Unit 23: Pharmacology — Long Questions

Drug discovery and development occur in two broad phases.

A. Stages of Drug Discovery:
1. Target Identification — scientists identify a specific molecule, such as a protein or enzyme, involved in causing the disease, which can be affected by a drug.
2. Target Validation — researchers confirm that the identified target plays an important role in the disease process through experiments that show acting on it produces therapeutic effects.
3. Lead Compound Identification — thousands of natural or synthetic compounds are screened to find substances (lead compounds) that interact effectively with the target.
4. Lead Optimization — lead compounds are modified to improve effectiveness, reduce toxicity, and enhance drug-like properties.

B. Drug Developmental Process 1. Preclinical Research — compounds are tested in vitro (cell culture) and in vivo (animals) for safety, toxicity and efficacy before human trials.
2. Clinical Trials — Phase 1 (20–100 healthy volunteers) tests safety and dosage; Phase 2 (100–300 patients) tests effectiveness and side effects; Phase 3 (1,000–3,000 patients) confirms efficacy and monitors adverse reactions.
3. FDA Drug Review — regulatory agencies (FDA or EMA) examine all clinical trial data to approve or reject the drug before it reaches the market.
4. Manufacturing and Marketing — once approved, the drug is produced on a large scale by pharmaceutical industries and made available for medical use.
5. Post-Marketing Surveillance — even after release, the drug is continuously monitored for long-term effects and rare side effects to ensure ongoing safety.

Antibiotics are drugs that treat bacterial infections by killing bacteria or stopping their growth. The four major classes are:

1. Penicillin — a bactericidal antibiotic derived from Penicillium fungi (discovered by Alexander Fleming, 1928), highly effective against Gram-positive bacteria such as streptococci and staphylococci. Mode of action: (a) it targets bacteria specifically because animal cells lack cell walls; (b) it interrupts the cross-linking of peptidoglycan (murein) chains, stopping new cell wall synthesis; (c) without structural integrity, the bacterial cell wall bursts (lysis), killing the bacterium; (d) some bacteria resist it by producing beta-lactamase enzymes.

2. Tetracycline — a bacteriostatic oral antibiotic derived from soil bacteria of the genus Streptomyces, used for infections like chlamydia and syphilis. Mode of action: it is effective against both Gram-positive and Gram-negative bacteria; it enters bacterial cells and reversibly binds to the 30S ribosomal subunit, preventing aminoacyl-tRNA from binding to the acceptor site, thereby blocking translation and protein synthesis (bacteriostatic — stops growth rather than killing).

3. Fluoroquinolones — synthetic bactericidal antibiotics derived as a byproduct of chloroquine (quinine) synthesis (discovered by George Lesher, 1962). Mode of action: they trap the enzymes involved in DNA replication, causing double-strand DNA breaks that kill the bacteria; they inhibit Type II topoisomerases — specifically Topoisomerase IV in Gram-positive bacteria (blocking separation of replicated DNA) and DNA Gyrase in Gram-negative bacteria (blocking DNA uncoiling during replication).

4. Sulfonamides — synthetic, bacteriostatic compounds derived from sulfanilamide (discovered by Gerhard Domagk, 1932), used for urinary tract and skin infections. Mode of action: they are selectively toxic to bacteria because bacteria must synthesize folate themselves while humans absorb it from food; sulfonamides act as competitive inhibitors of the enzyme that makes folate from para-amino benzoic acid (PABA), blocking folic acid synthesis needed for DNA synthesis and bacterial growth; they are often combined with trimethoprim for a stronger bactericidal effect and are broad-spectrum, acting on both Gram-positive and Gram-negative bacteria.

Monoclonal antibodies are artificially laboratory-produced molecules that enhance the immune system's ability to fight against pathogens. They target specific antigens, which makes them effective for treating cancer, autoimmune disorders, and infectious diseases. They are integral to personalized medicine, allowing treatment to be tailored to each patient's unique biology, and modern technologies allow thousands of potential antibodies to be tested simultaneously, reducing development timelines and enabling faster responses to urgent health challenges such as infectious diseases and cancer.

Advantages of monoclonal antibodies (i) Compared to traditional drugs, they offer lower toxicity and the potential for long-lasting effects.
(ii) They have the least side effects compared to conventional chemotherapeutics.
(iii) They show high specificity, binding to a single target with minimal variability.
(iv) They provide targeted therapy in cancer, reducing damage to healthy tissues.
(v) They are easy to prepare and can be used for research purposes.
(vi) They reduce the risk of drug interactions.