Download Anti-amebiasis Drugs

Ass.Prof. Jinan Abdul-Amir S. Al-Hussaini
Pharmacology (Theorical)
Lec. No. (
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Antiprotozoal and Antihelmintic drugs
Malaria:
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Malaria is caused by plasmodium whose sporozoiteswas inoculated to initiate human infection by
anopheline mosquito.
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Four species of plasmodium cause human malaria:
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Plasmodium falciparum → responsible for nearly all serious complicationsand deaths.
P. vivax .
P. malariae .
P. ovale→ seldom
ParasiteLife Cycle
I.
II.
Asexual stage in human:
①
Primary exoerythrocyticstage: sporozoites invade liver cells → schizonts —— incubation
period
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Asexual erythrocytic stage: merozoitesinvade erythrocytes, trophozoites→ schizonts, rupture host
erythrocytes → repeated cycles —— cause clinical illness
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Secondary exoerythrocytic stage: In P vivax and P ovale infections, a dormant hepatic stage,
hypnozoite → relapses.
Sexual stage in anopheline mosquito:
①
Sexual stage gametocytesalso 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.
1- Chloroquine
A synthetic 4-aminoquinoline formulated as the phosphate salt for oral use.
Pharmacokinetics:
1- Rapidly and almost completely absorbed from the gastrointestinal tract.
2- Very large apparent volume of distribution of 100-1000 L/kg.
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3- Necessitate the use of a loading dose to rapidly achieve effective serum concentrations.
4- Slowly released from tissues and metabolized.
5- Principally excreted in the urine.
Pharmacological Effects:
1- 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 hemoglobinbreakdown product, heme, into hemozoin and thus
eliciting parasite toxicity due to the buildup of free heme. ④pH↑→ plasmodium protease
activity↓
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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 Uses:
1- 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 Cautions:
1- Usually very well tolerated, even with prolonged use.
2- Pruritus is common.
3- Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of visio, and urticaria are
uncommon.
4- Dosing after meals may reduce some adverse effects.
5- Rare reactions include hemolysis in G6PD-deficient persons, impaired hearing, confusion, psychosis,
seizures, hypotension, ECG changes.
6- teratogenesis
2- 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, 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.
 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.
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1- Parenteral treatment of severe falciparum malaria
2- Oral treatment of falciparum malaria
3- Malarial chemoprophylaxis.
4- Babesiosis
Adverse Effects and Cautions:
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Cinchonism: tinnitus, headache, nausea, dizziness, flushing, visual disturbances.
Cardiovascular effects: severe hypotension and arrhythmia can follow too-rapid intravenous infusion.
Idiosyncrasy: hemolysis with G6PD deficiency.
Others: hypoglycemia through stimulation of insulin release, stimulate uterine contractions.
3- 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 proteinbound, 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:
1- Chemoprophylaxis.
2- Treatment: mainly for chloroquine-resistant falciparum malaria.
Adverse Effects and Cautions:
1- Nausea, vomiting, diarrhea, abdominal pain—— dose-dependent
2- Neuropsychiatric toxicities: dizziness, headache, behavioral disturbances, psychosis, seizures.
4- Malaridine
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Developed by China.
blood schizonticidal activity.
Treatment for all types malaria, including chloroquine-resistant falciparum malaria.
Mechanism: destroy parasite compound membrane and food vacuoles.
5- Artemisinin
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Extracted from yellow flower mug wort.
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:
6- Artemether and Artesunate
7- Dihydroartemisinin
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8- Primaquine: Synthetic 8-aminoquinoline.
Pharmacological Effects:
1- Against hepatic stages of malaria parasites.
2- The only available agent active against the dormant hypnozoite stages of P vivax and P ovale.
3- Also gametocidal against the four human malaria species.
Clinical Uses:
1- Therapy (Radical Cure) of Acute Vivax and Ovale Malaria: chloroquine + primaquine.
2- Terminal Prophylaxis of Vivax and Ovale Malaria: prevent a relapse.
3- Chemoprophylaxis of Malaria: protection against falciparum and vivax malaria. But potential toxicities of
long-term use limited its routinely administration.
4- 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.
5- Pneumocystis carinii infection: clindamycin+primaquine → mild to moderate pneumocystosis
Adverse Effects and Cautions:
1- Nausea, epigastric pain, abdominal cramps, headache.
2- Hemolysis or methemoglobinemia, especially in persons with G6PD deficiency or other hereditary
metabolic defects.
9- Pyrimethamine
Pharmacokinetics:
 Slowly but adequately absorbed from the gastrointestinal tract.
 Slowly eliminated and excreted from urine.
Pharmacological Effects:
1- Kill schizonts of primary exoerythrocytic stage.
2- Act slowly against premature schizonts of erythrocytic stage.
3- No action against gametocytes, but can inhibit development of plasmodium in mosquito.
4- Inhibit plasmodial dihydrofolate reductase → inhibiting breeding of plasmodium.
Adverse Effects and Cautions:
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Gastrointestinal symptoms, skin rashes.
Interfering folic acid metabolism in human → megalocyte anemia, granulocytopenia.
Acute intoxication
Teratogenesis.
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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:
a) Control symptoms: chloroquine.
b) Cerebral malaria: chloroquine phosphate, quinine bimuriate, artemisinin —— injection.
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c)
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2.
Chloroquine-resistant falciparum malaria: quinine, mefloquine, artemisinin.
Dormant hypnozoite stages : pyrimethamine + primaquine.
Prophylaxis: pyrimethamine, chloroquine
Combination therapy:
a) chloroquine + primaquine: symptom stages.
b) pyrimethamine + primaquine: dormant hypnozoite stages.
c) 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 and trophozoite.
Cysts → small intestine → little trophozoites (ileocecum)
cysts (colon) —— asymptomatic intestinal infection, source of infection
big trophozoites (tissues of intestine) —— intestinal amebiasis → extraintestinal infection
1- Metronidazole
A 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.
Pharmacokinetics:
1- Oral metronidazole is readily absorbed and permeates all tissues by simple diffusion.
2- Protein binding is low (<20%).
3- Through blood brain barrier.
4- Metabolizing in liver.
5- 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.
3- Anti-anaerobic bacteria.
4- Anti-giardiasis.
Adverse Effects and Cautions:
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Nausea, 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.
2- Emetine and Dehydroemetine
 Emetine, 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 Uses.
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 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 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:
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low selection → also inhibiting protein synthesis of eukaryocyte.
Toxicity increase with length of therapy.
Cardiac toxicity: arrhythmias, congestive heart failure, hypotention, ECG changes.
Neuromuscular blockade: muscle weakness and discomfort.
Local stimulation: pain and tenderness in the area of injection.
Gastrointestinal tract discomfort: nausea, vomiting.
Not be used in patients with cardiac or renal disease, in young children, or in pregnancy.
3- Diloxanide
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Diloxanide 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.
4- Paromomycin
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Aminoglycoside 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.
5- 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
1- Metronidazole
Anti-schistosomiasis Drugs
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Schistosoma including:
 Schistosoma japonicum
 Schistosoma mansoni
 Schistosoma haematobium
1- Antimony potassium tartrate: inhibition of phosphofructokinase, treatment of schistosomiasis. But
greater toxicity, long treatment course, i.v. limit its uses.
2- Praziquantel: A synthetic isoquinoline-pyrazine derivative.
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Pharmacological Effects:
1- Effective in the treatment of schistosome infections of all species and most other trematode and
cestode infections, including cysticercosis.
2- Against adult worms and immature stages.
Mechanisms:
Increases cell membrane permeability to calcium → vacuolization, marked contraction, spastic paralysis,
dislodgement, death.
Clinical Uses:
1- Schistosomiasis, Clonorchiasis and Opisthorchiasis, Paragonimiasis, Taeniasis and Diphyllobothriasis,
Neurocysticercosis, Hydatid disease.
2- Other parasites: fasciolopsiasis, metagonimiasis, heterophyiasis.
Adverse Reactions:
1- Mild and trainsient.
2- 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 Drugs
1- Wuchereria bancrofti
2- Brugia malayi
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Parasitize in lymphatic system.
1- Diethylcarbamazine
A synthetic piperazine derivative. Rapidly absorbed from the gastrointestinal tract; excreted rapidly in the
presence of acidic urine.
Pharmacologic Effects and Mechanisms
1- Immobilizes microfilariae (which results in their displacement in tissues) and alters their surface
structure, making them more susceptible to destruction by host defense mechanisms.
2- Adult parasites are killed more slowly. Against adult worms is unknown.
Clinical Uses:
1- The drug should be taken after meals.
2- Wuchereria bancrofti, Brugia malayi , Brugia timori, and Loa loa.
3- Tropical Eosinophilia.
Adverse Reactions:
1- Drug-induced Reactions: mild and transient, headache, malaise, anorexia, nausea.
2- 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).
2- Tapeworms.
3- Flukes (trematodes)
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1- Mebendazole
A synthetic benzimidazole that has a wide spectrum of anthelmintic activity and a low incidence of adverse
effects.
Pharmacokinetics:
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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:
1- Inhibits microtubule synthesis in nematodes, thus irreversibly impairing glucose uptake. Intestinal
parasites are immobilized or die slowly.
2- Kills hookworm, ascaris, and trichuris eggs.
Clinical Uses:
1- Pinworm infection.
2- Ascaris lumbricoides, Trichuris trichiura , Hookworm, and Trichostrongylus.
3- Other infections: intestinal capillariasis, trichinosis, taeniasis, strongyloidiasis, dracontiasis.
Adverse Effects and Cautions:
1- Low-dose: nearly free adverse effects.
2- Diarrhea, abdominal pain is infrequent.
3- High-dose: pruritus, rash, eosinophilia, reversible neutropenia, musculoskeletal pain, fever, transient liver
function abnormalities, alopecia, glomerulonephritis, agranulocytosis.
2- Albendazole
 A benzimidazole carbamate.
 A 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:
1- Administered on an empty stomach when used against intraluminal parasites but with a fatty meal
when used against tissue parasites.
2- Ascariasis, Trichuriasis, and Hookworm and Pinworm infections.
3- Strongyloidiasis.
4- Hydatid Disease
5- Neurocysticercosis.
6- Other infections: cutaneous larva migrans, gnathostomiasis.
3- Piperazine:
 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 myoneural junction.
 Neurotoxic adverse effects.
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4- Levamizole:
 A 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.
5- Pyrantel
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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 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.
6- Pyrvinium Embonate
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A dye.
Not absorb orally.
treatment of pinworm.
Selectively interfering energy metabolism enzymatic system.
Inhibiting glucose-transporting enzymatic system.
Red feces.
7- Niclosamide
 A salicylamide derivative.
 Treatment of most tapeworm infection.
Pharmacologic Effects :
1- 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.
2- With the death of the parasite, digestion of scoleces and segments begins.
Clinical Uses:
1- Given in the morning on an empty stomach.
2- The tablets must be chewed thoroughly and are then swallowed with water.
3- Niclosamide can be used as an alternative drug for the treatment of intestinal fluke infections.
Adverse Effects and Cautions:
1- Infrequent, mild and transitory.
2- Nausea, vomiting, diarrhea, and abdominal discomfort.
8- Praziquantel
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 Effective 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.
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