RELATIONSHIP OF Concentration and Response Dr. Mohd Bin Makmor Bakry, PhD, RPh Senior Lecturer in Clinical Pharmacy Intensive Care Preceptor Universiti Kebangsaan Malaysia Kuala Lumpur

FACTORS THAT INFLUENCE DRUG CONCENTRATION  Drug administration –Dose Increase in dose will increase the drug concentration.Increase in dose will increase the drug concentration. –Interval The shorter the duration the higher the concentration.The shorter the duration the higher the concentration. –Route of administration Intravenous is superior than oralIntravenous is superior than oral

FACTORS THAT INFLUENCE DRUG CONCENTRATION (CONT’)  Absorption –The bioavailability Route of administrationRoute of administration –The salt factor Percentage of pure active compound in the salt.Percentage of pure active compound in the salt. eg.: PHT Na = 0.92, THP = 0.8 x Aminophyllineeg.: PHT Na = 0.92, THP = 0.8 x Aminophylline –Absorption sites The gut functionThe gut function –Short gut syndrome, post gastectomy Muscular pHMuscular pH –Myositis (acidic pH) Blood flowBlood flow Drug interactionsDrug interactions

FACTORS THAT INFLUENCE DRUG CONCENTRATION (CONT’)  Distribution –The volume of distribution Increase in volume (body water) may reduce hydrophilic drug concentration.Increase in volume (body water) may reduce hydrophilic drug concentration. Third space lost, large amount of water accumulate outside the tissue.Third space lost, large amount of water accumulate outside the tissue. –eg.: ascites, bullae and vesicle –Compartment model 2 compartment model, early administration Cp will be high, after distribution completed the Cp will be reduced. eg. DGX2 compartment model, early administration Cp will be high, after distribution completed the Cp will be reduced. eg. DGX –Drug interactions Depletion from protein binding. eg. PHT with PhenylbutazoneDepletion from protein binding. eg. PHT with Phenylbutazone

FACTORS THAT INFLUENCE DRUG CONCENTRATION (CONT’)  Metabolism –Inducers and inhibitors –Liver function  Excretion –Liver and kidney functions –Drug interactions Urinary acidifier, eg. Na phosphate, NH 4 Cl, H 2 CO 3Urinary acidifier, eg. Na phosphate, NH 4 Cl, H 2 CO 3 Urinary alkalizer, eg. Na citrate, ascorbic acidUrinary alkalizer, eg. Na citrate, ascorbic acid Renal blood flow adjuster, eg. NSAIDsRenal blood flow adjuster, eg. NSAIDs

DRUG CONCENTRATION TERMS Cp % of population who response 50 a a b b Cp ECLC ? Subtherapeutic Therapeutic ? Toxic

CONCENTRATION-RESPONSE RELATIONSHIP FOR SPECIFIC DRUG  Gentamicin Response rate (%) Maximum peak Cp : MIC

 Digoxin CONCENTRATION-RESPONSE RELATIONSHIP FOR SPECIFIC DRUG (CONT’) % change in ventricular rate from pretreatment Plasma DGX concentration

 Digoxin (cont’) Percentage of patient Plasma DGX concentration Non-toxicToxic CONCENTRATION-RESPONSE RELATIONSHIP FOR SPECIFIC DRUG (CONT’)

 Theophylline Theophylline Concentration Normalized improvement in FEV 1 CONCENTRATION-RESPONSE RELATIONSHIP FOR SPECIFIC DRUG (CONT’)

 Theophylline (cont’) Nausea InsomniaDiarrhea Persistent vomiting GI bleeding Seizures Cardiac arrhythmia ArrhythmiaSeizures Theophylline Concentration (  mol/L) CONCENTRATION-RESPONSE RELATIONSHIP FOR SPECIFIC DRUG (CONT’)

 Phenytoin t (months) Plasma PHT Concentration = seizure attack CONCENTRATION-RESPONSE RELATIONSHIP FOR SPECIFIC DRUG (CONT’)

 Phenytoin (cont’) Dose Plasma PHT Concentration INDIVIDUALIZATION CONCENTRATION-RESPONSE RELATIONSHIP FOR SPECIFIC DRUG (CONT’)

 Phenytoin (cont’) Plasma PHT Concentration Mental changes Nystagmus on 45° deviation Ataxia Nystagmus on far lateral CONCENTRATION-RESPONSE RELATIONSHIP FOR SPECIFIC DRUG (CONT’)

TARGET RANGE TERMS T P T = TroughP = Peak

THE TARGET RANGE  Aminoglycosides –Gentamicin/NetilmycinT <2 P 4-10 mg/L –AmikacinT <10 P mg/L  Vancomycin T P mg/L  Digoxin T mcg/L  Antiepileptics –PhenytoinT mg/L –CarbamazepineT 4-12 mg/L  Theophylline T mg/L  Ciclosporin A varies  Lithium T mEq/L  Phenobarbital T mg/L  Salicylates mg/L

SAMPLING GUIDELINES  DrugWhen to SampleIdeal time  AminoglycosidesP: 30 min post dose15 H T: just before the next dose  VancomycinP: 1H post 1H infusion24 H T: Just before the next dose  PhenytoinT: Just before the next dose5 – 14 D  CarbamazepineT: Just before the next dose7 – 12 D  Vaproic acidT: Just before the next dose4 D  Theophylline (PO) T: Just before the next dose2 D  Aminophylline(IV)18 – 24 H after starting or2 D changing a MD given as constant infusion  DigoxinT: Just before the next dose5 D (> 6 hours post dose)  Ciclosporin AC 2hour 17 – 40 H

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