Chemotherapy of parasitic infections.ppt

CHEMOTHERAPY OF PARASITIC INFECTIONS By Gemechu Zeleke (BPharm, MSc, PhD) School of Pharmacy, JU Email: [email protected] 06/28/24 13:43...

CHEMOTHERAPY OF PARASITIC INFECTIONS By Gemechu Zeleke (BPharm, MSc, PhD) School of Pharmacy, JU Email: [email protected] 06/28/24 13:43 1  MODULE OUTLINE Chemotherapy of parasitic infections – Chemotherapy of the protozoal infection Malaria, Amebiasis, Giardiasis, ANTIPROTOZOAL DRUGS Trichomoniasis, Leishmaniasis – Chemotherapy of helminth infections Nematodes (Roundworms), Cestodes (Flatworms) , Trematodes (Flukes) 06/28/24 13:43 2  Malaria 06/28/24 13:43 3  Human Malaria Five species of Plasmodium – P. falciparum. – P. vivax, – P. malariae, & – P. ovale – P. knowlis All may cause severe illness; P falciparum causes most of the serious complications and deaths. The effectiveness of antimalarial agents varies between parasite species and between stages in their life cycles. 06/28/24 13:43 4  Parasite Lifecycle The mosquito becomes infected by taking human blood that contains sexual form of the parasites. The sporozoites that develop in the mosquito are then inoculated into humans at its next feeding. In the exoerythrocytic stage, the sporozoites multiply in the liver to form tissue schizonts. 06/28/24 13:43 5  Parasite Life Cycle… Then, parasites escape from the liver into the bloodstream as merozoites. The merozoites invade red blood cells, multiply in them to form blood schizonts, and finally rupture the cells, releasing a new crop of merozoites. The gametocytes (the sexual stage) form and are released into the circulation, where they may be taken in by another mosquito. 06/28/24 13:43 6  Parasite Life Cycle… P falciparum and P malariae have only one cycle of liver cell invasion and multiplication, and liver infection ceases spontaneously in less than 4 weeks. Then, multiplication is confined to the red blood cells. So, treatment that eliminates these species from the red blood cells four or more weeks after inoculation of the sporozoites will cure these infections. 06/28/24 13:43 7  Parasite Life Cycle… In P vivax and P ovale infections, sporozoites also induce in hepatic cells the dormant stage (the hypnozoite) that causes subsequent recurrences (relapses) of the infection.  Therefore, treatment that eradicates parasites from both the red cells and the liver is required to cure these infections. 06/28/24 13:43 8  Lifecycle of malaria parasite 06/28/24 13:43 9  Drug classification Classified by their selective actions on the parasite's lifecycle. Tissue schizonticides:  Drugs that eliminate tissue schizonts or hypnozoites in the liver – Primaquine Blood schizonticides:  Drugs that act on blood schizonts – Chloroquine, Quinine, Amodiaquine, Proguanil, Pyrimethamine, Mefloquine 06/28/24 13:43 10 Cont … Gametocides  Drugs that prevent infection in mosquitoes by destroying gametocytes in the blood – Primaquine for P falciparum and chloroquine for P vivax, P malariae, and P ovale Sporonticidal  Drugs that render gametocytes non- infective in the mosquito. – Pyrimethamine, Proguanil. 06/28/24 13:43 11  Artemisinins 06/28/24 13:43 12 Cont … None of these drugs prevent infection except for pyrimethamine and proguanil which prevent maturation of P falciparum hepatic schizonts. Blood schizonticides do destroy circulating plasmodia. Primaquine destroys the persisting liver hypnozoites of P vivax and P ovale. 06/28/24 13:43 13  Classification of Antimalarial drugs 06/28/24 13:43 14  Artemisinin and derivatives Artemisinin is a sesquiterpene lactone endoperoxide derived from Artemisia annua. Artemisinin is water insoluble and can only be used orally. Three semisynthetic derivatives with improved potency and bioavailability. – Dihydroartemisinin- Dihydroartemisinin (water soluble; oral administration); – Artemether-(lipid Artemether soluble; oral, intramuscular, & rectally); – Artesunate-(water Artesunate soluble; oral, intravenous, intramuscular, and rectally) 06/28/24 13:43 15   The endoperoxide moiety is responsible for the antimalarial activity The derivatives display improved potency and bioavailability and have largely replaced the use of artemisinin. 06/28/24 13:43 16  Artemisinins and derivatives As a class, the artemisinins are potent and fast- acting antimalarials. They are particularly well suited for the treatment of severe P. falciparum malaria and are also effective against the asexual erythrocytic stages of P. vivax. Artemisinins generally are not used alone because of their limited ability to eradicate infection completely. Now play a key role in the combination therapy of drug-resistant infections. 06/28/24 13:43 17 Artemisinins and derivatives… Antiparasitic Activity These compounds act rapidly against the asexual erythrocytic stages (blood schizont) of P. vivax and P. falciparum. – Artemisinin and its analogs are very rapidly acting blood schizonticides against all human malaria parasites. They have gametocytocidal activity for immature, but not mature gametocytes, but do not affect either primary or latent liver stages. 06/28/24 13:43 18 Artemisinins and derivatives… Artemisinin action involves two steps – First, heme iron within the parasite catalyzes cleavage of the endoperoxide bridge. – This is followed by rearrangement to produce a carbon-centered radical that alkylates and damages macromolecules in the parasite, likely including the ortholog of sarco/endoplasmic reticulum Ca2+-ATPase. 06/28/24 13:43 19 Artemisinins and derivatives… Absorption after oral dosing typically is 30% or less. Half-lives after oral administration are 30– 60 minutes for artesunate and dihydroartemisinin, and 2–3 hours for artemether. Artemisinin, artesunate, and artemether are rapidly metabolized to the active metabolite dihydroartemisinin. Mainly metabolized by glucuronidation. 06/28/24 13:43 20 Artemisinins and derivatives… Clinical uses Treating uncomplicated malaria – Dose (mg) of Artemether + Lumefantrine given twice daily for 3 days 5 to < 15Kg 20 + 120 15 to < 25Kg 40 + 240 25 to < 35Kg 60 + 360 For the treatment of severe P. falciparum malaria – Intravenous Artesunate is superior compared with intravenous quinine. – Artesunate and Artemether rectally. 06/28/24 13:43 21 Artemisinins and derivatives… Adverse Effects & Cautions ACTs have low toxicity and are considered safe for use in nonpregnant adults and children. Nausea, vomiting, diarrhea, and dizziness. Rare serious toxicities include neutropenia, anemia, hemolysis, elevated liver enzymes, and allergic reactions. 06/28/24 13:43 22  Chloroquine Pharmacokinetics Chloroquine is a synthetic 4- aminoquinoline formulated as the phosphate salt for oral use. rapidly and almost completely absorbed from the gastrointestinal tract; and is rapidly distributed to the tissues. From these sites it is slowly released and metabolized (liver dealkylation). The drug readily crosses the placenta. 06/28/24 13:43 23  Chloroquine… highly an effective blood schizonticide. moderately effective against gametocytes of P. vivax, P. ovale, and P. malariae, but not against those of P falciparum. not active against the pre-erythrocytic plasmodium and does not effect radical cure. 06/28/24 13:43 24  Chloroquine… Chloroquine probably acts by concentrating in parasite food vacuoles, prevent the polymerization of heme into hemozoin, and thus eliciting parasite toxicity due to the buildup of free heme. – The drug-heme complexes is thought to kill the parasites via oxidative damage to membranes, digestive proteases. 06/28/24 13:43 25  Chloroquine… Selective toxicity for malarial parasites depends on a chloroquine- concentrating mechanism in parasitized cells. – Chloroquine's concentration in normal erythrocytes is 10-20 times that in plasma; – In parasitized erythrocytes, its concentration is about 25 times that in normal erythrocytes. 06/28/24 13:43 26  Chloroquine… Clinical use Chloroquine is highly effective against the erythrocytic forms of P. vivax, P. ovale, P. malariae, P. knowlesi, and chloroquine-sensitive strains of P. falciparum.  Chloroquine rapidly controls the clinical symptoms and parasitemia of acute malarial attacks. Chloroquine is widely used to treat P. vivax; however, resistant strains have been detected in many endemic regions. For P. falciparum this drug has been largely replaced by artemisinin-based combination therapies. 06/28/24 13:43 27  Chloroquine… Chloroquine is very effective in chemoprophylaxis against all forms of malaria. The drug has no activity against latent tissue forms of P. vivax or P. ovale. Treat hepatic amebiasis. – Chloroquine and hydroxychloroquine have also been used as secondary drugs to treat a variety of chronic diseases because both alkaloids concentrate in lysosomes and have anti- inflammatory properties. 06/28/24 13:43 28  Chloroquine… Prophylaxis for infections with chloroquine-sensitive P. falciparum, P. vivax, P. malariae, and P. ovale Chloroquine phosphate is available for oral administration. Adults take 500 mg chloroquine phosphate weekly starting 1-2 weeks before entering an endemic area and continuing for 4 weeks after leaving. The pediatric dosage is 8.3 mg/kg chloroquine phosphate is taken orally. Prophylaxis for infections with drug-resistant strains of P. falciparum or P. vivax Atovaquone-proguanil (MALARONE) is available for oral dosing only – A fixed-combination tablet containing 250mg atovaquone and 100mg proguanil hydrochloride (adult tablet) or – 62.5mg atovaquone and 25 g proguanil hydrochloride (pediatric tablet). 06/28/24 13:43 29  Chloroquine… Mechanisms of Resistance P falciparum chloroquine resistance transporter (Pfcrt) 06/28/24 Antimycobacterial Drugs 30  Chloroquine… Adverse Effects Chloroquine is very safe. However, its safety margin is narrow, and a single dose of 30 mg/kg may be fatal. Gastrointestinal symptoms, mild headache, pruritus, anorexia, malaise Blurring of vision Irreversible retinopathy, ototoxicity, and myopathy. Discoloration of the nail beds and mucous membranes Hemolytic anemia in patients with Glu-6-P dehydrogenase deficiency. 06/28/24 13:43 31  Chloroquine… Contraindications In patients with a history of epilepsy, myasthenia gravis, liver damage, alcoholism, or neurologic or hematologic disorders, psoriasis – may precipitate acute attacks of these diseases. 06/28/24 13:43 32  Quinine rapidly acting, highly effective blood schizonticide against the four malaria parasites. The drug's molecular mechanism is unclear – Forms complexes with double stranded DNA and prevents strand separation gametocidal for P vivax and P ovale but not very effective against P falciparum gametocytes. 06/28/24 13:43 33  Pharmacokinetics rapidly absorbed widely distributed in body tissues. Bulk of the drug is metabolized in the liver excreted for the most part in the urine. Excretion is accelerated in acid urine. 06/28/24 13:43 34  Clinical Uses Parenteral Treatment of Severe P. falciparum malaria Oral treatment of P. falciparum malaria resistant to chloroquine – Usually in combination with pyrimethamine and sulfonamide Prophylaxis Other Uses: Quinine sulfate sometimes relieves night time leg cramps. 06/28/24 13:43 35  Adverse Effects often causes – nausea, vomiting, hypoglycemia. Cinchonism a less common effect and manifested by – headache, nausea, slight visual disturbances, dizziness, and mild tinnitus and may subside as treatment continues. Hemolytic anemia in patients with Glu-6-P dehydrogenase deficiency Severe toxicity like – fever, skin eruptions, gastrointestinal symptoms, deafness, visual abnormalities, central nervous system effects (syncope, confusion), and quinidine-like effects occurs rarely. Black water fever- dark urine with renal failure 06/28/24 13:43 36  Primaquine Tissue schzonticide and gametocide that forms redox compounds which act as cellular oxidants well absorbed orally completely metabolized excreted in the urine. active against the late hepatic stages (hypnozoites and schizonts) of P vivax and P ovale and – radical cure of these infections. 06/28/24 13:43 37  Primaquine… It is highly active against the primary exoerythrocytic stages of P falciparum. When used in prophylaxis with chloroquine, it protects against P vivax and P ovale. highly gametocidal against the four malaria species. 06/28/24 13:43 38  Primaquine… Clinical Uses Treat relapsing malaria Eradicates the liver stages of P. vivax and P. ovale Interrupt transmission of malaria – Gametocidal for all Plasmodium sp. Pneumocystis carinii pneumonia 06/28/24 13:43 39  Adverse Effects generally well tolerated. infrequently causes – nausea, epigastric pain, abdominal cramps, and headache. Serious adverse effects – leukopenia and agranulocytosis are rare. Hemolytic anemia in patients with Glu-6-P dehydrogenase deficiency. 06/28/24 13:43 40  Proguanil and Pyrimethamine dihydrofolate reductase inhibitors. slowly but adequately absorbed from the gastrointestinal tract. slow acting blood schizonticides against susceptible strains of all four malarial species. 06/28/24 13:43 41  Cont… Proguanil (but not pyrimethamine) has a marked effect on the primary tissue stages of susceptible P falciparum and therefore may have causal prophylactic action. Resistance to both is found worldwide for P falciparum and somewhat less ubiquitously for P vivax. 06/28/24 13:43 42  Clinical uses Chemoprophylaxis Treatment of Chloroquine-Resistant Falciparum Malaria Toxoplasmosis treatment 06/28/24 13:43 43  Adverse Effects well tolerated. In the high doses pyrimethamine causes megaloblastic anemia, agranulocytosis and thrombocytopenia – leucovorin calcium is given concurrently 06/28/24 13:43 44  Mefloquine Blood schizonticide with unkown MOA Long half life (17 days) owing to extensive enterohepatic recirculation and binding to tissue and plasma proteins Excreted in feces Used in the prophylaxis and treatment of choloroquine resistant P. falciparum Less toxic than quinine May cause NV, dizziness, seizures, hallucinations and depression 06/28/24 13:43 45  Summery Infections Treatment Severe - Artesunate (i.v. or i.m.) 2.4 mg/kg immediately, then at 12, malaria: 24 h & daily, or - Artemether (i.m) 3.2mg/kg initial dose followed by 1.6 mg/kg daily, or - Quinine dihydrochloride (20 mg/kg) by slow intravenous infusion Uncomplicated - Artemether 1.4–4 mg/kg + lumefantrine 10–16 mg/kg twice for : P. 3 days , or falciparum and - Artesunate 4 mg/kg + amodiaquine 10 mg/kg once daily for 3 chloroquine- days , or resistant P. - Artesunate 4 mg/kg + mefloquine 8.3 mg/kg once daily for 3 vivax infections days , or - Dihydroartemisinin 4 mg/kg + piperaquine 18 mg/kg once daily 3 days, or - Artesunate 4 mg/kg + pyronaridine 7.5–15 mg/kg, once daily for 3 days Uncomplicated - Chloroquine: 10 mg base/kg po immediately (Day 1), followed chloroquine- by sensitive: P. 10 mg base/kg po at 24 hours (Day 2), then vivax, P. ovalea, 5 mg base/kg po at 48 hour 10 (Day 3) P. malariae infections Pregnant - P. falciparum during first trimester of pregnancy: oral quinine Women (10 mg/kg salt or 8.3 mg/kg base three times a day for seven days). - P. vivax: chloroquine in all trimesters. 06/28/24 13:43 46 - Chloroquine-resistant P. falciparum and P. vivax infection:  Chemotherapy of other protozoal infections Amebiasis, giardiasis, trichomoniasis, trypanosomiasis, leishmaniasis 06/28/24 13:43 47  Amebiasis 06/28/24 13:43 48  Amebiasis Amebiasis is infection with Entamoeba histolytica (anaerobic parasite). Many individuals remain asymptomatic. In other individuals, E. histolytica trophozoites invade into the colonic mucosa with resulting colitis and bloody diarrhea (amebic dysentery). In a smaller proportion of patients, E. histolytica trophozoites invade through the colonic mucosa, reach the portal circulation, and travel to the liver, where they establish an amebic liver abscess. 06/28/24 13:43 49  Amebiasis… Metronidazole and tinidazole are a drugs of choice for the treatment of amebic colitis, amebic liver abscess, and any other extraintestinal form of amebiasis. Metronidazole is so well absorbed in the gut, levels may not be therapeutic in the colonic lumen, and it is less effective against cysts.  Hence patients with amebiasis (amebic colitis or amebic liver abscess) also should receive a luminal agent to eradicate the E. histolytica trophozoites residing within the gut lumen. 06/28/24 13:43 50  Amebiasis… Luminal agents are also used to treat asymptomatic individuals found to be infected with E. histolytica. The non-absorbed aminoglycoside paromomycin and the 8- hydroxyquinoline compound iodoquinol are two effective luminal agents. 06/28/24 13:43 51  Metronidazole & Tinidazole Metronidazole, a nitroimidazole, is the drug of choice in the treatment of extraluminal amebiasis. Tinidazole, a related nitroimidazole, better tolerated than metronidazole, and it offers simpler dosing regimens. Oral metronidazole and tinidazole are readily absorbed. The half-life of unchanged drug is 7.5 hours for metronidazole and 12-14 hours for tinidazole. Metronidazole and its metabolites are excreted mainly in the urine. 06/28/24 13:43 52  Metronidazole & Tinidazole… Metronidazole is a prodrug; it requires reductive activation of the nitro group by susceptible organisms. Its selective toxicity toward anaerobic and microaerophilic pathogens such as T. vaginalis, E. histolytica, and G. lamblia and various anaerobic bacteria derives from their energy metabolism, which differs from that of aerobic cells. – These organisms, unlike their aerobic counterparts, contain electron transport components such as ferredoxins, Ferredoxins are small Fe-S proteins that have a sufficiently negative redox potential to donate electrons to metronidazole. 06/28/24 13:43 53 06/28/24 13:43 54  Metronidazole or tinidazole Clinical indications – Metronidazole or tinidazole is the drug of choice in the treatment of all tissue infections with E histolytica. – Metronidazole is the treatment of choice for giardiasis. – Metronidazole is the treatment of choice for trichomoniasis. 06/28/24 13:43 55  Metronidazole or tinidazole… Adverse Effects & Cautions Nausea, headache, dry mouth, or a metallic taste in the mouth. Infrequent adverse effects include vomiting, diarrhea, insomnia, weakness, dizziness, thrush, rash, dysuria, dark urine, vertigo, paresthesias, and neutropenia. Taking the drug with meals lessens gastrointestinal irritation Metronidazole has a disulfiram-like effect, so that nausea and vomiting can occur if alcohol is ingested during therapy. 06/28/24 13:43 56  Metronidazole or tinidazole… Drug interaction Metronidazole has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. Phenytoin and phenobarbital may accelerate elimination of the drug, while cimetidine may decrease plasma clearance. 06/28/24 13:43 57  Paromomycin Paromomycin sulfate is an aminoglycoside antibiotic that is not significantly absorbed from the gastrointestinal tract. It is used only as a luminal amebicide and has no effect against extraintestinal amebic infections. The small amount absorbed is slowly excreted unchanged, mainly by glomerular filtration. However, the drug may accumulate with renal insufficiency and contribute to renal toxicity. 06/28/24 13:43 58  Paromomycin… Paromomycin is an effective luminal amebicide that appears to have similar efficacy and probably less toxicity than other agents. Adverse effects: abdominal distress and diarrhea. Paromomycin should be avoided in patients with significant renal disease and used with caution in persons with GI ulcerations. 06/28/24 13:43 59  Giardiasis Giardiasis, caused by the flagellated protozoan Giardia intestinalis. Infection results from ingestion of the cyst form of the parasite, which is found in fecaly contaminated water or food. Giardia is a zoonosis, and cysts shed from animals or from infected humans can contaminate recreational and drinking water supplies. Giardia was the most common cause of waterborne outbreaks of diarrhea. 06/28/24 13:43 60  Giardiasis… Human-to-human transmission via the fecal-oral route is especially common among children in day- care centers and nurseries Infection with Giardia results in one of three syndromes:  Asymptomatic carrier state -excrete Giardia cysts and serve as a source for new infections,  Acute self-limited diarrhea- watery, foul- smelling stools, abdominal distension, and flatus  Chronic diarrhea- mal-absorption and weight loss 06/28/24 13:43 61  Giardiasis… Chemotherapy with a 5-day course of metronidazole usually is successful. A single dose of tinidazole probably is superior to metronidazole for the treatment of giardiasis. The non-absorbed aminoglycoside paromomycin has been used to treat pregnant women. Furazolidone is also indicated. 06/28/24 13:43 62  Trichomoniasis Trichomoniasis is caused by the flagellated protozoan Trichomonas vaginalis. This organism inhabits the genitourinary tract of the human host, where it causes vaginitis in women and, uncommonly, urethritis in men. Metronidazole remains the drug of choice for the treatment of trichomoniasis. Tinidazole, another nitroimidazole that was approved and appears to be better tolerated than metronidazole. 06/28/24 13:43 63  Toxoplasmosis Caused by the obligate intracellular protozoan Toxoplasma gondii. The four most common routes of infection in humans are (1) ingestion of undercooked meat containing tissue cysts; (2) ingestion of vegetable matter contaminated with soil containing infective oocysts; (3) direct oral contact with feces of cats shedding oocysts; and (4) transplacental fetal infection with tachyzoites from acutely infected mothers. The acute illness is usually self-limiting, and treatment rarely is required. Individuals who are immunocompromised, however, are at risk of developing toxoplasmic encephalitis from reactivation of tissue cysts deposited in the brain. (in patients with AIDS) 06/28/24 13:43 64  Toxoplasmosis The primary treatment for toxoplasmic encephalitis consists of the antifolates pyrimethamine and sulfadiazine along with folinic acid. However, therapy must be discontinued in about 40% of cases because of toxicity owing primarily to the sulfa compound. In this instance, clindamycin can be substituted for sulfadiazine without loss of efficacy. Alternative regimens combining azithromycin, clarithromycin, atovaquone, or dapsone with either trimethoprim-sulfamethoxazole or pyrimethamine and folinic acid are less toxic but also less effective than the combination of pyrimethamine and sulfadiazine. 06/28/24 13:43 65  Leishmaniasis Leishmaniasis is a complex vector-borne zoonosis caused by about 20 different species of obligate intramacrophage protozoa of the genus Leishmania. – The parasite multiply inside the macrophages and can be transmitted to humans by the bites of sandflies. It is a fatal disease unless treated. Classified into cutaneous, mucocutaneous, diffuse cutaneous, and visceral (kala azar) forms. Cutaneous forms are self-limiting, with cures within 3 to 18 months after infection. However, this form of the disease can leave disfiguring scars. The drugs include: Miltefosine, Amphotericin, Pentamidine isethionate 06/28/24 13:43 66  Leishmaniasis Pentamidine isethionate and miltefosine constitute the therapeutic arsenal available for systemic treatment of leishmaniasis. Pentavalent antimonials are the oldest drugs and are still considered first-line treatments against most forms of leishmaniasis. However, their adverse effects—cardiotoxicity, particularly evident in HIV–VL co-infection; renal failure; and pancreatitis—represent limitations of this treatment modality. In addition, antileishmanial drugs face specific difficulties penetrating inside the macrophages to reach parasites. 06/28/24 13:43 67  Miltefosine Miltefosine, is the drug of choice for visceral (kala azar) leishmaniasis treatment. The drug also appears to have promise for the treatment of the cutaneous disease. Miltefosine is an alkylphosphocholine analog. Miltefosine disturb the lipid-dependent cell signaling pathway and induce apoptosis. 06/28/24 13:43 68  Miltefosine… Miltefosine is well absorbed orally and distributed throughout the human body. Oral miltefosine is for treatment of cutaneous or visceral leishmaniasis (100 mg/kg daily for 28 days). A similar dosing schedule has shown efficacy against cutaneous disease. It cannot be given intravenously because it has hemolytic activity. Adverse effects: vomiting, diarrhea , Elevated hepatic transaminases and serum creatinine. 06/28/24 13:43 69  Amphotericin B Amphotericin B for the treatment of visceral leishmaniasis. It is a highly effective antileishmanial agent. Amphotericin complexes with ergosterol precursors in the cell membrane, forming pores that allow ions to enter the cell. Amphotericin B is nephrotoxic. 06/28/24 13:43 70  Amphotericin B… The recommended dose for the treatment of visceral leishmaniasis is 3 mg/kg per day intravenously for days 1 to 5, 14, and 21, with the dose being increased to 4 mg/kg and extended to days 1 to 5, 10, 17, 24, 31, and 38 for immunosuppressed patients The efficacy depends on the patient's immunological status. 06/28/24 13:43 71  Amphotericin B… Adverse Effects Fever, chills, muscle spasms, vomiting, headache Hypotension (related to infusion) Renal damage associated with decreased renal perfusion (a reversible) and renal tubular injury (irreversible). Anaphylaxis, liver damage and anemia occurs infrequently. 06/28/24 13:43 72  Liposomal amphotericin B The FDA approved liposomal amphotericin B Is effective for the treatment of cutaneous and visceral leishmaniasis. Amphotericin is a highly effective antileishmanial agent that cures nearly 100% of the cases of visceral leishmaniasis in clinical studies, and a drug of choice for antimonial-resistant cases. The lipid preparations of the drug have reduced toxicity, but the cost of the drug and the difficulty of administration remain a problem in endemic regions. 06/28/24 13:43 73  Anthelmintics 06/28/24 13:43 74  Helminthic infestations  Helminths (worms) are multicellular organisms that infect very large numbers of humans and cause a broad range of diseases. Groups of helminths include (1)Intestinal nematodes (roundworms), (2)Tissue-invading nematodes (tissue roundworms and filariae), (3)Cestodes (tapeworms), and (4)Trematodes (flukes) They enter the human host via contaminated food, bites of carrier insects, or direct penetration of the skin. 06/28/24 13:43 75  Nematode Infestations (Intestinal) Ascariasis (Giant Enterobiasis (Pinworm Roundworm Infestation) Infestation) Most prevalent. Adult pinworms inhabit the ileum and Ascariasis is usually asymptomatic. large intestine. However, serious complications can also result. Trichuriasis (Whipworm Hookworm Infestation Infestation) It is most common in rural areas Larvae and adult worms inhabit the where hygiene is poor. large intestine. Adult hookworms attach to the wall of the small intestine and suck Strongyloidiasis blood. As a result, it is associated with (Threadworm Infestation) Larval and adult threadworms inhabit chronic blood loss and anaemia. the small intestine. 06/28/24 13:43 76  Nematode Infestations (Extraintestinal)  Lymphatic Filarial Infestation Wuchereria bancrofti and Brugia malayi are filarial nematodes that invade the lymphatic system. Result in elephantiasis.  Onchocerciasis (River Blindness) Onchocerca volvulus is a filarial nematode. Heavy infestation with O. volvulus causes dermatologic and ophthalmic symptoms. Dermatologic manifestations include subcutaneous nodules. 06/28/24 13:43 77  Cestode (tapeworms) Infestations  Taeniasis (Beef and Pork Tapeworm Infestation) Taeniasis is acquired by eating undercooked beef or pork that contains tapeworm larvae.  Trematode Infestations Schistosomiasis (Blood Fluke) Infestations 06/28/24 13:43 78  Anthelmintic drugs 06/28/24 13:43 79  Mebendazole Mebendazole is a synthetic benzimidazole that has a wide spectrum of anthelminthic activity. Mebendazole acts by inhibiting microtubule synthesis, thus prevent microtubule-dependent uptake of glucose. It kills hookworm, Ascaris, and Trichuris eggs. It indicated for use in ascariasis, trichuriasis, hookworm and pinworm infections. It can be taken before or after meals; the tablets should be chewed before swallowing. Mebendazole is nearly free of adverse effects. Mebendazole is teratogenic in animals and therefore contraindicated in pregnancy. 06/28/24 13:43 80  Albendazole Albendazole is a benzimidazole carbamate. After oral administration, it rapidly undergoes first-pass metabolism in the liver to the active metabolite albendazole sulfoxide. Albendazole is a broad-spectrum oral anthelminthic. Albendazole is active against many cestode and nematode parasites. Albendazole inhibits polymerization of tubulin and thereby prevents formation of cytoplasmic microtubules. As a result, microtubule-dependent uptake of glucose is prevented. 06/28/24 13:43 81  Albendazole… Clinical Uses Ascariasis, trichuriasis, hookworm and pinworm infections. Albendazole is administered on an empty stomach when used against intraluminal parasites but with a fatty meal when used against tissue parasites. Adverse Effects Albendazole is generally well tolerated. Mild and transient epigastric distress, diarrhea, headache, nausea, dizziness, lassitude, and insomnia can occur. Mild to moderate liver impairment (in 16% of patients). Bone marrow suppression: granulocytopenia, agranulocytosis. 06/28/24 13:43 82  Ivermectin  Ivermectin, a semisynthetic macrocyclic lactone derived from the soil actinomycete Streptomyces avermitilis, is a mixture of avermectin B1a and B1b.  Ivermectin is active against many nematodes. Currently, the drug has two approved indications: onchocerciasis (a major cause of blindness worldwide) and intestinal strongyloidiasis.  Ivermectin is active against the tissue microfilariae of O. volvulus (the cause of onchocerciasis), but not against the adult form.  Ivermectin can also be used to kill ectoparasite. 06/28/24 13:43 83  Ivermectin… They are an agonist of glutamate-gated chloride channels (GluCIs) followed by hyperpolarization leading to flaccid paralyze nematodes and arthropods. Recently, MDA of ivermectin to humans is recommended by WHO for treatment and prevention of onchocerciasis, lymphatic filariasis, strongyloidiasis, and scabies in poor-resource settings. Clinical use: Onchocerciasis Strongyloidiasis It has been used with diethylcarbamazine and albendazole for the control of W bancrofti, but it does not kill adult worms. Infrequent adverse effects: fatigue, dizziness, nausea, vomiting, abdominal pain, and rashes. 06/28/24 13:43 84  Piperazine Piperazine is an alternative for the treatment of ascariasis, with cure rates over 90% when taken for 2 days, but it is not recommended for other helminth infections. It is readily absorbed orally. For ascariasis, the dosage of piperazine is 75 mg/kg (maximum dose, 3.5 g) orally once daily for 2 days. Adverse effects: nausea, vomiting, diarrhea, abdominal pain, dizziness, and headache. Piperazine should not be given to pregnant women, patients with impaired renal or hepatic function. 06/28/24 13:43 85  Piperazine… Mechanism of action Piperazine binds directly and selectively to muscle membrane GABA receptors, presumably causing hyperpolarization of nerve endings, resulting in flaccid paralysis of the worm. Piperazine is highly effective against Ascaris lumbricoides and Enterobius vermicularis. The predominant effect of piperazine on Ascaris is a flaccid paralysis that results in expulsion of the worm by peristalsis. 06/28/24 13:43 86  Praziquantel Praziquantel is a synthetic isoquinoline-pyrazine derivative. Praziquantel appears to increase the permeability of trematode and cestode cell membranes to calcium, resulting in paralysis, and death. Plasma concentrations of praziquantel increase when the drug is taken with a high-carbohydrate meal. 06/28/24 13:43 87  Praziquantel… Clinical indications Schistosomiasis A drug of choice for all forms of schistosomiasis. – The dosage is 20 mg/kg per dose for two (S mansoni and S haematobium) or three (S japonicum and S mekongi) doses at intervals of 4–6 hours. Taeniasis – A single dose of praziquantel, 5–10 mg/kg, results in nearly 100% cure rates for T saginata, and T solium infections. – Mild and transient adverse effects which persist for about 1 day are common. 06/28/24 13:43 88  Diethylcarbamazine  Diethylcarbamazine, a synthetic piperazine derivative, is rapidly absorbed from the gastrointestinal tract.  Diethylcarbamazine is a drug of choice in the treatment of filariasis, loiasis, and tropical eosinophilia.  Diethylcarbamazine immobilizes microfilariae and alters their surface structure, displacing them from tissues and making them more susceptible to destruction by host defense mechanisms. 06/28/24 13:43 89  Thiabendazole Thiabendazole is a benzimidazole compound. Thiabendazole is an alternative to ivermectin or albendazole for the treatment of strongyloidiasis. 06/28/24 13:43 90  Summery 06/28/24 13:43 91  THANKS ! 06/28/24 13:43 92