1 / 47

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

morse
Download Presentation

Anti-Parasitic Drugs

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related