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Antiparasitic Drugs Fen-Fei Gao Overview 一.Antimalarial drugs 二.Anti-amebiasis drugs and Anti-trichomoniasis drugs 三.Anti-schistosomiasis drugs and Anti-filariasis drugs 四.Anthelmintic drugs Malaria(疟疾) • Malaria is caused by plasmodium (疟原虫) whose sporozoites(子孢子) was inoculated to initiate human infection by anopheline mosquito(按蚊). • Four species of plasmodium cause human malaria: – Plasmodium falciparum (恶性疟) → responsible for nearly all serious complications(并发症) and deaths. – P vivax (间日疟) benign malaria – P malariae (三日疟) – P ovale(卵圆形疟) → seldom Parasite(寄生虫) Life Cycle I. Asexual stage in human: ① ② ③ II. Primary exoerythrocytic(红细胞外) stage: sporozoites(子孢子) invade liver cells → schizonts(裂殖体)—— incubation period Asexual erythrocytic stage: merozoites(裂殖子) invade erythrocytes, trophozoites(滋养体) → schizonts, rupture host erythrocytes → repeated cycles —— cause clinical illness Secondary exoerythrocytic stage: In P vivax and P ovale infections, a dormant(静止的) hepatic stage, hypnozoite(睡眠子孢子) → relapses(复发) Sexual stage in anopheline mosquito: • Sexual stage gametocytes(配子体) also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites. Drug Classification • Classified by their selective actions on different phases of the parasite life cycle: 1. Tissue schizonticides(杀组织裂殖体药): eliminate developing or dormant(静止) liver forms. 2. Blood schizonticides: act on erythrocytic parasites. 3. Gametocides(杀配子体药): kill sexual stages and prevent transmission to mosquitoes. • No one available agent can reliably effect a radical cures. Control symptoms Chloroquine • A synthetic 4-aminoquinoline formulated as the phosphate salt for oral use. • Pharmacokinetics – Rapidly and almost completely absorbed from the gastrointestinal tract. – Very large apparent volume of distribution of 100-1000 L/kg. – Necessitate the use of a loading dose to rapidly achieve effective serum concentrations. – Slowly released from tissues and metabolized. – Principally excreted in the urine. • Pharmacological Effects 1. Antimalarial action: ①highly effective blood schizonticide. ② Moderately effective against gametocytes of P vivax, P ovale, and P malariae but not against those of P falciparum. ③ not active against liver stage parasites. 2. 3. Mechanism: ① plasmodium aggregates chloroquine. ②chloroquine incorporated into DNA chain of plasmodium → inhibit proliferation. ③ chloroquine prevents the polymerization(聚合作用) of the hemoglobin(血 红蛋白) breakdown product, heme(血红素), into hemozoin(疟原虫色素) and thus eliciting parasite toxicity due to the buildup of free heme. ④ pH↑→ plasmodium protease activity↓ Resistance: very common among strains of P falciparum and uncommon but increasing for P vivax. The mechanism of resisitance to chloroquine is resistant strains excretes drug more rapidly. Killing Amibic trophozoites : chloroquine reaches high liver concentrations. Immunosuppression action: • Clinical Uses 1. Treatment: nonfalciparum and sensitive falciparum malaria. Primaquine(伯氨喹) must be added for the radical cure of P vivax and P ovale, because chloroquine does not eliminate dormant liver forms of these species. 2. Chemoprophylaxis: for without resistant falciparum malaria in malarious regions. 3. Amebic liver abscess(阿米巴肝脓肿): not effective in the treatment of intestinal or other extrahepatic amebiasis. • Adverse Effects and Cautions – Usually very well tolerated, even with prolonged use. – Pruritus(瘙痒) is common. – Nausea, vomiting, abdominal pain, headache, anorexia(食欲 缺乏), malaise(不适), blurring of vision(视力模糊), and urticaria(风疹) are uncommon. – Dosing after meals may reduce some adverse effects. – Rare reactions include hemolysis in G6PD-deficient persons, impaired hearing, confusion, psychosis, seizures, hypotension, ECG changes. – teratogenesis Control symptoms Quinine • Quinine and quinidine remain first-line therapies for falciparum malaria——especially severe disease. • Quinine is an alkaloid derived from the bark of the cinchona tree(金鸡纳树皮), a traditional remedy for intermittent fevers(间歇性热) from South America. • Quinine is the levorotatory stereoisomer of quinidine. • Rapidly absorbed after oral administration. • Metabolized in the liver and excreted in the urine. • Pharmacological Effects – Highly effective blood schizonticide against the four species of human malaria paresites. – Gametocidal against P vivax and P ovale but not P falciparum. – Not active against liver stage parasites. – Depressing cardiac contractility and conduction, lengthening refractory period, exciting uterine smooth muscle, depressing central nervous system, little antipyretic-analgesic effect. • Clinical Uses: mainly for chloroquine-resistant falciparum malaria, especially for cerebral malaria. – Parenteral(胃肠外的) treatment of severe falciparum malaria – Oral treatment of falciparum malaria – Malarial chemoprophylaxis – Babesiosis(巴贝西虫病) • Adverse Effects and Cautions 1. Cinchonism: tinnitus(耳鸣), headache, nausea, dizziness(眩晕), flushing(面红), visual disturbances 2. Cardiovascular effects: severe hypotension and arrhythmia can follow too-rapid intravenous infusion. 3. Idiosyncrasy: hemolysis with G6PD deficiency. 4. Others: hypoglycemia through stimulation of insulin release, stimulate uterine contractions Control symptoms Mefloquine • A synthetic 4-quinoline methanol that is chemically related to quinine. • Pharmacokinetics – Only be given orally because severe local irritation occurs with parenteral use. – Well absorbed. – Highly protein-bound, extensively distributed in tissues, and eliminated slowly. t1/2 is 20 days. • Pharmacological Effects: – Strong blood schizonticidal activity against P falciparum and P vivax, but not active against hepatic stages or gametocytes. • Clinical Uses – Chemoprophylaxis: – Treatment: mainly for chloroquine-resistant falciparum malaria. • Adverse Effects and Cautions – Nausea, vomiting, diarrhea, abdominal pain—— dose-dependent – Neuropsychiatric toxicities: dizziness, headache, behavioral disturbances, psychosis, seizures. Control symptoms Malaridine • Developed by China. • blood schizonticidal activity. • Treatment for all types malaria, including chloroquine-resistant falciparum malaria. • Mechanism: destroy parasite compound membrane and food vacuoles. Control symptoms Artemisinin • Extracted from yellow flower mugwort. • Kill trophozoites of erythrocytes. • quick and effective. maybe kill earlier period trophozoites. • Through blood-brain barrie, treatment for cerebral malaria. • recurrence rate is high. • Resistence. • Interaction with others antimalarial drugs: Control symptoms • Artemether and Artesunate • Dihydroartemisinin Control relapse and transmission Primaquine • Synthetic 8-aminoquinoline. • Pharmacological Effects – Against hepatic stages of malaria parasites. – The only available agent active against the dormant hypnozoite(睡眠子孢子) stages of P vivax and P ovale. – Also gametocidal against the four human malaria species. • Clinical Uses – Therapy (Radical Cure) of Acute Vivax and Ovale Malaria: chloroquine + primaquine – Terminal Prophylaxis of Vivax and Ovale Malaria: prevent a relapse – Chemoprophylaxis of Malaria: protection against falciparum and vivax malaria. But potential toxicities of long-term use limited its routinely administration. – Gametocidal Action: A single dose of primaquine (45 mg base) can be used as a control measure to render P falciparum gametocytes noninfective to mosquitoes. This therapy is of no clinical benefit to the patient but will disrupt transmission – Pneumocystis carinii(卡氏肺孢子虫) infection: clindamycin(克 林霉素)+primaquine → mild to moderate pneumocystosis • Adverse Effects and Cautions • Nausea, epigastric(腹上部的) pain, abdominal cramps(痛性痉挛), headache. • Hemolysis or methemoglobinemia(高铁血红蛋 白血症), especially in persons with G6PD deficiency or other hereditary metabolic defects. Etiological factor prophylaxis Pyrimethamine • Pharmacokinetics – Slowly but adequately absorbed from the gastrointestinal tract. – Slowly eliminated and excreted from urine. • Pharmacological Effects – Kill schizonts of primary exoerythrocytic stage. – Act slowly against premature schizonts of erythrocytic stage. – No action against gametocytes, but can inhibit development of plasmodium in mosquito. – Inhibit plasmodial dihydrofolate reductase → inhibiting breeding of plasmodium. • Adverse Effects and Cautions – Gastrointestinal symptoms, skin rashes. – Interfering folic acid metabolism in human → megalocyte anemia, granulocytopenia. – Acute intoxication – Teratogenesis Etiological factor prophylaxis Sulfonamides and Sulfone • Competing dihydropteroatesye synthase with PABA → inhibiting to form dihydrofolic acid → inhibiting production of purines and synthesis of nucleic acids. • Only inhibiting plasmodial of exoerythrocytic stage • Not used as single agents for the treatment. Combination with other agents. Rational Use of Antimalarial Drugs 1. Choice of Antimalarial Drugs: – – Control symptoms: chloroquine Cerebral malaria: chloroquine phosphate, quinine bimuriate, artemisinin —— injection Chloroquine-resistant falciparum malaria: quinine, mefloquine, artemisinin Dormant hypnozoite stages : pyrimethamine + primaquine Prophylaxis: pyrimethamine, chloroquine – – – 2. Combination therapy: chloroquine + primaquine: symptom stages pyrimethamine + primaquine: dormant hypnozoite stages Combination of drugs with different mechanisms: therapeutic effect↑, resistance↓ Anti-amebiasis Drugs • Amebiasis is infection with Entamoeba histolytic. • Amebiasis is transmitted through gastrointestinal tract. • Ameba has two stages of development: cyst(包 囊) and trophozoite(滋养体). Cysts → small intestine → little trophozoites (ileocecum) cysts (colon) —— asymptomatic intestinal infection, source of infection big trophozoites (tissues of intestine) —— intestinal amebiasis Metronidazole • A nitroimidazole(硝基咪唑类). The nitro group of metronidazole is chemically reduced in anaerobic(厌氧 的) bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antimicrobial activity. • Pharmacokinetics – Oral metronidazole is readily absorbed and permeates all tissues by simple diffusion. – Protein binding is low (<20%) – Through blood brain barrier – Metabolizing in liver. – Excreted mainly in the urine. • Pharmacological Effects and Clinical Uses 1. Anti-amebiasis: kills E histolytic trophozoites but not cysts. Treatment of all tissue infections with E histolytic. No effection against luminal parasites and so must be used with a luminal amebicide to ensure eradication of the infection. 2. Anti-trichomoniasis(滴虫病): 3. Anti-anaerobic bacteria(厌氧细菌): 4. Anti-giardiasis(梨形鞭毛虫病): • Adverse Effects and Cautions – Nausea, headache, dry mouth, a metallic taste in the mouth. – Infrequent: vomiting, diarrhea, rash, insomnia, neutropenia, …… – Rare: severe central nervous system toxicity ( ataxia, encephalopathy(脑病), seizures)——drug withdrawal – Has a disulfiram(双硫仑,乙醛脱氢酶抑制药)-like effect, so that nausea and vomiting can occur if alcohol is ingested during therapy. Emetine and Dehydroemetine • Emetine, an alkaloid derived from ipecac(吐根), and dehydroemetine, a synthetic analog, are effective against tissue trophozoites of E histolytic . • Because of major toxicity concerns they have been almost completely replaced by metronidazole. • Administered subcutaneously (preferred) or i.m. (but never i.v.) because oral preparations are absorbed erratically(不规律). • Pharmacological Effects and Clinical Uses • kills E histolytic trophozoites of histolytic tissues but no effection against luminal trophozoites. a luminal amebicide should also be given. • Rapidly alleviate severe intestinal symptoms, used to treat amebic dysentery(痢疾) for the minimum period because of toxicity. • Occasionally as alternative therapies for amebic liver abscess. • Mechanisms Inhibiting peptidyl-tRNA transposition → inhibiting elongation of peptide chain → inhibiting protein synthesis → interfering cleavage and breeding of trophozoites • Adverse Effects and Cautions low selection → also inhibiting protein synthesis of eukaryocyte. Toxicity increase with length of therapy. 1. Cardiac toxicity: arrhythmias, congestive heart failure, hypotention, ECG changes 2. Neuromuscular blockade: muscle weakness and discomfort 3. Local stimulation: pain and tenderness in the area of injection. 4. Gastrointestinal tract discomfort: nausea, vomiting Not be used in patients with cardiac or renal disease, in young children, or in pregnancy. Diloxanide • Diloxanide furoate(糠酸盐) is a dichoroacetamide(二 氯乙酰胺) derivative. • Effective luminal amebicide but is not active against tissue trophozoites. • The unabsorbed diloxanide in the gut is the active antiamebic substance. • Effective for asymptomatic luminal infections. • It is used with a tissue amebicide, usually metronidazole. • Adverse Effects: flatulence(胃肠气胀), nausea, abdominal cramps(痛性痉挛), rashes, abortion(流产). Paromomycin • Aminoglycoside(氨基糖苷) antibiotic. • Not significantly absorbed from the gastrointestinal tract. • Only as a luminal amebicide and has no effect against extraintestinal amebic infections. • inhibiting protein synthesis → kill trophozoites; • inhibiting symbiosis flora → indirectly inhibiting ameba protozoa. Chloroquine • • Chloroquine reaches high liver concentrations → treatment of amebic liver abscess. Not effective in the treatment of intestinal or other extrahepatic amebiasis. Anti-trichomoniasis Drugs • Metronidazole • Acetarsol (乙酰胂胺) Anti-schistosomiasis Drugs • Schistosoma including: – Schistosoma japonicum (epidemic in China) – Schistosoma mansoni – Schistosoma haematobium • Antimony potassium tartrate —— inhibition of phosphofructokinase(磷酸果糖激酶) —— treatment of schistosomiasis. But greater toxicity, long treatment course, i.v. limit its uses. Praziquantel • A synthetic isoquinoline-pyrazine derivative. • Pharmacological Effects – Effective in the treatment of schistosome(血吸虫) infections of all species and most other trematode(吸虫) and cestode(绦虫) infections, including cysticercosis(囊虫病). – Against adult worms and immature stages. • Mechanisms – Increases cell membrane permeability to calcium → vacuolization, marked contraction, spastic paralysis, dislodgement(赶出), death. • Clinical Uses – Schistosomiasis(血吸虫病) – Clonorchiasis(支睾吸虫病) and Opisthorchiasis(后睾吸虫 病) – Paragonimiasis(肺吸虫病) – Taeniasis(绦虫病) and Diphyllobothriasis(裂头绦虫病) – Neurocysticercosis(神经囊虫病) – Hydatid(棘球蚴) disease – Other parasites: fasciolopsiasis(姜片虫病), metagonimiasis(后殖吸虫病), heterophyiasis(异形吸虫病) • Adverse Reactions – Mild and trainsient. – Headache, dizziness, drowsiness, lassitude(疲倦) – low-grade fever, pruritus(瘙痒), and skin rashes (macular(斑疹的) and urticarial(荨麻疹))—due to the release of foreign protein from dying worms. Anti-filariasis Drugs • Epidemic in China: – Wuchereria bancrofti(班氏丝虫, 吴策线虫) – Brugia malayi(布鲁丝虫, 马来丝虫) • Parasitize in lymphatic system. Diethylcarbamazine • A synthetic piperazine derivative. Rapidly absorbed from the gastrointestinal tract; excreted rapidly in the presence of acidic urine. • Pharmacologic Effects and Mechanisms – Immobilizes microfilariae(微丝蚴) (which results in their displacement in tissues) and alters their surface structure, making them more susceptible to destruction by host defense mechanisms. – Adult parasites are killed more slowly. Against adult worms is unknown. • Clinical Uses – 1. 2. • The drug should be taken after meals. Wuchereria bancrofti(班氏丝虫), Brugia malayi(马来丝虫), Brugia timori, and Loa loa(罗阿丝虫) Tropical Eosinophilia(嗜酸性细胞增多) Adverse Reactions – – Drug-induced Reactions: mild and transient, headache, malaise(不适), anorexia(食欲缺乏), nausea, …… Reactions induced by Dying Parasites: release of foreign proteins. Eosinophilia and leukocytosis. Papular(丘疹的) rash, muscle or joint pains. Anthelmintic Drugs • Classification of Helminth ① Roundworms (nematodes) —— epidemic in China ② Tapeworms ③ Flukes (trematodes) Mebendazole • A synthetic benzimidazole(苯并咪唑) that has a wide spectrum of anthelmintic activity and a low incidence of adverse effects. • Pharmacokinetics – – – – Oral absorption <10% First pass elimination is high. Protein-binding >90% Excreted mostly in the urine, a portion of absored drug and its derivatives are excreted in the bile. – Absorption is increased if the drug is ingested with a fatty meal. • Pharmacologic Effects – Inhibits microtubule(微管) synthesis in nematodes(线虫), thus irreversibly impairing glucose uptake. Intestinal parasites are immobilized or die slowly. – Kills hookworm, ascaris(蛔虫), and trichuris(鞭虫) eggs. • Clinical Uses – Pinworm(蛲虫) infection – Ascaris lumbricoides(蛔虫), Trichuris trichiura (鞭虫), Hookworm, and Trichostrongylus(毛圆线虫) – Other infections: intestinal capillariasis(毛细线虫病), trichinosis(旋毛虫病), taeniasis(绦虫病), strongyloidiasis(类 圆线虫病), dracontiasis(麦地那丝虫病), et al. • Adverse Effects and Cautions – Low-dose: nearly free adverse effects. – Diarrhea, abdominal pain is infrequent. – High-dose: pruritus(瘙痒), rash, eosinophilia(嗜酸 性细胞增多), reversible neutropenia(嗜中性白血 球减少症), musculoskeletal pain(肌肉骨胳痛), fever, transient liver function abnormalities, alopecia(脱发), glomerulonephritis(肾小球肾炎), agranulocytosis(粒细胞缺乏) Albendazole • A benzimidazole carbamate(氨基甲酸酯) • A broad-spectrum oral anthelmintic for treatment of hydatid(包虫囊) disease and cysticercosis(囊虫病), pinworm infection, ascariasis(蛔虫病), trichuriasis(鞭虫病), strongyloidiasis(类圆线虫病), and infections with both hookworm(钩虫) species. • Effect better than Mebendazole. • Clinical Uses – Administered on an empty stomach when used against intraluminal parasites but with a fatty meal when used against tissue parasites. 1. Ascariasis(蛔虫病), Trichuriasis(鞭虫病), and Hookworm and Pinworm(蛲虫) infections. 2. Strongyloidiasis(类圆线虫病) 3. Hydatid(棘球蚴) Disease 4. Neurocysticercosis(神经猪囊尾蚴病) 5. Other infections: cutaneous larva migrans(幼虫迁 徙), gnathostomiasis(颚口线虫病)…… Piperazine • Treatment of ascariasis(蛔虫病). • No longer recommended for treatment of pinworm(蛲 虫) infection, because a 7-day couse of treatment is required. • Not useful in hookworm infection, trichuriasis(鞭虫病), or strongyloidiasis(类圆线虫病). • Causes flaccid(弛缓性) paralysis of ascaris by blocking acetylcholine at the myoneural(肌神经的) junction. • Neurotoxic adverse effects. Levamizole • A synthetic imidazothiazole(咪唑噻唑) derivative and the L isomer of D,Ltetramisole(四咪唑). • Highly effective in eradicating ascaris and trichostrongylus(毛圆线虫属) and moderately effective against both species of hookworm. • Inhibiting succinic dehydrogenase(琥珀酸脱氢 酶) → energy↓ → flaccid paralysis • Immunomodulating effect. Pyrantel • A tetrahydropyrimidine(四氢嘧啶) derivative. • A broad-spectrum anthelmintic • Highly effective for the treatment of pinworm(蛲虫), ascaris, and Trichostrongylus orientalis(东方毛圆线虫属) infections. • Moderately effective against both species of hookworm but less so against N americanus. • Not effective in trichuriasis(鞭虫病) or strongyloidiasis(类圆线 虫病). • Oxantel, an analog of pyrantel, is effective against in trichuriasis; the two drugs have been combined for their broad-spectrum anthelmintic activity. • Effective against mature and immature forms of helminths within the intestinal tract but not against migratory stages in the tissues or against ova(卵). • Inhibition of cholinesterase —— a depolarizing neuromuscular blocking agent → spastic paralysis • Used with caution in patients with liver dysfunction. • No combination with piperazine because of antagonistic action. Pyrvinium Embonate • • • • A dye. Not absorb orally. treatment of pinworm(蛲虫) Selectively interfering energy metabolism enzymatic system • Inhibiting glucose-transporting enzymatic system • Red feces(粪便) Niclosamide • A salicylamide derivative • Treatment of most tapeworm(绦虫) infection. • Pharmacologic Effects – Scoleces(头节) and segments of cestodes(绦虫) — but not ova — are rapidly killed on contact with nicolsamide due to the drug’s inhibition of oxidative phosphorylation or to its ATPase-stimulating property. – With the death of the parasite, digestion of scoleces and segments begins. • Clinical Uses – Given in the morning on an empty stomach. – The tablets must be chewed thoroughly and are then swallowed with water. Niclosamide can be used as an alternative drug for the treatment of intestinal fluke infections. • Adverse Effects and Cautions – Infrequent, mild and transitory. – Nausea, vomiting, diarrhea, and abdominal discomfort. Praziquantel • Effective in the treatment of schistosome(血吸 虫) infections of all species and most other trematode(吸虫) and cestode(绦虫) infections, including cysticercosis(囊虫病). • A first choice in the treatment cestodiasis.