pharmacokinetics by af8c4VO

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									Useful revision guide

Instant Clinical Pharmacology
E.J. Begg


Useful information on individual drugs
(although a bit old now)

Basic Clinical Pharmacokinetics (2nd Edition)
M.E. Winter
Drug dosing

Important factors
  • concentration of drug in plasma

   • rate of drug elimination

   • rate of drug absorption
Therapeutic window




                     Toxic level

                     Minimum
  Cp
                     therapeutic level




                       time
        Revision of pharmacokinetic terms

              Plasma
              Concn
              (Cp)                      zero
                             1st


                                          time


1st order elimination
        rate of elimination depends on plasma concentration
                 C = C0e-kt      (k= rate constant of elimination)

Half life (t1/2)
        time for plasma concentration to fall by 50%

Zero order elimination (pseudo zero order)
        rate of elimination is constant and independent of plasma concentration
Zero order elimination
Half life varies with concentration




    Plasma
    Concn
    (Cp)



                                  time
Volume of distribution (Vd)

                Vd = dose
                      C0

Volume of water in which a drug would have to be distributed to give its
plasma concentration at time zero.
Can be larger than total body volume
                frusemide        7 litres
                aspirin          14 litres
                propranolol      273 litres
                digitoxin        38 liters       4 ml min-1
                digoxin          640 litres      130ml min -1

Plasma clearance (ClP)
                volume of blood cleared of its drug content in unit time
                CP= ClM + ClR + ClB + …….
     Bioavailability (F)
     measure of the amount of drug absorbed into the general circulation

     Area under the curve (AUC)
             obtained from the plasma concentration v time plot
             gives a measure of the amount of drug absorbed

         Foral = AUCoral
                 AUCiv
        iv                                   Clearance = F. dose
                                                          AUC
Cp

                                 oral

                                     time
Same drug, same dose different formulation
• different amounts absorbed
• different peak concentration
• different AUCs



Cp




                                     time
Therapeutic window
 Same drug, same route, different doses



                                          Toxic level

                                          Minimum
  Cp
                                          therapeutic level




                                            time
Different rates of absorption
(different routes of administration)

Assume the bioavailability is the same (i.e. 1 for all routes)


                                Slower the rate of absorption
        iv                      • time to peak longer
                                • amplitude of peak is less
Cp
                    sc          • longer drug in body


                                    oral


                                           time
Two compartment model


       plasma                       tissues


     elimination



                   Redistribution + elimination
      Plasma
      Concn
      (Cp)                                        e.g. thiopentone
                          elimination



                                    time
Intravenous infusion


                       At steady state
                       rate of infusion = rate of elimination
                                        = Css.Clearance

                                           Css (plateau)

Cp               C = Css(1- e-kt)
                           Time to 90 % of Css = 4 t1/2


                                       time
Half life    hours   steady state

Lignocaine   2       8 hours

Valproate    6       24 hours

Digoxin      32      6 days

Digitoxin    161     28 days
Rising phase of the infusion   Height of plateau is
curve is governed by the       governed by the rate of infusion
rate of elimination



                                         2X mg min-1


Cp                                       X mg min-1




                                     time
 Dosing interval




                   MTL
Cp




                   time
Multiple dosing

      At Steady State
      amount administered = amount eliminated between doses



                                              Cavss


Cp
                       Rising phase of the curve is still
                       governed by the rate of elimination



                                    time
Loading dose(s)
           Loading dose = Cpeak . Volume of distribution




Cp




                                 time
Tetracycline t1/2 = 8 hours

500mg loading dose followed by 250mg every 8 hours
           Cavss =    F . Dose
                      Clearance. T           T = dosing interval




                                     Cavss




Reducing the dose AND reducing the interval
Cavss remains the same but fluctuation in Cp is less
    Drug plasma concentration monitoring is helpful for drugs

•that have a low therapeutic index

•that are not metabolized to active metabolites

•whose concentration is not predictable from the dose

•whose concentration relates well to either the therapeutic effect
or the toxic effect, and preferably both

•that are often taken in overdose
For which specific drugs is drug concentration monitoring helpful?

   The important drugs are:
    • aminoglycoside antibiotics (plasma or serum)
    • ciclosporin (whole blood)
    • digoxin and digitoxin (plasma or serum)
    • lithium (serum)
    • phenytoin (plasma or serum)
    • theophylline (plasma or serum)
    • paracetamol and salicylate (overdose) (plasma or serum).



Other drugs are sometimes measured:
   • anticonvulsants other than phenytoin (eg carbamazepine, valproate)
   • tricyclic antidepressants (especially nortriptyline)
   • anti-arrhythmic drugs (eg amiodarone).
    The uses of monitoring are

• to assess adherence to therapy

• to individualize therapy

• to diagnose toxicity

• to guide withdrawal of therapy

• to determine whether a patient is already taking a drug before starting therapy
(eg theophylline in an unconscious patient with asthma)

• in research (eg to monitor for drug interactions in post-marketing surveillance
using population pharmacokinetics).
Altered pharmacokinetic profile

• liver metabolism
        Disease
        Pharmacogenetics (cytochrome P450 polymorphisms)

• renal impairment
        Disease
        Elderly

								
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