Pharmacokinetics

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Pharmacokinetics

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

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