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Fate of the drug

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

K.M.C. Mangalore.
Biotransformation:Metabolism
Chemical alteration of the drug in
a living organism is called bio-
transformation.
Lipid soluble →Water soluble
So that not reabsorbed in Kidney
Site-Mainly liver
Others-Kidney, lungs, plasma
Metabolism: Consequences
 End result is usually inactivation of a drug- But
intermediate product need not be!
1. Active→Inactive
Eg. Phenytoin → p-Hydroxyphenytoin
2. Active→Active
Eg.Codeine → Morphine,
3. Active → Toxic. Eg. P.Mol →NABQI
4. Inactive → Active,
-Prodrug
Eg. Prednisone→ Prednisolone
L-Dopa →Dopamine
Metabolism:Phases: I & II

Phase II Phase I Metabolite


(Eg.INH)

Most drugs are metabolized by


many pathways, simultaneously or
sequentially –producing a variety
of metabolites
Biotransformation
Administered drug Excreted
[Lipid soluble] [water soluble]
[Non-Polar] [Polar]
[Lipophilic] [Hydrophilic]
By
Phase I and Phase II reactions

Catalyzed by enzymes

Microsomal and Non-microsomal enzymes


Metabolism:Phase I[Non-synthetic]
1. Oxidation:
Addition of O2/Removal of H+
Eg. Phenytoin, Phenobarbitone, Propranolol

2. Reduction:
Opp.of Oxidation
Eg. Choramphenicol, Methadone

3. Hydrolysis:
Addition of water
Eg.Esters-Procaine, Succinylcholine,
Amides- Procainamide, Lignocaine
4. Others-Cyclization and decyclization

End product active or inactive


Metabolism: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 conjugation Eg.Morphine, Paracetamol


Acetylation Eg.INH, Dapsone

Glycine conjugation Eg.Salicylic acid, Nicotinic


acid
Sulphate conjugation Eg.Sex steroids

Glutathione conjugation Eg.Paracetamol


Methylation Eg.Adrenaline, Dopamine
Biotransformation:Catalyzed by Enzymes
Microsomal Non-Microsomal
In endoplasmic  Cytoplasm,
reticulum Mitochondria of liver
Most of Phase I cells and plasma
and some Phase II  Most of Phase II and
[Glucuronide some Phase I [Some
conjugation] oxidation, most
Inducible reduction and
CYP450
hydrolysis]
 Not inducible
 Eg. CYP2D6
 Genetic polymorphism
Enzyme induction and Inhibition
Induction Inhibition
 Inducers: Rifampicin,  Inhibitors: Chloramphenicol,
Phenytoin, Barbiturate, Cipro, E.Mycin
Carbamazapine  Warfarin &
 Increase synthesis of Micro E.Mycin→Increased
enzymes→Accelerate the incidence of bleeding
metabolism of substrate  Quick
 Rifampicin X OCP
 Reduced efficacy
 Increased toxicity-P.mol and
alcoholics
 Beneficial –Phenobarbitone in
newborn jaundice
 Long time
Factors affecting Biotransformation
1. Age-Extremes of age enzymes may be
deficient Eg.Chloramphenicol in premature babies
causes Gray baby syndrome.
2. Malnutrition:- metabolism due to  enz.
proteins.
3. Liver disease:-  metabolism-- … so..dose of
drug
4. Genetic: Genetically determined variation in
metabolism
 Slow and fast acetylators-INH
 SCH
Prodrug
 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
Excretion-Kidney

Tubular
Glomerular Tubular
reabsorption
Renal Filtration secretion
excretion
Glomerular Filtration

Mol.size
Depends on Renal blood
flow
 Plasma protein binding
Tubular secretion-Active

 Carrier mediated
 Not affected by PPB
 Penicillin, Probenecid, Quinine
 May use same carrier-Non-
specific
 Probenecid inhibits penicillin
secretion
Tubular Reabsorption-Passive
 Depends on pH and ionization
 Strongly acidic and alkaline-Unionized-
Excreted
 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 Vit-
C-in Amphetamine poisoning
Factors affecting renal excretion
Excretion-Other routes
 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.circulation
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 Elimination
 Fundamental PK Parameters:
1. Vol.of distribution
2. B.A
3. Clearance
THE CLEARANCE OF A DRUG IS THE
THEORETICAL VOLUME OF PLASMA FROM WHICH
THE DRUG IS COMPLETELY REMOVED IN UNIT
TIME
Rate of elimination
CL= …………………………
Plasma conc.( C)
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 Amount of the drug in the body is


eliminated 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
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.
196.5 198 199
193.5
Steady state
187.5 [Plataeu principle]

175
98 99
96.5
150 93.5

87.5
100
100
75

50
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
Clinical Importance of Half Life
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.
Factors Influencing Drug dosage
4-5 half lives for steady state
Short half life → repeated admn.
Long half life→Takes long time to
reach steady state
So loading dose is given for
immediate effect
Maintainance dose is given to
maintain steady state
Therapeutic drug monitoring-TDM
 Monitoring drug therapy by measuring plasma
conc.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-AMINOGYCOSIDES
5. When Pt. does not respond without reason
Fixed Dose Combinations[FDC]
Advantages Disadvantages
 Better Pt.compliance  Inflexible dose ratio
 Synergistic effect  Incompatible PK
Estrogen+Progesterone  Increased toxicity-with
wrong combinations
 Reduced side effect
 Ignorance of contents
Aspirin+P.mol
 Prevents microbial
resistance
INH+Rifampin+PZI
 Improved efficacy Eg?
Levodopa+Carbidopa
How to prolong duration of action
of a drug?
 Prolong absorption from site of administration
 Oral- SR tablets, CR. ?Eg
 Parenteral: Less soluble form, oily prep, adrenaline
 TTS ?Eg
 Increase PPB ?Eg
 Slow down Metabolism ?Eg
 Reduce Renal Excretion ?Eg

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