Section 15. 感染性疾病与抗感染药 (Infection disease andAnti-infective drugs) 第四部分
Part 11. Anti-parasitic drugs (抗寄生虫药)
Part 11. Anti-parasitic drugs A. Anti-malarial drugs(抗疟药) B. Anti-amebiasis and anti-tricho-moniasis drugs(抗阿米巴病和抗滴虫病药) C. Anti-schistosomiasis and anti-filariasis drugs(抗血吸虫病和抗丝虫病药) D. Anthelmintic drugs(抗肠蠕虫药)
Anti-malarial drugs A. 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.
Anti-malarial drugs Antimalarialdrugs-Malarialparasite • 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 disease malaria.
Anti-malarial drugs Antimalarial drugs - Parasite Life Cycle
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.
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.
Anti-malarial drugs • Thebradysporozoitesenter liver cells, then go into hypnozoite(休眠期),they become todormancytes(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 rel-apse.
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)andschizonts,thenreleasemany merozoites. • There are a lot of symptoms in this stage. • Chloroquine(氯喹), Quinine(奎宁), and Artemisinin(青蒿素)are effective to thisstage,theycancontrolthesymptoms, and prevent attack of malaria.
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 in-fective sporozoites(子孢子), which invad-es salivary gland, become the source of infection. • Pyrimethamine can inhibit the deve-lopment of ♂ and ♀ gametocytes in mos-quito to control transmission of malaria. • Primaquine can kill various gameto-cytesof subtertian and tertian malaria.
Anti-malarial drugs Antimalarialdrugs-DrugClassification • Tissue schizonticides裂殖体杀灭剂eliminate developing or dormant liver forms; • Blood schizonticides act on erythrocytic parasites; • Gametocides杀配子药kill sexual stages and prevent transmission to mosquitoes. • No one available agent can reliably effect a radical cure, ie, eliminate both hepatic and erythrocytic stages. • Few available agents are causal prophylactic drugs, ie, capable of preventing erythrocytic infection.
Anti-malarial drugs Antimalarialdrugs-Chloroquine(氯喹) • Chloroquine is a synthetic 4-aminoquinoline derivate
Anti-malarial drugs Chloroquine Antimalarialdrugs-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.
Anti-malarial drugs Chloroquine Antimalarialdrugs-Chloroquine • Pharmacological effects • 2. Immune inhibition • Treatment of rheumatoid arthritis, lupus erythematosus • 3. Extraintestinal amebiasis • Amoeba trophozoite amebic liver abscess
Anti-malarial drugs Chloroquine Antimalarialdrugs-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 ↓
Anti-malarial drugs (2)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.
Anti-malarial drugs (3)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).
Anti-malarial drugs Chloroquine • (4)Adverse reaction: • Rare at the usual antimalarial dosages • 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.
Anti-malarial drugs Otherangentskillerythrocyticparasites • Quinine • Mefloquine甲氟喹 • Pyronaridine 咯萘啶 • Artemisinin青蒿素 • Artemether and artesunate • 蒿甲醚和青蒿琥酯
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).
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.
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.
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.
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.
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
Anti-malarial drugs Antimalarialdrugs-Pyrimethamine • Pharmacological effects • Inhibition of proliferation of sporozoite子孢子to schizont 裂殖体 • Prophylaxis of infections • Mechanism of actions • Dihydrofolate reductase inhibitor • Adverse effects • Folate metabolism disturbtance
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).
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
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 exo-erythrocytic 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.
Anti-malarial drugs primethamine (2)Clinical uses: • Itis mainly used to prevent malaria, the first chosen drug for malarial prev-ention. • (3)Adverse reaction: • 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.
Anti-malarial drugs 3. Summarization: (1)Selection of antimalarial drugs: ①Symptom control: Chloroquine; ②Cerebral malaria: Artemisinin, im. Quinine dihydrochloride, iv gtt; 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).
B. Anti-amebiasis and anti-trichomoniasis drugs (抗阿米巴病和抗滴虫病药)
Life cycle of amebic parasite: 当机体抵抗力 包囊小滋养体大滋养体肠壁肝、脑、肺 在小肠下段伪足, 溶组织酶引起肠外阿米巴病 阿米巴痢疾 包囊排出体外 B1. Anti-amebiasis drugs(amebicides) 当机体抵 抗力强时
B1. Anti-amebiasis drugs (amebicides) Amebiasis is infection with Entamoeba histolytica, A tiny, one-celled organism.
Features of Amebiasis Extraintestinal Amebiasis Intestinal Amebiasis
B1. Anti-amebiasis drugs (amebicides) Multiplication and life cycle of E histolytica
Anti-amebiasis drugs • Classification of amebiasis: • Luminal amebiasis(): • Amebic dysentery(阿米巴痢疾),Asyptomatic carrier(无症状带虫者) • Systemic amebiasis: • Amebic hepatitis(阿米巴肝炎), • hepatic abscess(阿米巴肝脓肿) • Mixed amebiasis.
Anti-amebiasis drugs • The drugs used in amebiasis: • Metronidazole(甲硝唑), Tinidazole(替硝唑); • Emetine(依米丁), Dehydroemetine; • Halogenate quinolines(卤化喹啉类): • Chiniofon(喹碘仿), Clioquinol(氯碘羟喹), Diiodohydroxyquinoline(双碘喹啉); • Diloxannide(二氯尼特); • Paromomycin(巴龙霉素); • Chlorpromaquin(氯喹), etc.
Anti-amebiasis drugs Metronidazole(甲硝唑, 灭滴灵) • (1)Pharmacological effects & clinical uses: • ①Anti-amebiasis effects: • It has potent amebicidal activity to large trophozoite(大滋养体) grown, but no affect to small trophozoite(小滋养体). • Effective toacute amebic dysenteryandall systemic amebiasis,but ineffec-tive toasyptomatic passers. • Therefore, it need be used comban-tion of purely intestinal amebicides, such asdiloxanide to radically treatment.
Anti-amebiasis drugs • ②Anti-trichomoniasis effects: • Metronidazole can kill Trichomonas vaginalis(阴道毛滴虫)directly. • After oral administration, it is absorbed fast, distribute to the whole body, and secreted into vaginal secretion(in female), sperm(in male) and urine. • Therefore, it is effective toTrichomonas infection of male and female. • Its curative rate(治愈率) reach 90%.
Anti-amebiasis drugs • ③Anti-anaerobic bacteria infection: • The sensitive anaerobic bacteria to metronidazoleincluding: • ▲All anaerobic cocci(所有的厌氧球菌); • ▲G-anaerobic bacillus(G-厌氧杆菌) and G+ spore anaerobic bacillus(G+芽孢厌氧杆菌); • Therefore, this drug is used to treat: • 1)vary anaerobic bacteria infection of pelvic cavity and abnormal cavity; • 2)peridentitis(牙周炎); • 3)infection of helicobacter pylori (HP) also,HP is the main cause of gastric and duodenal ulcer.