Unit 3: Chemotherapy – Anti-TB, Antifungals, Antivirals, Antimalarials & More

Semester 6

BP602T

Chemotherapy – Anti-TB, Antifungals, Antivirals, Antimalarials & More

This unit covers the pharmacology of chemotherapeutic agents against a wide range of pathogens: Mycobacterium tuberculosis (anti-TB drugs, RIPE regimen, MDR-TB management), M. leprae (anti-leprotic, WHO MDT), fungi (polyenes, azoles, echinocandins), viruses (anti-herpes, anti-HIV/ART, anti-influenza, anti-hepatitis), helminths (anthelmintics), malaria parasites (antimalarials, ACT), and amoebae (antiamoebic agents). The focus is on mechanism of action, clinical use, adverse effects, and drug resistance.

Syllabus & Topics

1Antitubercular Agents – RIPE Regimen: Standard 6-month regimen for drug-sensitive TB: Intensive phase (2 months): Rifampicin + Isoniazid + Pyrazinamide + Ethambutol (RIPE). Continuation phase (4 months): Rifampicin + Isoniazid (RI). MOA: Isoniazid (inhibits mycolic acid synthesis, InhA; bactericidal for actively growing bacilli), Rifampicin (inhibits RNA polymerase; bactericidal, sterilizing activity), Pyrazinamide (kills semi-dormant bacilli in acidic environment), Ethambutol (inhibits arabinosyltransferase; prevents resistance emergence).
2Anti-TB – Drug-Resistant TB: MDR-TB: resistant to at least Isoniazid AND Rifampicin (the two most powerful drugs). XDR-TB: MDR + resistance to fluoroquinolone + injectable agent. MDR-TB treatment: 18-24 months with second-line drugs — Levofloxacin/Moxifloxacin, Bedaquiline (ATP synthase inhibitor — breakthrough drug), Linezolid, Clofazimine, Cycloserine, Ethionamide, Capreomycin/Amikacin (injectable). Directly Observed Therapy (DOTS/NTEP) — patient takes medication under supervision to ensure adherence.
3Antileprotic Agents – WHO MDT: Leprosy (Hansen’s disease) caused by M. leprae. WHO Multi-Drug Therapy (MDT): Paucibacillary (PB, 1-5 lesions): Rifampicin (monthly supervised) + Dapsone (daily self-administered) × 6 months. Multibacillary (MB, >5 lesions): Rifampicin + Dapsone + Clofazimine × 12 months. Dapsone: inhibits DHPS (like sulfonamides), ADR: hemolytic anemia (G6PD def), methemoglobinemia. Clofazimine: phenazine dye, anti-inflammatory + antimycobacterial. ADR: red-brown skin discoloration.
4Antifungal Agents – Classification: (1) Polyenes: Amphotericin B (binds ergosterol → pore formation → fungicidal; gold standard for severe systemic mycoses; nephrotoxic — use lipid formulations). Nystatin (topical only). (2) Azoles: Fluconazole (oral, CSF penetration — cryptococcal meningitis, candidiasis), Itraconazole (broader, aspergillosis), Voriconazole (drug of choice for invasive aspergillosis), Ketoconazole (largely replaced). (3) Echinocandins: Caspofungin, Micafungin — inhibit β-1,3-glucan synthase → ↓cell wall glucan → fungicidal vs Candida. (4) Others: Griseofulvin (dermatophytes, binds tubulin), Terbinafine (squalene epoxidase inhibitor — onychomycosis).
5Antiviral Agents – Anti-Herpes: Acyclovir: acyclic guanosine analog, activated by viral thymidine kinase → triphosphate → inhibits viral DNA polymerase + chain terminator. Drug of choice for HSV and VZV infections. Valacyclovir: L-valyl ester prodrug of acyclovir → ↑oral bioavailability. Ganciclovir: more active vs CMV (also activated by viral UL97 kinase). ADR: neutropenia, thrombocytopenia. Foscarnet: pyrophosphate analog, directly inhibits viral DNA polymerase (no kinase activation needed — used for acyclovir-resistant HSV/CMV).
6Antiviral – Antiretrovirals (ART): Classes: (1) NRTIs: Zidovudine (AZT), Lamivudine (3TC), Tenofovir (TDF/TAF), Emtricitabine (FTC) — chain terminators. (2) NNRTIs: Efavirenz, Nevirapine — allosteric RT inhibitors. (3) Protease Inhibitors: Lopinavir/r, Atazanavir/r (boosted with Ritonavir = pharmacokinetic enhancer). (4) Integrase Inhibitors (INSTIs): Dolutegravir, Raltegravir — preferred 1st-line. (5) Entry inhibitors: Maraviroc (CCR5 antagonist), Enfuvirtide (fusion inhibitor). Current 1st-line: TDF/TAF + 3TC/FTC + Dolutegravir. ART is lifelong — suppresses viral load to undetectable.
7Antiviral – Anti-Influenza & Anti-HBV/HCV: Anti-influenza: Oseltamivir, Zanamivir (neuraminidase inhibitors — prevent viral release from infected cells). Amantadine/Rimantadine: M2 ion channel blockers (influenza A only, widespread resistance → largely obsolete). Anti-HBV: Entecavir, Tenofovir (NRTIs). Anti-HCV: DAAs (Direct-Acting Antivirals): Sofosbuvir (NS5B polymerase inhibitor) + Ledipasvir/Velpatasvir (NS5A inhibitor) → cure rates >95%. Ribavirin: broad-spectrum (RSV, HCV adjunct).
8Anthelmintics: Albendazole/Mebendazole: benzimidazoles → inhibit β-tubulin polymerization → ↓glucose uptake. Broadest spectrum. Albendazole preferred (better absorption). Diethylcarbamazine (DEC): filaricidal (W. bancrofti, LF). Ivermectin: activates glutamate-gated Cl⁻ channels → paralysis. Onchocerciasis, Strongyloides, LF (mass drug administration). Praziquantel: ↑Ca²⁺ permeability → spastic paralysis → tegumental damage. Drug of choice for ALL schistosome species + tapeworms. Niclosamide: tapeworms (uncouples oxidative phosphorylation).
9Antimalarial Drugs: Blood schizonticides (clinical cure): Chloroquine (inhibits heme polymerase; CQ-resistant P. falciparum common), ACT (Artemisinin-based Combination Therapy — WHO first-line for P. falciparum: Artesunate + Amodiaquine or Artemether + Lumefantrine), Quinine (severe malaria — IV), Mefloquine (prophylaxis). Tissue schizonticides: Primaquine (ONLY drug killing hypnozoites → radical cure of P. vivax/ovale; also gametocytocide). Causal prophylaxis: Atovaquone-Proguanil (Malarone). ADR: Primaquine → hemolysis in G6PD deficiency; Chloroquine → retinopathy; Mefloquine → neuropsychiatric.
10Antiamoebic Agents: Amoebic dysentery and liver abscess caused by Entamoeba histolytica. Tissue (systemic) amoebicides: Metronidazole (drug of choice for invasive amoebiasis — amoebic dysentery, liver abscess), Tinidazole (longer t½, single-dose regimens), Chloroquine (hepatic amoebiasis only), Emetine/Dehydroemetine (toxic, reserved for severe cases). Luminal amoebicides: Diloxanide furoate (drug of choice for asymptomatic cyst passers), Iodoquinol, Paromomycin (aminoglycoside, also luminal). Treatment of invasive amoebiasis: Metronidazole (tissue) FOLLOWED BY Diloxanide (luminal to eliminate cysts).

Learning Objectives

RIPE Rationale: Explain the role of each drug in the RIPE regimen and why combination therapy is mandatory in TB.

MDR-TB: Define MDR-TB and XDR-TB and list the second-line drugs used in their management.

Antifungal Classes: Compare polyenes, azoles, and echinocandins by mechanism, spectrum, and adverse effects.

ART Regimen: State the current WHO-recommended first-line ART regimen and explain its rationale.

Antimalarial Targets: Classify antimalarial drugs based on the stage of the malaria parasite they target.

Exam Prep Questions

Q1. Why Is Combination Therapy Mandatory in TB?

Mycobacterium tuberculosis has a high spontaneous mutation rate that can produce drug-resistant strains. For example, resistance may occur in approximately 1 in 10⁶ organisms for Isoniazid and 1 in 10⁸ organisms for Rifampicin. Since a typical tuberculosis cavity may contain 10⁸–10⁹ bacteria, resistant mutants are likely to exist even before treatment begins.

If only a single drug is used, susceptible bacteria are killed while resistant organisms survive and multiply, leading to treatment failure. Therefore, multiple drugs are given simultaneously so that a bacterium would need resistance to all of them at the same time—an extremely unlikely event. The standard initial regimen often includes four drugs: Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol, commonly known as the RIPE regimen.

Q2. What Is the Difference Between ARV and ART?

Antiretroviral drugs (ARVs) refer to individual drugs used to treat infection with Human immunodeficiency virus. Examples include Zidovudine or Tenofovir.

Antiretroviral therapy (ART) refers to the complete treatment regimen, which combines multiple ARV drugs to suppress HIV replication. Combination therapy is necessary because HIV mutates rapidly and develops resistance quickly if only one drug is used. The commonly recommended regimen includes two nucleoside reverse transcriptase inhibitors plus one integrase inhibitor, such as Tenofovir + Lamivudine + Dolutegravir.

Q3. Why Must Invasive Amoebiasis Be Treated With Both Tissue and Luminal Amoebicides?

Entamoeba histolytica exists in two main forms in the human body: invasive trophozoites in tissues and cysts within the intestinal lumen. Metronidazole is effective against tissue trophozoites that cause conditions such as amoebic dysentery and liver abscess. However, it is less effective against cysts present in the intestinal lumen.

If treatment is stopped after metronidazole alone, the remaining cysts can lead to relapse and continued transmission of infection. Therefore, a luminal amoebicide such as Diloxanide furoate is given after metronidazole therapy to eradicate cysts from the intestine and prevent recurrence.

Q4. What Is ACT and Why Is It the Gold Standard for Plasmodium falciparum Malaria?

Artemisinin based combination therapy (ACT) combines a fast-acting artemisinin derivative with a longer-acting partner antimalarial drug. Artemisinin derivatives such as Artesunate or Artemether rapidly reduce parasite numbers by killing a large proportion of parasites within the first 24 hours.

The partner drug, such as Lumefantrine or Mefloquine, eliminates the remaining parasites and prevents recrudescence. This combination approach speeds parasite clearance, reduces the chance of drug resistance, and achieves cure rates exceeding 95%. Because of these advantages, the World Health Organization recommends ACT as the first-line treatment for malaria caused by Plasmodium falciparum worldwide.