Antimalarial Drugs
Standard Answer:
(2023 Main, 2015, 2013 Resit, 2011 — recurs) Classification (by chemical structure and stage of parasite life cycle targeted): 1. 4-Aminoquinolines: Chloroquine, Amodiaquine — blood schizonticides; inhibit haem polymerase (haem detoxification protein) in the parasite food vacuole, allowing toxic free haem to accumulate and kill the parasite. 2. Quinoline-methanols: Quinine, Mefloquine — blood schizonticides, similar haem-toxicity mechanism, used particularly for severe/resistant malaria (quinine) and prophylaxis (mefloquine). 3. Artemisinin derivatives: Artesunate, Artemether, Dihydroartemisinin — generate free radicals via cleavage of the endoperoxide bridge (activated by intraparasitic haem/iron), damaging parasite proteins/membranes; rapid-acting blood schizonticides, now first-line as Artemisinin-based Combination Therapies (ACTs). 4. Antifolates: Sulfadoxine-pyrimethamine (sequential blockade of folate synthesis, similar principle to cotrimoxazole), Proguanil. 5. 8-Aminoquinolines: Primaquine, Tafenoquine — the only agents active against hypnozoites (dormant liver stage of P. vivax/ovale) — used for radical cure/relapse prevention; requires G6PD testing first (risk of haemolysis in deficiency). 6. Antibiotics (adjunctive): Doxycycline, Clindamycin — used in combination, particularly for prophylaxis or with quinine. How effects of blood schizonticides vary with level of parasitaemia: Blood schizonticides act on the intraerythrocytic asexual stages responsible for clinical disease. At low parasitaemia, standard doses achieve rapid clearance with low risk of complications. At high parasitaemia (severe malaria), the sheer parasite biomass means (a) drug must penetrate a much larger number of infected cells, (b) rapid parasite killing can precipitate complications from released parasite antigens/toxins and haemolysis (including risk of “blackwater fever” with quinine in G6PD-normal but heavily parasitized patients), and (c) severe malaria requires parenteral therapy (IV artesunate preferred over quinine per WHO guidelines) because oral absorption may be unreliable in a systemically unwell patient, and faster, more reliable parasite clearance is needed to prevent progression to cerebral malaria/multiorgan failure. Artemisinin — pharmacokinetics, mechanism, clinical usefulness: • Mechanism as above (free radical generation via endoperoxide bridge). • Pharmacokinetics: rapid absorption, short plasma half-life (necessitating combination with a longer-acting partner drug to eliminate residual parasites and prevent recrudescence/resistance — the basis of ACTs), extensive first-pass metabolism. • Clinical usefulness: fastest-acting antimalarial class available, effective against multidrug-resistant P. falciparum, used in both uncomplicated (oral ACT) and severe malaria (IV artesunate, now preferred over quinine due to superior mortality outcomes in trials). Distinguishing Artemisinin and Chloroquine mechanisms: Chloroquine acts by inhibiting haem polymerization in the parasite food vacuole (concentration-dependent accumulation in the vacuole via ion-trapping due to its weak-base property); artemisinin acts via free-radical generation from endoperoxide bridge cleavage, a distinct and more rapidly parasiticidal mechanism, explaining why chloroquine resistance (widespread, due to efflux pump mutations, e.g., PfCRT) does not confer cross-resistance to artemisinins. Justification for ACTs as first-line therapy for uncomplicated malaria: Combining a fast-acting artemisinin derivative (rapidly reduces parasite biomass, providing rapid clinical improvement) with a longer-acting partner drug (e.g., lumefantrine, mefloquine, amodiaquine — eliminates residual parasites after the artemisinin component is cleared) achieves rapid symptom relief, reduces the risk of recrudescence, and — critically — reduces the risk of resistance developing to either drug, since parasites surviving one drug are likely to be killed by the other (mutual protection principle, analogous to combination TB therapy). Mechanism of antifolate drug resistance in Plasmodium falciparum: Point mutations in the parasite genes encoding dihydrofolate reductase (DHFR) (target of pyrimethamine) and dihydropteroate synthase (DHPS) (target of sulfadoxine) reduce drug binding affinity while preserving enzymatic function, conferring resistance to sulfadoxine-pyrimethamine; resistance is cumulative with the number of point mutations acquired.
Antifungal Agents
Standard Answer:
(2023 Main, 2023 Resit, 2022 Main, 2021 Main, 2021 Resit, 2018/19, 2017 — recurs every year) Classification and principle of selective toxicity: Selective toxicity in antifungals is achieved by exploiting differences between fungal and human cell biology — chiefly the fungal cell wall (absent in human cells) and the fungal membrane sterol ergosterol (vs cholesterol in humans). • Polyenes: Amphotericin B, Nystatin — bind ergosterol in the fungal cell membrane, forming pores that cause leakage of cellular contents (K⁺, ions); some binding to human cholesterol occurs (lower affinity), accounting for toxicity (notably amphotericin B’s nephrotoxicity). • Azoles: Fluconazole, Itraconazole, Voriconazole, Ketoconazole — inhibit fungal CYP450 enzyme (lanosterol 14α-demethylase), blocking conversion of lanosterol to ergosterol; selectivity arises because fungal CYP450 is more sensitive to azole inhibition than human CYP450 (though at higher doses, human steroidogenic CYP450 can also be affected, especially by ketoconazole — endocrine side effects). • Allylamines: Terbinafine — inhibits fungal squalene epoxidase, blocking an earlier step in ergosterol synthesis, causing toxic accumulation of squalene; selective because squalene epoxidase in fungi is far more sensitive to terbinafine than the human enzyme. • Echinocandins: Caspofungin, Micafungin — inhibit (1,3)-β-D-glucan synthase, blocking synthesis of the fungal cell wall glucan component — a structure entirely absent in human cells, giving excellent selective toxicity and a favourable side effect profile. • Antimetabolites: Flucytosine — converted by fungal cytosine deaminase (largely absent/inactive in human cells) to 5-fluorouracil, which disrupts fungal DNA/RNA/ protein synthesis — selectivity based on differential enzyme expression. • Griseofulvin – disrupts fungal microtubule function (binds tubulin), used specifically for dermatophyte infections; deposits in keratin precursor cells, so newly formed skin/ hair/nails become resistant to fungal invasion. Terbinafine vs Griseofulvin comparison: • Terbinafine – inhibits squalene epoxidase (early ergosterol synthesis step); fungicidal against dermatophytes; oral and topical formulations; adverse effects: GI upset, headache, rare hepatotoxicity, taste disturbance. • Griseofulvin – disrupts fungal mitotic spindle (binds microtubules), fungistatic; requires prolonged treatment (weeks to months) since it must wait for new keratin growth to incorporate the drug; adverse effects: headache, GI upset, hepatotoxicity, photosensitivity, disulfiram-like reaction with alcohol, teratogenic, induces hepatic CYP450 (reduces efficacy of oral contraceptives/warfarin). • Terbinafine has largely superseded griseofulvin for dermatophyte/nail infections due to shorter treatment duration and higher cure rates. Fluconazole and Griseofulvin (short notes, 1980/90s question format): Fluconazole — well absorbed orally, good CSF penetration (useful in cryptococcal meningitis, especially in HIV/AIDS), relatively few side effects compared to ketoconazole, but is a CYP450 inhibitor (drug interactions with warfarin, phenytoin, sulfonylureas). Selectivity/synergism basis of Cotrimoxazole (as related to antifungal question on selective toxicity/synergism, 2016): Combination of sulfamethoxazole and trimethoprim — sequential blockade of bacterial/ parasitic folate synthesis pathway (as detailed in Section 1, Q12b); selective toxicity arises because mammalian cells obtain folate from the diet (lack the target enzymes, dihydropteroate synthase is entirely absent in humans), while bacteria and some protozoa/ fungi must synthesize folate de novo.
Tuberculosis and Leprosy Chemotherapy
Standard Answer:
(2023 Main, 2023 Resit, 2022 Main, 2021 Main, 2021 Resit, 2018/19, 2015, 2010 — recurs heavily) Peculiarities/challenges of mycobacterial chemotherapy vs other bacterial infections: 1. Slow growth rate – M. tuberculosis divides very slowly (~18-24 hr generation time vs ~20 minutes for many bacteria), meaning treatment must be prolonged (6+ months) since most antibiotics target actively dividing cells. 2. Intracellular location – the organism resides within macrophages, requiring drugs with good intracellular penetration. 3. Waxy, lipid-rich (mycolic acid) cell wall – impermeable to many standard antibiotics, restricting the range of effective agents. 4. Presence of dormant/persister organisms – within caseous granulomas (low oxygen, low pH environments), requiring drugs active in these special microenvironments (e.g., pyrazinamide, active specifically in the acidic intracellular/caseous environment). 5. High propensity for acquired drug resistance with monotherapy, due to spontaneous chromosomal mutation and the large bacterial burden in cavitary disease — necessitating multi-drug combination therapy for the entire treatment course. First-line anti-tuberculosis agents: Rifampicin, Isoniazid, Pyrazinamide, Ethambutol (RIPE) — standard regimen: 2 months of all four (intensive phase) followed by 4 months of Rifampicin + Isoniazid (continuation phase). Goals of anti-tubercular chemotherapy and how first-line agents meet them: 1. Rapid bactericidal killing of actively dividing bacilli (isoniazid is the most potent early bactericidal agent). 2. Sterilization – killing of slow-growing/dormant persisters in different microenvironments (rifampicin kills semi-dormant organisms with sporadic metabolic activity; pyrazinamide specifically kills organisms in the acidic intracellular/caseous environment). 3. Prevention of emergence of drug resistance – achieved by combining multiple agents with different mechanisms, since the probability of a bacillus having spontaneous resistance mutations to all drugs simultaneously is negligible (ethambutol’s main role is as a “resistance-preventing” companion drug). Rifampicin (mechanism, pharmacology): Inhibits bacterial DNA-dependent RNA polymerase, blocking mRNA synthesis; broad-spectrum bactericidal activity, active against both rapidly dividing and semi-dormant mycobacteria. Notable for: potent hepatic CYP450 induction (major cause of drug interactions — reduces efficacy of oral contraceptives, warfarin, antiretrovirals, etc.), orange-red discolouration of body fluids (harmless but important to counsel patients), hepatotoxicity, flu-like syndrome with intermittent dosing. Isoniazid (mechanism, pharmacology): Prodrug activated by mycobacterial catalase-peroxidase (KatG); the activated form inhibits InhA (enoyl-ACP reductase), blocking synthesis of mycolic acids, essential components of the mycobacterial cell wall — highly selective for actively dividing mycobacteria (minimal effect on other bacteria, since mycolic acid synthesis is unique to mycobacteria). Adverse effects: peripheral neuropathy (due to interference with pyridoxine/vitamin B6 metabolism — prevented by co-administering pyridoxine), hepatotoxicity, drug-induced lupus. Metabolism by hepatic N-acetyltransferase (NAT2) shows genetic polymorphism — “slow acetylators” have higher plasma levels and greater risk of peripheral neuropathy/toxicity, while “fast acetylators” may have reduced efficacy/higher risk of hepatotoxic metabolite formation. Comparing mechanisms of INH and Dapsone: Isoniazid inhibits mycolic acid synthesis (specific to mycobacterial cell wall, as above). Dapsone (used for leprosy and as an alternative in Pneumocystis/toxoplasmosis prophylaxis) is a sulfone that, like sulfonamides, competitively inhibits dihydropteroate synthase, blocking bacterial folate synthesis — mechanistically analogous to sulfonamides rather than to isoniazid, despite both being used in mycobacterial disease (dapsone for M. leprae, isoniazid for M. tuberculosis). Treatment of tuberculosis and leprosy: • TB, first-line failure/drug-resistant TB: Second-line agents include fluoroquinolones (levofloxacin, moxifloxacin), injectable aminoglycosides/polypeptides (amikacin, capreomycin), and newer agents (bedaquiline — ATP synthase inhibitor; delamanid) for multidrug-resistant TB (MDR-TB, resistant to at least isoniazid and rifampicin). • Leprosy: Multidrug therapy with Dapsone + Rifampicin + Clofazimine (WHO-recommended regimen), duration and combination depending on paucibacillary vs multibacillary classification — multidrug therapy prevents the resistance that occurred historically with dapsone monotherapy.
Antibacterial Agents and Antimicrobial Resistance
Standard Answer:
(2023 Main, 2022 Main, 2021 Resit, 2017, 2016, 2013, 2012, Part II Resit, “THEORY” — recurs extensively) Classification of antimicrobials by mechanism of action: 1. Cell wall synthesis inhibitors: β-lactams (Penicillins, Cephalosporins, Carbapenems, Monobactams), Glycopeptides (Vancomycin) 2. Protein synthesis inhibitors: ◦ 30S ribosomal subunit: Aminoglycosides (gentamicin), Tetracyclines ◦ 50S ribosomal subunit: Macrolides (erythromycin), Chloramphenicol, Clindamycin, Linezolid 3. Nucleic acid synthesis inhibitors: Fluoroquinolones (DNA gyrase/topoisomerase IV inhibitors), Rifampicin (RNA polymerase inhibitor), Metronidazole (DNA damage in anaerobes) 4. Cell membrane disruptors: Polymyxins (colistin), Daptomycin 5. Antimetabolites (folate synthesis inhibitors): Sulfonamides, Trimethoprim Structure and detailed mechanism of cell wall synthesis inhibitors: Bacterial cell walls contain peptidoglycan, a mesh of alternating N-acetylglucosamine and N-acetylmuramic acid chains cross-linked by peptide bridges. β-lactam antibiotics (penicillins, cephalosporins) structurally mimic the terminal D-alanyl-D-alanine of the peptidoglycan precursor and bind covalently to penicillin-binding proteins (PBPs) — transpeptidase enzymes responsible for the final cross-linking step — irreversibly inhibiting them. This prevents proper cell wall cross-linking, weakening the wall, and (especially in actively dividing bacteria) triggers autolysin-mediated cell lysis due to unopposed osmotic pressure. Selective toxicity arises because human cells lack a cell wall/ peptidoglycan entirely. Mechanism of resistance to β-lactams and how it is overcome: • Major mechanism: production of β-lactamases (penicillinases/cephalosporinases) — bacterial enzymes that hydrolyse the β-lactam ring, inactivating the drug. • Other mechanisms: alteration of PBP target (e.g., mecA gene in MRSA producing PBP2a with low β-lactam affinity), reduced outer membrane permeability (Gram-negatives), efflux pumps. • Overcome by: combining with β-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam — themselves weak antibacterials but irreversibly inhibit β-lactamase, protecting the partner β-lactam), using β-lactamase-resistant penicillins (e.g., cloxacillin, methicillin — though MRSA resistance via PBP2a defeats these), or using structurally distinct agents (carbapenems, resistant to most common β-lactamases, though carbapenemases are an emerging problem). General mechanisms of acquired antimicrobial resistance: 1. Enzymatic inactivation of the drug (β-lactamases, aminoglycoside-modifying enzymes). 2. Target modification – altered PBPs (MRSA), altered ribosomal binding sites (macrolide resistance via ribosomal methylation), altered DNA gyrase (fluoroquinolone resistance). 3. Reduced permeability/altered porins – reduces intracellular drug accumulation (common in Gram-negatives, e.g., Pseudomonas). 4. Efflux pumps – actively pump drug out of the bacterial cell (tetracycline resistance, fluoroquinolone resistance). 5. Bypass pathways – e.g., alternative folate synthesis pathways bypassing sulfonamide/ trimethoprim blockade. ◦ Genetic basis: spontaneous chromosomal mutation, or acquisition of resistance genes via plasmids, transposons, or bacteriophage transduction (horizontal gene transfer) — allowing rapid spread of resistance between and across bacterial species. Mechanisms delaying emergence of resistance: • Combination therapy (as in TB treatment) — reduces the probability of spontaneous resistance to all agents simultaneously. • Adequate dosing and full completion of treatment course (avoiding sub-therapeutic exposure that selects for resistant subpopulations). • Antimicrobial stewardship — restricting unnecessary/inappropriate antibiotic use. • Infection control measures to prevent spread of resistant strains. Mechanism, adverse effects of Streptomycin, Tetracycline, Chloramphenicol: • Streptomycin (aminoglycoside) – binds the 30S ribosomal subunit, causing misreading of mRNA codons and inhibiting initiation of protein synthesis; requires oxygen-dependent uptake (ineffective against anaerobes); adverse effects: ototoxicity (vestibular and cochlear, often irreversible), nephrotoxicity, neuromuscular blockade (rare, at high doses). • Tetracycline – binds the 30S ribosomal subunit, blocking binding of aminoacyl-tRNA to the mRNA-ribosome complex (bacteriostatic); adverse effects: teeth discolouration and bone growth inhibition in children/fetus (chelates calcium — contraindicated in pregnancy and children under 8), photosensitivity, GI upset, hepatotoxicity (high IV doses), phototoxic, do not give with dairy/antacids (chelation reduces absorption). • Chloramphenicol – binds the 50S ribosomal subunit, inhibiting peptidyl transferase (bacteriostatic); adverse effects: aplastic anaemia (rare, idiosyncratic, non-dose-related — the most feared toxicity, limiting use to serious infections without alternatives), dose-dependent reversible bone marrow suppression, “Grey baby syndrome” in neonates (due to immature hepatic glucuronidation, leading to drug accumulation, cardiovascular collapse — reflects reduced Phase II conjugation capacity in neonates). Extended-spectrum penicillin (named example, e.g., Piperacillin): Extended-spectrum (antipseudomonal) penicillins retain the β-lactam mechanism (PBP inhibition) with an extended spectrum covering Gram-negative organisms including Pseudomonas aeruginosa; often combined with a β-lactamase inhibitor (e.g., piperacillin-tazobactam) for broader coverage including β-lactamase-producing organisms; used for serious hospital-acquired/ nosocomial infections. Requirements for successful antimicrobial therapy: 1. Accurate identification of the causative organism and its sensitivity (culture/sensitivity testing). 2. Adequate drug penetration to the site of infection (e.g., CNS infections require agents crossing the blood-brain barrier). 3. Achieving and maintaining an adequate concentration at the infection site for a sufficient duration. 4. Host factors — adequate immune function to assist in clearing the pathogen, absence of contraindications (allergy, renal/hepatic impairment). 5. Patient compliance/adherence to the full prescribed course. Sulfonamides — adverse effects and rationale for combining with trimethoprim: • Adverse effects: hypersensitivity reactions (including Stevens-Johnson syndrome), crystalluria/nephrotoxicity (mitigated by adequate hydration), haemolysis in G6PD deficiency, kernicterus risk in neonates (displaces bilirubin from albumin — contraindicated near term/in neonates). • Rationale for combining sulfamethoxazole with trimethoprim (cotrimoxazole): see sequential blockade discussion (Section 1 Q12b, Section 5 Q2) — synergistic, often bactericidal (rather than merely bacteriostatic) effect from sequential inhibition of two steps in bacterial folate synthesis, and reduces the emergence of resistance to either agent alone.
Gentamicin and Metronidazole in Combination Therapy
Standard Answer:
(2023 Main, 2021 Main) Mechanisms: • Gentamicin (aminoglycoside) – irreversibly binds the 30S ribosomal subunit, causing misreading of the genetic code and inhibition of protein synthesis; bactericidal; primarily effective against aerobic Gram-negative bacteria (uptake into bacterial cells is an oxygen-dependent active transport process, hence ineffective against anaerobes). • Metronidazole – a prodrug; within anaerobic/microaerophilic organisms, its nitro group is reduced by bacterial ferredoxin-like electron transport proteins (a reaction that does not occur efficiently in aerobic conditions/human cells), generating cytotoxic free radical/nitroso intermediates that cause DNA strand breakage, killing the organism; effective against anaerobic bacteria and certain protozoa (Trichomonas, Giardia, Entamoeba histolytica). Rationale for combination: Gentamicin covers aerobic Gram-negative organisms while metronidazole covers anaerobes — together providing broad coverage for mixed aerobic-anaerobic infections (e.g., intra-abdominal sepsis, pelvic infections, diabetic foot infections), which commonly involve both types of organisms and cannot be adequately treated by either drug alone.
Sequential Inhibition
Standard Answer:
(2023 Resit, 2022 Main, 2021 Main — recurs) See Section 1, Q12b for full detail. Sequential inhibition (sequential blockade) is a form of drug synergism where two agents inhibit consecutive steps of the same biosynthetic pathway, producing an effect greater than either alone and often converting a bacteriostatic combination into a bactericidal one. Classic example: trimethoprim-sulfamethoxazole, blocking dihydropteroate synthase (sulfamethoxazole) and dihydrofolate reductase (trimethoprim) — sequential steps in bacterial folate/nucleotide synthesis.
Anticancer (Antineoplastic) Agents
Standard Answer:
(2021 Resit, 2018 Paper II, 2017, 2016, 2013 — recurs) Classification with examples and mechanisms: 1. Alkylating agents: Cyclophosphamide, Chlorambucil (nitrogen mustards), Busulfan — form covalent cross-links between DNA strands (via alkylation of guanine N7), preventing DNA replication and transcription; cell-cycle non-specific. 2. Antimetabolites: Methotrexate (folate antagonist, inhibits dihydrofolate reductase), 5-Fluorouracil (pyrimidine analogue, inhibits thymidylate synthase), 6-Mercaptopurine (purine analogue) — interfere with nucleotide synthesis; mostly S-phase specific. 3. Antitumour antibiotics: Doxorubicin (intercalates DNA, inhibits topoisomerase II, generates free radicals — notable for dose-dependent cardiotoxicity), Bleomycin (causes DNA strand breaks via free radical generation — notable for pulmonary fibrosis), Dactinomycin. 4. Plant alkaloids/mitotic inhibitors: Vincristine/Vinblastine (bind tubulin, inhibit microtubule polymerization, arrest mitosis at metaphase), Paclitaxel (stabilizes microtubules, preventing depolymerization). 5. Topoisomerase inhibitors: Etoposide (topoisomerase II), Irinotecan/Topotecan (topoisomerase I). 6. Hormonal agents: Tamoxifen (SERM, used in ER-positive breast cancer), Aromatase inhibitors (Anastrozole), Leuprolide (GnRH agonist, used in prostate cancer via downregulation of gonadotroph receptors after initial flare). 7. Targeted/biologic agents: Trastuzumab (anti-HER2 monoclonal antibody), Imatinib (BCR-ABL tyrosine kinase inhibitor). Common adverse effects of anticancer drugs: Bone marrow suppression (leading to anaemia, neutropenia/infection risk, thrombocytopenia/bleeding), nausea/vomiting, alopecia, mucositis/GI toxicity (rapidly dividing normal tissues most affected — reflecting the lack of true selective toxicity of most cytotoxic chemotherapy, which targets rapidly dividing cells generally, both malignant and normal), infertility/gonadal toxicity, and specific organ toxicities characteristic of individual drugs (e.g., doxorubicin cardiotoxicity, bleomycin pulmonary fibrosis, cisplatin nephrotoxicity/ototoxicity, vincristine peripheral neuropathy). Pharmacodynamics/side effects of a named nitrogen mustard (Cyclophosphamide): Prodrug activated by hepatic CYP450 to phosphoramide mustard (the active alkylating metabolite) and acrolein (a toxic byproduct responsible for haemorrhagic cystitis — mitigated by co-administration of mesna, which binds/neutralizes acrolein in the urine, and adequate hydration). Used in lymphomas, leukaemias, solid tumours, and (at lower doses) as an immunosuppressant in autoimmune disease. Adverse effects: myelosuppression, haemorrhagic cystitis, alopecia, gonadal toxicity, secondary malignancy risk (long-term). Mechanisms of resistance to alkylating agents: increased DNA repair capacity (enhanced nucleotide excision repair removing alkylated bases), increased intracellular glutathione/ glutathione-S-transferase (conjugates and inactivates the alkylating agent), decreased drug uptake or increased efflux (P-glycoprotein-mediated), and reduced apoptotic response to DNA damage (e.g., p53 pathway mutations). Role of hormonal therapy in breast cancer: In hormone-receptor (ER/PR)-positive breast cancer, tumour growth is driven by estrogen signalling; Tamoxifen (a SERM) competitively blocks estrogen receptors in breast tissue (acting as an antagonist there, while paradoxically acting as a partial agonist in endometrium and bone — accounting for its endometrial cancer risk and bone-protective effect); Aromatase inhibitors (anastrozole, letrozole) block peripheral conversion of androgens to estrogens (the main estrogen source in postmenopausal women), used specifically in postmenopausal patients. Hormonal therapy provides effective, relatively well-tolerated long-term adjuvant treatment/ prevention of recurrence in hormone-sensitive disease. Pharmacology of 5-Fluorouracil: A pyrimidine analogue; converted intracellularly to FdUMP, which forms a stable ternary complex with thymidylate synthase and the folate cofactor, irreversibly inhibiting the enzyme and blocking synthesis of thymidine nucleotides required for DNA synthesis (also incorporated into RNA, disrupting its processing/function). Used in colorectal, breast, and other solid tumours, and (topically) in skin cancers/actinic keratosis. Adverse effects: myelosuppression, mucositis, diarrhoea, hand-foot syndrome, cardiotoxicity (rare), neurotoxicity (with capecitabine, an oral prodrug).
Antiviral and HIV/AIDS Chemotherapy
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(2017, 2012, 2010 Paper II) Therapeutic options for treatment failure with HAART: 1. Genotypic/phenotypic resistance testing to guide selection of an active regimen. 2. Switching to a new combination regimen using drugs from classes not previously used or to which resistance has not developed (e.g., switching from an NNRTI-based to a protease inhibitor- or integrase inhibitor-based regimen). 3. Use of newer-class agents – integrase strand transfer inhibitors (Dolutegravir, Raltegravir), CCR5 antagonists (Maraviroc, requiring tropism testing), fusion inhibitors (Enfuvirtide), or newer-generation agents with activity against resistant strains (e.g., Darunavir, Etravirine). 4. Optimizing adherence support, since resistance often arises from suboptimal adherence allowing viral replication in the presence of sub-therapeutic drug levels. Discussion of any two options: • Resistance testing–guided regimen change: genotypic testing detects specific resistance mutations, allowing rational selection of a new combination predicted to remain active, rather than empirical switching. • Integrase inhibitors (e.g., Dolutegravir): block HIV integrase, the enzyme responsible for inserting viral DNA into the host genome — a mechanism distinct from reverse transcriptase or protease inhibitors, hence generally retaining activity in patients who have failed regimens based on the older drug classes; also has a high barrier to resistance and good tolerability, making it now a preferred first-line and salvage option. Antiviral targeting in rational drug design: Modern antiviral drug design targets virus-specific enzymes/processes absent in human cells to achieve selective toxicity — e.g., HIV reverse transcriptase (absent in human cells, which use DNA-dependent DNA/RNA polymerases, not RNA-dependent DNA polymerase), HIV protease (cleaves viral polyproteins, a step essential for producing mature infectious virions), HIV integrase, and viral entry/fusion proteins (gp41, CCR5 co-receptor). This target-based approach (rather than earlier broad nucleoside-analogue approaches alone) underlies the development of protease inhibitors, integrase inhibitors, and entry inhibitors, forming the basis of modern combination antiretroviral therapy (HAART), which combines agents from different classes to achieve durable viral suppression and minimize resistance emergence.
Immunosuppressive Agents
Standard Answer:
(25th February question set) • Cyclosporine: Binds cyclophilin (an intracellular immunophilin); the complex inhibits calcineurin, a phosphatase required to dephosphorylate and activate the transcription factor NFAT, which normally translocates to the nucleus to induce IL-2 gene transcription. By blocking IL-2 production, cyclosporine selectively suppresses T-lymphocyte activation and proliferation. Used in organ transplantation (prevention of rejection) and some autoimmune diseases. Adverse effects: nephrotoxicity (dose-limiting), hypertension, hirsutism, gingival hyperplasia, tremor, increased risk of infection and malignancy (particularly lymphoma/skin cancers) due to immunosuppression. • Azathioprine: A prodrug converted to 6-mercaptopurine, then to thioinosine monophosphate, which inhibits de novo purine synthesis, impairing DNA/RNA synthesis in rapidly proliferating lymphocytes. Metabolized partly by thiopurine methyltransferase (TPMT) — patients with low TPMT activity (genetic polymorphism) are at risk of severe myelosuppression at standard doses. Used in transplantation and autoimmune disease (e.g., inflammatory bowel disease, rheumatoid arthritis). Adverse effects: myelosuppression, hepatotoxicity, increased infection/malignancy risk, GI upset. • Dexamethasone (as immunosuppressive agent): A potent synthetic glucocorticoid; suppresses immune function through multiple genomic mechanisms — inhibition of NF-κB and AP-1 mediated transcription of pro-inflammatory cytokines (IL-1, IL-2, IL-6, TNF-α), induction of lipocortin-1 (inhibiting phospholipase A2 and thus prostaglandin/ leukotriene synthesis), reduced lymphocyte proliferation and induction of lymphocyte apoptosis, and redistribution of circulating lymphocytes away from the bloodstream. Used in transplant rejection prophylaxis/treatment, autoimmune diseases, and as an anti-inflammatory/antiemetic in oncology settings. Adverse effects (with chronic use): Cushingoid features, hyperglycemia, osteoporosis, adrenal suppression (requiring tapering rather than abrupt withdrawal), increased infection risk, peptic ulceration, mood disturbance.
Miscellaneous — Alkylating Agent Subclasses
Standard Answer:
(Part II Resit Paper II) Subclasses of alkylating agents with examples: 1. Nitrogen mustards: Cyclophosphamide, Chlorambucil, Melphalan 2. Nitrosoureas: Carmustine, Lomustine (notably lipid-soluble, cross blood-brain barrier — used in CNS tumours) 3. Alkyl sulfonates: Busulfan (used in chronic myeloid leukaemia, conditioning regimens pre-bone marrow transplant) 4. Platinum compounds (mechanistically similar, cross-link DNA though not classical “alkylating” agents in strict chemical terms): Cisplatin, Carboplatin, Oxaliplatin 5. Triazenes: Dacarbazine, Temozolomide Mechanism of action of alkylating agents: Transfer alkyl groups to nucleophilic sites on DNA (commonly the N7 position of guanine), forming DNA cross-links (intrastrand or interstrand) that prevent DNA strand separation during replication/transcription, and cause mispairing/strand breaks; effect is largely cell-cycle non-specific, though most damaging to rapidly dividing cells. Five major side effects: Bone marrow suppression, nausea/vomiting, alopecia, gonadal toxicity/infertility, secondary malignancy (particularly leukaemia, with long-term use), and (specific to cyclophosphamide) haemorrhagic cystitis.