General

Pharmacology
Elimination
Dr.U.P.Rathnakar
MD.DIH.PGDHM
Microsomal Enzyme induction
Drug A
Metabolism[24hrs] Enzyme
Drug B
[Inducer]
Enzyme+Enzyme+Enzyme+Enzyme
Metabolism[6hrs]
Effect
=No drug effect
OCP
Metabolism[24hrs] Enzyme
Drug B
[Rifampicin]
Enzyme+Enzyme+Enzyme+Enzyme
Metabolism[6hrs]
Prevents pregnancy
=Pregnancy!
+
+
Microsomal Enzyme inhibition
Drug A
[Toxic]
Metabolism[24hrs] Enzyme
Drug B
[Inhibitor]
Metabolism[72hrs]
Effect
=Drug accumulates
Warfarin
Metabolism[24hrs] Enzyme
Drug B
[Erythrymycin]
Enzyme
Metabolism[72hrs]
Anticogulant
=Bleeding
+
+
Enzyme
Drug A
[Toxicity]
Warfarin
[Toxicity]
Non-microsomal enzymes
Genetic polymorphism
INH
Long duration of action=Lower dose
Non-microsomal Enzyme
Slow acetylators
[40% of polpulation]
INH
Short duration of action=Higher dose
Non-microsomal Enzyme
Fast acetylators
[40% of polpulation]
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
Renal
excretion
Glomerular
Filtration
Tubular
secretion
Tubular
reabsorption



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

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 NH
4
cl 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 BileReabsorbed 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 orderAs the plasma concn.increases Zero
orderEnzymes 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.
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]
Clinical Importance of Half Life

t 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 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


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
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