Micro 4 Antiparasiticals: antiprotozoal agents. PHRM 203 Allison Beale
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1 Micro 4 Antiparasiticals: antiprotozoal agents PHRM 203 Allison Beale
2 Parasites Bedbug Organisms which live at the expense of another Ectoparasites Lives on outside of host (mites, lice) Endoparasites Lives on inside of host Intracellular (e.g., plasmodia) Extracellular (e.g., amoeba, worms) Eukaryotes Single-celled (protozoa) to multicellular (helminthes to arthropods {fleas}) Elephantiasis caused by filarial worm, Wuchereria bancrofti 2
3 Obligate parasites Most parasites are obligate but many have free living stages Facultative parasites Not normally parasitic but won t pass up the opportunity Accidental parasites Attach or enter wrong host, may or may not survive but can be very pathogenic Permanent parasites Adult lives in or on host Temporary parasites Eat and run Parasitism Toxoplasma gondii cyst in brain tissue Toxoplasmosis/body_Toxoplasmosis_il3.htm 3
4 Parasitic Protozoal Disease Amebiasis 3rd leading cause of parasitic death globally Giardiasis Cryptosporidiosis Malaria Leading cause of morbidity and mortality globally Toxoplasmosis Intracellular Endoparasite Extracellular Endoparasite Entamoeba histolytica Plasmodium vivax amoeboid form inside RBC 4
5 Amebiasis: amoebic dysentery Affects 10% of humans 90% = E. dispar or E. histolytica Extra-intestinal infections Abscesses in liver, lung, chest, brain, genitalia Treat with: " Chloroquine phosphate (Aralen) " Dehydroemetine (Mebadin) " Nitroimidazoles " Metronidazole (Flagyl) " Tinidazole (Tindamax) To kill cysts in lower colon Aminoglycoside " Paromomycin (Humatin, not absorbed) Halogenated hydroxyquinoline " Iodoquinol (Yodoxin) Amoebic abscess in liver may produce BROWN pus Entamoeba dispar causes an asymptomatic infection 5
6 Metronidazole (Flagyl) Kinetics/dynamics ~100% bioavailability, PRODRUG with hepatic metabolism, mostly renal excretion Phenobarbital & phenytoin excretion, cimetidine excretion Indications 1. Protozoal infections, including amebiasis and trichomoniasis 2. Anaerobic G or bacterial infections, including very serious infections of the abdomen, skin, bones and joints, CNS, lungs, etc. (CDAD, bacterial vaginosis, meningitis) 3. Rosacea Metronidazole Metformin PO, IV infusion, Topical 6
7 Metronidazole (Flagyl) Contraindications/warnings Hypersensitivity to metronidazole 1st trimester of pregnancy Candidiasis may be worsened by Flagyl Disulfiram-like reaction with alcohol May cause psychosis in alcoholics taking disulfiram P450 inducers/inhibitors alter availability of Flagyl Phenobarbital, phenytoin, cimetidine Warfarin effects (PT ) Boxed warning: Potential carcinogen Convulsions and peripheral neuropathy - use with caution in patients with CNS disease Caution in Crohn s Disease patients risk of breast and colon cancer 7
8 Metronidazole (Flagyl) ADRs Nausea Headache Anorexia Dry mouth Metallic taste!! Used off label for: Prophylaxis in rape Pelvic inflammatory disease Crohn s disease 8
9 Giardia: Transmission to Humans Flagellated protozoan: Giardia intestinalis Most common GI protozoan in the US Oral ingestion of cysts Fecal-oral transmission through contaminated water Human to human = 2nd most common mode of trans. May be asymptomatic Kids in day care 20-50% cyst passage Men who have sex with men up to 20% cyst passage People in custodial institutions Foodborne transmission Zoonotic transmission: pets, feral animals & livestock cases/year in Hawaii! 9
10 Giardia: Tinidazole (Tindamax) Kinetics/dynamics ~100% bioavailability PO (take with food, NOT alcohol) Phase I metabolism, liver/kidney excretion Indications PO Giardiasis Trichomoniasis (most common curable STD) Amebiasis Bacterial vaginosis in non-pregnant women Contraindications Hypersensitivity 1st Trimester of pregnancy Nursing mothers Boxed warning: Potential carcinogen 10
11 Giardia: Tinidazole (Tindamax) Warnings (ADRs) CNS Convulsions Transient peripheral neuropathies causing numbness or paresthesia Ataxia, vertigo, giddiness/drowsiness Urogenital Opportunistic infections with Candida vaginitis (fungal infection) Dark urine Blood Dyscrasias Transient neutropenia and leukopenia Musculoskeletal Arthralgias, myalgias and arthritis GI Discolored tongue, metallic taste in the mouth Diarrhea or constipation Do not consume alcohol while taking tinidazole! (Disulfiram-like rxn) 11
12 Cryptosporidiosis C. parvum & C. muris Diarrhea & biliary disease Spread by Direct human-human contact Contaminated H 2 O Zoonotic Treatment Normal adults & kids " Nitazoxanide (Alinia) B Immunocompromised Unremitting GI & biliary D. Highly active antiretroviral therapy (HAART) to restore immune function Small enough to avoid filtration and resistant to chlorine - they can be a problem in aquatic venues and day care centers Cryptosporidium parvum collected from a fecal sample and stained using monoclonal antibodies conjugated to fluorescein. 12
13 Cryptosporidiosis: Nitazoxanide (Alinia) B Kinetics/dynamics Prodrug - only FDA approved drug in US for Cryptosporidiosis Suspension 70% bioavailable Metabolized to tizoxanide, etc. Tizoxanide 99%PPB 70% feces, 30% urine Indications Diarrhea caused by Giardia lamblia and Cryptosporidium parvum Contraindications and warnings Allergy PO ~3,000 cases/year in US 10% HIV patients will have crypto Oocyst can remain infective for months in cool/moist environment. Incubation ~ 5 days 13
14 4+ species of obligate intracellular protozoans in the genus Plasmodium P. falciparum 80% of cases, 90% of deaths Mostly Sub-Saharan Africa P. vivax Seldom fatal, common Asia, L. America, Africa P. ovale More rare, similar to vivax W. Africa, SE Asia, Indonesia P. malariae Milder, only 3 day cycle Africa, SE Asia, Indonesia, S. America, West Pacific Islands Malaria mala aria = bad air in Italian Plasmodium falciparum in RBCs Anopheles mosquito 14
15 Clinical Presentation: Malaria Typical onset 7-21 days post infection Up to 1 year ~1400 cases/year in US, 140 of which are severe Cycle of chills/fever/sweating lasting 8-10 hrs 1, 2, or 3 day cycle linked to replication cycle of parasite 2 day = tertian fever (P. falciparum, vivax and ovale) 3 day = quartan fever (P. malariae) Flu-like symptoms Jaundice, kidney failure Seizures 15
16 PO PO PO Malaria prophylaxis Chloroquine sensitive P. falciparum, vivax, malariae, & ovale " Chloroquine (Aralen) D Resistant P. falciparum & vivax " Atovaquone-proguanil (Malarone) " Mefloquine (Lariam) C " Doxycycline (Vibramycin) D " Primaquine " Artesunate (herbal) Kills plasmodia in RBCs only Kills plasmodia in liver Centuries of use, kills plasmodia in RBCs 16
17 Malaria: Chloroquine (Aralen) Kinetics/dynamics ~100% PO bioavailability, ~50% PPB Heavy tissue sequestration Hepatic metabolism, renal excretion Indications Prophylaxis and treatment of acute malarial attacks Extra-intestinal amebiasis Contraindications Retinal or visual field changes Hypersensitivity PO G6PD May cause permanent vision changes: words disappear, foggy vision 17
18 Malaria: Chloroquine (Aralen) Boxed warning: For malaria and/or extraintestinal amoebiasis Warnings Resistant strains are widespread Psoriasis may be exacerbated Use with care in G6PD deficient people Very toxic (potentially fatal) to children Calculate kids dose based on wt. As little as 1 gram (base) may be fatal to kids Tablets = 500 mg = 300 mg free base May cause auditory nerve damage May cause retinal damage in fetus risk of seizures in combo with mefloquine G6PD 18
19 ADRs Malaria: Chloroquine (Aralen) Can cause permanent vision changes Auditory words disappear & vision becomes Deafness, tinnitus foggy Musculoskeletal Myopathy or neuromyopathy leading to weakness and atrophy of muscles and depressed tendon reflexes GI Nausea, vomiting, diarrhea Skin Pigment changes, pruritus, photosensitivity, hair loss/ bleaching Hematological Rare: aplastic anemia, and blood dyscrasias CNS Convulsions, headaches, psychosis, delirium, vivid dreams 19
20 Malaria: Mefloquine (Lariam) Kinetics/dynamics Well absorbed PO, food absorption Indications: prophylaxis and treatment of malaria (it doesn t kill the hepatic phase) Contraindications: Hypersensitivity (to mefloquine, quinine or quinidine) Acute depression, generalized anxiety disorder, psychosis, schizophrenia or any other major psychiatric disorder History of convulsions PO Risk of seizures increased when chloroquine + mefloquine given 20
21 Malaria: Mefloquine (Lariam) It s a substrate and inhibitor of P-GP! Warnings + halofantrine (another antimalarial) the risk of fatal arrhythmias Mefloquine may cause psychiatric symptoms including anxiety, paranoia, depression, hallucinations, EXTREMELY VIVID DREAMS that are prodromal to more serious event Risk of suicide + quinine or quinidine the risk of CV effects + quinine or chloroquine may the risk of convulsions No Ketoconazole w/in 15 wks of mefloquine Up to 95% get corneal micro deposits 21
22 Malaria: Doxycycline (Vibramycin) Kinetics/dynamics Readily absorbed, PPB varies. PO, IV infusion Excreted in bile/urine in active form Indications Doxycycline is indicted in a very large array of bacterial (both Gram and ), protozoal and rickettsial infections Bacterial: Plague (Yersinia pestis), anthrax, Leptospirosis, Lyme s disease Protozoal: Malaria and Entamoeba sp. Rickettsial: Rocky Mt. Spotted fever, Q fever, etc. 22
23 Malaria: Doxycycline (Vibramycin) Contraindications/warnings Hypersensitivity to any tetracycline Discoloration of teeth up to age 8 Pseudomembranous colitis Decreased bone formation (including fetal) Photosensitivity Syrups contain sodium metabisulfate Allergic reactions, especially in asthmatics 23
24 50% of wild pigs in HI are carriers of Toxoplasmosis Toxoplasmosis Single-cell organism Obligate intracellular protozoan parasite Toxoplasma gondii Global Distribution 30-50% human prevalence Reservoir host - Cats Uncommon cause of human disease Except: Pregnant women & fetus Immunocompromised persons Association with schizophrenia? 24
25 Toxoplasma: Risk for Severe Disease Congenitally infected fetuses and newborns Estimated cases each year in the U.S. Immunologically impaired individuals, most commonly with defects in T-cell-mediated immunity Hematologic malignancies Bone marrow and solid organ transplants AIDS, e.g. leading to toxoplasmic encephalitis Folic acid synthesis inhibitor (e.g., pyrimethamine) #1 cause of focal CNS disease in HIV patients 25
26 Congenital toxoplasmosis 26
27 cases/year in US, 50% of which are in Hawaii! Bacterial zoonosis Contaminated surface water Mimics other diseases Dengue (viral) Malaria (protozoal) Typhus (rickettsial) Symptoms Fever/chills, myalgia, diarrhea Jaundice, renal failure, hemorrhage, pneumonitis Treatment " Penicillin, amoxicillin " Doxycycline Leptospirosis Spirochete bacteria 27
28 18,000+ cases in US (2010), making it the most common vector-borne disease Cause Borrelia burgdorferi Transmitted by Ixodes tick bite Symptoms Rash, fever, arthritis, neuropathy Treatment " Cefuroxime axetil " Penicillin or amoxicillin " Doxycycline " Erythromycin (if allergic to others) Lyme Disease Spirochete bacteria Characteristic bull s eye rash - CDC 28
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