Katzung’s Basic & Clinical Pharmacology, Reading assignments: Katzung’s Basic & Clinical Pharmacology, 13th Edi ,Ch-52&53,p886-917; Dr.Sanjib Das

IV.Antiparasitic Chemotherapy: A.Basic Principles of Antiparasitic Chemotherapy B.Antiprotozoal Chemotherapy 1. Antimalarials Know the infectious cycles of the Plasmodia and which stages are susceptible to different antimalarials Understand the effect of drug resistance on the clinical use of antimalarials 2. Other antiprotozoal drugs Know the mechanism of action, clinical uses, and adverse effects associated with these drugs C. Anthelminthic Agents Know mechanisms of action against intestinal and extra-intestinal parasites Know drugs used clinically in North America (limit to infections by Ascaris, pinworm, hookworm, tapeworm)

1. Antimalarials 2. Anti-protozoal drugs ARTEMISININ CHLOROQUINE MEFLOQUINE PRIMAQUINE PYRIMETHAMINE-SULFADOXINE (FANSIDAR) 2. Anti-protozoal drugs METRONIDAZOLE TRIMETHOPRIM-SULFAMETHOXAZOLE PYRIMETHAMINE-SULFONAMIDE PENTAMIDINE

Anti-Parasitic Chemotherapy: Anti-Malarials Life cycle of malaria parasites Four species of protozoan-- Plasmodium falciparum Plasmodium malariae Plasmodium vivax Plasmodium ovale First two single cycle, second two multiple cycles Key point-- Several drugs affect blood schizonts, only primaquine affects tissue schizonts https://www.youtube.com/watch?v=qMNmOsl5_e4

Anti-Malarials: Chloroquine Mechanism Alters metabolism of hemoglobin by parasite, also blocks nucleic acid synthesis Pharmacokinetics Oral or parenteral Rapid, complete absorption; wide distribution Excreted in urine, 25% as metabolite Loading dose necessary for acute treatment Clinical Uses "Highly effective blood schizonticide“ Acute-- Clears parasitemia from all four Plasmodia Curative for P. malariae and P. falciparum Used with primaquine for P. vivax and P. ovale Prophylactic-- Begin 1 week before travel, continue four weeks after return Preferred drug for prophylaxis against all four species The mechanism of action of chloroquine in Plasmodium falciparum malaria is elimination of a. Secondary tissue schizonts b. Exoerythrocytic schizonts c. Erythrocytic stage d. Asexual forms e. Sporozoites The answer is c. Chloroquine is a 4- aminoquinoline derivative that selectively concentrates in parasitized red blood cells. It is a weak base, and its alkalinizing effect on the acid vesicle of the parasite effectively destroys the viability of the parasite.

Chloroquine Adverse Effects-- Generally well tolerated GI, mild headache; may exacerbate psoriasis or porphyria Visual impairment occurs with long-term or high-dose therapy Resistance-- Widespread in South America, Africa, Asia "P-glycoprotein" pumping mechanism Block with verapamil in vitro

Anti-Malarial Chemotherapy Mefloquine Mechanism unknown Pharmacokinetics Only oral-- too irritating for parenteral Well absorbed and distributed Metabolized in liver, excreted in feces Adverse effects—CNS, possible psychotropic effects Clinical Uses-- Chloroquine-resistant malaria Fansidar (Pyrimethamine-Sulfadoxine)-- Anti-folate combination, typical effects Well absorbed and distributed, Excreted in urine Clinical Use-- Effective blood schizonticide for P. falciparum Slow-acting; cannot be used alone for acute attacks Multi-drug resistance to fansidar and chloroquine common

Anti-Malarial Chemotherapy Atovaquone plus proguanil Mechanism of action (1) Atovaquone selectively inhibits parasite mitochondrial electron transport (2) Proguanil’s metabolite cycloguanil, inhibits dihydrofolate reductase Used to prevent or treat acute, uncomplicated P. falciparum malaria Adverse effects (1) GI distress (2) Increased hepatic transaminase (3) Headache (4) Dizziness Quinine and Quinidine Still used to treat uncomplicated chloroquine-resistant P. falciparum malaria Cinchonism (1) Overdose of quinine or its natural source, cinchona bark (2) Symptoms (a) Flushed and sweaty skin (b) Ringing of the ears (tinnitus) (c) Blurred vision (d) Impaired hearing (e) Confusion

Anti-Malarial Chemotherapy: Tissue Schizonticides Primaquine-- Tissue schizonticide Oral, well absorbed and distributed, extensively metabolized Metabolites are intracellular oxidants Used in combination with chloroquine for prophylaxis or cure of P. vivax, P. ovale GI distress, hemolytic anemia in G6PDH deficiency Artemisinin— Traditional Chinese medicine Oral, very short t ½ Activated by oxidative metabolism—free radicals, alkylation Rapidly-acting blood schizonticide—particularly useful for multi-drug resistant P. falciparum 1. A 27-year-old female has just returned from a trip to Southeast Asia. In the past 24 hours, she has developed shaking, chills, and a temperature of 104?F. A blood smear reveals Plasmodium vivax. Which of the following agents should be used to eradicate the extraerythrocytic phase of the organism? a. Primaquine b. Pyrimethamine c. Quinacrine d. Chloroquine e. Chloroguanide The answer is a. (Hardman, pp 977–978.) Primaquine is effective against the extraerythrocytic forms of P. vivax and P. ovale and is thus of value in a radical cure of malarial infection. It also attacks the sexual forms of the parasite, rendering them incapable of maturation in the mosquito and making it valuable in preventing the spread of malarial infection.

Other Anti-Protozoal Drugs: Metronidazole & Tinidazole Mechanism Tissue amebicide Nitroimidazole-- activated by electron donation & produce free radicals as MOA. Particularly effective for anaerobic/hypoxic sites Pharmacokinetics Oral or IV Well absorbed and distributed, including CNS, bone Cleared in urine following hepatic metabolism Clinical Uses Urogenital trichomoniasis (Trichomonas vaginalis) Giardiasis (Giardia) Amebiasis (Entamoeba histolytica) Aspiration pneumonia Anaerobic bacterial infections below diaphragm (including Clostridium difficile, Bacteroides fragilis ,Gardinella vaginalis & Acne Rosacea). H. Pylori {used with bismuth & amoxycillin (or tetracycline) as ‘triple therapy’}. Adverse Effects Nausea, headache, Dry mouth, Stomatitis, metallic taste, leukopenia, cystitis, Reversible peripheral neuropathy (free redical injury) Disulfiram effect Protozoa Bacteria #H.Pylori responsible for 100% occurrence of duodenal ulcers ,75% occurrence of gastric ulcers #H.Pylori responsible for 1.Recurrence 2.precipitation of Malignancy by increasing turn over of diff.types of Gastric cells. #Economic Regimen :Bismuth+Metronidazole+Tetracycline #Expensive Regimen:Clarithromycin+Amoxycillin+Omeprazole An women previously diagnosed with a duodenal ulcer and is currently taking medication for her condition. developed profound nausea, vomiting, sweating, hyperventilation, tachycardia, and vertigo .after having few glasses of wine. Which of the following medications is most likely responsible for her latest symptoms? Or A 35-year-old female complains of itching in the vulval area. Hangingdrop examination of the urine reveals trichomonads. What is the preferred treatment for trichomoniasis? a. Doxycycline b. Pyrimethamine c. Pentamidine d. Emetine e. Metronidazole 2. The mechanism of action of metronizaole

A 21-year-old female is taking medication for a recently diagnosed medical problem. While at a college party, she develops facial flushing, headache, nausea, vomiting, and abdominal cramps immediately after having an alcoholic drink. This patient is most likely being treated for which conditions? Patients receiving metronidazole treatment commonly develop symptoms like those described above shortly after ethanol consumption. Metronidazole is commonly used to treat trichomonas vaginitis and bacterial vaginosis. Metronidazole’s interaction with alcohol is thought to result from its inhibition of alcohol oxidizing enzymes, which causes acetaldehyde to accumulate and thus the unpleasant effects. Disulfiram is an aldehyde dehydrogenase inhibitor that also causes acetaldehyde accumulation and a similar adverse reaction with ethanol consumption. Disulfiram is used in recovering alcoholics to prevent them from relapsing to alcohol use.

Other Anti-Protozoal Drugs: Pentamidine Mechanism -- unknown Pharmacokinetics IV, IM or aerosol Concentrates in liver, spleen, kidneys Slowly released from those sites Doesn't enter CNS Clinical Use Aerosol used for treatment/prophylaxis against Pneumocystis pneumonia (PCP) Adverse Effects Can cause respiratory stimulation followed by depression; hypotension, anemia Adverse effects less common with aerosol administration

Other Anti-Protozoal Drugs: Iodoquinol Used for the local treatment of acute and chronic intestinal amebiasis Used for asymptomatic cyst passers Paromomycin An aminoglycoside Acts locally on ameba Used to treat acute and chronic intestinal amebiasis

3. Anthelminthic drugs ALBENDAZOLE IVERMECTIN PRAZIQUANTEL THIABENDAZOLE MEBENDAZOLE PYRANTEL PAMOATE

Anti-Helmintic Chemotherapy Target is multi-cellular organism Mobility/contractile systems in parasites are important targets Mebendazole-- Wide spectrum anti-helmintic Given orally, less than 10% absorbed Rapidly metabolized, excreted in urine Mechanism-- Blocks microtubule synthesis, blocks vesicle and organelle movement Effective against pinworm, hookworm, Ascaris Dose limited by GI effects; Possibly embryotoxic

Anti-Helmintic Chemotherapy Albendazole-- Wide spectrum anti-helmintic Rapidly and completely metabolized in liver, conjugates excreted in urine Interferes with microtubule aggregation, alters glucose uptake Praziquantel-- Effective treatment for all schistosomes, some trematodes and cestodes 80% bioavailability after oral dosing Rapidly and extensively metabolized, cleared in urine Parent is active species Increases membrane permeability to Ca2+,resulting in contraction and paralysis Headache, dizziness, drowsiness may occur 1.Drug useful in cestode & trematode infections

Anti-Helmintic Chemotherapy Thiabendazole and mebendazole Mechanism of action: block microtubule formation Uses Thiabendazole (broad spectrum):, cutaneous larva migrans, strongyloidiasis (alternative drug) Mebendazole: ascariasis, trichuriasis, hookworm, pinworm (Enterobius vermicularis), cysticercosis (Taenia solium), Echinococcus infestations Adverse effects: abdominal pain, diarrhea 1.Thiabendazole, a benzimidazole derivative, is an antihelminthic drug used primarily to treat infections caused by a. Ascaris lumbricoides (roundworm) b. N. americanus (hookworm) c. Strongyloides d. Enterobius vermicularis e. Taenia saginata (flatworm) The answer is c. Thiabendazole has been shown to be effective against Strongyloides, cutaneous larva migrans, and Trichuris. Adverse effects consist of nausea, vertigo, headache, and weakness. Treatment usually involves oral administration for several days. It has been found to be ineffective in Ascaris, N. americanus, E. vermicularis, and T. saginata.

Anti-Helmintic Chemotherapy Pyrantel pamoate Mechanism of action Acts as a depolarizing neuromuscular blocking agent on the nicotinic receptor Increases the effects of acetylcholine and inhibits cholinesterase in the worm Uses: ascariasis, pinworm (E. vermicularis), hookworm, whipworm (Trichuris trichiura), Trichostrongylus Adverse effects: nausea, vomiting, diarrhea, anorexia Ivermectin Mechanism of action: increases chloride permeability, thus polarizing cells, which leads to paralysis Uses: strongyloidiasis, onchocerciasis 1.The mechanism of action by which pyrantel pamoate is effective for the treatment of Necator americanus (hookworm) disease is a. Interference with cell-wall synthesis b. Interference with cell division c. Inhibition of neuromuscular transmission d. Interference with protein synthesis e. Depletion of membrane lipoproteins The answer is c. Pyrantel pamoate is an antihelminthic that acts primarily as a depolarizing neuromuscular blocker. In certain worms, a spastic neuromuscular paralysis occurs, resulting in the expulsion of the worms from the intestinal tract of the host. Pyrantel also exerts its effect against parasites via release of acetylcholine and inhibition of cholinesterase.

strongyloidiasis tremetodes & cestodes PCP

A 55-year-old construction worker had a mild respiratory infection with flu-like symptoms that resolved in less than 2 weeks. Two months later, a chest radiograph revealed numerous diffuse calcific densities confirming a diagnosis of primary histoplasmosis. Which of the following binds to ergosterol and would be appropriate for treating this patient? Amphotericin B Flucytosine Itraconazole Nystatin Terbinafine Answer: A Amphotericin B & nystatin bind to ergosterol; toxicity due to binding to cholesterol in host cells

A 39-year-old woman has dermatis and pneumonitis with eosinophilia caused by Strongyloides stercoralis (strongyloidiasis). Which of the following medications will paralyze the worm by intensifying GABA-mediated transmission in the worm and would be appropriate for treating the condition of this patient? Chloroquine Ivermectin Praziquantel Primaquine Thiabendazole Answer: B Ivermectin paralyzes worms by increasing chloride permeability

PowerPoint Slides Several of the PowerPoint slides are Copyright © 2002-04, the  American Society for Pharmacology and Experimental Therapeutics (ASPET). All rights reserved. Some of slides in this session are from the above mentioned format and are free for use by members of ASPET.  Some others are from various sources like text book, recommended books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA). Core concepts of various USMLE High yield review series like Kaplan ,BRS etc. are thoroughly explored & integrated whenever necessary