MECHANISMS OF DRUG ACTION

MECHANISMS OF DRUG ACTION

A.                Interaction with receptors

1.                  Agonists interact with specific cellular constituents, known as receptors, and elicit an observable biological response. Agonists have both affinity for the receptor and intrinsic activity.

2.                  Partial agonists interact with the same receptors as full agonists but are unable to elicit the same maximum response. Partial agonists have lower intrinsic activity than full agonists; however, their affinity for the receptor can be greater than, less than, or equal to that of full agonists.

3.                  Antagonists inhibit the actions of agonists.

a. Pharmacological antagonists bind to the same receptor as the agonist, either at the same site or at an allosteric site. They have affinity for the receptor but lack intrinsic activity. Pharmacological antagonists can be subdivided into reversible, irreversible, competitive, and noncompetitive categories similar to enzyme inhibitors

b. Chemical antagonists react with one another, resulting in the inactivation of both compounds.

(1)               The anticoagulant heparin, an acidic polysaccharide, is chemically antagonized by protamine, a basic protein, via an acid-base interaction.

(2)               Chelating agents can be used as antidotes for metal poisoning. Ethylene diamine tetraacetic acid (EDTA) chelates calcium and lead; penicillamine chelates copper; and dimercaprol chelates mercury, gold, antimony, and arsenic.

c. Functional (or physical) antagonists produce antagonistic physiological actions through binding at separate receptors. The adrenergic and cholinergic nervous systems frequently produce this type of antagonism. Acetylcholine constricts the pupil by acting on receptors that control the circular muscles of the eye, whereas norepinephrine dilates the pupil by acting on receptors that control ocular dilator muscles.

B.                 Interaction with enzymes

1. Activation, or increased enzyme activity, can result from induction of enzyme protein synthesis by such drugs as barbiturates, phenytoin and other antiepileptics, rifampin, antihistamines, griseofulvin, and oral contraceptives.

a. Allosteric binding. A drug can enhance enzyme activity by allosteric binding, which triggers a conformational change in the enzyme system and thus alters its affinity for substrate binding.

b. Coenzymes play a role in optimizing enzyme activity. Coenzymes include: vitamins (particularly the vitamin-B complex) and cofactors—mainly metallicions such as sodium (Na+), potassium (K+), magnesium (Mg++), calcium (Ca++), zinc (Zn++), and iron (Fe++). Coenzymes activate enzymes by complexation and stereochemical interaction.

2. Inhibition, or decreased enzyme activity, can result from drugs that interact with the apoenzyme, the coenzyme, or even the whole enzyme complex. The drug might modify or destroy the apoenzyme's protein conformation, react with the coenzyme (thus reducing the enzyme system's capacity to function), or bind with the enzyme complex (rendering it unable to bind with its substrate).

a.                  Reversible inhibition results from a noncovalent interaction between the enzyme and the drug. The drug is free to associate and dissociate with the enzyme, and an equilibrium exists between bound and free drug.

b.                  Irreversible inhibition results from a stable, covalent interaction between the enzyme and the drug. Once bound to the enzyme, the drug is not able to dissociate.

c.                   Competitive inhibition occurs when there is mutually exclusive binding of the substrate and the inhibitor. While it is possible for competitive inhibitors to bind to allosteric sites, these inhibitors are usually structurally similar to the natural substrates and compete with the substrates for common binding sites. Competitive inhibition can be overcome by increasing the concentration of the substrate.

d.                  Noncompetitive inhibition occurs when a drug binds to an allostericsite on the enzyme. This binding induces a conformational change in the enzyme that inhibits enzyme action, even if a substrate is bound to the enzyme. Increasing substrate concent ration does not overcome this type of inhibition.

C. Interaction with DNA/RNA formation and function

1. Inhibition of nucleotide biosynthesis occurs when folate, purine, and pyrimidine antimetabolites interfere with the biosynthesis of purine and pyrimidine building blocks.

a. Folic acid analogs (e.g., methotrexate, trimetrexate) inhibit purine and thymidylate synthesis by inhibiting dihydrofolate reductase.

b. Purine analogs (e.g., 6-mercaptopurine, thioguanine) act as antagonists in the synthesis of purine bases. These analogs do not act as active inhibitors until they are converted to their respective nucleotides.

c. Pyrimidine analogs (e.g., 5-fluorouracil) inhibit the synthesis of thymidylic acid by inhibiting thymidine synthetase. As with purine analogs, pyrimidine analogs are not active until they are converted to their respective nucleotides.

2. Inhibition of DNA or RNA biosynthesis occurs when drugs interfere with nucleic acid synthesis. These drugs are used primarily as antineoplastic agents for cancer chemotherapy.

a. Drugs that interfere with DNA replication and function include intercalating agents (e.g., the anthracyclines, dactinomycin), alkylating agents (e.g., nitrogenmustards, nitrosoureas), and antimetabolites.

b. Drugs that can damage and destroy DNA include compounds that produce freeradicals (e.g., bleomycin, the anthracyclines) and compounds that inhibit topoisomerases (e.g., epipodophyllotoxins, mitoxantrone, irinotecan, topotecan).

c. Drugs that interfere with microtubule assembly in the metaphase of cell mitosis include the vinca alkaloids and paclitaxel.

D. Inhibition of protein synthesis

1. Tetracyclines interfere with protein synthesis by inhibiting transfer RNA ( tRNA) binding to the ribosome and blocking the release of completed peptides from the ribosome.

2. Chloramphenicol and erythromycin (which compete for the same binding site) bind to the ribosome and inhibit peptidyl transferase, blocking formation of the peptide bond and interrupting formation of the peptide chain.

3. Aminoglycosides decrease the fidelity of transcription by binding to the ribosome, which permits formation of an abnormalinitiation complex and prohibits addition of amino acids to the peptide chain. In addition, aminoglycosides cause misreading of the messenger RNA (mRNA) template, so that incorrect amino acids are incorporated into the growing polypeptide chain.

4. Quinupristin and dalfopristin, in combination, constrict the exit channel on ribosomal RNA (rRNA). This action prevents newly synthesized polypeptides from being released and in turn inhibits further protein synthesis.

E. Interaction with cell membranes

1. Digitalis glycosides inhibit the cell membrane's sodium-potassium pump, inhibiting the influx of K+ and the out flow of Na+ .

2. Quinidine affects the membrane potential of myocardial membranes by prolonging both the polarized and depolarized states.

3. Local anesthetics block impulse conduct ion in nerve cell membranes by interfering with membrane permeability to Na+ and K+ .

4. Polyene antifungal drugs (e.g., amphotericin B, nystatin) affect cell membrane permeability, causing leakage of cellular constituents.

5. Certain antibiotics (e.g., polymyxin B, colistin) affect cell membrane permeability through an unknown mechanism.

6. Acetylcholine increases membrane permeability to cations.

7. Omeprazole and lansoprazole inhibit the H+ /K+ pump (located in parietal cell membranes) , thus decreasing the efflux of protons into the stomach.

8. Several antineoplastic agents exert their actions by initially binding to cellular determinants (CDs) expressed by tumor cells.

a. Gemtuzumab ozogamicin binds with CD33 expressed by leukemic cells and immature myelomonocytic cells.

b. Alemtuzumab, a monoclonal antibody, binds to the CD52 antigen expressed on B-lymphocytes, T-lymphocytes, and various other cells.

F. Nonspecific action

1. Structurally nonspecific drugs form a monomolecular layer over entire areas of certain cells. Because they involve such large surfaces, these drugs are usually given in relatively large doses.

2. Drugs that act by nonspecific action include the volatile general anesthetic gases (e.g., ether, nitrous oxide), some depressants (e.g., ethanol, chloral hydrate), and many antiseptic compounds (e.g., phenol, rubbing alcohol) .