Anti-parasitic drugs ( 抗寄生虫药 )

1. Anti-parasitic drugs(抗寄生虫药) huifang Tang tanghuifang@zju.edu.cn

2. Anti-parasitic drugs 1. Anti-malarial drugs(抗疟药) 2. Anti-schistosomiasis and anti-filariasis drugs(抗血吸虫病和抗丝虫病药) 3. Anti-amebiasis and anti-trichomoniasis drugs(抗阿米巴病和抗滴虫病药) 4. Anthelmintic drugs(抗肠蠕虫药)

3. Part1 1. Anti-malarial drugs(抗疟药)

4. Part1 Antimalarial drugs (抗疟药) • The malarial parasite(Plasmodium)(疟原虫), is a very small, single-cell blood organism. • It lives as a parasite in other organisms, namely man and mosquito. • The parasite is the cause of the tropical (热带)disease malaria(疟疾).

5. Anti-malarial drugs Anti-malarial drugs(抗疟药) 1. Biology of malarial parasite: (1)Classification of malaria: Human malaria is caused by 4 species of malarial parasite(plasmodium,疟原虫), include: P.falciparum(恶性疟原虫), P.vivax(间日疟原虫), P.malariae(三日疟原虫), P.ovale(卵形疟原虫). Common malaria in our country aresubtertian malaria(恶性疟) andtertianmalaria(间日疟). The conditions of tertian malariaare milder, therefore, itis calledbenign malaria(良性疟)too.

6. Anti-malarial drugs Parasite Life Cycle

8. Anti-malarial drugs Antimalarialdrugs-DrugClassification • Tissue schizonticides 组织裂殖体杀灭剂 • eliminate developing or dormant liver forms(红外期裂殖体); • ---For control the prevention(预防) and relapse (复发) • Blood schizonticides 血裂殖体杀灭剂 • act on erythrocytic parasites(红内期裂殖体); • ---For control the symptom (症状) • 3. Gametocides杀配子药kill sexual stages and prevent transmission to mosquitoes. • ---For control the communication(传播)

10. Anti-malarial drugs (2)Life cycle of malarial parasite: Although malaria can be transmitted by transfusion of infected blood, human beings are infected more commonly by sporozoites(子孢子) injected by the bite of infected female mosquitoes. ①Asexual propagated stage in human body; ②Sexual propagated stage in female mosquitoes.

11. Anti-malarial drugs ①Asexualpropagatedstageinhuman body: ▲Exo-erythrocytic stage: There are two types of sporozoites of tertian malaria(间日疟), that is: Tackysporozoite(速发型子孢子),and Bradysporozoite(迟发型子孢子). The tackysporozoites leave the circula-tion and localized in liver cells, then they rapidly transform, multiply and develop into schizonts(裂殖体) and merozoites(裂殖子). There are no symptoms in this stage.

12. Anti-malarial drugs Thebradysporozoitesenter liver cells, then go into hypnozoite(休眠期), they become to dormancytes(休眠子), which is the source of tertian malaria relapse. • Pyrimethamine(乙胺嘧啶)can kill tacky-sporozoites in the exo-erythrocyticstage. • Primaquine(伯氨喹)can kill bradyspor-ozoites to radically treattertian malaria (间日疟), and prevent tertian malaria relapse.

13. Anti-malarial drugs ▲Erythrocytic stage: The schizonts(裂殖体) then rupture, each releasing thousands of merozoites (裂殖子), then enter the circulation and invade erythrocytes, initiate the eryth-rocytic stage, and transform trophozoite (滋养体) and schizonts, then release many merozoites. There are a lot of symptoms in this stage. Chloroquine(氯喹), Quinine(奎宁), and Artemisinin(青蒿素)are effective to this stage, they can control the symptoms, and prevent attack of malaria.

14. Anti-malarial drugs ②Sexual propagated stage in female mosquitoes: Some erythrocytic malarial parasites differentiate into sexual forms known as gametocytes(配子体). The ♂ and ♀ gametocytes in the gut of the mosquito combine to thezygote(合子), which develops in the gut wall to infective sporozoites(子孢子), which invades salivary gland, become the source of infection. Pyrimethamine can inhibit the development of ♂ and ♀ gametocytes in mosquito to control transmission of malaria. Primaquine can kill various gametocytes of subtertian and tertian malaria.

15. Anti-malarial drugs Chloroquine(氯喹) • Chloroquine is a synthetic 4-aminoquinoline derivate

16. Anti-malarial drugs Chloroquine Pharmacological effects • 1. Antimalarial effects: erythrocytic stage • Rapid schizonticidal(裂殖体杀灭剂)activity against all infections of malaria species . • gametocytocidal(杀配子体)against P. vivax, P. malariae and P. ovale as well as immature gametocytes (stages 1-3) of P. falciparum. • The effects are fast and lasting. • The symptoms will vanish after oral administration of chloroquine in 24~48 h, blood malarial parasites disappear in 48 ~72 h, the recurrence rate in one month is low.

17. Anti-malarial drugs Chloroquine Pharmacological effects • 2. Immune inhibition • Treatment of rheumatoid arthritis, lupus erythematosus • 3. Extraintestinal amebiasis • Amoeba trophozoite amebic liver abscess

18. Anti-malarial drugs Chloroquine Mechanism of actions • Accumulation in erythrocyte→PH↑ → malarial pigment sythesis↓ • Haemoglobin-quinoline喹啉 compound → haemoglobin accumulate in plasmodium ↑ • Insert in the double stranded DNA helix → DNA replication and RNA transcription ↓

19. Anti-malarial drugs ADME of chloroquine: Chloroquine well absorbed after oral administration; Tmax = 3~5 hr, t½> 1 week; Widely distributed, the concentration in liver, lung, and kidney is higher 200 ~ 700 times than blood; The concentration in erythrocyte is higher 20 ~ 30 times than plasma; the concentration in infected erythrocyte by malarial parasite is higher 25 times than normal erythrocyte.

20. Anti-malarial drugs Clinical uses: Chloroquine ①Malaria: ▲to control the symptoms of benign malaria(良性疟); ▲to cure subtertian malaria(恶性疟); ▲symptomatic prevention in epidemic area(疫区的症状性预防). ②Amebiasis(阿米巴病): It can kill amebic trophozoite(滋养体), to treat systemic amebiasis(肠外阿米巴病), such as amebic hepatitis(阿米巴肝炎) and amebic hepatic abscess(阿米巴肝脓肿). ③Immune disease(免疫性疾病).

21. Anti-malarial drugs Adverse reaction Chloroquine Rare at the usual antimalarial dosage Pruritus (搔痒症) common among dark-skinned people. Transient headaches, nausea, vomiting, gastrointestinal symptoms and "blurred vision“. Others: aplastic blood and neurological disorders, such as polyneuritis多发性神经炎, ototoxicity, seizures and neuromyopathy.

22. Anti-malarial drugs Otherangentskillerythrocyticparasites Quinine 奎宁 Mefloquine甲氟喹 Pyronaridine 咯萘啶 Artemisinin青蒿素 Artemether and artesunate 蒿甲醚和青蒿琥酯

23. Anti-malarial drugs Quinine(奎宁) quinine Quinineis the chief alkaloid of cincho-na(金鸡纳), the bark of the South Ameri-can cinchona tree. (1)Anti-malarial action and clinical uses: Quinineacts primarily as a blood schi-zontocide(杀裂殖体药) to control the clini-cal symptoms; It is a gametocide for gametocytes(配子体) of P. vivax(间日疟原虫) & P. malariae(三日疟原虫) also, but not effective for game-tocytes of P. falciparum(恶性疟原虫).

24. Anti-malarial drugs quinine Quinineis more toxic and less effective than chloroquine. but,it is especially valuable to treat: ①chloroquine-resistant and multidrug-resistant subtertian malaria(耐氯喹和多药耐受的恶性疟), ②severe cerebral malaria(严重的脑型疟). (2)Adverse reaction:more. ①Cinchonism(金鸡纳反应): ringing in the ears(耳鸣), headache, nausea, disturbed vision, etc.

25. Anti-malarial drugs quinine ②Myocardial depression(心肌抑制作用): to reduce myocardial contractility, and slow down conduction and prolong refra-ctory period,but weaker thanquinidine (奎尼丁, dextrogyre of quinine). ③Stimulating womb(兴奋子宫): can induce abortion, not to be take by pregnant woman. ④Idiosyncrasy(特异质反应): acute hemolytic reaction.

26. Anti-malarial drugs Mefloquine(甲氟喹) mefloquine (1)Anti-malarial action: It isan efficient schizontocide in ery-throcytic stage, effective to chloroquine-resistant subtertian malaria. (2)Clinical uses: ①to treat chloroquine-resistant subter-tian malaria. ②to prevent and control the symptoms of benign malaria, once/two week. (3)Adverse reaction: GI reaction, nervous and pschic reaction.

27. Anti-malarial drugs Artemisinin(Qinghaosu, 青蒿素) (1)Anti-malarial action: It isa highly efficient malariacide of schizonts in erythrocytic stage. The effects are faster than that of chloroquine, and effective to chloroquine-resistant subtertian malaria,especially effective to cerebral malaria. (2)Clinical uses: to treat chloroquine-resistant subter-tian malaria,and to treatbenign malaria also. but its recurrence rate is high. (3)Adverse reaction: less, GI reaction, occasionally serum GPT.

28. Anti-malarial drugs Primaquine(伯氨喹) primaquine (1)Anti-malarial action: can kill dormancytes(休眠子) of tertian malaria and various gametocytes(配子体) of subtertian malaria. Owing to elimination fast, the effects are not lasting. Pharmacological effects Highly active against the gametocytes配子体 of all malaria species →dissemination ↓ Active against hypnozoites迟发型子孢子of the relapsing malarial parasites The only drug currently used for the treatment of relapsing malaria

29. Anti-malarial drugs primaquine Antimalarialdrugs-Primaquine (2)Mechanism of actions Inhibition of coenzyme Q Inhibition of reduction of NADP (3)Clinical uses: ①use it withchloroquineto radically treat benign malaria(良性疟); ②to prevent transmission ofsubterti-an malaria(恶性疟).

30. Anti-malarial drugs primaquine (3)Adverse reaction: Itstoxicity is large nervous system :Transient dizziness , nausea, vomiting, gastrointestinal symptoms blood system:Acute hemolytic anemia(急性溶血性贫血), methemoglobinemia高铁血红蛋白血症

31. Anti-malarial drugs Pyrimethamine(乙胺嘧啶) primethamine (1)Anti-malarial action: ①It can killschizonts(裂殖体) of subter-tian malarial parasites and benign mala-rial parasites in exoerythrocytic stage; ②It can also killimmature schizonts of erythrocytic stage; ③It can not kill gametocytes(配子体), but can inhibit development of sporop-hytes(孢子体) in mosquito. Mechanism of actions Dihydrofolate reductase inhibitor

32. Anti-malarial drugs primethamine (2)Clinical uses: Itis mainly used to prevent malaria, the first chosen drug for malarial prevention. (3)Adverse reaction: Folate metabolism disturbtance Its toxicity is less. But long-term and larger dose admi-nistration, it can cause megaloblastic anemia(巨红细胞贫血). This adverse reaction can be treated by formyl tetrahydrofolic acid(甲酰四氢叶酸). In addition, once large dose can cause acute intoxication.

33. Anti-malarial drugs 3. Summarization: (1)Selection of antimalarial drugs: ①Symptom control: Chloroquine; ②Cerebral malaria: Artemisinin, im. Quinine dihydrochloride, iv gtt(静脉滴注); ③Chloroquine-resistant subtertian malaria: Artemisinin, Quinine, Mefloquine; ④Resting stage: Pyrimethamine + Primaquine; ⑤Prevent transmission: Pyrimethamine. (2)Combined administration: Chloroquine + Primaquine; Pyrimethamine + Primaquine(防止复发).

34. Atovaquone(阿托伐醌) • Atovaquone, a hydroxynaphthoquinone(羟基萘醌) , was initially developed as an antimalarial agent • 选择性地抑制疟原虫线粒体的电子传递，减少吡啶的生物合成 • 抑制红内期疟原虫发育 • 对血裂殖体具有活性 • 对早期的配子体期也有活性

35. Proguanil(氯胍，百乐君) • 为双胍衍生物，在体内主要被P450 CYP2C19代谢成具有活性的环氯胍(cycloguanil)。 • 抑制二氢叶酸还原酶，与磺胺类药物合用，后者抑制二氢叶酸合成酶，对疟原虫的叶酸代谢产生双重阻断作用，从而使其核酸合成受到抑制，细胞核不能分裂繁殖。 • 对红内期和红外期疟原虫的发育具有活性，被认为是一种作用缓慢的杀血裂殖体药物。

36. Atovaquone/Proguanil (Malarone,马拉隆) • A fixed combination of atovaquone (250 mg) and proguanil (100 mg) • 对大多数疟原虫株(包括恶性疟、三日疟、卵型疟、间日疟的红内期和多种疟原虫的红外期)均具有活性，但对间日疟的睡眠子孢子却无作用。 • 两药分别干扰疟原虫嘧啶生物合成的不同路径。 • 阿托伐醌选择性地抑制疟原虫线粒体的电子转运，减少吡啶的生物合成，使线粒体的膜电位陡然降低，因而阻止了疟原虫的繁殖； • 环氯胍则通过抑制疟原虫的二氢叶酸还原酶，耗竭嘧啶核酸库存，从而导致核酸合成和细胞复制受到破坏。、 • 尽管机制还不十分清楚，但二药对细胞内不同发育期的疟原虫是具有协同作用的，研究表明，由于氯胍的配合，阿托伐醌只需较低的血浓度就能显著降低疟原早线粒体的膜电位。 • 适应证：预防和治疗脑型疟疾(恶性疟疾) (包括对氯喹已产生耐药性的脑型疟疾)

37. 氯喹 阿莫地喹 奎宁 奎尼丁 甲氟喹 伯氨喹 磺胺多辛-乙胺嘧啶 氯胍 多西环素 卤泛曲林 苯芴醇 青蒿素 阿托伐醌/氯胍(马拉隆)

39. Part2 Anti-schistosomiasis drugs(抗血吸虫药)

41. Schistosomiasis(血吸虫病) is caused by Schistosoma(血吸虫, 裂体吸虫) infection. • There are five kinds of Schistosoma caused Schistosomiasis of human: • S. japonia(日本血吸虫), • S. heamatobium (埃及血吸虫), • S. mansoni(曼索血吸虫), • S. intercalatum(间插血吸虫) • S. mekongi (湄公血吸虫). • In our country, the schistosomiasis is caused mainly by S. japonia.

43. 肝硬化主征 巨 脾 腹 水 门脉高压

44. Anti-schistosomiasis drugs • In the past, the drug treated schisto-somiasis was PAT(酒石酸锑钾, potassium antimony tartrate), its course of treat-ment was longer, the toxicity larger, need iv administration, and the ADRs were severe. • Since 1970’, praziquantel(吡喹酮) had bediscovered, because its ADRs is less, praziquantel became the main drug to treat schistosomiasis.

45. Anti-schistosomiasis drugs Praziquantel(吡喹酮) praziquantel (1)Anti-parasite effects: It is a highly effective and broad spectrum anti-parasite drug. • schistosoma(血吸虫) • clonorchis sinensis(华支睾吸虫, 即“肝吸虫”) • lung fluke(肺吸虫) • fasciolopsis(布氏姜片虫, 即“肠吸虫”) • certain intestinal parasites(e.g. tapeworm(绦虫). Mechanism of anti-schistosoma effects: It can increase the membrane permeability to certain monovalent and divalent cation, particularly Ca2+, to cause schistosoma muscular contraction and spastic paralysis.

46. Anti-schistosomiasis drugs (2)Clinical uses: praziquantel ①Schistosomiasis(血吸虫病): It is effective to both acute & chronicschistosomiasis. To acute schistosomiasis: It is to bring down the fever, and alleviate the systematic symptoms fast, the late results reach 90%; To chronic schistosomiasis: The curative effect is well too, only 1～2 days of course of treatment, the late results reach 90% too. To the later period patients with cardiac and hepatic complication: can accept the course of treatment smoothly.

47. Anti-schistosomiasis drugs praziquantel ②Clonorchiasis(华枝睾吸虫病): It is the first-chosen drug. ③Other trematode(其他吸虫): Used to treat paragonimiasis(肺吸虫病) and fasciolopsiasis(姜片虫病). It is the first-chosen drug. ④Taeniasis(绦虫病): Including imago(成虫) & larva(幼虫) of various tapeworm(绦虫) infective disease, such as cysticercisis(囊虫症——猪囊虫尾蚴病) and hydatidosis(包虫病——由细粒棘球绦虫的幼虫引起). It is the first-chosen drug too.

48. Anti-schistosomiasis drugs praziquantel (3)Adverse reaction less and lighter (than potassium anti-mony tartrate, 酒石酸锑钾). After oral administration, it can cause abdominal pain, nausea, dizziness, and headache in short-term.

49. C. anti-filariasis drugs (抗丝虫病药)

50. Anti-filariasis drugs 下肢象皮肿 阴囊象皮肿