UTI/STDs, Chemotherapy of Malignancy & Immunopharmacology
This unit covers three distinct but important areas: (1) Chemotherapy of urinary tract infections and sexually transmitted diseases — specific drug regimens for common UTI pathogens and STDs. (2) Chemotherapy of malignancy — the pharmacology of anticancer drugs including alkylating agents, antimetabolites, anticancer antibiotics, plant alkaloids, and hormonal therapy. (3) Immunopharmacology — the pharmacology of agents that modulate the immune system (immunostimulants, immunosuppressants), monoclonal antibodies, and the emerging field of biosimilars.
Syllabus & Topics
- 1UTI Chemotherapy: Most common pathogen: E. coli (~80%). Uncomplicated UTI (cystitis): Nitrofurantoin (first-line, concentrated in urine, minimal systemic levels), Cotrimoxazole (TMP-SMX), Fosfomycin (single-dose). Complicated UTI/Pyelonephritis: Fluoroquinolones (Ciprofloxacin, Levofloxacin), Cephalosporins (Ceftriaxone), Aminoglycosides (hospitalized patients). Methenamine: urinary antiseptic for prophylaxis (releases formaldehyde in acidic urine). Phenazopyridine: urinary analgesic (not antimicrobial — orange-red discoloration of urine).
- 2STD Chemotherapy: Gonorrhea (Neisseria gonorrhoeae): Ceftriaxone (single IM dose) + Azithromycin (single oral dose). Syphilis (Treponema pallidum): Benzathine Penicillin G (single IM dose for primary/secondary; extended for tertiary). Chlamydia: Azithromycin (single dose) or Doxycycline (7 days). Trichomoniasis: Metronidazole or Tinidazole (single dose). Genital Herpes: Acyclovir/Valacyclovir (episodic or suppressive therapy). HIV: ART (lifelong). HPV: Vaccination (Gardasil 9) — prevention.
- 3Chemotherapy of Malignancy – Principles: Cancer cells: uncontrolled proliferation, loss of differentiation, invasion, metastasis. Cell cycle: G₁ → S (DNA synthesis) → G₂ → M (mitosis) → G₀ (resting). Cell cycle-specific drugs: effective against actively dividing cells (antimetabolites → S phase, vinca alkaloids → M phase). Cell cycle-nonspecific: kill cells regardless of phase (alkylating agents, antibiotics). Combination chemotherapy: ↑efficacy, ↓resistance, ↓toxicity (different MOA, non-overlapping toxicities). Dose-limiting toxicity: bone marrow suppression for most agents.
- 4Alkylating Agents: Form covalent bonds (alkyl groups) with DNA bases → cross-linking of DNA strands → prevents replication/transcription → cell death. Cell cycle-nonspecific. Nitrogen mustards: Cyclophosphamide (most widely used alkylating agent; prodrug activated by hepatic CYP450 → phosphoramide mustard + acrolein; ADR: hemorrhagic cystitis from acrolein → prevented by Mesna), Mechlorethamine (first alkylating agent used clinically), Chlorambucil (CLL), Melphalan (multiple myeloma). Others: Busulfan (CML), Nitrosoureas (Carmustine — crosses BBB → brain tumors), Platinum compounds: Cisplatin (testicular cancer, ovarian — ADR: severe nephrotoxicity, metoclopramide), Carboplatin (less nephrotoxic).
- 5Antimetabolites: Structural analogs of normal metabolites → incorporated into biosynthetic pathways → block DNA/RNA synthesis. Cell cycle-specific (S phase). Folate antagonist: Methotrexate (inhibits DHFR → ↓THF → ↓purine/pyrimidine synthesis; used in ALL, choriocarcinoma, RA, psoriasis; ADR: mucositis, pancytopenia — rescued by Leucovorin/folinic acid). Pyrimidine analogs: 5-Fluorouracil (5-FU, inhibits thymidylate synthase → ↓dTMP), Cytarabine (Ara-C, incorporated into DNA → chain termination — AML). Purine analogs: 6-Mercaptopurine (6-MP, inhibits purine synthesis — ALL maintenance), Azathioprine (prodrug of 6-MP — immunosuppressant).
- 6Anticancer Antibiotics: Doxorubicin (Adriamycin): intercalates DNA + inhibits topoisomerase II + generates free radicals → DNA damage. Most widely used anticancer antibiotic. ADR: cardiotoxicity (dose-dependent, cumulative — irreversible cardiomyopathy; limit lifetime dose; Dexrazoxane is cardioprotective). Red discoloration of urine. Bleomycin: causes DNA strand breaks via free radical generation. ADR: pulmonary fibrosis (dose-limiting — monitor pulmonary function). Dactinomycin (Actinomycin D): intercalates DNA → blocks RNA polymerase. Wilms’ tumor in children.
- 7Plant Alkaloids & Hormonal Agents: Vinca alkaloids: Vincristine, Vinblastine — bind tubulin → inhibit microtubule assembly → mitotic arrest (M phase). Vincristine ADR: neurotoxicity (peripheral neuropathy). Taxanes: Paclitaxel, Docetaxel — stabilize microtubules (opposite of vincas) → prevent disassembly → mitotic arrest. Paclitaxel ADR: hypersensitivity, peripheral neuropathy. Topoisomerase inhibitors: Etoposide (topo II), Irinotecan/Topotecan (topo I). Hormonal: Tamoxifen (ER antagonist — breast cancer), Flutamide (androgen receptor antagonist — prostate cancer). Targeted therapy: Imatinib (BCR-ABL tyrosine kinase inhibitor — CML, revolutionized treatment).
- 8Immunostimulants: Agents that enhance immune response. Specific: Vaccines (active immunization — stimulate specific antibody/T-cell response), Immunoglobulins (passive immunization). Non-specific: Interferons (IFN-α: HBV, HCV, hairy cell leukemia; IFN-β: multiple sclerosis; IFN-γ: chronic granulomatous disease). BCG vaccine: non-specific immunostimulant for bladder cancer (intravesical). Levamisole: immunomodulator, used as adjunct in colon cancer. Colony-Stimulating Factors: G-CSF (Filgrastim — ↑neutrophils after chemotherapy), Erythropoietin (EPO — anemia of chronic kidney disease).
- 9Immunosuppressants: Suppress immune response — used in organ transplantation (prevent rejection), autoimmune diseases (RA, SLE, IBD). Calcineurin inhibitors: Cyclosporine (binds cyclophilin → inhibits calcineurin → ↓IL-2 → ↓T-cell activation; cornerstone of transplant immunosuppression; ADR: nephrotoxicity, hypertension, gingival hyperplasia, hirsutism), Tacrolimus (FK506, binds FKBP-12 → same calcineurin inhibition, 100x more potent than cyclosporine). mTOR inhibitors: Sirolimus (Rapamycin) — inhibits T-cell proliferation. Antimetabolites: Azathioprine (prodrug → 6-MP → inhibits purine synthesis), Mycophenolate mofetil (inhibits IMPDH → selective T/B cell suppression). Corticosteroids: Prednisolone — broad anti-inflammatory and immunosuppressive.
- 10Monoclonal Antibodies (mAbs): Engineered antibodies that target specific antigens. Naming: -ximab (chimeric), -zumab (humanized), -umab (fully human). Examples: Rituximab (anti-CD20, B-cell lymphoma), Trastuzumab (anti-HER2, breast cancer), Infliximab (anti-TNFα, RA/IBD), Bevacizumab (anti-VEGF, colorectal cancer — inhibits angiogenesis), Nivolumab/Pembrolizumab (anti-PD-1, checkpoint inhibitors — various cancers). ADR: infusion reactions, infections (immunosuppression), autoimmune-like reactions.
- 11Biosimilars & Targeted Therapy: Biosimilars: biological products that are HIGHLY SIMILAR (not identical — unlike chemical generics) to an approved reference biologic. Must demonstrate: (1) similar quality, (2) similar safety, (3) similar efficacy in clinical trials (totality of evidence). Examples: biosimilar Trastuzumab, biosimilar Rituximab. Cost 20-30% less than reference biologics → improved access. NOT called ‘generic biologics’ — biological manufacturing is complex (living cell systems). Targeted therapy: drugs designed to inhibit specific molecular targets in cancer cells (e.g., Imatinib targets BCR-ABL kinase in CML).
Learning Objectives
Exam Prep Questions
Q1. Why Is Combination Chemotherapy Used in Cancer?
Cancer cells can rapidly develop resistance to single anticancer drugs. Therefore, Combination chemotherapy is used to improve treatment effectiveness. This strategy combines drugs that act through different mechanisms so cancer cells are attacked through multiple biological pathways. It also allows the use of drugs with non-overlapping toxicities so each can be given at effective doses without excessive side effects. In addition, drugs may target different phases of the cell cycle and often produce synergistic effects.
A classic example is the MOPP regimen used in Hodgkin lymphoma, which includes Mechlorethamine, Vincristine, Procarbazine, and Prednisolone.
Q2. What Is the Difference Between Cyclosporine and Tacrolimus?
Cyclosporine and Tacrolimus are widely used to prevent organ transplant rejection. Both drugs inhibit the enzyme Calcineurin, which reduces the production of the cytokine Interleukin 2 and prevents activation of T lymphocytes.
Cyclosporine works by binding to the intracellular protein Cyclophilin, whereas tacrolimus binds to FKBP12. The resulting complexes inhibit calcineurin and suppress T-cell activation. Tacrolimus is about 100 times more potent than cyclosporine.
Cyclosporine commonly causes adverse effects such as nephrotoxicity, hypertension, gingival hyperplasia, and hirsutism. Tacrolimus also causes nephrotoxicity but is more associated with neurotoxicity and new-onset diabetes mellitus, while gingival hyperplasia and hirsutism are uncommon. Because of its greater potency and improved outcomes, tacrolimus is now commonly preferred in many transplant protocols.
Q3. What Is a Biosimilar and How Is It Different From a Generic Drug?
A Generic drug is a medicine that is chemically identical to a reference small-molecule drug in terms of active ingredient, strength, purity, and dosage form. Demonstrating bioequivalence is usually sufficient to prove therapeutic equivalence.
A Biosimilar, however, is a biological product that is highly similar but not completely identical to the original biologic drug. Biologic medicines are produced using living cells, so small structural variations are unavoidable. Therefore, biosimilars require extensive comparative studies—including analytical characterization, functional assays, animal studies, and clinical trials—to demonstrate similarity in safety, efficacy, and immunogenicity. Biosimilars follow an abbreviated regulatory pathway but still require more evidence than generic small-molecule drugs.
Q4. What Are Checkpoint Inhibitors?
Immune checkpoint inhibitors are monoclonal antibodies that enhance the immune system’s ability to recognize and destroy cancer cells. Cancer cells often evade immune attack by activating immune checkpoint proteins such as Programmed cell death protein 1, Programmed death ligand 1, and CTLA 4. These proteins normally suppress immune responses and prevent excessive immune activation.
Checkpoint inhibitors block these proteins, reactivating T cells so they can identify and destroy cancer cells. Examples include Nivolumab, Pembrolizumab, Atezolizumab, and Ipilimumab. These therapies have revolutionized the treatment of cancers such as melanoma, lung cancer, and renal cell carcinoma, although they may cause immune-related adverse reactions such as colitis, hepatitis, and thyroiditis.