Enzyme Inhibition and Kinetics of Elimination helps us understand the major concept of Pharmacokinetics in Pharmacology. It would cover some important topics from the perspective of drug Elimination and Kinetics followed.

1. Enzyme Inhibition
&
Kinetics of Elimination
Presentation By:
Ms. Stuti Srivastava
Assistant Professor
Axis Institute of Pharmacy
Kanpur

2. Enzyme Inhibition:
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• Some chemicals (heavy metal salts, strong acids and alkalies, formaldehyde,
phenol, etc.) denature proteins and inhibit all enzymes non-selectively.
• They have limited medicinal value restricted to external application only.
• However, selective inhibition of a particular enzyme is a common mode of drug
action. Such inhibition is either competitive or non-competitive.

3. (i) Competitive (equilibrium type):
The drug being structurally similar competes with the normal substrate for the
catalytic binding site of the enzyme so that the product is not formed or a
nonfunctional product is formed, and a new equilibrium is achieved in the presence
of the drug.
Such inhibitors increase the kM but the Vmax remains unchanged, i.e. higher
concentration of the substrate is required to achieve ½ maximal reaction velocity,
but if substrate concentration is sufficiently increased, it can displace the inhibitor
and the same maximal reaction velocity can be attained.
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4. A non-equilibrium type of enzyme inhibition can also occur with drugs which react
with the same catalytic site of the enzyme but either form strong covalent bonds or
have such high affinity for the enzyme that the normal substrate is not able to
displace the inhibitor, e.g.
• Organophosphates react covalently with the esteretic site of the enzyme
cholinesterase.
• Methotrexate has 50,000 times higher affinity for dihydrofolate reductase than the
normal substrate DHFA.
In these situations, kM is increased and Vmax is reduced.
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5. (ii) Noncompetitive:
The inhibitor reacts with an adjacent site and not with the
catalytic site, but alters the enzyme in such a way that it loses
its catalytic property.
Thus, kM is unchanged but Vmax is reduced.
For example:
 Acetazolamide — Carbonic anhydrase
 Aspirin, indomethacin — Cyclooxygenase
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7. Kinetics of Elimination:
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It is a rational dosage regimens and used to modify them according to individual
needs. There are three fundamental pharmacokinetic parameters, viz.
 Bioavailability (F)
 Volume of distribution (V)
 Clearance (CL)
Drug elimination is the sum total of metabolic inactivation and excretion.
Drug is eliminated only from the central compartment (blood) which is in
equilibrium with peripheral compartments including the site of action.

8. Depending upon the ability of the body to eliminate a drug, a
certain fraction of the central compartment may be considered
to be totally ‘cleared’ of that drug in a given period of time to
account for elimination over that period.
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9. Clearance (CL):
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The clearance of a drug is the theoretical volume of plasma from which the drug is
completely removed in unit time (analogy creatinine clearance). It can be calculated
as
CL = Rate of elimination/C
where C is the plasma concentration.
For majority of drugs the processes involved in elimination are not saturated over
the clinically obtained concentrations, they follow either of the following:

10. First order kinetics:
The rate of elimination is directly proportional to the drug
concentration, CL remains constant; or a constant fraction of the drug
present in the body is eliminated in unit time.
This applies to majority of drugs which do not saturate the elimination
processes (transporters, enzymes, blood flow, etc.) over the therapeutic
concentration range.
Axis Institute of Pharmacy, Kanpur 10

11. Zero order kinetics:
The rate of elimination remains constant irrespective of drug
concentration, CL decreases with increase in concentration; or
a constant amount of the drug is eliminated in unit time, e.g.
ethyl alcohol.
This is also called capacity limited elimination or Michaelis-
Menten elimination.
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12. Plasma half-life:
The Plasma half-life (t½) of a drug is the time taken for its plasma
concentration to be reduced to half of its original value.
Mathematically, elimination t½ is
t½ = ln2/k
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13. Loading dose: This is a single or few quickly repeated doses given in the beginning
to attain target concentration rapidly.
Maintenance dose: This dose is one that is to be repeated at specified intervals
after the attainment of target Concentration, so as to maintain the same by balancing
elimination.
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