Dr. Rathnakar U.P.

MD.DIH.PGDHM
Departments of Pharmacology
Kasturba Medical College,
Mangalore
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Drug Excretion
Removal of drug and its metabolites from
body
Kidney
Lungs
Bile
Sweat
Saliva
Tears
Milk
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Excretion-Kidney
Renal
excretion
Glomerular
Filtration
Tubular
secretion
Tubular
reabsorption
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Glomerular Filtration
20% is filtered
Water & solutes
Mol.size [20000]
Plasma protein binding
Depends on Renal blood
flow
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Tubular secretion-Active
80% is delivered to peritubular capillaries
Carrier mediated-without water!
Secretion may be retarded very little
even though the drug is mostly bound.
Not affected by PPB
Penicillin[80%bound], Probenecid, Quinine
May use same carrier-Non-specific
Probenecid inhibits penicillin secretion
21

Tubular Reabsorption-Passive
99% reabsorbed
digoxin and aminoglycoside-polar-not
absorbed
Depends on, lipid solubility pH and ionization
Strongly acidic and alkaline-Unionized-
Excreted
Eg. Acidification of urine NH
4
cl or Vit-C-in
Amphetamine poisoning
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Factors affecting renal excretion
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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
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Clearance
Fundamental
PK Parameters:
1. F
2. aVD
3. CL

The clearance of a drug is the theoretical volume of plasma
from which the drug is completely removed in unit time.
Renal clearance (CL
ren
) + metabolic clearance (CL
met
) +
routes of elimination (faeces, breath, etc.).

17
5g/ml x 60ml/hr
10g/ml

=300ml/hr
10
= 30ml/hr
=0.5ml/mt


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Clearance


Rate of elimination
Plasma conc.(C)

5g/ml x 60ml/hr
10g/ml

=300ml/hr
10
= 30ml/hr
=0.5ml/mt


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Kinetics of Elimination:
First and Zero Order
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, aspirin, ethanol
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First, Zero and Mixed order
First order
[Constant fraction]
Time Drug A Remaining
%
0 16 100
1 8 50%
2 4 25%
3 2 12.5%
4 1 6.25%
5 0.5 3.12%
6 0.25 1.5%
Zero order
[Constant amount]
Remaining %
Drug B
100% 16
87.5% 14
75% 12
62.5% 10
50% 8
37.5% 6
25% 4
Mixed order
[Saturation,Michelis-Menten, capacity
limited]
Remaining %
Drug C
100% 16
50% 8
25% 4
18.75% 3
12.5% 2
6.25% 1
0
1hr
2hrs
First
Zero
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PLASMA HALF LIFE- 1/2
It is the time required for the plasma conc. of the
drug to be reduced to half of its original value.
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44
34
24
14
4
50%-5h
50%-2h
50%-1h
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Plasma half life and First order Plasma half life and Zero order
Half life
100 mg administered[100%]
1 t
1/2
50mg 50%
2 t
1/2
25mg 75%
3t
1/2
12.5 mg 87.5%
4t
1/2
6.25.mg 93.75%
REMEMBER
1. Take 4-5 half lives for 95% elimination of a drug,
after a single dose
2. 4-5 half lives to reach steady state after repeated
administration

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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 half lives to reach steady state concn., after
repeated administration
Steady state
[Plataeu principle]
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Steady state is reached for all doses
Steady state is not reached for
Larger doses doses
Ethanol, phenytoin and
salicylate
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t
1/2
=0.693 x Volume of distribution[V]
Plasma clearance [CL]
Equation indicates that a long terminal half-life
can be
1. Associated to a large volume of distribution
(Vd) or/and
2. Attributable to a small plasma clearance.
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7
10L/mt
10L/mt
6
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.

5
Factors Influencing Drug dosage

4-5 half lives for steady state
Short half life repeated admn.
Long half lifeTakes long time to
reach steady state
So loading dose is given for
immediate effect
Maintenance dose is given to
maintain steady state
4
Indicated
No value
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

Response easily measurable-
BP, Blood sugar, diuretics
Drugs activated in the body
Hit and run drugs-effect lasts
longer than the drug. Eg.
Omeprazole
Drugs with irreversible action.
Eg. Organophosphorous
compounds

Therapeutic drug monitoring [TDM]
Monitoring drug therapy by measuring
plasma conc.of drugs.
3
Targeted drug delivery


Liposomes
Drug releasing implants
2
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
End