Antiparasitic Drugs

Overview Antimalarial drugs Anti-amebiasis drugs and Anti-

trichomoniasis drugs Anti-schistosomiasis drugs and Anti-

filariasis drugs Anthelmintic drugs

MalariaMalaria is caused by plasmodium whose

sporozoites was inoculated to initiate human infection by anopheline mosquito.

Four species of plasmodium cause human malaria: Plasmodium falciparum → responsible for

nearly all serious complications and deaths.P vivax P malariae P ovale → seldom

benign malaria

Parasite Life CycleI. Asexual stage in human:

① Primary exoerythrocytic stage: sporozoites invade liver cells → schizonts —— incubation period

② Asexual erythrocytic stage: merozoites invade erythrocytes, trophozoites→ schizonts, rupture host erythrocytes → repeated cycles —— cause clinical illness

③ Secondary exoerythrocytic stage: In P vivax and P ovale infections, a dormant hepatic stage, hypnozoite → relapses

II. Sexual stage in anopheline mosquito:• Sexual stage gametocytes 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: eliminate

developing or dormant liver forms.2. Blood schizonticides: act on erythrocytic

parasites.3. Gametocides: kill sexual stages and

prevent transmission to mosquitoes. No one available agent can reliably effect

a radical cures.

ChloroquineA 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.

Control symptoms

Pharmacological Effects1. Antimalarial action: ①highly effective blood

schizonticide. ②Moderately 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.

Mechanism: ① plasmodium aggregates chloroquine. ②chloroquine incorporated into DNA chain of plasmodium → inhibit proliferation. ③ chloroquine prevents the polymerizationof the hemoglobin breakdown product, heme, into hemozoin and thus eliciting parasite toxicity due to the buildup of free heme. ④pH↑→ 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.

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

3. Immunosuppression action:

Clinical Uses1. Treatment: nonfalciparum and sensitive

falciparum malaria. Primaquine 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: not effective in the treatment of intestinal or other extrahepatic amebiasis.

Adverse Effects and CautionsUsually very well tolerated, even with prolonged

use.Pruritus is common.Nausea, vomiting, abdominal pain, headache,

anorexia, malaise, blurring of vision, and urticaria 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 and quinidine remain first-line

therapies for falciparum malaria——especially severe disease.

Quinine is an alkaloid derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America.

Quinine is the levorotatory stereoisomer of quinidine.

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

urine.

Control symptoms

Pharmacological EffectsHighly 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 treatment of severe falciparum

malariaOral treatment of falciparum malariaMalarial chemoprophylaxisBabesiosis

Adverse Effects and Cautions1. Cinchonism: tinnitus, headache, nausea,

dizziness, flushing, visual disturbances2. 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

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.

Control symptoms

Clinical UsesChemoprophylaxis: 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.

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 symptoms

Primaquine Synthetic 8-aminoquinoline.Pharmacological Effects

Against hepatic stages of malaria parasites. The only available agent active against the

dormant hypnozoite stages of P vivax and P ovale.

Also gametocidal against the four human malaria species.

Control relapse and transmission

Clinical UsesTherapy (Radical Cure) of Acute Vivax and Ovale

Malaria: chloroquine + primaquineTerminal Prophylaxis of Vivax and Ovale Malaria:

prevent a relapseChemoprophylaxis 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 infection: clindamycin +primaquine → mild to moderate pneumocystosis

Adverse Effects and CautionsNausea, epigastric pain, abdominal cramps,

headache.Hemolysis or methemoglobinemia,

especially in persons with G6PD deficiency or other hereditary metabolic defects.

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.

Etiological factor prophylaxis

Adverse Effects and CautionsGastrointestinal symptoms, skin rashes.Interfering folic acid metabolism in human →

megalocyte anemia, granulocytopenia.Acute intoxicationTeratogenesis

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.

Etiological factor prophylaxis

Rational Use of Antimalarial Drugs1. 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 DrugsAmebiasis is infection with Entamoeba

histolytic.Amebiasis is transmitted through

gastrointestinal tract.Ameba has two stages of development:

cyst and trophozoite.Cysts → small intestine → little trophozoites

(ileocecum)

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

MetronidazoleA nitroimidazole. The nitro group of

metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antimicrobial activity.

PharmacokineticsOral metronidazole is readily absorbed and

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

Pharmacological Effects and Clinical Uses1. 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: 3. Anti-anaerobic bacteria: 4. Anti-giardiasis:

Adverse Effects and CautionsNausea, headache, dry mouth, a metallic taste

in the mouth.Infrequent: vomiting, diarrhea, rash, insomnia,

neutropenia, ……Rare: severe central nervous system toxicity

( ataxia, encephalopathy, seizures)——drug withdrawal

Has a disulfiram-like effect, so that nausea and vomiting can occur if alcohol is ingested during therapy.

Emetine and DehydroemetineEmetine, an alkaloid derived from

ipecac, 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.

Pharmacological Effects and Clinical Useskills 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 for the minimum period because of toxicity.

Occasionally as alternative therapies for amebic liver abscess.

MechanismsInhibiting 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 changes2. Neuromuscular blockade: muscle weakness

and discomfort3. 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.

DiloxanideDiloxanide furoate is a dichoroacetamide

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, nausea,

abdominal cramps, rashes, abortion.

ParomomycinAminoglycoside 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 DrugsMetronidazoleAcetarsol

Anti-schistosomiasis DrugsSchistosoma including:

Schistosoma japonicum (epidemic in China) Schistosoma mansoni Schistosoma haematobium

Antimony potassium tartrate —— inhibition of phosphofructokinase —— treatment of schistosomiasis. But greater toxicity, long treatment course, i.v. limit its uses.

PraziquantelA synthetic isoquinoline-pyrazine

derivative.Pharmacological Effects

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

Against adult worms and immature stages.Mechanisms

Increases cell membrane permeability to calcium → vacuolization, marked contraction, spastic paralysis, dislodgement, death.

Clinical UsesSchistosomiasisClonorchiasis and OpisthorchiasisParagonimiasisTaeniasis and DiphyllobothriasisNeurocysticercosisHydatid diseaseOther parasites: fasciolopsiasis, metagonimiasis,

heterophyiasis

Adverse ReactionsMild and trainsient.Headache, dizziness, drowsiness, lassitude low-grade fever, pruritus, and skin rashes

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

Anti-filariasis DrugsEpidemic in China:

Wuchereria bancrofti Brugia malayi

Parasitize in lymphatic system.

DiethylcarbamazineA synthetic piperazine derivative. Rapidly

absorbed from the gastrointestinal tract; excreted rapidly in the presence of acidic urine.

Pharmacologic Effects and MechanismsImmobilizes microfilariae(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 The drug should be taken after meals.1. Wuchereria bancrofti, Brugia malayi, Brugia

timori, and Loa loa2. Tropical Eosinophilia

Adverse Reactions Drug-induced Reactions: mild and transient,

headache, malaise, anorexia, nausea, …… Reactions induced by Dying Parasites:

release of foreign proteins. Eosinophilia and leukocytosis. Papular rash, muscle or joint pains.

Anthelmintic Drugs Classification of Helminth

① Roundworms (nematodes) —— epidemic in China

② Tapeworms ③ Flukes (trematodes)

MebendazoleA synthetic benzimidazole that has a

wide spectrum of anthelmintic activity and a low incidence of adverse effects.

PharmacokineticsOral 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 synthesis in nematodes,

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

Kills hookworm, ascaris, and trichuris eggs.Clinical Uses

PinworminfectionAscaris lumbricoides, Trichuris trichiura ,

Hookworm, and TrichostrongylusOther infections: intestinal capillariasis,

trichinosis, taeniasis, strongyloidiasis, dracontiasis, et al.

Adverse Effects and CautionsLow-dose: nearly free adverse effects.Diarrhea, abdominal pain is infrequent.High-dose: pruritus, rash, eosinophilia,

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

AlbendazoleA benzimidazole carbamateA broad-spectrum oral anthelmintic for

treatment of hydatid disease and cysticercosis, pinworm infection, ascariasis, trichuriasis, strongyloidiasis, and infections with both hookworm 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, Trichuriasis, and Hookworm and Pinworm infections.

2. Strongyloidiasis3. Hydatid Disease4. Neurocysticercosis5. Other infections: cutaneous larva migrans,

gnathostomiasis……

PiperazineTreatment 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 myoneural junction.

Neurotoxic adverse effects.

LevamizoleA synthetic imidazothiazole derivative and

the L isomer of D,L-tetramisole.Highly effective in eradicating ascaris and

trichostrongylus and moderately effective against both species of hookworm.

Inhibiting succinic dehydrogenase → energy↓ → flaccid paralysis

Immunomodulating effect.

PyrantelA tetrahydropyrimidine derivative.A broad-spectrum anthelminticHighly 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 of helminths within the intestinal tract but not against migratory stages in the tissues or against ova.

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 EmbonateA dye.Not absorb orally.treatment of pinwormSelectively interfering energy metabolism

enzymatic systemInhibiting glucose-transporting enzymatic

systemRed feces

Niclosamide A salicylamide derivativeTreatment of most tapeworm infection.Pharmacologic Effects

Scoleces and segments of cestodes —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 UsesGiven 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 CautionsInfrequent, mild and transitory.Nausea, vomiting, diarrhea, and abdominal

discomfort.

PraziquantelEffective in the treatment of schistosome

infections of all species and most other trematode and cestode infections, including cysticercosis.

A first choice in the treatment cestodiasis.