General Pharmacology

Pharmacokinetics-2 Dr.U.P.RathnakarMD.DIH.PGDHM24DISTRIBUTIONReversible transfer of drugs between body fluid compartmentsAfter absorption drug enters various body fluid compartments.Plasma Interstitial fluid compartment Cellular fluid compartment.

23Body compartments4 L28 L10 LPlasmaCellularInterstitial

Drug enters bodyPlasma compartment: Large mol.wt.Bound to plasma proteinsCannot cross capillariesRemains trapped in vascular compartment [4L]

Extracellular fluid: Low mol.wt.HydrophilicCan cross capillaries(Slit junc)Can not enter cells(Cross plasma membrane-Not lipid soluble)Remains in Plasma+InterstitiaL fluid[14L]

Total body water: Low mol.wt.LipophilicCan cross capillariesCan enter cells (Cross plasma membrane)Distrbutes in vol. of 60% of body wt.[42L]

Other sites: In pregnancy-FetusFat-Thiopental

Usually drugs not confined One compt.22V.DFactors affectingLipidsolubility & Ionization- Plasma protein bindingTissue binding- Disease-CHF, UremiaFat

21

Drug in beakerDrug + Charcoal in beakerDrug=10mgConcn=20mg/LaVD=10/20mg/L =0.5L =Vol.of beaker

Drug=10mgConcn=2mg/LaVD=10/2mg/L =5L =Much more thanVol.ofBeakerand charcoal

Apparent Volume of DistributionV= Total drug in the body Plasma concn.20Apparent volume of distributionaVD: The volume that would accommodate all the drug in the body, if the concn.throughout was the same as in plasma

Lipid insoluble: Small aVD-Eg.Gentamicin-.25L/kg

Highly protein bound-Eg.Diclofenac-0.15L/kg.

Highly tissue bound-Eg.Morphine-3.5L/kg

High vol. of distribution-poisoning-difficult to remove by dialysis 19Redistribution

Highly lipid soluble Thiopentone-i.vDistributed to organs with high blood flow. Eg.Brain site of actionUnconciousLess vascular areasEg.Fat, musclePlasma concn.fallsConcious[Drug withdrawn from brain]Redistribution10 Sec10 Mts18Blood Brain BarrierBBBONLY Lipid soluble and unionized drugs crossAnesthetics, BarbituratesMeningitis increase permeability- Impermeable substances Cross!

17Placental barrierBet.mother and fetusLipid soluble and unionized cross-anesthetics, alcoholHigh mol.wt.do not-insulin Teratogenicity ( Teratos = Monster)Tetracyclines, Thalidomide, Anti-cancer drugs, Sex hormones

16Plasma protein bindingDrug ABSORPTION Enters circulation Binds to plasma proteins[acidic to albumin, basic to a-acid glycoprotein]

Bound- inactiveTemp. storage site, Long duration,Hemodialysis not effective Free form-Active15Plasma protein binding: Clinical Imp.Favors drug absorptionAffects VdDelays metabolism, excretion,Not available for actionStorage siteDisplacement reactions-14Biotransformation[Metabolism]AndExcretionDr.U.P.RathnakarMD.DIH.PGDHMFate of the drug

13Biotransformation:Metabolism

Chemical alteration of the drug in a living organism is called bio-transformation.Lipid soluble Water solubleSo that not reabsorbed in KidneySite-Mainly liverOthers-Kidney, lungs, plasma

12Metabolism: ConsequencesEnd result is usually inactivation of a drug- But intermediate product need not be!ActiveInactiveEg. Phenytoin p-Hydroxyphenytoin2.ActiveActiveEg.Codeine Morphine,3.Active Toxic. Eg. P.Mol NABQIInactive Active,-ProdrugEg. Prednisone Prednisolone L-Dopa Dopamine

11Metabolism:Phases: I & II

Most drugs are metabolized by many pathways, simultaneously or sequentially producing a variety of metabolites Phase II(Eg.INH)Phase I Metabolite10BiotransformationAdministered drug[Lipid soluble][Non-Polar][Lipophilic]Excreted[water soluble][Polar][Hydrophilic]

ByPhase I and Phase II reactionsCatalyzed by enzymesMicrosomal and Non-microsomal enzymes9Metabolism:Phase I[Non-synthetic]Oxidation: Addition of O2/Removal of H+Eg. Phenytoin, Phenobarbitone, Propranolol

Reduction: Opp.of OxidationEg. Choramphenicol, Methadone

Hydrolysis: Addition of waterEg.Esters-Procaine, Succinylcholine, Amides- Procainamide, LignocaineOthers-Cyclization and decyclization

End product active or inactive8Metabolism:Phase II(Synthetic)Conjugation of a drug or phase I metabolite with endogenous substrate Glucuronic acid, Sulfuric acid, Acetic acid- Making it water soluble for excretion.End product usually inactive

Glucuronide conjugationEg.Morphine, ParacetamolAcetylationEg.INH, DapsoneGlycine conjugationEg.Salicylic acid, Nicotinic acidSulphate conjugationEg.Sex steroidsGlutathione conjugationEg.ParacetamolMethylationEg.Adrenaline, Dopamine7Biotransformation:Catalyzed by EnzymesMicrosomalIn endoplasmic reticulumMost of Phase I and some Phase II [Glucuronide conjugation]InducibleCYP450 Eg. CYP2D6

Non-MicrosomalCytoplasm, Mitochondria of liver cells and plasmaMost of Phase II and some Phase I [Some oxidation, most reduction and hydrolysis]Not inducible Genetic polymorphism6Enzyme induction and InhibitionInductionInducers: Rifampicin, Phenytoin, Barbiturate, CarbamazapineIncrease synthesis of Micro enzymesAccelerate the metabolism of substrateRifampicin X OCPReduced efficacyIncreased toxicity-P.mol and alcoholicsBeneficial Phenobarbitone in newborn jaundiceLong timeInhibitionInhibitors: Chloramphenicol, Cipro, E.MycinWarfarin & E.MycinIncreased incidence of bleedingQuick5Microsomal Enzyme inductionDrug AMetabolism[24hrs]EnzymeDrug B[Inducer]Enzyme+Enzyme+Enzyme+EnzymeMetabolism[6hrs]Effect=No drug effectOCPMetabolism[24hrs]EnzymeDrug B[Rifampicin]Enzyme+Enzyme+Enzyme+EnzymeMetabolism[6hrs]Prevents pregnancy=Pregnancy! + +4Microsomal Enzyme inhibitionDrug A[Toxic]Metabolism[24hrs]EnzymeDrug B[Inhibitor]Metabolism[72hrs]Effect=Drug accumulatesWarfarinMetabolism[24hrs]EnzymeDrug B[Erythrymycin]EnzymeMetabolism[72hrs]Anticogulant=Bleeding + +EnzymeDrug A[Toxicity]Warfarin[Toxicity]3Non-microsomal enzymesGenetic polymorphismINHLong duration of action=Lower doseNon-microsomal EnzymeSlow acetylatorsINHShort duration of action=Higher doseNon-microsomal EnzymeFast acetylators2Factors affecting Biotransformation Age-Extremes of age enzymes may be deficient Eg.Chloramphenicol in premature babies causes Gray baby syndrome.Malnutrition:- metabolism due to enz. proteins. Liver disease:- metabolism-- so..dose of drugGenetic: Genetically determined variation in metabolismSlow and fast acetylators-INHSCH

1ProdrugInactive drugConverted to active form by metabolismImproved B.A.-L-Dopa and DopamineProlongs duration of action- FluphenazineImproves taste- Clindamycin palmitateReduces ADE-BacampicillinMethenamine release Formaldehyde in acidic urinelastDrug ExcretionRemoval of drug and its metabolites from bodyKidneyLungsBileFecesSweatSaliva TearsMilk28