Biotransformation BDS
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Transcript of Biotransformation BDS
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Dr.U.P.RathnakarDr.U.P.Rathnakar MD.DIH.PGDHMMD.DIH.PGDHMK.M.C. Mangalore.K.M.C. Mangalore.
Fate of the drug
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Biotransformation:Metabolism
Chemical alteration of the drug ina living organism is called bio-transformation.Lipid soluble Water soluble
So that not reabsorbed in KidneySite-Mainly liver
Others-Kidney, lungs, plasma
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Metabolism: ConsequencesEnd result is usually inactivation of a drug- Butintermediate product need not be!
1. Active InactiveEg. Phenytoin p-Hydroxyphenytoin
2. Active ActiveEg.Codeine Morphine,
3. Active Toxic. Eg. P.Mol NABQI4. Inactive Active,
-ProdrugEg. Prednisone PrednisoloneL-Dopa Dopamine
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Metabolism:Phases: I & II
Most drugs are metabolized bymany pathways, simultaneously orsequentially producing a varietyof metabolites
Phase II (Eg.INH)
Phase I Metabolite
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BiotransformationAdministered drug
[Lipid soluble]
[Non-Polar][Lipophilic]
Excreted[water soluble]
[Polar][Hydrophilic]By
Phase I and Phase II reactions
Catalyzed by enzymes
Microsomal and Non-microsomal enzymes
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Metabolism:Phase I[Non-synthetic]1. Oxidation:
Addition of O2/Removal of H+Eg. Phenytoin, Phenobarbitone, Propranolol
2. Reduction:Opp.of OxidationEg. Choramphenicol, Methadone
3. Hydrolysis :Addition of waterEg.Esters-Procaine, Succinylcholine,
Amides- Procainamide, Lignocaine4. Others-Cyclization and decyclization
End product active or inactive
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Metabolism:Phase II(Synthetic )Conjugation of a drug or phase I metabolite withendogenous substrate Glucuronic acid, Sulfuric acid,Acetic acid- Making it water soluble for excretion.
End product usually inactive
Glucuronide conjugation Eg.Morphine, Paracetamol
Acetylation Eg.INH, DapsoneGlycine conjugation Eg.Salicylic acid, Nicotinic
acidSulphate conjugation Eg.Sex steroids
Glutathione conjugation Eg.Paracetamol
Methylation Eg.Adrenaline, Dopamine
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Biotransformation:Catalyzed by EnzymesMicrosomal Non-Microsomal
In endoplasmicreticulumMost of Phase Iand some Phase II[Glucuronideconjugation]
InducibleCYP450Eg. CYP2D6
Cytoplasm,Mitochondria of livercells and plasmaMost of Phase II andsome Phase I [Someoxidation, most
reduction andhydrolysis]Not inducibleGenetic polymorphism
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Enzyme induction and InhibitionInduction Inhibition
Inducers: Rifampicin,Phenytoin, Barbiturate,CarbamazapineIncrease synthesis of Microenzymes Accelerate themetabolism of substrate
Rifampicin X OCPReduced efficacyIncreased toxicity-P.mol andalcoholicsBeneficial Phenobarbitone innewborn jaundiceLong time
Inhibitors: Chloramphenicol,Cipro, E.Mycin
Warfarin &E.Mycin Increasedincidence of bleedingQuick
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Factors affecting Biotransformation1. Age-Extremes of age enzymes may be
deficient Eg.Chloramphenicol in premature babiescauses Gray baby syndrome.
2. Malnutrition:- metabolism due to enz.proteins.
3. Liver disease:- metabolism-- so..dose ofdrug4. Genetic: Genetically determined variation in
metabolismSlow and fast acetylators-INHSCH
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Prodrug
Inactive drugConverted to active form by metabolism
Improved B.A.-L-Dopa and DopamineProlongs duration of action- FluphenazineImproves taste- Clindamycin palmitateReduces ADE-BacampicillinMethenamine release Formaldehyde inacidic urine
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Drug ExcretionRemoval of drug and its metabolites from bodyKidneyLungsBileFecesSweatSalivaTearsMilk
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Excretion-Kidney
Renalexcretion
GlomerularFiltration
Tubularsecretion
Tubularreabsorption
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Glomerular Filtration
Mol.size
Depends on Renal bloodflowPlasma protein binding
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Tubular secretion-Active
Carrier mediatedNot affected by PPB
Penicillin, Probenecid, QuinineMay use same carrier-Non-
specificProbenecid inhibits penicillinsecretion
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Tubular Reabsorption-Passive
Depends on pH and ionization
Strongly acidic and alkaline-Unionized-ExcretedWeakly acidic-Ionized in alkalinemedium-not absorbed. Eg. Alkaline urineand aspirin toxicity
Weakly basic-Ionized in acidic urineEg. Acidification of urine NH4cl or Vit-C-in Amphetamine poisoning
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Factors affecting renal excretion
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Excretion-Other routesLungs: Alcohol, G.A,Faeces : Drugs not absorbed and secreted withbileBile:Excreted in Bile Reabsorbed from smallintestine-This cycle is E.H.circulationEg.E.Mycin
Skin: As and HgSaliva : KI, phenytoin. LiMilk:Milk acidic Alkaline drugs ionized andaccumulate. Eg. Tetracycline ADE in infant
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Kinetics of EliminationFundamental PK Parameters:
1. Vol.of distribution2. B.A3. Clearance
THE CLEARANCE OF A DRUG IS THETHEORETICAL VOLUME OF PLASMA FROM WHICHTHE DRUG IS COMPLETELY REMOVED IN UNIT TIME
Rate of elimination
CL= Plasma conc.( C)
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Elimination: First and Zero Order Kinetics
A constant Fraction of the drug in the
body is eliminated per unit time-First order kinetics : Most drugs
A constant A mount of the drug in the body iseliminated per unit time-
Zero order kinetics : Alcohol
To start with First order As the plasma concn.increases Zero order Enzymes get saturated
Saturation kinetics. Eg.Phenytoin
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PLASMA HALF LIFE-t1/2
It is the time required for the plasma conc. of thedrug to be reduced to half of its original value
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100
50
150
75
175
87.5
187.5
93.5
193.5
96.5
196.5
98
198
99
199
100
Takes 4-5 halflives to reach steady state concn.Steady state[Plataeu principle
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Elimination First order
100 mg administered[100%]1 t1/2 50mg 50%
2 t1/2 25mg 75%3t1/2 12.5 mg 87.5%4t1/2 6.25.mg 93.75%Take 4-5 halflives for completeelimination of a drug
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Clinical Importance of Half Lifet helps to determine theduration of action of thedrug.
To determine the frequencyof drug administration.
To determine the time takento achieve the steady state.
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Factors Influencing Drug dosage
4-5 half lives for steady stateShort half life repeated admn.Long half life Takes long time toreach steady stateSo loading dose is given forimmediate effectMaintainance dose is given tomaintain steady state
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Therapeutic drug monitoring-TDMMonitoring drug therapy by measuring plasmaconc.of drugs.Indications
1. Drugs with low margin of safety-Digoxin,Lithium
2. To check Pt. compliance. 3. If individual variations are large.- TCA.
4. Potentially toxic drugs used in presence of
renal failure-AMINOGYCOSIDES5. When Pt. does not respond without reason
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Fixed Dose Combinations[FDC ]
Advantages DisadvantagesBetter Pt.complianceSynergistic effect
Estrogen+ProgesteroneReduced side effectAspirin+P.mol
Prevents microbialresistanceINH+Rifampin+PZI
Improved efficacy
Levodopa+Carbidopa
Inflexible dose ratioIncompatible PK
Increased toxicity-withwrong combinationsIgnorance of contents
Eg?
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How to prolong duration of actionof a drug?Prolong absorption from site of administrationOral- SR tablets, CR. ?EgParenteral: Less soluble form, oily prep, adrenaline
TTS ?EgIncrease PPB ?EgSlow down Metabolism ?Eg
Reduce Renal Excretion ?Eg
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