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KINETICS OF ELIMINATION
SIVANAGESWARARAO MEKALA
ASSISTANT PROFESSOR
DEPT OF CLINICAL PHARMACOLOGY
The four most important parameters governing drug
disposition are :
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clearance
volume of distribution
half-life
bioavailability
Clearance (CL):
The clearance of a drug is the theoretical volume of plasma from
which the drug is completely removed in unit time.
Clearance (CL) = __Rate of elimination___
Plasma conc. of the drug
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When clearance is constant, the rate of drug elimination is
directly proportional to drug concentration.
KINETICS OF ELIMINATION:
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Zero order
First order
FIRST ORDER KINETICS:
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For most drugs, clearance is constant over the concentration
range encountered in clinical settings, and the rate of drug
elimination is directly proportional to concentration

This is referred to as first-order elimination.
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Here a constant fraction of drug present in the body is
eliminated in unit time

The t1/2 of the drugs will always remain constant
Half life of a drug following first order
kinetics would remain constant irrespective of dose
For first order kinetics, Clearance is calculated
from the dose divided by the AUC

CL =
Dose
AUC
ZERO ORDER OR
CAPACITY LIMITED KINETICS
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The rate of elimination remains constant irrespective of drug
concentration
OR
a constant amount of drug is eliminated in unit time
ZERO ORDER (LINEAR) KINETICS:
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Rate of elimination is constant and is unrelated to the amount
of drug in the body.
1hr
10mg
2hr
20mg
3hr
30mg
10hr 100mg
e.g.-ethyl alcohol
Zero order kinetics – t ½  with dose since CL progressively
 as dose is increased.
Half life of the drug is never constant
FIRST ORDER TO ZERO ORDER
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Phenytoin
Tolbutamide
Theophylline
Warfarin
Aspirin
Phenytoin, Aspirin
↓
At low doses, follow first order kinetics
As the plasma
conc. increases
Elimination processes get saturated
↓
Kinetics changes over to zero order
(saturation kinetics)
PLASMA HALF LIFE
It is the time required for the plasma concentration of the drug to decrease by 50%
of its original value .
•
Initial rapidly declining (α) phase –
due to distribution
• Later less declined (β) phase –
due to elimination
• At least two half-lives (distribution t1/2 and
elimination t1/2) can be calculated from the
two slopes.
The elimination half-life derived from the β slope is simply called the half life of the
drug .
Mathematically ,elimination t1/2 is = ln2/k
* ln2 is the natural logarithm of 2 (or 0.693)
* k is the elimination rate constant of the drug.
i.e. the fraction of the total amount of the drug in the body which is removed
per unit time .
Eg: 2g of drug present in the body & 0.1g is eliminated every hour
then k =0.1/2=0.05 or 5% per hour .
k=CL/v , therefore t1/2 =0.693xV/CL

1 t1/2 =
2 t1/2 =
3 t1/2 =
4 t1/2 =

Nearly complete elimination occurs in 4 -5 half life
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Half life of Aspirin is 4hrs, Digoxin =40 hrs,
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First order kinetics – t1/2 remains constant because V and CL do not change
with dose
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Zero order kinetics – t1/2 increases with dose because CL progressively
decreases as dose is increased (elimination process get saturated)
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50% drug is eliminated ;
75% ; (50% + 25%)
87.5% ; ( 75% +12.5%)
93.75% (87.5% + 6.25%)
Digitoxin is 7 days.
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Half life is useful in estimating :
time to reach steady state concentration
duration of drug action
time for plasma concentration to fall after the drug has stopped
determine the frequency of drug administration
LOADING DOSE
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Single or few quickly repeated doses given in the beginning to
attain target concentration rapidly
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loading dose= Target Plasma conc X Vd
bioavailability
Single dose –
Loading dose
7
Plasma Concentration
6
Therapeutic
level
5
4
3
Repeated doses –
Maintenance dose
2
1
0
0
5
10
15
Time
20
25
30
MAINTENANCE DOSE
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Drugs are administered in such a way so as to maintain a
steady state of drug in the body
THERAPEUTIC DRUG MONITORING
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Monitoring drug therapy by measuring plasma concentration
of a drug for the benefit to patient by achieving maximum
therapeutic benefit with minimum side effects.
INDICATIONS
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With narrow therapeutic index/low safety margin
Eg: Digoxin , Phenytoin, carbamazepine ,Gentamicin
Antidepressants , Lithium.
Altered physiological states affecting drug concentration
Check patient compliance
Poisonings
Failure of drug response without any reason
Drug response
Used for adjustment of doses
To check bioavailability
FIXED DOSE COMBINATION
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It is the combination of two or more drugs in a single
pharmaceutical combination
Advantages:
 Increases patient compliance
 Synergistic combination.
Eg: Sulfamethoxazole + Trimethoprim: Cotrimoxazole
Levodopa + Carbidopa: Parkinsonism
Estrogen + Progesterone : Oral contraceptive

Reduced side effects - the side effect of one component may be
counteracted by the another
Eg: thiazide +potassium sparing diuretic
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Reduced cost
Prevents emergence of antimicrobial resistance
Increased efficacy (produce Max effect of the drug)
Disadvantages:
 The patient may not actually need all the drugs present in a
combination: he is subjected to additional side effects and
expense .
 Inflexible fixed dose ratio
 Incompatible pharmacokinetics
 Difficult to identify one particular drug causing harmful effect
 Increased toxicity due to inappropriate combinations
 Physician and pharmacists ignorance of the contents.
FIXED DOSE COMBINATION: FDC (FIXED DOSE RATIO
COMBINATIONS) 
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Levodopa + Carbidopa: Parkinsonism
Isoniazid + Rifampicin + Pyrazinamide: Tuberculosis.
Ferrous sulfate + Folic acid: Anemia of pregnancy.
Sulfamethoxazole + Trimethoprim: Cotrimoxazole.
Amoxicillin + Clavulanic acid: Augmentin.
Estrogen + Progesterone : Oral contraceptive
Aspirin + Codeine: As an analgesic.
PROLONGATION OF DRUG ACTION
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To decrease frequency of drug administration and improve
compliance
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Avoiding large fluctuations in plasma concentration
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Maintaining the drug effect overnight without disturbance
METHODS
A. For orally administered drug:
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Enteric coated e.g., erythromycin
Sustained release preparation e.g: Diclofenac
B. For parenterally administered drug:
1) By decreasing the vascularity of the absorbing surface :
This is achieved by adding a vasoconstrictor to the drug .
Eg: Adrenaline with local anesthetics
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Adrenaline prolongs the duration of action and reduce the systemic
toxicity of local anesthetics. And also minimizes bleeding in the operative
field .
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Adding Adrenaline is contraindicated in cardiovascular disease patients .
2) By decreasing the solubility :
Decreasing the solubility of the drug by combining it with a water insoluble
compound .
Eg: Injection penicillin G has a duration of action of 4-6 hours
Injection penicillin G +Procaine : procaine penicillin G has a duration of
action of 12-24 hours and also less painful.
3) Injecting the drug in oily solution :
Depot progestins (depot medroxy progesterone acetate )
4) Pellet implantation :
Norplant for contraception
5)Pilocarpine ocusert and progestasert
6)Transdermal patch
7) By increasing the plasma protein binding of the drug :
Eg: Sulphadiazine is less bound to plasma proteins and has
duration of action of 6 hours .
Sulphadoxine is highly protein bound and has a duration
of action of one week
8) By inhibiting the drug metabolism :
Anticholinesterases (Physostigmine ,neostigmine )prolongs
the duration of action of Ach by inhibiting the cholinesterases
9) By delaying renal excretion of the drug :
Probenecid prolongs duration of action of
pencillin/Cephalosporins
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