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🧬 Comprehensive Pharmacology Study Notes

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1. ANTIPROTOZOAL DRUGS

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1.1 Metronidazole & Tinidazole (Nitroimidazoles)

• Prodrugs activated by pyruvate:ferredoxin oxidoreductase (PFOR) in anaerobic/microaerophilic organisms
• Reduced intermediate forms DNA strand breaks → cell death
• Selective toxicity because mammalian cells lack PFOR

• Excellent oral bioavailability; widely distributed (crosses blood-brain barrier)
• Hepatic metabolism; renally excreted
• Tinidazole: longer half-life, single-dose regimens effective

• GI: nausea, metallic taste, anorexia
• Disulfiram-like reaction with alcohol (must avoid alcohol)
• Neurotoxicity (peripheral neuropathy, seizures) with prolonged use
• Potential mutagenicity (avoid in 1st trimester; use paromomycin in pregnancy)

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1.2 Chloroquine (Antimalarial – 4-Aminoquinoline)

• Concentrates in parasite food vacuole
• Inhibits heme polymerization → toxic free heme accumulates → kills parasite
• Also has anti-inflammatory properties

• Plasmodium vivax, P. ovale, P. malariae, chloroquine-sensitive P. falciparum
• Prophylaxis in chloroquine-sensitive areas
• Amoebic liver abscess (second line)

• Well absorbed orally; large volume of distribution; very long half-life (1–2 months)
• Hepatic metabolism

• GI distress, headache, dizziness
• Pruritus (especially in Africans)
• Retinopathy (dose-related, cumulative) — monitor eyes with long-term use
• Cardiomyopathy/QT prolongation at high doses

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1.3 Artemisinin & Derivatives (Artesunate, Artemether, Dihydroartemisinin)

• Endoperoxide bridge cleaved by heme iron → free radicals → alkylation of parasite proteins
• Rapid action; active against all asexual stages including ring forms

• First-line for severe / uncomplicated P. falciparum malaria (in combination as ACT — Artemisinin-based Combination Therapy)
• Artesunate IV: treatment of choice for severe/cerebral malaria
• ACT combinations: artemether–lumefantrine; artesunate–amodiaquine; artesunate–mefloquine

• Nausea, vomiting, dizziness
• Transient neutropenia
• Neurotoxicity at very high experimental doses (not seen clinically at standard doses)
• Embryotoxic in animal models — avoid in 1st trimester

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1.4 Primaquine (8-Aminoquinoline)

• Active against hepatic hypnozoites and gametocytes
• Generates reactive oxygen species via oxidative metabolites

• Radical cure of P. vivax and P. ovale (eliminates dormant liver forms/hypnozoites)
• Gametocidal for P. falciparum (reduces transmission)
• Prophylaxis in causal setting

• Hemolytic anemia in G6PD-deficient patients ← CRITICAL; screen before use
• Methemoglobinemia
• GI distress

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1.5 Quinine & Quinidine

• P. falciparum malaria (esp. chloroquine-resistant); IV quinidine for severe malaria (when artesunate unavailable)
• With doxycycline or clindamycin for combination therapy

• Tinnitus, headache, nausea, visual disturbances
• QT prolongation (cardiac arrhythmias)
• Hypoglycemia (stimulates insulin secretion)
• Hemolytic anemia

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1.6 Drugs for Leishmaniasis

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1.7 Drugs for African Trypanosomiasis (Sleeping Sickness)

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1.8 Drugs for Chagas Disease (T. cruzi)

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1.9 Nitazoxanide

• Broad-spectrum antiprotozoal/antiparasitic
• Inhibits PFOR enzyme activity
• Uses: Cryptosporidium parvum, Giardia, E. histolytica
• Approved for giardiasis and cryptosporidiosis in immunocompetent children

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1.10 Paromomycin (Aminoglycoside)

• Active luminal amebicide; also active against Giardia, Cryptosporidium
• Safe in pregnancy (not absorbed systemically)
• Also used topically for cutaneous leishmaniasis

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2. ANTI-TUBERCULAR DRUGS

• Intensive phase (2 months): 4-drug regimen kills actively dividing bacilli
• Continuation phase (4 months): eliminates persisting organisms

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2.1 Isoniazid (INH)

• Prodrug activated by Mycobacterium catalase-peroxidase (KatG)
• Active form inhibits InhA (enoyl-ACP reductase) → blocks mycolic acid synthesis → disrupts cell wall
• Bactericidal for actively dividing bacilli; bacteriostatic for resting

• Excellent oral absorption; crosses BBB (useful in TB meningitis)
• Acetylated by NAT2 (N-acetyltransferase 2):
  • Fast acetylators → lower drug levels (more common in Asian populations)
  • Slow acetylators → higher drug levels, more prone to toxicity

• Hepatotoxicity — most serious; risk increases with age, alcohol
• Peripheral neuropathy — due to pyridoxine (B₆) deficiency; prevent with B₆ supplementation (routine in malnourished patients)
• Drug-induced lupus (anti-histone antibodies)
• CNS effects (seizures, psychosis — rare)

• KatG mutations → cannot activate INH (most common)
• InhA promoter mutations → overexpression of target
• ahpC mutations (compensatory)

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2.2 Rifampin (Rifampicin)

• Inhibits DNA-dependent RNA polymerase (β-subunit, rpoB gene) → blocks mRNA synthesis
• Bactericidal; sterilizing activity — kills semi-dormant bacilli in macrophages

• Oral; hepatic metabolism; biliary excretion; powerful CYP450 inducer (CYP3A4, 2C9)
• Turns body fluids orange-red (urine, tears, sweat) — warn patients; can stain contact lenses

• Hepatotoxicity (especially with INH)
• GI disturbance
• Drug interactions (major): reduces efficacy of oral contraceptives, antiretrovirals (protease inhibitors), warfarin, azoles, etc. due to CYP induction
• Flu-like syndrome (with intermittent dosing)
• Thrombocytopenia

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2.3 Pyrazinamide (PZA)

• Prodrug converted to pyrazinoic acid by pyrazinamidase (pncA gene product)
• Active at acidic pH (inside macrophage lysosomes) → kills intracellular semi-dormant bacilli
• Mechanism not fully known; disrupts membrane potential and transport

• Hepatotoxicity (most serious)
• Hyperuricemia → gout (inhibits renal urate secretion)
• Arthralgia
• GI disturbance

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2.4 Ethambutol (EMB)

• Inhibits arabinosyl transferase (embB gene) → blocks arabinogalactan synthesis → disrupts cell wall
• Bacteriostatic

• Optic neuritis → retrobulbar neuritis → loss of visual acuity / red-green color blindness — dose-related, usually reversible if caught early
• Baseline and monthly visual acuity testing required
• Hyperuricemia (mild)

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2.5 Rifapentine

• Long-acting rifamycin; once-weekly or once-daily dosing
• Used in new 4-month TB regimen: Rifapentine + Moxifloxacin + INH + PZA
• 1200 mg/day
• Similar mechanism and resistance profile to rifampin; same CYP induction

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2.6 Second-Line TB Drugs

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2.7 Drug Resistance Definitions

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3. ANTHELMINTIC DRUGS

• Nematodes (roundworms): Ascaris, Trichuris, Ancylostoma, Necator, Strongyloides, filarial worms
• Trematodes (flukes): Schistosoma, Fasciola, Clonorchis, Paragonimus
• Cestodes (tapeworms): Taenia solium, T. saginata, Diphyllobothrium, Echinococcus

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3.1 Benzimidazoles: Albendazole & Mebendazole

• Bind selectively to parasite β-tubulin → inhibit microtubule polymerization
• Secondary effects: inhibition of mitochondrial fumarate reductase, reduced glucose uptake, uncoupling of oxidative phosphorylation
• Selective toxicity: higher affinity for parasite β-tubulin vs. mammalian β-tubulin

• Soil-transmitted helminths: Ascariasis, trichuriasis, hookworm
• Neurocysticercosis (Taenia solium in CNS) — combine with dexamethasone + anticonvulsants
• Hydatid disease (Echinococcus) — adjunct to surgery
• Strongyloidiasis, giardiasis (less effective), cutaneous larva migrans

• Ascariasis, trichuriasis, hookworm, pinworm (Enterobius)
• Relatively ineffective for strongyloidiasis

• Reserved for Fasciola hepatica (liver fluke) — drug of choice

• GI: nausea, abdominal pain, diarrhea (especially high-dose albendazole)
• Elevated liver enzymes (with systemic albendazole use)
• Teratogenic in animals — avoid in pregnancy (especially 1st trimester)
• Neutropenia with prolonged high-dose treatment

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3.2 Ivermectin (Macrocyclic Lactone)

• Potentiates glutamate-gated chloride (GluCl) channels → hyperpolarization of nerve/muscle cells → paralysis and death of parasite
• Also potentiates GABA-gated chloride channels
• Selective toxicity: mammalian CNS lacks GluCl channels; blood-brain barrier prevents entry of ivermectin in mammals (except in MDR1/ABCB1 gene mutation → toxicity in Collies)

• Onchocerciasis (river blindness — Onchocerca volvulus) — first choice; kills microfilariae; mass drug administration programs
• Lymphatic filariasis (W. bancrofti) — in combination with albendazole ± diethylcarbamazine
• Strongyloidiasis — drug of choice (more effective and better tolerated than thiabendazole)
• Scabies — oral (for crusted/Norwegian scabies or treatment failures)
• Lice (pediculosis capitis) — topical formulation
• Cutaneous larva migrans

• Generally well tolerated
• Mazzotti reaction / Jarisch-Herxheimer-like reaction — fever, rash, hypotension from dying microfilariae (esp. in onchocerciasis); give preemptive antihistamines/steroids
• Avoid in Loa loa high microfilaremia (>30,000/mL) — encephalopathy risk
• CNS toxicity in patients with impaired blood-brain barrier

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3.3 Praziquantel

• Increases membrane permeability to Ca²⁺ → muscle spasm (contraction), vacuolization and tegument disruption → immune recognition and killing
• Also interferes with glucose uptake

• Schistosomiasis — drug of choice for all species (S. mansoni, S. haematobium, S. japonicum)
• Cysticercosis (Taenia solium) — combined with albendazole for neurocysticercosis
• Liver flukes: Clonorchis sinensis, Opisthorchis spp.
• Intestinal flukes; adult Taenia infections

• GI: nausea, abdominal pain, diarrhea
• CNS: headache, dizziness
• Allergic reactions from dying worms
• NOT effective against Fasciola hepatica (use triclabendazole)
• Coadministration with rifampin decreases praziquantel levels (CYP induction)

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3.4 Diethylcarbamazine (DEC)

• Not fully understood
• Alters parasite surface structure → immune-mediated killing of microfilariae
• Potentiates arachidonic acid cascade → toxic to microfilariae

• Lymphatic filariasis (W. bancrofti, Brugia spp.) — drug of choice; kills microfilariae + some macrofilariae
• Loiasis (Loa loa) — drug of choice (avoid in high microfilaremia)
• Tropical pulmonary eosinophilia
• Used in triple-drug MDA (DEC + albendazole + ivermectin) for lymphatic filariasis elimination

• Direct drug effects: mild GI, headache
• Mazzotti-like reactions from parasite death: fever, urticaria, eosinophilia
• Encephalopathy in Loa loa patients with high microfilaremia (contraindicated if >8,000 mf/mL)
• Do NOT use in onchocerciasis (severe Mazzotti reaction)

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3.5 Niclosamide

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3.6 Pyrantel Pamoate

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Summary Table — Key Anthelmintics

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4. ANTIFUNGAL DRUGS

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4.1 Amphotericin B (Polyene)

• Binds ergosterol in fungal cell membrane → forms pores → leakage of K⁺, Na⁺, H⁺, Mg²⁺ → cell death
• Some toxicity from binding to mammalian membrane cholesterol (less affinity)
• Also has immunostimulatory effects (activates macrophages)

• Nephrotoxicity (most important) — dose-limiting; saline prehydration minimizes this; monitor creatinine, electrolytes
• Infusion-related reactions: fever, chills, rigors, headache, hypotension (30–60 min after infusion)
  • Premedicate with acetaminophen, diphenhydramine, ± meperidine for rigors
• Hypokalemia, hypomagnesemia (from renal tubular damage)
• Anemia (normochromic, normocytic — from reduced erythropoietin)
• Thrombophlebitis (with IV)

• Severe systemic fungal infections: cryptococcal meningitis, invasive aspergillosis, mucormycosis
• Visceral leishmaniasis (liposomal form)
• Often used when azoles fail or in immunocompromised patients

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4.2 Azoles (Imidazoles & Triazoles)

• Inhibit fungal cytochrome P450 enzyme lanosterol 14α-demethylase (CYP51) → blocks conversion of lanosterol → ergosterol
• Ergosterol depletion → abnormal membrane permeability and function
• Triazoles (itraconazole, fluconazole, voriconazole, posaconazole, isavuconazole) have greater selectivity for fungal CYP than mammalian → fewer side effects than imidazoles (ketoconazole)

• Hepatotoxicity (all azoles; most significant with ketoconazole)
• Drug interactions — azoles are CYP inhibitors (especially fluconazole, voriconazole) → increase levels of many drugs
• Voriconazole: visual disturbances (transient, common), photosensitivity, peripheral neuropathy, hallucinations
• Ketoconazole: adrenal suppression (inhibits cortisol synthesis), gynecomastia, impotence (inhibits testosterone synthesis)
• QT prolongation (especially with posaconazole, voriconazole)
• Teratogenic — avoid in pregnancy

• ERG11 mutations → altered CYP51 target → reduced drug binding
• Overexpression of efflux pumps (CDR1, MDR1)
• Upregulation of ergosterol biosynthesis
• Increasing resistance reported, especially Aspergillus fumigatus (azole-resistant)

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4.3 Echinocandins (Caspofungin, Micafungin, Anidulafungin)

• Inhibit β-(1,3)-D-glucan synthase (Fks1/Fks2 genes) → block cell wall synthesis → osmotic instability → fungal cell death
• Highly selective — mammalian cells have no β-glucan

• Invasive candidiasis (first-line, especially ICU/neutropenic patients)
• Candidemia, esophageal candidiasis
• Salvage therapy for invasive aspergillosis
• Empirical antifungal in febrile neutropenia

• IV only (poor oral bioavailability)
• Hepatic metabolism; large molecular weight — poor CNS penetration
• Long half-lives allowing once-daily dosing

• GI (nausea)
• Elevated liver enzymes (mild)
• Caspofungin: histamine-like infusion reactions (flushing, rash)
• Fewer drug interactions than azoles

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4.4 Flucytosine (5-FC)

• Converted by fungal cytosine deaminase to 5-fluorouracil (5-FU) → inhibits thymidylate synthase → blocks DNA synthesis
• Mammalian cells lack cytosine deaminase → selective toxicity

• NEVER used alone — rapid resistance emerges
• Combined with amphotericin B for cryptococcal meningitis (synergistic) — standard induction therapy
• Combined with fluconazole for severe candidiasis

• Bone marrow suppression (neutropenia, thrombocytopenia)
• Hepatotoxicity
• GI (nausea, diarrhea)
• Renally eliminated — dose adjust in renal failure (amphotericin B co-use worsens this)

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4.5 Allylamines & Other Topical Agents

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4.6 Summary: Antifungal Drug Classes

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Quick Reference: Mechanism Targets

Ergosterol SYNTHESIS    → Azoles (CYP51 inhibition), Allylamines (squalene epoxidase)
Ergosterol BINDING      → Polyenes (amphotericin B, nystatin) → pore formation
Cell WALL synthesis     → Echinocandins (β-1,3-glucan synthase)
DNA/RNA synthesis       → Flucytosine (→5-FU)
Microtubules / Mitosis  → Griseofulvin

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High-Yield Toxicity Summary

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