lipophyllic structurestructure

-affected by enzyme inducer and inhibitors-affected by enzyme inducer and inhibitorsPhase II conjugation to water soluble Phase II conjugation to water soluble

excreted by kidney, capacity limited stepexcreted by kidney, capacity limited step-the rule is metabolite inactive but -the rule is metabolite inactive but

exceptions are there e.g. diazepam, exceptions are there e.g. diazepam, codiene, ketaminecodiene, ketamine

EXCRETIONEXCRETION

-Clearance is different from excretion-Clearance is different from excretion

-if it exceeds RBF this means extrarenal -if it exceeds RBF this means extrarenal clearanceclearance

As biliary, pulmonary, milk, saliva and tearsAs biliary, pulmonary, milk, saliva and tears

-if the fraction of a drug excreted unchanged -if the fraction of a drug excreted unchanged small this means extensively metabolised so small this means extensively metabolised so dose to be adjusted in patients with liver dose to be adjusted in patients with liver impairmentimpairment

-basic drugs requires acidic urine to be -basic drugs requires acidic urine to be excreted and vice versaexcreted and vice versa

Mathematic modelsMathematic models

First order kinetics -ve exponential curveFirst order kinetics -ve exponential curve

T1/2 is independent on the amount of T1/2 is independent on the amount of drug but the amount eleminated each half drug but the amount eleminated each half life is proportional to amount presentlife is proportional to amount present

Mathematically by 5 half lives 97% of the Mathematically by 5 half lives 97% of the drug will be eliminateddrug will be eliminated

Most drugs undergo 1Most drugs undergo 1stst order kinetics order kinetics Zero order kinetics or saturation kinetics Zero order kinetics or saturation kinetics

seen in ethanol poisoning, phenytoin seen in ethanol poisoning, phenytoin overdoseoverdose

Compartment ModelsCompartment Models Math models designed to describe how drug Math models designed to describe how drug

conc in plasma changes with timeconc in plasma changes with time It gives us idea about VD ,t1/2 and It gives us idea about VD ,t1/2 and

characteristics of elimination processcharacteristics of elimination process One compartment model :theoretical assumptionOne compartment model :theoretical assumption

What are informations we can get by What are informations we can get by plotting Cp versus time in one plotting Cp versus time in one comprtment model?comprtment model?

-CP at time zero-CP at time zero

-VD = bolus/CP at time zero-VD = bolus/CP at time zero

-T1/2-T1/2

-elimination constant rate kel-elimination constant rate kel

-total body clearance =VD by kel-total body clearance =VD by kel

Two compartment modelTwo compartment model

The fall of CP occurs in 2 distinct The fall of CP occurs in 2 distinct phasesphases

-rapid decline or distribution phase-rapid decline or distribution phase

-slower or elimination phase-slower or elimination phase

A typical biexponential processA typical biexponential process

-in the same way rate constant for -in the same way rate constant for both phases can be detrmined by both phases can be detrmined by extrapolation on the graphextrapolation on the graph

Context sensitive half lifeContext sensitive half life

The time taken for Cp to fall by 50% The time taken for Cp to fall by 50% after an infusion designed to maintain after an infusion designed to maintain steady state level has been stopped .steady state level has been stopped .

-in 3 compartment model at steady state -in 3 compartment model at steady state both peripheral comp are in both peripheral comp are in equilibrium with C comp thus after equilibrium with C comp thus after stopping infusion the only way for cp to stopping infusion the only way for cp to fall is elimination ie the slower processfall is elimination ie the slower process

-remifent isCSHLT insensitive while fent -remifent isCSHLT insensitive while fent and thiop are sensitiveand thiop are sensitive

Hypnotic infusionHypnotic infusion

Context sensitive ½ Context sensitive ½ timetime

Narcotic infusionNarcotic infusion

CSHTCSHT

Practical applicationPractical application

By knowing VD ,T1/2 one can calculate By knowing VD ,T1/2 one can calculate both dose required and dosing interval both dose required and dosing interval to attain serum therapeutic levelto attain serum therapeutic level

Monitoring serum level of toxic druge Monitoring serum level of toxic druge like amikacin, gentamycinlike amikacin, gentamycin

Drugs given by continuous infusionDrugs given by continuous infusion

Loading dose =CPss .VDLoading dose =CPss .VD

infusion rate =Cpss .clearance (kel x infusion rate =Cpss .clearance (kel x VD)VD)

BET or 3 step infusion scheme for propfol BET or 3 step infusion scheme for propfol infusion to have CPss of 35 mg/Linfusion to have CPss of 35 mg/L

Choice of anesthetic drugs for day case Choice of anesthetic drugs for day case surgery with small VD ,short t1/2 and surgery with small VD ,short t1/2 and high plasma clearance i.e propofol+alf is high plasma clearance i.e propofol+alf is better than thiopentone+fentbetter than thiopentone+fent

Modify drug dose in elderly with altered Modify drug dose in elderly with altered VD protein binding and clearance VD protein binding and clearance

Design of TCI systems fed by CSHT. Design of TCI systems fed by CSHT.

Target controlled Target controlled infusion TCI infusion TCI