Lec 22. Anthelminths-Antiprotozoals, Dr. Panavelil- FS (2) PDF

ANTIPROTOZOAL AGENTS ANTHELMINTIC AGENTS (Anti-infective agents for parasitic infections) Thomas A. Panavelil, Ph.D., M.B.A. CDC CDC Information: CDC Drug Service, Division of Host Factors, informatio Center for Infectious Disease n (404) 639—3670, 8 AM to 4:30 PM EST Monday...

ANTIPROTOZOAL AGENTS ANTHELMINTIC AGENTS (Anti-infective agents for parasitic infections) Thomas A. Panavelil, Ph.D., M.B.A. CDC CDC Information: CDC Drug Service, Division of Host Factors, informatio Center for Infectious Disease n (404) 639—3670, 8 AM to 4:30 PM EST Monday through Friday.  After hour or holiday emergencies, call (404) 639- 2888.  Also 1-800-232-4636 (1-800-CDC- INFO) ORGANISMS: Anti- Trypanosomiasis: Trypanosoma gambiense, T. brucei: Protozoa Causes African trypanosomiasis or sleeping sickness. African trypanosomiasis is transmitted by tsetse flies. lTheagents protozoa are hemoflagellates. It is usually a progressive and fatal disease involving CNS (flagellat initially (febrile, lymphadenopathy, splenomegaly and myocarditis as symptoms) and then terminal cardiac failure. e classes): Trypanosoma cruzi (6 lineages): Causes South American Trypanosomiasis, Chagas’ disease Cardiomyopathy, megacolon and death are seen. Can also be transmitted by blood transfusion.  Treatments: Antiprotozo  Suramin (CDC): Polysulfonated naphthyl urea: Inhibits several al agents…… parasitic, enzymes, exact mechanism unknown.  Pentamidine (Pentam 300, Pentacarinat, Nebupent): DNA and RNA polymerase inhibition? Oxidative phosphorylation inhibitor?  Melarsoprol (Mel B, i.v.): A trivalent arsenical that binds to inhibits parasitic enzymes especially the sulfhydryl groups (more sensitive to parasitic enzymes than the host). Melarsoprol is used in the later stages of CNS involvement.  Eflornithine (Ornidyl) FDA approved: Parenteral formulation is available from the WHO. Inhibits polyamine biosynthesis in Trypanosoma. This inhibitor of ornithine decarboxylase is effective and the greatest hope for late-stage trypanosomiasis.  Wide range of hematological adverse effects. A topical formulation is available for reducing unwanted facial hair in women (Vaniqa)!  Nifurtimox (Lampit, CDC, a nitro-heterocyclic T. cruzi drug): Nifurtimox is suppressive and possibly curative. Produces intracellular free radicals that kill the organism. Used at the chronic stages of the disease with minimal effects!  Also used is BENZNIDAZOLE for Chagas disease  Treatment of African Trypanosomiasis Source: Katzung 14th edition First-Line Disease Stage Alternative Drugs Drugs West Early Pentamidine Suramin, eflornithine African 1 CNS Eflornithine Melarsoprol, eflornithine 1 involvement -nifurtimox 1 East Early Suramin Pentamidine African 1 CNS Melarsoprol involvement  Leishmaniasis: Leishmaniasi sLeishmaniasis & PAM has Visceral, Cutaneous & Mucocutaneous forms. The clinical spectrum of leishmaniasis ranges from a self-resolving cutaneous ulcer to a mutilating mucocutaneous disease and even to a lethal systemic illness. Sodium stibogluconate (Pentostam, parenteral)  The exact mechanism of Sodium stibogluconate is not known. Inhibits glycolysis & TCA cycle? Can cause cardiac and pancreas issues Miltefosine oral (Impavido)  Miltefosine is orally active drug for leishmaniasis. Mechanism of action of the drug binding to parasitic DNA/inhibits cytochrome c oxidase (ETC enzyme).  Also treats Naegleria fowleri infection-(causes Primary Amebic Meningoencephalitis-PAM & infection can be fatal)  Naegleria fowleri approved drug: Amphotericin B lipid formulations Giardiasis (common in USA, from contaminated water)with diarrhea, malabsorption): Caused by Giardia lamblia, the flagellate protozoa. Most infected people are asymptomatic. The organism can cause transient or persistent diarrhea. Cysts are common in contaminated water. Metronidazole (Flagyl) : Binds to proteins and DNA (electron acceptor) of the flagellate. PS: Antibacterial, Disulfiram like reaction Tinidazole (Fasigyn, Tindamax): Tinidazole is amebicidal, bactericidal, and trichomonacidal. Mechanistically in anaerobic organisms and cells, tinidazole disrupts DNA’s tertiary structure, and inhibits nucleic acid synthesis. Treats Giardiasis as a single dose Trichomoniasis (Genitourinary-sexually transmitted) Caused by Trichomonas vaginalis. In US, 3 million women are infected annually. Organism inhabits the genitourinary tract of the human host and causes vaginitis in women and urethritis in men.  Metronidazole (Flagyl, Metron): Oral single course is a successful in treating trichomoniasis. Partner symptomatic or asymptomatic should be treated. Resistant strains are prevalent.  Tinidazole (Fasigyn, Tindamax): Tinidazole is amebicidal, bactericidal, and trichomonacidal.  Mechanistically in anaerobic organisms and protozoal cells, Metronidazole & Tinidazole disrupts DNA’s tertiary structure (involves components of ETC), and inhibits nucleic acid synthesis.  Remember other applications of these drugs include treating anaerobic bacterial infections. Amebiasis, amebic dysentery: Amebic dysentery is caused by Entamoeba histolytica. Produces mild to severe dysentery and colitis. Drugs are classified into Luminal, Systemic and Mixed amebicides based on the site where the drug is therapeutically effective. Luminal amebicides:  Iodoquinol (8-hydroxy quinoline, Diodoquin, Yodoxin) as alternative for asymptomatic carriers. Iodoquinol can cause myelo- optic neuropathy.  Paromomycin (an aminoglycoside) works only against intestinal forms of E. histolytica. First line for Amebiasis and Giardiasis in pregnancy.  Tinidazole & Metronidazole most widely used Systemic amebicides:  Emetine (alkaloid derived from ipecac, Brazil root) and Dehydroemetine (Mebadin, Dametine, dehydroemetine less toxic than emetine):  They block chain elongation of proteins. IM is the preferred route.  Emetines are contraindicated in pregnancy and can cause significant cardiotoxicity. Reserved for extraintestinal amebiasis in patients who do not respond to or cannot receive metronidazole. Available through the CDC only.  Treatment of Amebiasis Ref: Katzung 14th edition Clinical Setting Drugs of Choice and Adult Dosage Alternative Drugs and Adult Dosage 2 Asymptomatic intestinal Luminal agent: Diloxanide furoate, 500 infection mg 3 times daily for 10 days or Iodoquinol, 650 mg 3 times daily for 21 days or Paromomycin, 10 mg/kg 3 times daily for 7 days Mild to moderate intestinal Metronidazole, 750 mg 3 times daily (or Luminal agent (see above) infection 500 mg IV every 6 hours) for 10 days plus either or Tetracycline, 250 mg 3 times daily for 10 Tinidazole, 2 g daily for 3 days days plus or Luminal agent (see above) Erythromycin, 500 mg 4 times daily for 10 days Severe intestinal infection Metronidazole, 750 mg 3 times daily (or Luminal agent (see above) 500 mg IV every 6 hours) for 10 days plus either or Tetracycline, 250 mg 3 times daily for 10 Tinidazole, 2 g daily for 3 days days plus or 2 2 Luminal agent (see above) Dehydroemetine or emetine, 1 mg/kg SC or IM for 3–5 days 2 2 Hepatic abscess, ameboma, Metronidazole, 750 mg 3 times daily (or Dehydroemetine or emetine, 1 mg/kg and other extraintestinal 500 mg IV every 6 hours) for 10 days SC or IM for 8–10 days, followed by (liver disease or abscess only) chloroquine, 500 mg Tinidazole, 2 g daily for 5 days twice daily for 2 days, then 500 mg daily plus for 21 days Luminal agent (see above) plus Luminal agent (see above)  Toxoplasmosis  Causative organism is Toxoplasma gondii. Cats and other felines are natural hosts. Transmitted to humans through raw or inadequately cooked meat contaminated with cyst, from vegetables carrying the oocytes, and direct contact with cats. Cats are the only animals that can shed oocytes that can infect other animals as well as man.  70% of adults in the US are seropositive. Clinical symptoms such as lymphadenopathy appear in immunocompetent patients and serious sickness mostly immunocompromised patients (encephalitis).  Pyrimethamine and sulfonamide (sulfadiazine): Long term use of the drug. Leucovorin is administered to protect against folate deficiency. Other folate synthesis inhibitors may not have effect in the treatment of toxoplasmosis.  Atovaquone (Mepron): (A synthetic hydroxy-naphthoquinone. It is highly lipophilic. It resembles ubiquinone. Inhibits mitochondrial ETC and related processes. Orally administered, 95% seen in feces. Rash fever etc. are adverse effects).  Atovaquone is used in toxoplasmosis and in AIDS patients to treat P. jirovecii pneumonia.  JFYI: In AIDS, toxoplasmic encephalitis is a major cause of death. Pneumocystosis (PCP, PJP): Fungal Disease PJP is the common life threatening opportunistic infection in immunocompromised patients. Molecular analysis of ribosomal RNA of P. carinii in 1988, resulted in reclassification of this protozoal parasite as fungi.  TMP-SMZ (discussed elsewhere)  Pentamidine (Pentam, a diamidine): Mechanism polymerase inhibition? Oxidative phosphorylation? Parenteral administration, renally cleared, half-life varies with patients status).  Atovaquone a mitochondrial electron transport chain (ETC) inhibitor used in severe pneumocystosis.  Dapsone (Application not Atypical mycobacterial infections though this this drug treats Mycobacterium leprae infections) PS: Sometimes Pneumocystis jirovecii is described as fungus as well as protozoan. Malaria: Malaria remains the world’s most devastating infection with 300 to 500 million clinical cases with about 3 million deaths a year. Multi-drug resistant strains of P. falciparum is a major challenge in developing countries. Most drugs are developed on the basis of their action against asexual erythrocytic forms of malaria parasite, that are responsible for the clinical illness.  Plasmodium falciparum (85%): Causes malignant tertian malaria, severe clinical signs, few relapses  Plasmodium vivax: Benign tertian malaria, milder clinical signs, dormant hepatic stage causes relapse  Plasmodium ovale: Similar to vivax  Plasmodium malariae: Quartan malaria, tropical, rare relapse. Read: difference in febrile paroxysms (high fever every 48 to 72 hours) in quartan, tertian, vivax malarias. Antimalarial Drugs: Erythrocytic cycle  Rapid acting: chloroquine, quinine, quinidine, mefloquine (for chloroquine and proguanil resistant malaria) and halofantrine (not in US).  Slow acting: Proguanil and pyrimethamine (inhibits plasmodial dihydrofolate reductase) Exoerythrocytic stage Tissue Schizonticides (prophylactic):  Drug of choice: Chloroguanide (Proguanil)  Alternative: Pyrimethamine Tissue schizonticides-preventing relapse:  Drug: Primaquine  Mechanism: Latent exo-erythrocytic form Gametocides-prevents infection in mosquito:  Mechanism: Destroys gametocytes in human blood and prevents vector transmission  Drug of choice: Primaquine for P. falciparum Chloroquine and Quinine for other species Antimalarial Drugs Antimalarial drugs.…… Chloroquine:  Mechanism: Inhibition of plasmodial heme polymerase (?), Intercalation with parasitic DNA (?)  Use: acute attacks of malaria, amebic dysentery, RA, Discoid LE,  Word wide resistant strains  Adverse: At proper concentrations, a safe drug. Rarely with high doses retinal damage, ototoxicity and visual disturbances Pyrimethamine:  Mechanism: Plasmodium dihydrofolate reductase inhibition  Use: with sulfonamide for chloroquine resistant P. falciparum Mefloquine (Lariam, a quinolone): Damages parasite membranes. Use orally in Chloroquine resistant P. falciparum Problems: CDC limits use to prevent resistance Antimalarials… Primaquine: Mechanism: Its oxidants are schizonticides that Inhibit plasmodial DNA replication. Use: The only antimalarial used clinically to eradicate latent tissue and hepatic forms responsible for relapses in P. vivax and P. ovale. Adverse: Anemias in patients with G6PDH deficiency, Methemoglobinemia and cyanosis at high doses Quinine (Qualaquin): Oral in combination with doxycycline or Sulfadiazene- pyrimethamine combination. A reserve drug for chloroquine resistant strains useful in asexual erythrocytic forms, not active against exoerythrocytic forms). Mechanism: Affects DNA synthesis. Use: blood schizonticide for chloroquine resistant falciparum Adverse: Cinchonism (hearing, visual, CNS), Over-dose abortion, Hemolysis with pregnancy AntiMalarial Drugs…… Proguanil: Mechanism: Inhibits DHF reductase Use: with chloroquine in prophylaxis Available in USA only in combination with Atovaquone for malaria Tafenoquine (Arakoda) Approved for Plasmodium as a single dose radical cure (no relapse?). Mechanism unknown. Atovaquone; Proguanil (Malarone, Malarone pediatric): An oral antimalarial combination. Plasmodium falciparum exhibits a high incidence of resistance to both atovaquone and proguanil as single agents for the treatment of malaria. The combination, however, has potent synergistic antimalarial activity. Proguanil is a synthetic biguanide derivative of pyrimidine and is actually a prodrug for the active drug cycloguanil. Mechanism of Action: The combination of atovaquone; proguanil has potent synergistic antimalarial activity; ETC & folate reductase inhibitors. Pharmacokinetics: Atovaquone; Proguanil is administered orally as a tablet and should be administered with food or a milky drink. AntiMalarials… Artemether; Lumefantrine (Coartem): Artemether; lumefantrine is an artemisinin (sweet wormwood, a Chinese herb) combination drug for the treatment of malaria. Exact mechanism is not clear, but they both inhibit DNA replication and translation. Lumefantrine (Benflumetol) is a long-acting anti-malarial drug. Both drugs kill blood schizonticides and are synergistic in action. They also prevent resistance to some extent. Lumefantrine is an organochloride. Artemether: lumefantrine is very useful against drug-sensitive and drug-resistant Plasmodium falciparum. Picture OF SWW from my backyard.   Teratogenic Antiprotozoals: Adverse (Embryotoxic)  GI disturbance  Nausea  Anorexia  Vomiting  Pruritus  Dizziness  Tinnitus  Fatigue etc.  Concepts:  In the USA mostly seen are ANTI-WORM intestinal nematodes. DRUGS  Parasites, egg and the larvae (Anthelmin are identified in the feces. tic drugs)  Intestinal infections, a cathartic prior to oral dosage may increase efficiency of treatment. Anti-worm drugs may be toxic.  Pregnancy and GI ulcerations are contraindicated.  Anti-Worm drugs Nematodes (Round worms) Mebendazole (Vermox) & Albendazole (Albenza, Valbazen): Mechanism: A benzimidazole, inhibits microtubule synthesis of the parasite. Parasite is thus expelled with the feces. Usage: round worm (Ascaris), pinworm (Enterobius), hookworm (Necator and Ancyclostoma), whipworm (Trichuris) Problems: few, detoxified in liver, contraindicated in pregnancy. Cost rest of the world: 4 to 10 cents per dose Cost US: $200 to $400 per dose Pyrantel pamoate (Antiminth, Combantrin, Ascarel, Pinrid): Given along with mebendazole. Treats roundworms and pinworms. Being a depolarizing neuromuscular blocking agent, it causes paralysis and release of their hold to the intestinal wall. Poorly absorbed and the effect is in the tract only. Ivermectin (Stromectol): Given orally, against onchocerciasis (river blindness) caused by Onchocerca. The drug binds to parasites chloride channels causing hyperpolarization, paralysis and death. Ivermectin also is used in the treatment of nematodes such as cutaneous larva currens (an autoinfection caused by penetration of the perianal skin by infectious larvae as they are excreted in the feces) and localized and disseminated cutaneous larva migrans (involving migration of immature (larval) worms in various parts of the body). Filariasis, Elephantiasis Wucheria bancrofti, is a tissue nematode that causes filariasis (tropical eosinophilia), and in severe cases chronic elephantiasis (adult worms in lymphatic vessels causing edema). The vector is mosquitos. This disease of the tropics infects 200 million people.  Diethylcarbamazine (Hetrazan) is effective against microfilariae, not against adult worms in lymph nodes. The drug affects microfilarial surface membranes and affects microfilarial musculature by hyperpolarization.  Other Drugs: Ivermectin, Albendazole Cestodes (Flatworms, tapeworms) & Trematodes Cestodes: Niclosamide (Niclocide) Tablet, Chewable Mechanism: Inhibits parasite’s oxidative phosphorylation, stimulates ATPase. Not effective for the ova, therefore a laxative must me administered orally prior to the treatment to purge the bowel. Alcohol is contraindicated. Usage: for Taenia Problems: very few, nausea, vomiting diarrhea, not effective against encysted larvae. Therefore treat for more than 5 days. Trematodes & Cestodes: Praziquantel (Biltricide) treats all species. Trematodes are leaf shaped flat worms. Depending on the tissue they infect they are called liver, lung, intestinal or Blood flukes (Schistosoma). Mechanism: Increases Calcium permeability of the membranes and paralyses worm musculature (Disturbs calcium ion homeostasis). Use: Schistosomiasis and other flukes (causing cysticercosis). Also cestodes such as Taenia (pork and beef tape worms). In cysticercosis of the eye, Praziquantel is contraindicated because the destruction of the organism in the may damage the organ. Problems: mild, transient dizziness, drowsiness, headache.