biotransformation bds

8/14/2019 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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biotransformation bds

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