Antiparasitic DrugsAntiparasitic Drugs

Fen-Fei GaoFen-Fei Gao

OverviewOverview

一．一．Antimalarial drugsAntimalarial drugs

二．二．Anti-amebiasis drugs and Anti-Anti-amebiasis drugs and Anti-trichomoniasis drugstrichomoniasis drugs

三．Anti-schistosomiasis drugs and Anti-Anti-filariasis drugs

四．Anthelmintic drugs

MalariaMalaria

• Malaria is caused by plasmodium whose Malaria is caused by plasmodium whose sporozoites was inoculated to initiate sporozoites was inoculated to initiate human infection by anopheline mosquito.human infection by anopheline mosquito.

• Four species of plasmodium cause human Four species of plasmodium cause human malaria: malaria: – PlasmodiumPlasmodium falciparumfalciparum → → responsible for responsible for

nearly all serious complicationsand deathsnearly all serious complicationsand deaths..– P vivaxP vivax – P malariaeP malariae – P ovaleP ovale→ → seldom

benign malaria

Parasite Life CycleParasite Life Cycle

I.I. Asexual stage in humanAsexual stage in human::① Primary exoerythrocytic stage exoerythrocytic stage: sporozoites: sporozoites invade invade

liver cells → schizontsliver cells → schizonts———— incubation periodincubation period②② Asexual erythrocytic stageAsexual erythrocytic stage: merozoites invade : merozoites invade

erythrocytes, trophozoites→ schizonts, rupture host erythrocytes, trophozoites→ schizonts, rupture host erythrocytes → repeated cycles erythrocytes → repeated cycles ———— cause clinical cause clinical illnessillness

③ Secondary exoerythrocytic stageexoerythrocytic stage: In : In P vivaxP vivax and and P P ovaleovale infections, a dormant hepatic stage, infections, a dormant hepatic stage, hypnozoite → hypnozoite → relapsesrelapses

II.II. Sexual stage in anopheline mosquitoSexual stage in anopheline mosquito::• Sexual stage gametocytes also develop in Sexual stage gametocytes also develop in

erythrocytes before being taken up by mosquitoes, erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.where they develop into infective sporozoites.

Malaria transmission life cycleMalaria transmission life cycle::• Sporozoites Sporozoites tissue schizonts (in liver) tissue schizonts (in liver)

merozoites infect RBC (blood merozoites infect RBC (blood schizonts)schizonts) rupture of RBC (clinical rupture of RBC (clinical attack) attack) new crops of merozoites new crops of merozoites

• Sexual formSexual form: some merozoites : some merozoites differentiate into male & female differentiate into male & female gametocytes gametocytes ingested by a mosquito ingested by a mosquito where they form where they form SporozoitesSporozoites humanhuman

• P. malariae & p. falciparumP. malariae & p. falciparum have have one one cyclecycle of liver invasion and end by the of liver invasion and end by the 4th week i.e. no relapse occurs.4th week i.e. no relapse occurs.

• P.ovale & p. vivaxP.ovale & p. vivax have dormant have dormant stages (stages (hypnozoiteshypnozoites) in the liver. ) in the liver. These hypnozoites may rupture These hypnozoites may rupture months or years later causing months or years later causing relapse of the attacks.relapse of the attacks.

Blood SchizonticidesBlood Schizonticides

Chloroquine (4- aminoquinoline derivative)Chloroquine (4- aminoquinoline derivative)Mechanism of actionMechanism of action:: • Inhibits synthesis of DNA and RNA in the Inhibits synthesis of DNA and RNA in the

plasmodium.plasmodium.• Increases pH of the vacules in the parasite, so Increases pH of the vacules in the parasite, so

prevent its utilization of erythrocyte prevent its utilization of erythrocyte hemoglobin.hemoglobin.

Uses:Uses:• Acute attack 600 mg base (4 tab.) then 300 mg Acute attack 600 mg base (4 tab.) then 300 mg

after 6 h. then 150 mg bid for two more days.after 6 h. then 150 mg bid for two more days.• Add 100 mg proguanil/ day (2 tab.) in Add 100 mg proguanil/ day (2 tab.) in

chloroquine-resistant area.chloroquine-resistant area.

Chemoprophylaxis:Chemoprophylaxis:• 300 mg base (2 tab.) / week, 300 mg base (2 tab.) / week, • one week before entering the one week before entering the

endemic area endemic area • & 4 weeks after leaving.& 4 weeks after leaving.

Other uses:Other uses:

• Amebic liver abscess (as chloroquine is Amebic liver abscess (as chloroquine is concentrated in the liver).concentrated in the liver).

• Anti-inflammatory in autoimmune diseases Anti-inflammatory in autoimmune diseases e.g. rheumatoid arthritis (unknown e.g. rheumatoid arthritis (unknown mechanism).mechanism).

A/EA/E: GIT upset, rash, headache, peripheral : GIT upset, rash, headache, peripheral neuritis, cardiac depressant, retinal neuritis, cardiac depressant, retinal damage (damage (don’t use chloroquin> 5 years don’t use chloroquin> 5 years without regular ophthalmic examination),without regular ophthalmic examination), toxic psychosis and precipitates porphyria.toxic psychosis and precipitates porphyria.

QuinineQuinine::Mechanism of actionMechanism of action: : • Inhibits DNA strand separation.Inhibits DNA strand separation.• Inhibits transcription and protein synthesis.Inhibits transcription and protein synthesis.Uses:Uses:• Chloroquine-resistant Chloroquine-resistant P. falciparumP. falciparum (orally). (orally).• Cerebral malaria (i.v infusion 10 mg/kg over 4 Cerebral malaria (i.v infusion 10 mg/kg over 4

h.). it could repeated at an intervals of 8-12 h. h.). it could repeated at an intervals of 8-12 h. until patient can take the drug orally.until patient can take the drug orally.

A/E:A/E: • CinchonismCinchonism i.e. headache, dizziness, & tinnitus. i.e. headache, dizziness, & tinnitus.• Inhibits cardiac conductivity, hemolysis in G-6-P Inhibits cardiac conductivity, hemolysis in G-6-P

D and black water fever (intravascular D and black water fever (intravascular hemolysis).hemolysis).

Quinidine:Quinidine:• It is the dextro-isomer of quinine.It is the dextro-isomer of quinine.• It is used when quinine is not available.It is used when quinine is not available.Mefloquine:Mefloquine:• Its mechanism of action is unknown.Its mechanism of action is unknown.UsesUses: : • treatment & prophylaxis of treatment & prophylaxis of chloroquine-chloroquine-

resistant P. falciparum.resistant P. falciparum.A/EA/E: GIT upset, headache, dizziness, : GIT upset, headache, dizziness,

syncope, extrasystoles & seizures.syncope, extrasystoles & seizures.

Halofantrine:Halofantrine:• Unknown mechanism of action.Unknown mechanism of action.• Used Used only by oral routeonly by oral route in P. in P.

falciparum falciparum cerebral malaria.cerebral malaria.• NoNo parenteral preparation. parenteral preparation.• NotNot used for prophylaxis. used for prophylaxis.• Not Not used during pregnancy unless used during pregnancy unless

benefit outweighs the risk.benefit outweighs the risk.

QinghaosuQinghaosu ( (ArtemisininArtemisinin):):

• It is a Chinese herbal medicine was used as It is a Chinese herbal medicine was used as antipyreticantipyretic..

• It is a blood schizonticide against It is a blood schizonticide against all types of all types of malaria including chloroquine-resistant p. malaria including chloroquine-resistant p. falciparum.falciparum.

• Unknown mechanism of action.Unknown mechanism of action.

Uses:Uses:

• P. falciparum P. falciparum cerebral malariacerebral malaria (oral & parenteral). (oral & parenteral).

• NotNot used used prophylactically.prophylactically.

• NotNot used in used in pregnancypregnancy as it is emberytoxic in rats. as it is emberytoxic in rats.

Antifolates (sulfonamides & sulfones):Antifolates (sulfonamides & sulfones):

Synergistic blockade of folic acid synthesisSynergistic blockade of folic acid synthesis• SulfonamideSulfonamide inhibits dihydropteroate inhibits dihydropteroate

synthetase, so inhibits folic acid synthesis.synthetase, so inhibits folic acid synthesis.• Pyrimethamine and proguanilPyrimethamine and proguanil inhibit inhibit

dihydrofolate reductase, so inhibit dihydrofolate reductase, so inhibit tetrahydrofolate (folinic acid synthesis). tetrahydrofolate (folinic acid synthesis).

Fansidar:Fansidar:• It is a combination of It is a combination of sulfadoxin and sulfadoxin and

pyrimethamine.pyrimethamine.• It is used in It is used in chloroquine-resistant p. falciparumchloroquine-resistant p. falciparum..• Not Not used for used for prophylaxis prophylaxis as it causes as it causes

agranulocytosis & Stevens-Johnson syndrome.agranulocytosis & Stevens-Johnson syndrome.A.E:A.E:• SulfonamideSulfonamide: rashes, kidney damage, hemolysis : rashes, kidney damage, hemolysis

& GIT upset.& GIT upset.• PyrimethaminePyrimethamine: folic acid deficiency, : folic acid deficiency,

agranulocytosis & Stevens-Johnson syndrome.agranulocytosis & Stevens-Johnson syndrome.DisadvantagesDisadvantages:: slow blood schizonticide activity, slow blood schizonticide activity,

drug resistance & numerous & serious adverse drug resistance & numerous & serious adverse effects.effects.

C/I:C/I: pregnancy & nursing women, G-6-PD, renal pregnancy & nursing women, G-6-PD, renal impairment & children under 2 months of age.impairment & children under 2 months of age.

Atovaquone:Atovaquone:• Unknown mechanism of action.Unknown mechanism of action.• Used alone for treatment of pneumocytosis Used alone for treatment of pneumocytosis

and toxoplasmosis in patients with AIDS.and toxoplasmosis in patients with AIDS.• Atovaquone +Atovaquone + proguanil proguanil (malarone)(malarone) for for

treatment & prophylaxistreatment & prophylaxis of chloroquine- of chloroquine-resistant resistant P. falciparumP. falciparum..

A/EA/E: fever, rashes, cough, nausea, vomiting, : fever, rashes, cough, nausea, vomiting, diarrhea, headache & insomnia.diarrhea, headache & insomnia.

Tissue SchizonticideTissue Schizonticide

Primaquine (8- aminoquinoline derivative):Primaquine (8- aminoquinoline derivative):• It is a tissue schizonticide. It is a tissue schizonticide. • It has a cellular oxidant activity and possibly It has a cellular oxidant activity and possibly

interferes with mitochondria function.interferes with mitochondria function.• Gametocide, so inhibits infection transmission by Gametocide, so inhibits infection transmission by

mosquito.mosquito.Uses:Uses:• Eradication of liver stages (hypnozoites) of Eradication of liver stages (hypnozoites) of P.vivaxP.vivax & &

P.P.ovaleovale, after standard chloroquine therapy to prevent , after standard chloroquine therapy to prevent

relapse.relapse.• It should not be given if there is risk of reinfection.It should not be given if there is risk of reinfection.A/E:A/E: GIT upset, pruritis, headache, GIT upset, pruritis, headache,

methemoglobinemia, hemolysis especially in G-6-PD.methemoglobinemia, hemolysis especially in G-6-PD.

Treatment of malariaTreatment of malaria

P. vivax, P. ovale & P. malariae:P. vivax, P. ovale & P. malariae:

ChloroquineChloroquine

NBNB: It is also allowed in pregnancy.: It is also allowed in pregnancy.

P. Falciparum P. Falciparum (most cases are chloroquine-(most cases are chloroquine-resistant):resistant):

• Quinine 600 mg salt/8hQuinine 600 mg salt/8h till patient become better till patient become better and blood is free of parasites (usually in 3-5 days). and blood is free of parasites (usually in 3-5 days).

• Followed by a single dose of Followed by a single dose of fansidar (3 tablets).fansidar (3 tablets).

• In pregnancy 7-day course of quinine alone In pregnancy 7-day course of quinine alone should be givenshould be given..

Alternative therapyAlternative therapy• Mefloquine 20 mg base/kg up to a maximum Mefloquine 20 mg base/kg up to a maximum

of 1.5 g in two divided doses 8 hours apart.of 1.5 g in two divided doses 8 hours apart.• Mefloquine is contraindicated in pregnancy.Mefloquine is contraindicated in pregnancy.Cerebral malaria:Cerebral malaria:• Quinine 10 mg/kg i.v infusion over 4 h. Quinine 10 mg/kg i.v infusion over 4 h.

could be repeated at intervals of 8-12 h. could be repeated at intervals of 8-12 h. until patient can take drug orally. until patient can take drug orally.

• Or Or Halofantrine: Halofantrine: orally onlyorally only• Or Or QinghaosuQinghaosu ( (ArtemisininArtemisinin): ): oral & i.voral & i.v

Chemoprophylaxis of Chemoprophylaxis of malariamalaria

Chloroquine-sensitive area:Chloroquine-sensitive area: • Chloroquine 150 mg base ( 2 tab/weekChloroquine 150 mg base ( 2 tab/week))Chloroquine-resistant area:Chloroquine-resistant area: • Chloroquine ( 2 tab/week) plus Chloroquine ( 2 tab/week) plus

proguanilproguanil100 mg (one or two tab/ day) 100 mg (one or two tab/ day) oror• Mefloquine Mefloquine 250 mg (one tab./ week)250 mg (one tab./ week)

ChloroquineChloroquine

• A synthetic 4-aminoquinoline formulated as A synthetic 4-aminoquinoline formulated as the phosphate salt for oral use.the phosphate salt for oral use.

• PharmacokineticsPharmacokinetics– Rapidly and almost completely absorbed from the Rapidly and almost completely absorbed from the

gastrointestinal tract.gastrointestinal tract.– Very large apparent volumeVery large apparent volume of distribution of of distribution of

100-1000 L/kg.100-1000 L/kg.– Necessitate the use of a loading dose to rapidly Necessitate the use of a loading dose to rapidly

achieve effective serum concentrations.achieve effective serum concentrations.– Slowly released from tissues and metabolized.Slowly released from tissues and metabolized.– Principally excreted in the urine.Principally excreted in the urine.

Control symptoms

• Pharmacological EffectsPharmacological Effects1.1. Antimalarial actionAntimalarial action: highly effective ①: highly effective ① blood blood

schizonticideschizonticide. Moderately effective against ②. Moderately effective against ②gametocytesgametocytes of of P vivaxP vivax, , P ovaleP ovale, and , and P malariaeP malariae but not but not against those of against those of PP falciparumfalciparum. ③. ③ not active against liver not active against liver stagestage parasites. parasites.

Mechanism: plasmodium ①Mechanism: plasmodium ① aggregates chloroquineaggregates chloroquine. . chloroquine ②chloroquine ② incorporated into DNAincorporated into DNA chain of plasmodium chain of plasmodium

→ inhibit → inhibit proliferation. chloroquine ③ chloroquine ③ prevents the prevents the polymerizationpolymerization((聚合作用 )) of of the hemoglobin( the hemoglobin(血红蛋白 ) ) breakdown product, breakdown product, hemeheme((血红素 ), into hemozoin(), into hemozoin(疟原虫色素 ) and thus eliciting parasite toxicity due to the buildup of ) and thus eliciting parasite toxicity due to the buildup of free heme. pH↑→ ④free heme. pH↑→ ④ plasmodium plasmodium protease activity↓

Resistance: very common among strains of Resistance: very common among strains of P falciparumP falciparum and uncommon but increasing for and uncommon but increasing for P vivaxP vivax. The mechanism . The mechanism of resisitance to chloroquine is resistant strains excretes of resisitance to chloroquine is resistant strains excretes drug more rapidly. drug more rapidly.

2.2. Killing Amibic trophozoites Killing Amibic trophozoites : chloroquine reaches high : chloroquine reaches high liver concentrations.liver concentrations.

3. Immunosuppression action:

• Clinical UsesClinical Uses1.1. TreatmentTreatment: nonfalciparum and sensitive : nonfalciparum and sensitive

falciparum malaria. Primaquine(falciparum malaria. Primaquine(伯氨喹 ) ) must be added for the radical cure of must be added for the radical cure of P P vivax vivax and and P ovale,P ovale, because chloroquine because chloroquine does not eliminate dormant liver forms of does not eliminate dormant liver forms of these species.these species.

2.2. ChemoprophylaxisChemoprophylaxis: for without resistant : for without resistant falciparum malaria in malarious regions.falciparum malaria in malarious regions.

3.3. Amebic liver abscessAmebic liver abscess((阿米巴肝脓肿 ): not ): not effective in the treatment of intestinal or effective in the treatment of intestinal or other extrahepatic amebiasis.other extrahepatic amebiasis.

• Adverse Effects and CautionsAdverse Effects and Cautions– Usually very well tolerated, even with prolonged Usually very well tolerated, even with prolonged

use.use.– Pruritus(Pruritus(瘙痒 ) is common.) is common.– Nausea, vomiting, abdominal pain, headache, Nausea, vomiting, abdominal pain, headache,

anorexia(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

QuinineQuinine

• Quinine and quinidine remain first-line therapies Quinine and quinidine remain first-line therapies for falciparum malariafor falciparum malaria————especially severe especially severe disease.disease.

• Quinine is an alkaloid derived from the bark of Quinine is an alkaloid derived from the bark of the cinchona tree(the cinchona tree(金鸡纳树皮 ), a traditional ), a traditional remedy for intermittent fevers(remedy for intermittent fevers(间歇性热 ) from ) from South America.South America.

• Quinine is the levorotatory stereoisomer of Quinine is the levorotatory stereoisomer of quinidine.quinidine.

• Rapidly absorbed after oral administration.Rapidly absorbed after oral administration.• Metabolized in the liver and excreted in the urine.Metabolized in the liver and excreted in the urine.

Control symptoms

• Pharmacological EffectsPharmacological Effects– Highly effective blood schizonticide Highly effective blood schizonticide

against the four species of human against the four species of human malaria paresites.malaria paresites.

– Gametocidal against Gametocidal against P vivaxP vivax and and P ovaleP ovale but not but not P falciparum.P falciparum.

– Not active against liver stage parasites.Not active against liver stage parasites.– Depressing Depressing cardiac contractility and

conduction, lengthening refractory conduction, lengthening refractory period, period, exciting uterine smooth muscle, , depressing central nervous system, little depressing central nervous system, little antipyretic-analgesic effect.antipyretic-analgesic effect.

• Clinical UsesClinical Uses: mainly for : mainly for chloroquine-resistant falciparum chloroquine-resistant falciparum malaria, especially for cerebral malaria, especially for cerebral malaria.malaria.– Parenteral(Parenteral(胃肠外的 ) treatment of ) treatment of

severe falciparum malariasevere falciparum malaria– Oral treatment of falciparum malariaOral treatment of falciparum malaria– Malarial chemoprophylaxisMalarial chemoprophylaxis– Babesiosis(Babesiosis(巴贝西虫病 ))

• Adverse Effects and CautionsAdverse Effects and Cautions1.1. Cinchonism: tinnitus(Cinchonism: tinnitus(耳鸣 ), headache, ), headache,

nausea, dizziness(nausea, dizziness(眩晕 ), flushing(), flushing(面红 ), ), visual disturbancesvisual disturbances

2. Cardiovascular effects: severe hypotension and arrhythmia can follow too-rapid intravenous infusion.

3.3. Idiosyncrasy: hemolysis with G6PD Idiosyncrasy: hemolysis with G6PD deficiency.deficiency.

4.4. Others: hypoglycemia through stimulation Others: hypoglycemia through stimulation of insulin release, stimulate uterine of insulin release, stimulate uterine contractionscontractions

Mefloquine Mefloquine

• A synthetic 4-quinoline methanol that is A synthetic 4-quinoline methanol that is chemically related to quinine.chemically related to quinine.

• PharmacokineticsPharmacokinetics– Only be given orally because severe local Only be given orally because severe local

irritation occurs with parenteral use.irritation occurs with parenteral use.– Well absorbed.Well absorbed.– Highly protein-bound, extensively distributed in Highly protein-bound, extensively distributed in

tissues, and eliminated slowly. tissues, and eliminated slowly. tt1/21/2 is 20 days. is 20 days.

• Pharmacological EffectsPharmacological Effects: : – Strong blood schizonticidal activity against Strong blood schizonticidal activity against P P

falciparum falciparum and and P vivaxP vivax, but not active against , but not active against hepatic stages or gametocytes.hepatic stages or gametocytes.

Control symptoms

• Clinical UsesClinical Uses– Chemoprophylaxis: Chemoprophylaxis: – Treatment: mainly for chloroquine-Treatment: mainly for chloroquine-

resistant falciparum malaria.resistant falciparum malaria.

• Adverse Effects and CautionsAdverse Effects and Cautions– Nausea, vomiting, diarrhea, abdominal Nausea, vomiting, diarrhea, abdominal

painpain————dose-dependentdose-dependent– Neuropsychiatric toxicities: dizziness, Neuropsychiatric toxicities: dizziness,

headache, behavioral disturbances, headache, behavioral disturbances, psychosis, seizures.psychosis, seizures.

Malaridine Malaridine

• Developed by China.Developed by China.• blood schizonticidal activity.blood schizonticidal activity.• Treatment for all types malaria, Treatment for all types malaria,

including chloroquine-resistant including chloroquine-resistant falciparum malaria.falciparum malaria.

• Mechanism: destroy parasite Mechanism: destroy parasite compound compound membrane and food food vacuoles.vacuoles.

Control symptoms

Artemisinin Artemisinin

• Extracted from yellow flower mugwort.• Kill trophozoites of erythrocytes.Kill trophozoites of erythrocytes.• quick and effective. maybe kill earlier

period trophozoites.trophozoites.• Through blood-brain barrie, treatment for

cerebral malariacerebral malaria.• recurrence rate is high.• Resistence.• Interaction with others antimalarial drugs:

Control symptoms

•Artemether and Artemether and ArtesunateArtesunate

•DihydroartemisininDihydroartemisinin

Control symptoms

Primaquine Primaquine

• Synthetic 8-aminoquinoline.Synthetic 8-aminoquinoline.• Pharmacological EffectsPharmacological Effects

– Against hepatic stages of malaria Against hepatic stages of malaria parasites. parasites.

– The only available agent active against The only available agent active against the dormant hypnozoite(the dormant hypnozoite(睡眠子孢子 ) ) stages of stages of P vivaxP vivax and and P ovaleP ovale. .

– Also gametocidal against the four Also gametocidal against the four human malaria species.human malaria species.

Control relapse and transmission

• Clinical UsesClinical Uses– Therapy (Radical Cure) of Acute Vivax and Ovale Therapy (Radical Cure) of Acute Vivax and Ovale

Malaria: Malaria: chloroquine + primaquinechloroquine + primaquine– Terminal Prophylaxis of Vivax and Ovale Malaria: Terminal Prophylaxis of Vivax and Ovale Malaria:

prevent a relapseprevent a relapse– Chemoprophylaxis of Malaria: Chemoprophylaxis of Malaria: protection against protection against

falciparum and vivax malaria. But potential toxicities falciparum and vivax malaria. But potential toxicities of long-term use limited its routinely administration.of long-term use limited its routinely administration.

– Gametocidal Action: Gametocidal Action: A single dose of primaquine (45 A single dose of primaquine (45 mg base) can be used as a control measure to mg base) can be used as a control measure to render render P falciparum P falciparum gametocytes noninfective to gametocytes noninfective to mosquitoes. This therapy is of no clinical benefit to mosquitoes. This therapy is of no clinical benefit to the patient but will disrupt transmissionthe patient but will disrupt transmission

– Pneumocystis cariniiPneumocystis carinii((卡氏卡氏肺孢子虫 ) infection: ) infection: clindamycin(clindamycin(克林霉素 )+primaquine → mild to moderate pneumocystosis

• Adverse Effects and CautionsAdverse Effects and Cautions• Nausea, epigastric(Nausea, epigastric(腹上部的 ) pain, ) pain,

abdominal cramps(abdominal cramps(痛性痉挛 ), ), headache.headache.

• Hemolysis or methemoglobinemiaHemolysis or methemoglobinemia((高铁血红蛋白血症 ), especially in , especially in persons with G6PD deficiency or persons with G6PD deficiency or other hereditary metabolic defects.other hereditary metabolic defects.

Pyrimethamine Pyrimethamine

• PharmacokineticsPharmacokinetics– Slowly but adequately absorbed from the Slowly but adequately absorbed from the

gastrointestinal tract.gastrointestinal tract.– Slowly Slowly eliminated and ed and excreted from urine. from urine.

• Pharmacological EffectsPharmacological Effects– Kill schizonts of pschizonts of primary exoerythrocytic stage. exoerythrocytic stage.– Act slowly against Act slowly against premature schizonts of schizonts of

erythrocytic stage.erythrocytic stage.– No action against gametocytes, but can inhibit No action against gametocytes, but can inhibit

development of plasmodium in mosquito.of plasmodium in mosquito.– Inhibit plasmodial dihydrofolate reductase →

inhibiting breeding of plasmodium.plasmodium.

Etiological factor prophylaxis

• Adverse Effects and CautionsAdverse Effects and Cautions– Gastrointestinal symptoms, skin rashes.Gastrointestinal symptoms, skin rashes.– Interfering folic acid metabolism in

human → megalocyte anemia, granulocytopenia.

– Acute intoxication– Teratogenesis

Sulfonamides and Sulfone • Competing dihydropteroatesye synthase Competing dihydropteroatesye synthase

with PABA with PABA →→ inhibiting to form inhibiting to form dihydrofolic acid dihydrofolic acid →→ inhibiting inhibiting production of purines and synthesis of production of purines and synthesis of nucleic acids.nucleic acids.

• Only inhibiting Only inhibiting plasmodial of of exoerythrocytic stageexoerythrocytic stage

• Not used as single agents for the Not used as single agents for the treatment. Combination with other treatment. Combination with other agents.agents.

Etiological factor prophylaxis

Rational Use of Rational Use of Antimalarial DrugsAntimalarial Drugs

1.1. Choice of Antimalarial DrugsChoice of Antimalarial Drugs::– Control symptomsControl symptoms: chloroquine: chloroquine– Cerebral malariaCerebral malaria: chloroquine phosphate, quinine : chloroquine phosphate, quinine

bimuriate, artemisinin bimuriate, artemisinin ———— injection injection– Chloroquine-resistant falciparum malariaChloroquine-resistant falciparum malaria: quinine, : quinine,

mefloquine, artemisininmefloquine, artemisinin– Dormant hypnozoite stagesDormant hypnozoite stages : pyrimethamine + : pyrimethamine +

primaquineprimaquine– ProphylaxisProphylaxis: pyrimethamine, chloroquine: pyrimethamine, chloroquine

2.2. Combination therapyCombination therapy: : chloroquine + primaquinechloroquine + primaquine: symptom stages: symptom stages pyrimethamine + primaquinepyrimethamine + primaquine: dormant hypnozoite : dormant hypnozoite

stages stages Combination of drugs with different mechanismsCombination of drugs with different mechanisms: :

therapeutic effect↑, resistance↓therapeutic effect↑, resistance↓

Anti-amebiasis DrugsAnti-amebiasis Drugs

• Amebiasis is infection with Amebiasis is infection with Entamoeba histolytic.Entamoeba histolytic.

• Amebiasis is Amebiasis is transmitted through gastrointestinal tract.gastrointestinal tract.

• Ameba has two stages of Ameba has two stages of development: cyst(development: cyst( 包囊包囊 ) and ) and trophozoite(trophozoite( 滋养体滋养体 ).).CystsCysts → → small intestinesmall intestine → → little trophozoites little trophozoites

((ileocecum))

cysts (colon) ———— asymptomatic intestinal asymptomatic intestinal infectioninfection, , source of infectionbig trophozoites (tissues of intestine) ———— intestinal amebiasisintestinal amebiasis

→ → extraintestinal infectionextraintestinal infection

MetronidazoleMetronidazole

• A nitroimidazole(A nitroimidazole(硝基咪唑类硝基咪唑类 ). The nitro ). The nitro group of metronidazole is chemically group of metronidazole is chemically reduced in anaerobic(reduced in anaerobic(厌氧的 ) bacteria and ) bacteria and sensitive protozoans. Reactive reduction sensitive protozoans. Reactive reduction products appear to be responsible for products appear to be responsible for antimicrobial activity.antimicrobial activity.

• PharmacokineticsPharmacokinetics– Oral metronidazole is readily absorbed and Oral metronidazole is readily absorbed and

permeates all tissues by simple diffusion.permeates all tissues by simple diffusion.– Protein binding is low (<20%)Protein binding is low (<20%)– Through Through blood brain barrier– Metabolizing in liver.– Excreted mainly in the urine.

• Pharmacological Effects and Clinical Pharmacological Effects and Clinical UsesUses

1.1. Anti-amebiasis: kills Anti-amebiasis: kills EE histolytic histolytic trophozoites but not cysts. Treatment of trophozoites but not cysts. Treatment of all tissue infections with all tissue infections with EE histolytichistolytic. No . No effection against luminal parasites and effection against luminal parasites and so must be used with a luminal so must be used with a luminal amebicide to ensure eradication of the amebicide to ensure eradication of the infection.infection.

2.2. Anti-trichomoniasis(Anti-trichomoniasis(滴虫病滴虫病 ): ):

3.3. Anti-anaerobic bacteria(Anti-anaerobic bacteria(厌氧细菌 ): ):

4.4. Anti-giardiasis(Anti-giardiasis(梨形鞭毛虫病 ): ):

• Adverse Effects and CautionsAdverse Effects and Cautions– Nausea, headache, dry mouth, a metallic Nausea, headache, dry mouth, a metallic

taste in the mouth.taste in the mouth.– InfrequentInfrequent: vomiting, diarrhea, rash, : vomiting, diarrhea, rash,

insomnia, neutropenia, insomnia, neutropenia, …………– RareRare: severe central nervous system : severe central nervous system

toxicity ( ataxia, encephalopathy(toxicity ( ataxia, encephalopathy(脑病 ), ), seizures)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 Emetine and DehydroemetineDehydroemetine

• Emetine, an alkaloid derived from ipecac(Emetine, an alkaloid derived from ipecac(吐根 ), and dehydroemetine, a synthetic analog, ehydroemetine, a synthetic analog, are effective against tissue trophozoites of are effective against tissue trophozoites of EE histolytic histolytic ..

• Because of major toxicity concerns they have Because of major toxicity concerns they have been almost completely replaced by been almost completely replaced by metronidazole.metronidazole.

• Administered subcutaneously (preferred) or Administered subcutaneously (preferred) or i.m. (but never i.v.) because oral i.m. (but never i.v.) because oral preparations are absorbed erratically(preparations are absorbed erratically(不规律 ).).

• Pharmacological Effects and Clinical UsesPharmacological Effects and Clinical Uses• kills kills EE histolytic histolytic trophozoites of histolytic trophozoites of histolytic

tissues but no effection against luminal tissues but no effection against luminal trophozoites. a luminal amebicide should trophozoites. a luminal amebicide should also be given.also be given.

• Rapidly alleviate severe intestinal Rapidly alleviate severe intestinal symptoms, used to treat amebic symptoms, used to treat amebic dysentery(dysentery(痢疾 ) for the minimum period ) for the minimum period because of toxicity.because of toxicity.

• Occasionally as alternative therapies for Occasionally as alternative therapies for amebic liver abscess.amebic liver abscess.

• MechanismsMechanismsInhibiting peptidyl-tRNA transposition Inhibiting peptidyl-tRNA transposition

→ inhibiting elongation of peptide chain → inhibiting elongation of peptide chain → inhibiting protein synthesis → → inhibiting protein synthesis → interfering cleavage and breeding of interfering cleavage and breeding of trophozoites trophozoites

• Adverse Effects and CautionsAdverse Effects and Cautions low selection → also inhibiting protein low selection → also inhibiting protein

synthesis of eukaryocyte.synthesis of eukaryocyte. Toxicity increase with length of therapy.Toxicity increase with length of therapy.1.1. Cardiac toxicityCardiac toxicity: arrhythmias, congestive : arrhythmias, congestive

heart failure, hypotention, ECG changesheart failure, hypotention, ECG changes2.2. Neuromuscular blockadeNeuromuscular blockade: muscle weakness : muscle weakness

and discomfortand discomfort3.3. Local stimulationLocal stimulation: pain and tenderness in the : pain and tenderness in the

area of injection.area of injection.4.4. Gastrointestinal tract discomfortGastrointestinal tract discomfort: nausea, nausea,

vomitingvomiting Not be used in patients with cardiac or renal Not be used in patients with cardiac or renal

disease, in young children, or in pregnancy.disease, in young children, or in pregnancy.

DiloxanideDiloxanide

• Diloxanide furoate(Diloxanide furoate(糠酸盐 ) is a ) is a dichoroacetamide(dichoroacetamide(二氯乙酰胺二氯乙酰胺 ) derivative.) derivative.

• Effective luminal amebicide but is not active Effective luminal amebicide but is not active against tissue trophozoitesagainst tissue trophozoites..

• The unabsorbed diloxanide in the gut is the The unabsorbed diloxanide in the gut is the active antiamebic substance.active antiamebic substance.

• Effective for asymptomatic luminal infectionsEffective for asymptomatic luminal infections..• It is used with a tissue amebicide, usually It is used with a tissue amebicide, usually

metronidazole.metronidazole.• Adverse Effects: flatulence(Adverse Effects: flatulence(胃肠气胀 ), nausea, ), nausea,

abdominal cramps(abdominal cramps(痛性痉挛 ), rashes, abortion), rashes, abortion(( 流产流产 ).).

ParomomycinParomomycin

• Aminoglycoside(Aminoglycoside(氨基糖苷 ) antibiotic.) antibiotic.• Not significantly absorbed from the Not significantly absorbed from the

gastrointestinal tract.gastrointestinal tract.• Only as a luminal amebicide and has no Only as a luminal amebicide and has no

effect against extraintestinal amebic effect against extraintestinal amebic infections.infections.

• inhibiting protein synthesis → kill inhibiting protein synthesis → kill trophozoites;trophozoites;

• inhibitinginhibiting symbiosis flora → indirectlysymbiosis flora → indirectly inhibiting ameba protozoa. inhibiting ameba protozoa.

ChloroquineChloroquine

• Chloroquine reaches high liver Chloroquine reaches high liver concentrations → treatment of concentrations → treatment of amebic liver abscess.amebic liver abscess.

• Not effective in the treatment of Not effective in the treatment of intestinal or other extrahepatic intestinal or other extrahepatic amebiasis.amebiasis.

Anti-trichomoniasis Anti-trichomoniasis DrugsDrugs

• MetronidazoleMetronidazole• Acetarsol (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.

PraziquantelPraziquantel

• A synthetic isoquinoline-pyrazine derivative.A synthetic isoquinoline-pyrazine derivative.• Pharmacological EffectsPharmacological Effects

– Effective in the treatment of schistosome(Effective in the treatment of schistosome(血吸虫 ) ) infections of all species and most other infections of all species and most other trematode(trematode(吸虫 ) and cestode() and cestode(绦虫 ) infections, infections, including cysticercosis(including cysticercosis(囊虫病 )..

– Against adult worms and immature stages.Against adult worms and immature stages.

• MechanismsMechanisms– Increases cell membrane permeability to calcium Increases cell membrane permeability to calcium

→ vacuolization, marked contraction, → vacuolization, marked contraction, spastic paralysis, dislodgement(, dislodgement(赶出 ), death., death.

• Clinical UsesClinical Uses– Schistosomiasis(Schistosomiasis(血吸虫病 ))– Clonorchiasis(Clonorchiasis(支睾吸虫病 ) and Opisthorchiasis) and Opisthorchiasis((后睾吸虫病 ))

– Paragonimiasis(Paragonimiasis(肺吸虫病 ))– Taeniasis(Taeniasis(绦虫病 ) and Diphyllobothriasis() and Diphyllobothriasis(裂头绦虫病 ))

– Neurocysticercosis(Neurocysticercosis( 神经神经囊虫病 ))– Hydatid(Hydatid(棘球蚴 ) disease) disease– Other parasites: fasciolopsiasis(Other parasites: fasciolopsiasis(姜片虫病 ), ,

metagonimiasis(metagonimiasis(后殖吸虫病 ), heterophyiasis(, heterophyiasis(异形吸虫病 )

• Adverse ReactionsAdverse Reactions– Mild and trainsient.Mild and trainsient.– Headache, dizziness, drowsiness, Headache, dizziness, drowsiness,

lassitudelassitude– low-grade fever, pruritus), and skin

rashes (macular and urticarial)—due to the release of foreign protein from dying worms.

Anti-Anti-filariasis Drugs

• Epidemic in China: – Wuchereria bancrofti– Brugia malayi

• Parasitize in lymphatic system.

DiethylcarbamazineDiethylcarbamazine

• A synthetic piperazine derivative. Rapidly A synthetic piperazine derivative. Rapidly absorbed from the gastrointestinal tract; absorbed from the gastrointestinal tract; excreted rapidly in the presence of acidic excreted rapidly in the presence of acidic urine.urine.

• Pharmacologic Effects and MechanismsPharmacologic Effects and Mechanisms– Immobilizes microfilariae(Immobilizes microfilariae(微丝蚴微丝蚴 ) (which ) (which

results in their displacement in tissues) and results in their displacement in tissues) and alters their surface structure, making them alters their surface structure, making them more susceptible to destruction by host more susceptible to destruction by host defense mechanisms.defense mechanisms.

– Adult parasites are killed more slowly. Against Adult parasites are killed more slowly. Against adult worms is unknown.adult worms is unknown.

• Clinical UsesClinical Uses– The drug should be taken after meals.The drug should be taken after meals.

1.1. Wuchereria bancroftiWuchereria bancrofti((班氏丝虫 ), , Brugia malayiBrugia malayi((马来丝虫 ), ), Brugia timoriBrugia timori, and , and Loa loaLoa loa((罗阿丝虫 )

2. 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 China② Tapeworms ③ Flukes (trematodes)

MebendazoleMebendazole

• A synthetic benzimidazole that has a wide A synthetic benzimidazole that has a wide spectrum of anthelmintic activity and a spectrum of anthelmintic activity and a low incidence of adverse effects.low incidence of adverse effects.

• PharmacokineticsPharmacokinetics– Oral aOral 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.

– AAbsorption is increased if the drug is ingested with a fatty meal.

• Pharmacologic EffectsPharmacologic Effects – Inhibits microtubule synthesis in nematodes, Inhibits microtubule synthesis in nematodes,

thus irreversibly impairing glucose uptake. thus irreversibly impairing glucose uptake. Intestinal parasites are immobilized or die Intestinal parasites are immobilized or die slowly.slowly.

– Kills hookworm, ascaris, and trichuris eggs.Kills hookworm, ascaris, and trichuris eggs.

• Clinical UsesClinical Uses– Pinworm infectionPinworm infection– Ascaris lumbricoidesAscaris lumbricoides, , Trichuris trichiura Trichuris trichiura , ,

Hookworm, and TrichostrongylusHookworm, and Trichostrongylus– Other infections: intestinal capillariasis, Other infections: intestinal capillariasis,

trichinosis, taeniasis(, strongyloidiasis, trichinosis, taeniasis(, strongyloidiasis, dracontiasis, et al.dracontiasis, et al.

• Adverse Effects and CautionsAdverse Effects and Cautions– Low-dose: nearly free adverse effects.Low-dose: nearly free adverse effects.– Diarrhea, abdominal pain is infrequent.Diarrhea, abdominal pain is infrequent.– High-dose: pruritus,rash, eosinophiliaHigh-dose: pruritus,rash, eosinophilia), ,

reversible neutropenia, musculoskeletal reversible neutropenia, musculoskeletal pain, fever, transient liver function pain, fever, transient liver function abnormalities, alopecia, abnormalities, alopecia, glomerulonephritisglomerulonephritis, agranulocytosis

AlbendazoleAlbendazole

• A benzimidazole carbamateA benzimidazole carbamate• A broad-spectrum oral anthelmintic A broad-spectrum oral anthelmintic

for treatment of hydatid disease and for treatment of hydatid disease and cysticercosis, pinworm infection, cysticercosis, pinworm infection, ascariasis, trichuriasis, ascariasis, trichuriasis, strongyloidiasis, and infections with strongyloidiasis, and infections with both hookworm species.both hookworm species.

• Effect better than Mebendazole.Effect better than Mebendazole.

• Clinical UsesClinical Uses– Administered on an empty stomach Administered on an empty stomach

when used against intraluminal when used against intraluminal parasites but with a fatty meal when parasites but with a fatty meal when used against tissue parasites.used against tissue parasites.

1.1. Ascariasis, Trichuriasis, and Hookworm Ascariasis, Trichuriasis, and Hookworm and Pinwormand Pinworm infections.infections.

2.2. StrongyloidiasisStrongyloidiasis3.3. Hydatid DiseaseHydatid Disease4.4. NeurocysticercosisNeurocysticercosis5. Other infections: cutaneous larva

migrans, gnathostomiasis

PiperazinePiperazine

• Treatment of ascariasis• No longer recommended for treatment of

pinworm infection, because a 7-day couse of treatment is required.

• Not useful in hookworm infection, trichuriasis, or strongyloidiasis.

• Causes flaccid paralysis of ascaris by blocking acetylcholine at the myoneuraljunction.

• Neurotoxic adverse effects.

LevamizoleLevamizole

• A synthetic imidazothiazole derivative A synthetic imidazothiazole derivative and the L isomer of D,L-tetramisole.and the L isomer of D,L-tetramisole.

• Highly effective in eradicating ascaris Highly effective in eradicating ascaris and trichostrongylus and moderately and trichostrongylus and moderately effective against both species of effective against both species of hookworm.hookworm.

• Inhibiting succinic dehydrogenase → energy↓ → flaccid paralysis

• Immunomodulating effect.

PyrantelPyrantel

• A tetrahydropyrimidine derivative.• A broad-spectrum anthelmintic• Highly effective for the treatment of pinworm,

ascaris, and Trichostrongylus orientalis infections.

• Moderately effective against both species of hookworm but less so against N americanus.

• Not effective in trichuriasis or strongyloidiasis.• 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 Effective against mature and immature forms of helminths within the intestinal tract but not of helminths within the intestinal tract but not against migratory stages in the tissues or against migratory stages in the tissues or against ova.against ova.

• Inhibition of cholinesterase Inhibition of cholinesterase ———— a depolarizing a depolarizing neuromuscular blocking agent → neuromuscular blocking agent → spastic paralysis

• Used with caution in patients with liver dysfunction.

• No combination with piperazine because of antagonistic action.

Pyrvinium EmbonatePyrvinium Embonate

• A dye.A dye.• Not absorb orally.Not absorb orally.• treatment of pinworm• Selectively interfering energy

metabolism enzymatic system• Inhibiting glucose-transporting

enzymatic system• Red feces

Niclosamide Niclosamide

• A salicylamide derivativeA salicylamide derivative• Treatment of most tapeworm infection.Treatment of most tapeworm infection.• Pharmacologic EffectsPharmacologic Effects

– Scoleces and segments of cestodesScoleces and segments of cestodes——but but not ova not ova —— are rapidly killed on contact are rapidly killed on contact with nicolsamide due to the drugwith nicolsamide due to the drug’’s s inhibition of oxidative phosphorylation or inhibition of oxidative phosphorylation or to its ATPase-stimulating property.to its ATPase-stimulating property.

– With the death of the parasite, digestion of With the death of the parasite, digestion of scoleces and segments begins.scoleces and segments begins.

• Clinical UsesClinical Uses– Given in the morning on an empty stomach.Given in the morning on an empty stomach.– The tablets The tablets must be chewed thoroughlymust be chewed thoroughly and are and are

then swallowed with water.then swallowed with water. Niclosamide can be used as an alternative drug Niclosamide can be used as an alternative drug

for the treatment of for the treatment of intestinal fluke intestinal fluke infections.infections.

• Adverse Effects and CautionsAdverse Effects and Cautions– Infrequent, mild and transitory.Infrequent, mild and transitory.– Nausea, vomiting, diarrhea, and abdominal Nausea, vomiting, diarrhea, and abdominal

discomfort.discomfort.

PraziquantelPraziquantel

• Effective in the treatment of Effective in the treatment of schistosome infections of all species schistosome infections of all species and most other trematode and and most other trematode and cestode infections, including cestode infections, including cysticercosis.cysticercosis.

• A first choice in the treatment A first choice in the treatment cestodiasiscestodiasis.