Mechanisms of Drug Actions by Enzyme Inhibition Enzyme Inhibition by linzhengnd


									     Mechanisms of Drug Actions by
          Enzyme Inhibition
Enzyme Inhibition:

Drugs act within the cell by modifying normal biochemical reactions. Enzyme
inhibition may be reversible or non reversible; competitive or non-competitive.
Antimetabolites may be used which mimic natural metabolites. Gene functions may
be suppressed

 1_Direct Enzyme Inhibition:
    Inhibition caused by drugs may be either reversible or irreversible.

                               Reversible inhibition:
Reversible inhibitors bind to enzymes with non-covalent interactions such as
hydrogen bonds, hydrophobic interactions and ionic bonds.

It is divided into:

                                                                                    competitive in
 Competitive inhibitors are often similar in structure to the real substrate ,the
substrate and inhibitor cannot bind to the enzyme at the same time.

This type of inhibition can be overcome by sufficiently high concentrations of

uncompetitive inhibition

mixed inhibition
 The inhibitor can bind to the enzyme at the same time as the enzyme's

Non-competitive inhibition
            is a form of mixed inhibition where the binding of the inhibitor to the enzyme
            reduces its activity Irreversible    inhibition

                                                 Irreversible inhibition

            irreversible inhibitors usually covalently modify an enzyme, and inhibition cannot
            therefore be reversed. Irreversible inhibitors often contain reactive functional
            groups such as: nitrogen mustards, aldehydes, haloalkanes, alkenes, Michael
            acceptors, phenyl sulfonates fluorophosphonates

            Irreversible inhibitors are generally specific for one class of enzyme and do not
            inactivate all proteins.

                 And these are examples of drugs that inhibit different enzymes:

Substrate                 Enzyme                Products        Inhibitor                                  Uses

Acetylcholine             Acetylcholine         Choline;        Neostigmine         Myasthenia gravis and to
                          esterase              acetate                               reverse neuromuscular
Arachidonate              Cyclooxygenase        Prostanoids     Aspirin                    Heart disease and
Angiotensin (AT)I         AT converting         AT II           Captopril          Hypertension, heart failure,
                          enzyme                                                                   post-infarct
Hypoxanthine              Xanthine oxidase      Uric acid       Allopurinol                               Gout
HMG-CoA                   HMG-CoA               Mevalonic       Simvastatin        To lower blood cholesterol
                          reductase             acid
Folate                    Dihydrofolate         Tetrahydrof     Trimethoprim             With cotrimoxazole as
                          reductase             olate                                              antibacterial
Thymidine                 Viral reverse                         Zidovudine                         HIV infection
Deoxyribonucleotides      DNA polymerase        DNA             Cytarabine                       Anticancer drug

            Example: Inhibition of cyclooxygenase enzyme
            by some drugs.
            Cyclooxygenase enzyme: responsible for production of prostaglandins
            from arachidonic acid .
There are three isomers of it:


Control most of physiological function: renal function,gastric function,platelet


Responsible for production of allgesic and inflammatory prosta glandins.


Selectively inhibited by paracitamol.

     Drugs acting on cyclooxygenase enzyme.

    1_Non Steroid Anti Inflammatory
    They are non selective inhibitors of cox1 and cox2.

    So they are used as analgesic,anti inflammatory,antiplatelet aggregation and
    antipyretic.but their disadvantage is Pseudoallergy,gastritis,nephrotoxicity.

    Selective cox2 they are used as analgesic and anti inflammatory
    only.they do not cause side effects.


    Selective cox3 is used as analgesic,antipyretic.

    b) Suppression of Gene Function:

Many drugs act as suppressors of gene function including antibiotics, fungicides,
antimalarials and antivirals. Gene function may be suppressed in several steps of protein
synthesis or inhibition of nucleic acid biosynthesis. Many substances which inhibit nucleiacid
biosynthesis are very toxic since the drug is not very selective in its action between the
parasite and host

c) Antimetabolites:

The strategy of chemotherapy consists of exploiting the biochemical differences
between the host and parasite cells. Metabolites are any substances used or
produced by biochemical reactions. A drug which possesses a remarkably close
chemical similarity (mimic) to the normal metabolite is called an antimetabolite. The
antimetabolite enters a normal synthetic reaction by "fooling" an enzyme and
producing a counterfeit metabolite. The counterfeit metabolite inhibits another
enzyme or is an unusable fraudulent end product which cannot be utilized by the cell
for growth or reproduction. Such antimetabolites have been used as antibacterial or
anticancer agents.

        Mechanism of drug action by
                 enzyme activation
Various substances, including some drugs, stimulate in vivo the
activity of hepatic oxidative enzymes which metabolize drugs and
certain endogenous compounds, such as steroids and fatty acids.

An increase in the rate of metabolism of these compounds by the
so-called "drug-metabolizing enzymes" often results in an increased
rate of their elimination with a concomitant decrease in their
biological activity.

 There are also indications that a stimulation of the

(drug-metabolizing enzymes) may have therapeutic possibilities.

 For instance, in the case of infants unable to dispose of bilirubin
because of inadequately developed enzyme system, the stimulation
of the formation of the enzyme would be beneficial. The mechanism
of action of the drug-metabolizing enzymes and the mode of
stimulation of their activity by drugs are not adequately understood.
However, rapid progress is being made toward the understanding of
these complex problems.


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