Introduction to Anti-Tubercular Agents, Quinolones & Antiviral Agents
This unit covers three critical therapeutic categories. Anti-tubercular agents — first-line (RIPE: Rifampicin, Isoniazid, Pyrazinamide, Ethambutol) and second-line drugs for MDR-TB. Quinolone/Fluoroquinolone antibacterials — a purely synthetic class with well-defined SAR for UTI and systemic infections. Antiviral agents — including anti-herpes (Acyclovir), anti-HIV (NRTIs, NNRTIs, Protease inhibitors), and anti-influenza drugs.
Syllabus & Topics
- 1Isoniazid (INH): Isonicotinic acid hydrazide — simplest and most potent first-line anti-TB drug. Structure: pyridine ring with C-4 hydrazide group. MOA: prodrug — activated by mycobacterial catalase-peroxidase (KatG) → isonicotinoyl radical → inhibits InhA (enoyl-ACP reductase) → blocks mycolic acid synthesis (essential component of mycobacterial cell wall). Highly specific for Mycobacterium tuberculosis. Resistance: KatG mutations. Metabolism: N-acetyltransferase (NAT2) → acetylisoniazid. Slow acetylators: ↑toxicity (peripheral neuropathy — prevented by Pyridoxine/Vitamin B6 supplementation).
- 2Ethionamide: Structural analog of Isoniazid (thioamide instead of hydrazide). Second-line anti-TB drug for MDR-TB. Also inhibits InhA but activated by a different enzyme (EthA monooxygenase) → effective against some INH-resistant strains. More toxic than INH (GI intolerance, hepatotoxicity).
- 3Ethambutol: Diamine with two ethanol arms — S,S-(+) isomer is active. MOA: inhibits arabinosyltransferase (EmbB) → blocks arabinogalactan synthesis → disrupts mycobacterial cell wall. First-line drug (in RIPE regimen). Major toxicity: optic neuritis (dose-dependent, reversible if caught early → monthly visual acuity testing). SAR: both amino groups and both hydroxyl groups required. S,S-configuration essential (R,R-isomer inactive).
- 4Pyrazinamide: Pyrazine analog of nicotinamide. MOA: prodrug — converted to pyrazinoic acid by mycobacterial pyrazinamidase (PZA → POA). POA disrupts membrane energetics and inhibits fatty acid synthase I in M. tuberculosis. Uniquely active against semi-dormant bacilli in acidic environment (inside macrophages/caseous lesions) → essential in first 2-month intensive phase (shortens treatment from 9 to 6 months). Major ADR: hepatotoxicity, hyperuricemia (inhibits uric acid excretion).
- 5Para-Aminosalicylic Acid (PAS): Structural analog of PABA (p-aminobenzoic acid). MOA: competitive inhibitor of dihydropteroate synthase → anti-folate mechanism (like sulfonamides, but specific to mycobacteria). Second-line drug (MDR-TB). GI intolerance is dose-limiting. Granule formulation (PAS granules) improves tolerance.
- 6Rifampicin: Semi-synthetic ansamycin antibiotic from Amycolatopsis rifamycinica. Structure: complex naphthohydroquinone chromophore bridged by an aliphatic ansa chain with a piperazine at C-3. MOA: binds β-subunit of bacterial DNA-dependent RNA polymerase → blocks transcription initiation → bactericidal. Most powerful anti-TB drug (sterilizing activity). Potent CYP450 inducer (CYP3A4, 2C9) → extensive drug interactions (oral contraceptives, antiretrovirals, warfarin). Orange-red discoloration of body fluids.
- 7Other Anti-TB Antibiotics: Rifabutin: less potent CYP inducer than Rifampicin → preferred in HIV-TB coinfection (fewer interactions with antiretrovirals). Cycloserine: D-alanine analog → inhibits alanine racemase and D-Ala-D-Ala ligase → blocks peptidoglycan synthesis. Second-line, crosses BBB. CNS toxicity (seizures, psychosis). Capreomycin sulfate: cyclic peptide antibiotic, injectable, second-line for MDR-TB.
- 8Quinolones – SAR: Parent structure: 4-oxo-1,4-dihydroquinoline-3-carboxylic acid. MOA: inhibit bacterial DNA gyrase (topoisomerase II, gram-negative) and topoisomerase IV (gram-positive) → prevent DNA supercoiling → bactericidal. SAR: (1) C-3 carboxylic acid: ESSENTIAL for DNA gyrase binding. (2) C-4 keto group: ESSENTIAL (complexes with Mg²⁺). (3) C-6 Fluorine: ↑potency 10x, ↑penetration → ‘fluoroquinolones.’ (4) C-7 piperazine: ↑gram-negative, anti-pseudomonal (ciprofloxacin). (5) N-1 cyclopropyl: ↑potency (ciprofloxacin, moxifloxacin). (6) C-8 methoxy: ↑anti-anaerobic (moxifloxacin).
- 9Important Quinolones: Nalidixic acid: 1st generation, 1,8-naphthyridine (NOT quinolone), UTI only, no fluorine. Norfloxacin: 1st fluoroquinolone (6-F + 7-piperazine), UTI. Ciprofloxacin: N-1 cyclopropyl → most potent vs gram-negative, anti-pseudomonal, broadest use. Ofloxacin: oxazine ring fused to quinolone, racemic. Levofloxacin: S-isomer of ofloxacin, 2x potent. Moxifloxacin: C-8 methoxy + C-7 azabicyclo → excellent anaerobic + respiratory coverage (‘respiratory quinolone’).
- 10UTI Miscellaneous Agents: Furazolidone: nitrofuran derivative, inhibits MAO, used for giardiasis/bacterial diarrhea. Nitrofurantoin: nitrofuran, reduced by bacterial nitroreductases → reactive intermediates damage DNA. Used for uncomplicated UTI (concentrates in urine, minimal systemic levels). ADR: pulmonary fibrosis (rare, chronic use). Methenamine (Hexamethylenetetramine): decomposes in acidic urine (pH <5.5) to release formaldehyde → bactericidal. Urinary antiseptic for prophylaxis.
- 11Antiviral Agents – Overview: Viruses are obligate intracellular parasites → antiviral drugs must target virus-specific steps without harming host cells. Drug targets: (1) Viral attachment/entry (Amantadine). (2) Uncoating (Rimantadine). (3) DNA/RNA polymerase (Acyclovir, Zidovudine). (4) Protease (Saquinavir). (5) Reverse transcriptase (NRTIs: Zidovudine; NNRTIs: Delavirdine). (6) Integrase.
- 12Anti-Herpes Agents: Acyclovir: acyclic guanosine analog (missing the 2′ and 3′ carbons of the sugar ring). MOA: selectively phosphorylated by viral thymidine kinase (TK) → further phosphorylated by cellular kinases → acyclovir triphosphate → competitive inhibitor of viral DNA polymerase + chain terminator (no 3′-OH for next nucleotide). Highly selective for virus-infected cells (cellular TK cannot phosphorylate it efficiently). Ganciclovir: similar but with additional –CH₂OH → more active vs CMV (Cytomegalovirus). Idoxuridine: iodinated thymidine analog, topical for herpes keratitis. Trifluorothymidine (Trifluridine): fluorinated pyrimidine, topical anti-herpes.
- 13Anti-HIV Agents – NRTIs: Nucleoside Reverse Transcriptase Inhibitors — analogs of natural nucleosides that lack the 3′-OH group → incorporated into viral DNA → chain terminators. Zidovudine (AZT): thymidine analog with 3′-azido group (first approved anti-HIV drug, 1987). Didanosine (ddI): dideoxyinosine → converted to ddATP. Zalcitabine (ddC): dideoxycytidine (withdrawn). Lamivudine (3TC): L-enantiomer of dideoxycytidine → also active vs HBV. All NRTIs share common ADR: mitochondrial toxicity (lactic acidosis, lipoatrophy, peripheral neuropathy) because they also weakly inhibit mitochondrial DNA polymerase γ.
- 14Anti-HIV – NNRTIs & Protease Inhibitors: NNRTIs: Non-nucleoside RT inhibitors — bind allosteric site on RT → conformational change → inhibit polymerase activity. NOT substrate analogs. Loviride, Delavirdine. Protease Inhibitors: HIV protease cleaves Gag-Pol polyprotein into functional viral proteins → essential for viral maturation. PIs are peptidomimetic compounds that mimic the transition state of the peptide bond being cleaved. Saquinavir (first PI approved), Indinavir (kidney stones), Ritonavir (potent CYP3A4 inhibitor → used as ‘pharmacokinetic booster’ for other PIs).
- 15Ribavirin: Synthetic guanosine analog. Broad-spectrum antiviral (RSV, Hepatitis C, Lassa fever). MOA: multiple mechanisms — inhibits IMP dehydrogenase (↓GTP pool), incorporated into viral RNA → lethal mutagenesis, inhibits mRNA capping. Used in combination with interferon-α/PEG-interferon for Hepatitis C (now largely replaced by DAAs but still relevant). Major ADR: hemolytic anemia, teratogenicity (Category X).
Learning Objectives
Exam Prep Questions
Q1. Why Is the Fluorine at C-6 So Important in Quinolones?
Fluoroquinolone antibiotics contain a fluorine atom at the C-6 position of the quinolone ring, which greatly enhances antibacterial activity compared with earlier compounds like Nalidixic acid. The fluorine atom increases the drug’s binding affinity to bacterial enzymes such as DNA gyrase and Topoisomerase IV. It also improves cell penetration by increasing lipophilicity, enhances oral bioavailability, and expands the antibacterial spectrum from mainly gram-negative organisms to both gram-positive and gram-negative bacteria. Because of these advantages, nearly all modern quinolone antibiotics include the C-6 fluorine substitution.
Q2. How Does Acyclovir Selectively Target Virus-Infected Cells?
Acyclovir becomes pharmacologically active only after conversion to acyclovir triphosphate through three phosphorylation steps. The first phosphorylation step is carried out by Viral thymidine kinase, which is produced only in cells infected with herpes viruses such as Herpes simplex virus. Because uninfected cells lack this viral enzyme, acyclovir is not efficiently activated in normal cells. Once converted to its active triphosphate form, the drug inhibits viral DNA synthesis by blocking Viral DNA polymerase. This selective activation provides a high therapeutic index and makes acyclovir relatively safe.
Q3. What Is the Mechanism of Rifampicin’s Drug Interactions?
Rifampicin strongly induces hepatic drug-metabolizing enzymes. It activates the nuclear receptor Pregnane X receptor, which increases the transcription of several Cytochrome P450 enzymes such as CYP3A4, CYP2C9, and CYP2C19, as well as the drug transporter P-glycoprotein. As a result, many co-administered drugs are metabolized more rapidly, reducing their therapeutic effect. Examples include Warfarin, Oral contraceptives, antiretroviral agents, and immunosuppressants such as Cyclosporine. Because of this strong enzyme induction, careful monitoring for drug interactions is necessary when rifampicin is prescribed.
Q4. Why Is Pyrazinamide Essential in the Anti-TB Regimen?
Pyrazinamide plays a critical role in tuberculosis therapy because it can kill semi-dormant bacteria in acidic environments within infected tissues. It is converted into the active metabolite pyrazinoic acid, which accumulates in acidic sites such as macrophage lysosomes and necrotic lesions containing Mycobacterium tuberculosis. These environments are difficult for other drugs to penetrate effectively. The ability of pyrazinamide to act on persistent organisms during the intensive phase of treatment significantly shortened tuberculosis therapy from about 9–12 months to approximately 6 months, making it an essential component of modern anti-TB regimens.