Allosteric inhibition of enzymes

Sponsored Ads

  Binding of inhibitors to enzymes may be reversible, where the drug is free to

dissociate from the enzyme and an equilibrium is attained between free and bound

drug. Alternatively, the inhibitor may be  irreversibly  bound to the enzyme by a

covalent bond so that the enzyme is inactivated irreversibly and the effect of the drug

is continued even after complete drug elimination from the body. The effect may last

for weeks till the synthesis of a new enzyme. 

3- Interaction with cell membraces and ion channels: 

Digitalis glycosides inhibit cell membrane's Na+/K+ pump thus inhibiting the influx of K+ and the outflow of Na+

The anti-arrhythmic quinidine affects the membrane potential of myocardial

cell membranes by prolonging both the polarized and depolarized states.

Local anaesthetics affect the nerve cell membrane permeability to Na+ and K+

.

4- Interaction with DNA and RNA:

  Some drugs, known as  antimetabolites, interfere with  nucleotide bases

(purines and pyrimidines) synthesis by inhibition of dihydrofolate reductase, e.g.

methotrexate. 

  Other drugs are involved in the synthesis of false bases, e.g. purine analogues

(6-mercaptopurine) and  pyrimidine analogues  (5-fluorouracil). These agents,

therefore, inhibit DNA and RNA synthetic enzymes. 

Certain drugs interfere with  DNA replication and function including

intercalating agents  (e.g. dactinomycin) and  alkylating agents  (e.g. nitrogen

mustard). 

5- Inhibition of protein synthesis:

  Some drugs like tetracycline act by  inhibition of tRNA  binding to the

ribosomes. Chloramphenicol and erythromycin bind to the ribosome and  inhibit

peptidyl transferase  thus blocking the formation of the peptide bond. Quinupristin

and dalfopristin constrict the exit channel on rRNA  thus preventing the release of

newly synthesized polypeptides. 

6- Non-specific action:

  Some drugs act nonspecifically by forming a monomolecular layer over an

entire area of certain cells, e.g. volatile general anaesthetics  (like ether and nitrous

oxide),  some antidepressants (ethanol and chloral hydrate) and many antiseptics

Drug efficacy and potency:

Efficacy  is measured by the maximal effect attained by the drug. The drug is

more effective when it can attain a higher maximal effect.  Alternatively,  drug

potency is a comparison between drug doses (molar values) and a certain drug effect.

The more potent the drug, the less the dose (or log dose) required to produce the same

effect.

Comparison between drugs A, B and C regarding efficacy and potency

Drugs A and B have the same maximal effect (same efficacy). Drug C has a

lower efficacy. The dose required for drug B to produce 1/2 Emax  is higher

than that for drug A (B is less potent). Drug C is less potent than A or B. 

Combined drug action:

  Additive effect occurs when two different drugs with the same

pharmacological effect are given together yielding an effect equal in magnitude

to the sum of the individual drug effects, e.g. trimethoprim and

sulfamethoxazole (1 + 1 = 2). 

  Synergistic effect occurs when the two drugs with the same effect are

combined together to yield an effect greater in magnitude than the sum of the

individual effects, e.g. penicillin and gentamicin against pseudomonal

infections (1 + 1 = 3).

   Potentiation occurs when a drug lacking an effect alone is combined to a drug

with a pharmacologic effect resulting in increased effect of the latter, e.g.

combination of carbidopa with levodopa (1 + 0 = 2). 

Safety of drug action:

  There are two measures of drug safety:

i)  The therapeutic index of a drug is the ratio of the minimum dose toxic (TD)

for 50% of the population to the minimum dose causing an effect  (ED)  to

50% of the population.  

ii)  The margin of safety is more practical and is expressed by the ratio of the

minimum dose toxic for 0.1% of the population to the minimum dose

causing an effect to 99.9% of the population. 

  The wider the therapeutic index (or window), the more safe the drug is.

Alternatively, the narrow index requires drug monitoring as the drug moves from

effect to toxicity within a small dose interval.

 

Follow Us