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Anti-Parasitic Drugs

Anti-Parasitic Drugs. (Treatment Guide: Where is the parasite?). Objectives. Types of malaria requiring therapy for parasites in the liver Agents used for chloroquine-resistant malaria Names of important prototypes. Drugs of choice for: Amebiasis, giardiasis, trichomoniasis

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Anti-Parasitic Drugs

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  1. Anti-Parasitic Drugs (Treatment Guide: Where is the parasite?)

  2. Objectives • Types of malaria requiring therapy for parasites in the liver • Agents used for chloroquine-resistant malaria • Names of important prototypes • Drugs of choice for: • Amebiasis, giardiasis, trichomoniasis • Pneumocystosis • Toxoplasmosis • Roundworms • Flatworms • Flukes • Lice and scabies

  3. Malaria • Plasmodia • falciparum • Most severe; often resistant to chloroquine • ovale** • vivax** • malariae • knowlesi (in monkeys, sometimes humans) **Hepatic forms of the parasite can lead to recurrent infections

  4. Malaria Factoids • Worldwide, a child dies of malaria an average of every 20 seconds • More than 90% of deaths occur in sub-Saharan Africa • More 90% of deaths occur in children less than 5 years of age • More than 95% of the deaths are caused by P. falciparum

  5. Malaria Factoids • World Malaria Day – April 24 annually • Malaria vaccine in phase III clinical trials • Kenya Medical Research Institute/CDC • Phase II clinical trials indicated 53% reduction in malaria cases, children aged 5-17 months

  6. Inhibitors of Plasmodial Heme Metabolism

  7. Chloroquine • Mechanism of Action • Plasmodia degrade hemoglobin as a source of amino acids • Chloroquine enters plasmodial food vacuole, becomes trapped, and then blocks heme metabolism, leading to accumulation of a toxic intermediate. • Hydroxychloroquine is also available

  8. Chloroquine • Drug of choice for treatment and prophylaxis for travel to areas where chloroquine resistance is uncommon. • Active against P. ovale, malariae, knowlesi • Well tolerated at normal doses • Smooth muscle relaxant • Antiarrhythmic • Anti-inflammatory • Considered safe to use in pregnancy • “Bull’s eye” retinopathy at high doses

  9. Bulls-Eye Retinopathy

  10. Quinine and Quinidine • Probably also interfere with plasmodial heme metabolism; intercalates with plasmodial DNA • Cardiotoxicity • Quinidine is preferred IV form • Cinchonism (headache, blurred vision, tinnitus) • Other pharmacological effects • Antiarrhythmic • Muscle relaxant • Analgesic; antipyretic

  11. Mefloquine • For prophylaxis and treatment in areas where chloroquine resistant malaria is endemic • Also disrupts plasmodial heme metabolism • Can cause GI effects, arrhythmias • Bradycardia, prolonged QT interval • Very long half-life (~14 days) • Used once weekly for prophylaxis • Single dose can be effective for treatment • Psychiatric effects are possible; weird dreams

  12. Artimisinin and Derivatives • Primary agents used worldwide for chloroquine-resistant malaria • Artesunate is water-soluble, may be preferable for IV use in severe malaria • Artemether, artemotil, dihydroartemisinin • Probably inhibit heme metabolism • Possibly affect plasmodial ATPases

  13. Inhibitors of the Plasmodial Electron Transport Chain

  14. Primaquine • Drug of choice for eliminating parasites from the liver • P. vivax, P. ovale • Quinone metabolite may interfere with function of ubiquinone • GI effects are primary adverse reactions • Has been associated with hemolytic anemia and agranulocytosis

  15. Glucose-6-Phosphate Deficiency and Drug-Induced Hemolysis • “Oxidative stress” can be associated with a number of drugs • Primaquine a classic example • Some anti-cancer drugs (e.g., doxorubicin) • Superoxide radical (•O2-), hydrogen peroxide (H2O2) and other peroxides and radicals are formed • Glutathione (GSH; a tripeptide of glutamate, cysteine, and glycine) is an important protective mechanism against oxidative stress

  16. Glutathione (GSH)

  17. G6P-DH Deficiency & Hemolysis • GSH-dependent metabolism of peroxides (ROOH) causes formation of glutathione dissulfide (GSSG); catalyzed by glutathione peroxidase: ROOH + 2 GSH → ROH + H2O + GSSG • The GSSG must be converted back to the active, reduced form by glutathione reductase: GSSG + NADPH + H+→ 2 GSH + NADP+

  18. G6P-DH Deficiency & Hemolysis • In erythrocytes, the pentose phosphate pathway is the only source of NADPH • Glucose-6-phosphate dehydrogenase is the rate-limiting enzyme for the PPP • In patients with G6P-dh deficiency, the need for NADPH to regenerate GSH may be inadequate, leading to: • Depletion of reduced glutathione • Free radical attack on membranes; hemolysis

  19. Atovaquone • Also interferes with plasmodial electron transport chain • Usually mild adverse effects • Usually used in combination with proguanil (folate reductase inhibitor) in malaria • Also active against other protozoa • Pneumocystis carinii • Toxoplasmosis

  20. Protein Synthesis and Folate Antagonists Protein Synthesis Inhibitors Folate Antagonists Sulfadoxine and other sulfonamides Plasmodialfolatereductase inhibitors Pyrimethamine – usually combined with a sulfonamide Proguanil – usually combined with atovaquone (Melarone®) • Doxycycline • Tetracycline • Clindamycin

  21. Folate Antagonists

  22. IC50 Values for Folate Reductase (nM) Drug E. coliMalariaHumans Trimethoprim 7 1,8000 350,000 Pyrimethamine 2,500 0.5 1,800 Methotrexate 0.1 0.7 0.2

  23. Protein Synthesis and Folate Antagonists Protein Synthesis Inhibitors Folate Antagonists Sulfadoxine and other sulfonamides Plasmodialfolatereductase inhibitors Pyrimethamine – usually combined with a sulfonamide Proguanil – usually combined with atovaquone (Melarone®) • Doxycycline • Tetracycline • Clindamycin

  24. Artemisinin Combination Therapies • Combines artemisinin with another anti-malarial drug (a blood schizontocide) • WHO recommends for chloroquine-resistant malaria • Artemether & lumefantrine • Artesunate & • Mefloquine or • Amodiaquine or • Sulfadoxine & pyrimethamine • Dihydroartimisinin & piperaquine

  25. Therapeutic Regimens for Malaria (WHO Guidelines) • Uncomplicated P. falciparum • Artimisinin combination therapy • Complicated/severe P. falciparum • Artesunate & another blood schizontocide • Chloroquine-sensitive P. vivax • Chloroquine plus primaquine • Chloroquine-resistant P. vivax • Artimisinin combination therapy plus primaquine • P. ovale • Chloroquine plus primaquine • P. malariae or P. knowlesi • Chloroquine

  26. Summary of Anti-Malarials • Blood Schizontocides • Chloroquine • Quinine/quinidine • Mefloquine • Artimisinin • Atovaquone • Proguanil • Tetracyclines • Sulfonamides • Tissue Schizontocides • Primaquine

  27. Amebiasis

  28. Entamoeba histolytica • Spread by fecal-oral route • Infection often confined to intestinal lumen • Patients may be asymptomatic cyst passers • Ameba may enter liver via biliary duct • Severe systemic infections may involve extrahepatic tissues

  29. Systemic Metronidazole Atovaquone Chloroquine Tinidazole Luminal Diloxanide furoate Iodoquinol Paromomycin Amebicides

  30. Metronidazole • Effective against a number of amebic diseases • Entamoeba histolytica • Trichomonas vaginalis • Giardia • Effective against many anaerobic bacteria • Bacteroides, Clostridia • A ‘pro-drug’ that is reduced by microbes under anaerobic conditions to its active form. • Headache, GI distress most common effect • Metallic taste, disulfiram-like effect • Tinidazole a similar drug, same indications

  31. Other Protozoal Infections • Giardiasis (“Beaver Fever”) • Metronidazole • Trichomoniasis • Metronidazole • Pneumocystosis (Pneumocystis carinii) • Sulfamethoxazole & Trimethoprim • Atovaquone • Toxoplasmosis • Pyrimethamine & sulfadiazine • Babesiosis • Atovaquone & azithromycin

  32. Non-U.S. Protozoal Diseases • Leishmaniasis • Amphotericin B • Stodium stibogluconate (antimony drug) • Trypanosomiasis • African sleeping sickness • Chagas disease

  33. Helminthic Infections

  34. Worldwide Incidence of Worm and Fluke Infections

  35. Helminthic Infections • Many worms cannot multiply in humans • Each worm represents a separate ‘infection’ • Intestinal infestations • Can cause blockage, malnutrition, anemia • Usually respond to luminal drugs • Invasive (tissue) roundworms • Filaria, microfilaria • Treated with systemic drugs • Jarish-Herxheimer-like reactions (systemic inflammation, fever) can occur during therapy.

  36. Roundworms (Nematodes) • Luminal drugs • Albendazole • Binds tubulin and inhibits tubulin synthesis • Causes malformations of membranes • Sufficient absorption for some systemic effects • Mebendazole is mostly non-absorbed • Thiabendazole poorly tolerated • Pyrantel (otc) • Paralyzes worms

  37. Roundworms (Nematodes) • Systemic drugs • Ivermectin • Interrupts GABA transmission in worms • Drug of choice for onchocerciasis • Diethylcarbamazine • Seems to sensitize worms to phagocytosis • Drug of choice for filiariasis and loiasis

  38. Flatworms and Flukes • Praziquantel • For luminal infections (tapeworms) and systemic fluke infections • Increases permeability of parasite to calcium, causing paralysis and later disruption of tegument (outer coat) • No major adverse effects • GI, dizziness

  39. Ectoparasites Lice and Scabies

  40. Lice • Head louse Pediculosis humanis capitis • Must eradicate adult louse, nymphs, and nits (eggs) that are bound to hair shafts • Body louse Pediculosis humanis corpis • Pubic louse Phthirus pubis

  41. Non-Pharmacological Louse Control • Washing items in very hot water. • Seal non-washable items in a plastic bag for several weeks. • Extensive brushing to remove nits from hair shafts; specialized ‘nit-busting’ brushes are available

  42. Topical Drugs for Lice • Permethrin (1%) • Kills adults and nits • Prolonged pediculocidal action • Do not rinse off for at least 10 minutes • Pyrethrins (chrysanthemums) • Also found in household insect sprays • Lindane (gamma benzene hexachloride) • Malathion (an organophosphate insecticide) • Leave on site for at least 12 hours • Benzyl alcohol (0.9%)

  43. Systemic Drugs for Lice • Presumably enter louse from host blood that they ingest • Ivermectin • Also used for tissue roundworms • Sulfamethoxazole-trimethoprim • Indirect action on louse bacteria?

  44. Scabies (The itch) • Caused by a burrowing insect • Sarcoptes scabiei • Itching caused by inflammatory reaction to deposited eggs, feces • Itching will persist after insects are eradicated • May require antihistamines or corticosteroids

  45. Scabicides • Apply to entire body after warm bath • Leave on body for at least 8 hours • Permethrin (5%) • Lindane (Gamma benzene hexachloride) • Crotamiton • Sulfur (6% in petrolatum) • Applied 3 consecutive nights; safest for infants • Ivermectin orally?

  46. Good Luck with Everything

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