Pathology 23

• The course covers two components: Antifungal agents and Antiparasitic agents.
• The course also includes the classification of agents based on their mechanisms of action, rationale use, and potential adverse or side effects.
• Fungi classifications are also a part of the course.
• The course includes the mechanisms of action of antimicrobial agents, which can be cell wall synthesis inhibition (Echinocandins), inhibition of cell membrane (Polyene), disruption of cell membrane ergosterol synthesis (Azoles), inhibition of nucleic acid synthesis/antimetabolite (Flucytosine), or inhibition of mitosis (Griseofulvin).
• Echinocandins inhibit the enzyme (1,3) - beta - D - glucan synthase, leading to the cessation of fungal cell wall synthesis and cell damage.
• Examples of Echinocandins include Caspofungin, Anidulafungin, and Micafungin.
• Terbinafine weakens the cell membrane by acting on ergosterol synthesis.
• Terbinafine, also known as Lamisil, is highly lipophilic and keratophilic, highly concentrated in skin, nails and fatty tissues.
• Adverse effects of Terbinafine are mild and transient, including GIT upset and skin irritation.
• Flucytosine, also known as 5-fluorocytosine, is converted to 5-fluorouracil (5-FU, the active form) by the enzyme cytosine deaminase.
• Terbinafine is well absorbed orally, with poor CNS penetration.
• The mechanism of action of Flucytosine is to inhibit protein synthesis by replacing uracil with 5-FU in fungal RNA, and to inhibit DNA synthesis by inhibiting thymidylate synthase, resulting in no thymidine production.
• Terbinafine is indicated for dermatophytosis (fungicidal), onychomycosis, Malazsezia furfur infection, and mucocutaneous candidiasis (fungistatic).
• The spectrum of action of Flucytosine is narrow, including Candida, Cryptococcus neoformans, and agents of chromoblastomycosis.
• Terbinafine is available in oral (tablet) and topical formulations.
• Terbinafine inhibits ergosterol synthesis at a higher level, acting by interfering with the ability of fungi to make ergosterol.
• Flucytosine is usually combined with amphotericin B or azole group (fluconazole, itraconazole).
• Mannoproteins are β(1,6) - glucan β(1,3) - glucan Chitin Phospholipid bilayer of cell membrane β(1,3) glucan synthase Echinocandins Inhibition of β(1,3) glucan synthase Depletion of β(1,3) glucans in cell wall EchinocandinCaspofungin is active against Candida species and Aspergillus species and is effective in vitro against azole-resistant candida strains.
• Caspofungin is also effective against Histoplasma and Pneumocystis in mice and not effective against Cryptococcus neoformans, Fusarium, Rhizopus, or Paecilomyces.
• Atovaquone - proguanil (Malarone) is contraindicated in pregnant ladies in the first trimester.
• Quinine and Quinidine are derived from the chinchona tree.
• Pyrimethamine - sulfadiazine is also indicated for chloroquine-resistant uncomplicated P falciparum malaria.
• Artemether - lumefantrine is a combination of Artemether, a semisynthetic derivative of artemisinin, a sesquiterpene lactone, and Lumefantrine, a fluorene derivative, both of which are rapidly effective against all erythrocytic stages of malaria.
• Artemether - lumefantrine is indicated for first line therapy for uncomplicated malaria due to chloroquine-resistant P falciparum, P vivax and P ovale.
• Atovaquone - proguanil (Malarone) is a well-tolerated, oral fixed dose combination, with Atovaquone inhibiting parasite mitochondrial electron transport and Proguanil inhibiting the dihydrofolate reductase step in purine synthesis.
• Pyrimethamine - sulfadiazine is indicated for toxoplasmosis, not in pregnancy, and clindamycin for AIDS patients (intolerant to sulfadiazine).
• Artemether - lumefantrine is contraindicated in pregnant ladies in the first trimester.
• Pyrimethamine - sulfadiazine is contraindicated in pregnant ladies in the first trimester.
• Atovaquone - proguanil (Malarone) is indicated for chemoprophylaxis and first line therapy for uncomplicated malaria due to chloroquine-resistant P falciparum, P vivax and P ovale.
• Pyrimethamine - sulfadiazine is a combination of Pyrimethamine, a dihydrofolate inhibitor, and Sulfadiazine, an inhibitor of dihydropteroate synthetase, both of which are used to treat toxoplasmosis.
• Albendazole should be taken on an empty stomach for nematode infections but with fatty meals for tissue parasites.
• Indications for Diethylcarbamazine include lymphatic filariasis, tropical pulmonary eosinophilia, loasis, and side effects include mild gastrointestinal disturbances.
• Lindane blocks chloride channels on the gamma-aminobutyric acid (GABA) A receptors, with indications for the same and side effects including neurotoxicity and hematotoxicity.
• Side effects and cautions of Albendazole include mild gastrointestinal disturbances.
• Pyrethrin and Benzyl benzoate are other ectoparasiticides.
• Permethrin is a neurotoxin that causes sodium channel depolarization on axons, with indications for pediculosis (head lice & pubic lice) and scabies, and side effects including pruritis, burning, and stinging.
• Others (high dose) include alopecia, transient neutropenia, and bone marrow suppression.
• Albendazole is a broad spectrum anti-helminthic.
• Niclosamide, bithionol, ivermectin are other anthelmintic drugs.
• The mechanism of action (MOA) of Albendazole is similar to that of mebendazole.