BDS PK Class 3

General Pharmacology Elimination

Dr.U.P.Rathnakar MD.DIH.PGDHM

Microsomal Micro somal Enzyme induction Enzyme+Enzyme+Enzyme+Enzyme

Drug A + Drug B [Inducer]

Enzyme

Drug B [Rifampicin]

Metabolism[24hrs]

Effect

Enzyme+Enzyme+Enzyme+Enzyme

OCP +

Metabolism[6hrs] =No drug effect

Enzyme Prevents pregnancy

Metabolism[6hrs] =Pregnancy! Metabolism[24hrs]

Microsomal Enzyme inhibition Microsomal Drug A Metabolism[72hrs] =Drug accumulates [Toxicity] Drug A [Toxic]

Enzyme

Enzyme

Metabolism[24hrs]

Effect

+ Drug B [Inhibitor]

Warfarin [Toxicity] Metabolism[72hrs] =Bleeding

Enzyme

Warfarin + Drug B [Erythrymycin]

Enzyme Anticogulant

Metabolism[24hrs]

Non-microsomal Non-microsomal enzymes Genetic polymorphism Non-microsomal Enzyme INH

Long duration of action=Lower dose Slow acetylators [40% of polpulation] polpulation]

Non-microsomal Enzyme INH

Short duration of action=Higher dose Fast acetylators [40% of polpulation]

Factorss affecting Biotransf Factor Bio transformation ormation 1. Age-Extremes of age enzymes may be

deficient Eg.Chloramphenicol in premature babies causes Gray baby syndrome. 2. Maln Malnut utri riti tion on::- metabolism due to   enz. proteins. 3. Liver disease:-  metabolism-- … so..dose of drug 4. Genet netic: Genetically determined variation in metabolism  Slow and fast acetylators-INH  SCH

Prodrug •

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Inactive drug Converted to active form by metabolism Improved B.A.-L-Dopa and Dopamine Prolongs duration of action- Fluphenazine Improves taste- Clindamycin palmitate Reduces ADE-Bacampicillin Methenamine release Formaldehyde in acidic urine

Drug Excretion Removal of drug and its metabolites from body Kidney Lungs Bile Feces Sweat Saliva Tears Milk

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Excretion-Kidney

Renal excretion

Glomerular Filtration

Tubular secretion

Tubular reabsorption

Glomerular Filtration

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Mol.size Depends on Renal blood flow  Plasma protein binding

Tubular secretion-Active

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Carrier mediated Not affected by PPB Penicillin, Probenecid, Quinine May use same carrier-Nonspecific

Tubular Reabsorption-Passive •

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Depends on pH and ionization Strongly acidic and alkaline-UnionizedExcreted Weakly acidic-Ionized in alkaline medium-not absorbed. Eg. Alkaline urine and aspirin toxicity Weakly basic-Ionized in acidic urine Eg. Acidification of urine –NH4cl or VitC-in Amphetamine poisoning

Factors aff affecting ecting renal excretion

Excretion-Other routes •

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Lungs: Alcohol, G.A, Faeces: Drugs not absorbed and secreted

with bile Bile:Excreted in Bile Reabsorbed from small intestine-This cycle is E.H.circulatio E.H.circulationn Eg.E.Mycin Skin: As and Hg Saliva: KI, phenytoin. Li Milk:Milk acidic Alkaline drugs ionized and accumulate. Eg. Tetracycline ADE in infant →

→

→

Kinetics of Elimina Elimination tion Fundamental PK Parameters: 1. Vol. ol.of di distrib ributi ution 2. B.A 3. Clearance THE CLEARANCE OF A DRUG IS THE THEORETICALL VOLUME OF PLASMA THEORETICA FROM WHICH THE DRUG IS COMPLETELY REMOVED IN UNIT TIME. Rate of elimination •

CL=

…………………………

Plasma conc.( C)

Elimination: First and Zer Zero o Order Kinetics A constant Fraction of the drug in the body is eliminated eliminated per unit timeFirst order kinetics: kinetics: Most drugs

A constant  A  of the drug in the body is  Amount  mount  of eliminated eliminated per unit timeZero order kinetics: kinetics: Alcohol To start with First order→As the plasma concn.increases →Zero order←Enzymes get saturated………

Saturation kinetics. Eg.Phenytoin

First order

Zero order

PLASMA HALF LIFE- t1/2

It is the time required for the plasma conc. of the drug to be reduced to half of its original value.

Takes 4-5 halflives to reach steady state concn. 193.5

196.5

198

Steady state [Plataeu principle]

187.5 175 98 96.5

150

93.5 87.5

100 75 50

199

100

99

Clinical Importance of Half Lif Life e •

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t½ helps to determine the duration of action of the drug. To determine the frequency of drug administration. To determine the time taken to achieve the steady state.

Elimination 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 complete elimination of a drug

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Therapeutic Therap eutic drug monitoring-TD monitoring-TDM M Monitoring drug therapy by measuring plasma conc.of drugs. Indications 1. Dr Drug ugss wi with th lo low w ma marg rgin in of sa safe fety ty-Digoxin,Lithium 2. To chec checkk Pt. Pt. com complia plianc nce. e. 3. If ind indiv ivid idua uall varia variati tion onss are lar large ge..- TCA TCA.. 4. Poten Potenti tial ally ly toxi toxicc drug drugss used used in presen presence ce of renal failure-AMINOGYCOSID failure-AMINOGYCOSIDES ES 5. Wh When en Pt Pt.. does does no nott resp respon ond d with without out re reas ason on •

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How to prolong duration of action of a drug? Prolong absorption from site s ite of administration  Oral- SR tablets, CR. ?Eg Parenteral: Less soluble soluble form, oily prep,  Parenteral: adrenaline  TTS ?Eg Increase PPB ?Eg Slow down Metabolism ?Eg Reduce Renal Excretion ?Eg •

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