Enzymes

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Chapter: Essential pharmacology : Pharmacodynamics Mechanism Of Drug Action; Receptor Pharmacology

Almost all biological reactions are carried out under catalytic influence of enzymes; hence, enzymes are a very important target of drug action. Drugs can either increase or decrease the rate of enzymatically mediated reactions. However, in physiological systems enzyme activities are often optimally set.


ENZYMES

 

Almost all biological reactions are carried out under catalytic influence of enzymes; hence, enzymes are a very important target of drug action. Drugs can either increase or decrease the rate of enzymatically mediated reactions. However, in physiological systems enzyme activities are often optimally set. Thus, stimulation of enzymes by drugs, that are truly foreign substances, is unusual. Enzyme stimulation is relevant to some natural metabolites only, e.g. pyridoxine acts as a cofactor and increases decarboxylase activity. Several enzymes are stimulated through receptors and second messengers, e.g. adrenaline stimulates hepatic glycogen phosphorylase through β receptors and cyclic AMP. Stimulation of an enzyme increases its affinity for the substrate so that rate constant (kM) of the reaction is lowered (Fig. 4.2).


 



 

Apparent increase in enzyme activity can also occur by enzyme induction, i.e. synthesis of more enzyme protein. This cannot be called stimulation because the kM does not change. Many drugs induce microsomal enzymes.

 

Inhibition of enzymes is a common mode of drug action.

 

A.   Nonspecific inhibition

 

Many chemicals and drugs are capable of denaturing proteins. They alter the tertiary structure of any enzyme with which they come in contact and thus inhibit it. Heavy metal salts, strong acids and alkalies, alcohol, formaldehyde, phenol inhibit enzymes nonspecifically. Such inhibitors are too damaging to be used systemically.

 

B.    Specific inhibition

 

Many drugs inhibit a particular enzyme without affecting others. Such inhibition is either competitive or noncompetitive.

 

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 (Fig. 4.1A), and a new equilibrium is achieved in the presence of the drug. Such inhibitors increase the kM but the Vmax remains unchanged (Fig. 4.2), 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.

 

§  Physostigmine and neostigmine compete with acetylcholine for cholinesterase.

§  Sulfonamides compete with PABA for bacterial folate synthetase.

§  Moclobemide competes with catecholamines for monoamine oxidaseA (MAOA).

§  Captopril competes with angiotensin 1 for angiotensin converting enzyme (ACE).

§  Finasteride competes with testosterone for 5αreductase

§  Letrozole competes with androstenedione and testosterone for the aromatase enzyme.

§  Allopurinol competes with hypoxanthine for xanthine oxidase; is itself oxidized to alloxanthine (a non competitive inhibitor).

§  Carbidopa and methyldopa compete with levodopa for dopa decarboxylase.

 

A nonequilibrium 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.

 

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. Examples are given in the box.

N

 

Acetazolamide     — Carbonic anhydrase

 

Aspirin, indomethacin — Cyclooxygenase

 

Disulfiram           — Aldehyde dehydrogenase

 

Omeprazole         — H+ K+ ATPase

 

Digoxin               — Na+ K+ ATPase

 

Theophylline       — Phosphodiesterase

 

Propylthiouracil   — Peroxidase in thyroid

 

Lovastatin           — HMGCoA reductase

 

Sildenafil             — Phosphodiesterase5

 

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