Presentation on theme: "Useful revision guide Instant Clinical Pharmacology E.J. Begg Useful information on individual drugs (although a bit old now) Basic Clinical Pharmacokinetics."— Presentation transcript:
Useful revision guide Instant Clinical Pharmacology E.J. Begg Useful information on individual drugs (although a bit old now) Basic Clinical Pharmacokinetics (2 nd Edition) M.E. Winter
Drug dosing Important factors concentration of drug in plasma rate of drug elimination rate of drug absorption
Toxic level Minimum therapeutic level Cp time Therapeutic window
Revision of pharmacokinetic terms 1 st order elimination rate of elimination depends on plasma concentration C = C 0 e -kt (k= rate constant of elimination) Half life (t 1/2 ) time for plasma concentration to fall by 50% Zero order elimination (pseudo zero order) rate of elimination is constant and independent of plasma concentration Plasma Concn (Cp) time 1st zero
Plasma Concn (Cp) time Zero order elimination Half life varies with concentration
Volume of distribution (Vd) Vd = dose C 0 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 aspirin14 litres propranolol273 litres digitoxin38 liters4 ml min -1 digoxin640 litres130ml min -1 Plasma clearance (Cl P ) volume of blood cleared of its drug content in unit time C P = Cl M + Cl R + Cl B + …….
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 F oral = AUC oral AUC iv Clearance = F. dose AUC iv oral Cp time
Same drug, same dose different formulation different amounts absorbed different peak concentration different AUCs Cp time
Toxic level Minimum therapeutic level Same drug, same route, different doses Cp time Therapeutic window
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 time to peak longer amplitude of peak is less longer drug in body iv sc oral Cp time
Two compartment model plasma tissues elimination Plasma Concn (Cp) time Redistribution + elimination elimination e.g. thiopentone
At steady state rate of infusion = rate of elimination = Css.Clearance Css (plateau) Time to 90 % of Css = 4 t 1/2 Intravenous infusion Cp time C = Css(1- e -kt )
Lignocaine28 hours Valproate624 hours Digoxin326 days Digitoxin16128 days Half lifehourssteady state
X mg min -1 2X mg min -1 Rising phase of the infusion curve is governed by the rate of elimination Height of plateau is governed by the rate of infusion Cp time
Dosing interval MTL Cp time
Cavss At Steady State amount administered = amount eliminated between doses Multiple dosing time Cp Rising phase of the curve is still governed by the rate of elimination
Loading dose(s) time Cp Loading dose = Cpeak. Volume of distribution
Tetracycline t 1/2 = 8 hours 500mg loading dose followed by 250mg every 8 hours
Cavss = F. Dose Clearance. T Cavss Reducing the dose AND reducing the interval Cavss remains the same but fluctuation in Cp is less T = dosing interval
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).