Transcript Antiprotozoal Drugs

Antiparasitic Drugs
Fen-Fei Gao
Overview
一．Antimalarial drugs
二．Anti-amebiasis drugs and Anti-trichomoniasis
drugs
三．Anti-schistosomiasis drugs and Anti-filariasis
drugs
四．Anthelmintic drugs
Malaria(疟疾)
• Malaria is caused by plasmodium (疟原虫) whose
sporozoites(子孢子) was inoculated to initiate human
infection by anopheline mosquito(按蚊).
• Four species of plasmodium cause human malaria:
– Plasmodium falciparum (恶性疟) → responsible for nearly all
serious complications(并发症) and deaths.
– P vivax (间日疟)
benign malaria
– P malariae (三日疟)
– P ovale(卵圆形疟) → seldom
Parasite(寄生虫) Life Cycle
I.
Asexual stage in human:
①
②
③
II.
Primary exoerythrocytic(红细胞外) stage: sporozoites（子孢子）
invade liver cells → schizonts（裂殖体）—— incubation period
Asexual erythrocytic stage: merozoites(裂殖子) invade erythrocytes,
trophozoites(滋养体) → schizonts, rupture host erythrocytes →
repeated cycles —— cause clinical illness
Secondary exoerythrocytic stage: In P vivax and P ovale infections, a
dormant(静止的) hepatic stage, hypnozoite(睡眠子孢子) →
relapses(复发)
Sexual stage in anopheline mosquito:
•
Sexual stage gametocytes(配子体) 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(杀组织裂殖体药): eliminate
developing or dormant(静止) liver forms.
2. Blood schizonticides: act on erythrocytic parasites.
3. Gametocides(杀配子体药): kill sexual stages and
prevent transmission to mosquitoes.
•
No one available agent can reliably effect a
radical cures.
Control symptoms
Chloroquine
• A 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.
•
Pharmacological Effects
1.
Antimalarial action: ①highly effective blood schizonticide. ②
Moderately 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.


2.
3.
Mechanism: ① plasmodium aggregates chloroquine. ②chloroquine
incorporated into DNA chain of plasmodium → inhibit proliferation. ③
chloroquine prevents the polymerization(聚合作用) of the hemoglobin(血
红蛋白) breakdown product, heme(血红素), into hemozoin(疟原虫色素)
and thus eliciting parasite toxicity due to the buildup of free heme. ④
pH↑→ 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.
Killing Amibic trophozoites : chloroquine reaches high liver
concentrations.
Immunosuppression action:
•
Clinical Uses
1. Treatment: nonfalciparum and sensitive falciparum
malaria. Primaquine(伯氨喹) 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(阿米巴肝脓肿): not
effective in the treatment of intestinal or other
extrahepatic amebiasis.
• Adverse Effects and Cautions
– Usually very well tolerated, even with prolonged use.
– Pruritus(瘙痒) is common.
– Nausea, vomiting, abdominal pain, headache, 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
Control symptoms
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(金鸡纳树皮), a traditional remedy for
intermittent fevers(间歇性热) 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.
– Parenteral(胃肠外的) treatment of severe
falciparum malaria
– Oral treatment of falciparum malaria
– Malarial chemoprophylaxis
– Babesiosis(巴贝西虫病)
•
Adverse Effects and Cautions
1. Cinchonism: tinnitus(耳鸣), headache, nausea,
dizziness(眩晕), flushing(面红), visual
disturbances
2. 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
Control symptoms
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.
• Clinical Uses
– Chemoprophylaxis:
– 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.
Control symptoms
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 relapse
and transmission
Primaquine
• Synthetic 8-aminoquinoline.
• Pharmacological Effects
– Against hepatic stages of malaria parasites.
– The only available agent active against the dormant
hypnozoite(睡眠子孢子) stages of P vivax and P
ovale.
– Also gametocidal against the four human malaria
species.
• Clinical Uses
– Therapy (Radical Cure) of Acute Vivax and Ovale Malaria:
chloroquine + primaquine
– Terminal Prophylaxis of Vivax and Ovale Malaria: prevent a
relapse
– Chemoprophylaxis 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(卡氏肺孢子虫) infection: clindamycin(克
林霉素)+primaquine → mild to moderate pneumocystosis
• Adverse Effects and Cautions
• Nausea, epigastric(腹上部的) pain, abdominal
cramps(痛性痉挛), headache.
• Hemolysis or methemoglobinemia(高铁血红蛋
白血症), especially in persons with G6PD
deficiency or other hereditary metabolic defects.
Etiological factor
prophylaxis
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.
• Adverse Effects and Cautions
– Gastrointestinal symptoms, skin rashes.
– Interfering folic acid metabolism in human →
megalocyte anemia, granulocytopenia.
– Acute intoxication
– Teratogenesis
Etiological factor
prophylaxis
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:
–
–
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 Drugs
• Amebiasis is infection with Entamoeba histolytic.
• Amebiasis is transmitted through gastrointestinal
tract.
• Ameba has two stages of development: cyst(包
囊) and trophozoite(滋养体).
Cysts → small intestine → little trophozoites (ileocecum)
cysts (colon) —— asymptomatic intestinal infection, source of
infection
big trophozoites (tissues of intestine) —— intestinal
amebiasis
Metronidazole
• A nitroimidazole(硝基咪唑类). The nitro group of
metronidazole is chemically reduced in anaerobic(厌氧
的) bacteria and sensitive protozoans. Reactive
reduction products appear to be responsible for
antimicrobial activity.
• Pharmacokinetics
– Oral metronidazole is readily absorbed and permeates all
tissues by simple diffusion.
– Protein binding is low (<20%)
– Through blood brain barrier
– Metabolizing in liver.
– 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(滴虫病):
3. Anti-anaerobic bacteria(厌氧细菌):
4. Anti-giardiasis(梨形鞭毛虫病):
• Adverse Effects and Cautions
– Nausea, headache, dry mouth, a metallic taste in the
mouth.
– Infrequent: vomiting, diarrhea, rash, insomnia,
neutropenia, ……
– Rare: severe central nervous system toxicity ( ataxia,
encephalopathy(脑病), 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 Dehydroemetine
• Emetine, an alkaloid derived from ipecac(吐根), 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(不规律).
• Pharmacological Effects and Clinical Uses
• 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(痢疾) 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
 low selection → also inhibiting protein synthesis of
eukaryocyte.
 Toxicity increase with length of therapy.
1. Cardiac toxicity: arrhythmias, congestive heart failure,
hypotention, ECG changes
2. Neuromuscular blockade: muscle weakness and discomfort
3. 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.
Diloxanide
• Diloxanide furoate(糠酸盐) is a dichoroacetamide(二
氯乙酰胺) 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(胃肠气胀), nausea,
abdominal cramps(痛性痉挛), rashes, abortion(流产).
Paromomycin
• Aminoglycoside(氨基糖苷) 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 Drugs
• Metronidazole
• 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.
Praziquantel
• A synthetic isoquinoline-pyrazine derivative.
• Pharmacological Effects
– Effective in the treatment of schistosome(血吸虫) infections
of all species and most other trematode(吸虫) and
cestode(绦虫) infections, including cysticercosis(囊虫病).
– Against adult worms and immature stages.
• Mechanisms
– Increases cell membrane permeability to calcium →
vacuolization, marked contraction, spastic paralysis,
dislodgement(赶出), death.
• Clinical Uses
– Schistosomiasis(血吸虫病)
– Clonorchiasis(支睾吸虫病) and Opisthorchiasis(后睾吸虫
病)
– Paragonimiasis(肺吸虫病)
– Taeniasis(绦虫病) and Diphyllobothriasis(裂头绦虫病)
– Neurocysticercosis(神经囊虫病)
– Hydatid(棘球蚴) disease
– Other parasites: fasciolopsiasis(姜片虫病),
metagonimiasis(后殖吸虫病), heterophyiasis(异形吸虫病)
• Adverse Reactions
– Mild and trainsient.
– Headache, dizziness, drowsiness, lassitude(疲倦)
– low-grade fever, pruritus(瘙痒), and skin rashes
(macular(斑疹的) and urticarial(荨麻疹))—due to
the release of foreign protein from dying worms.
Anti-filariasis Drugs
• Epidemic in China:
– Wuchereria bancrofti(班氏丝虫, 吴策线虫)
– Brugia malayi(布鲁丝虫, 马来丝虫)
• Parasitize in lymphatic system.
Diethylcarbamazine
• A synthetic piperazine derivative. Rapidly
absorbed from the gastrointestinal tract;
excreted rapidly in the presence of acidic urine.
• Pharmacologic Effects and Mechanisms
– Immobilizes microfilariae(微丝蚴) (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
–
1.
2.
•
The drug should be taken after meals.
Wuchereria bancrofti(班氏丝虫), Brugia malayi(马来丝虫),
Brugia timori, and Loa loa(罗阿丝虫)
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 China
② Tapeworms
③ Flukes (trematodes)
Mebendazole
• A synthetic benzimidazole(苯并咪唑) that has a wide
spectrum of anthelmintic activity and a low incidence
of adverse effects.
• Pharmacokinetics
–
–
–
–
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
– Inhibits microtubule(微管) synthesis in nematodes(线虫),
thus irreversibly impairing glucose uptake. Intestinal parasites
are immobilized or die slowly.
– Kills hookworm, ascaris(蛔虫), and trichuris(鞭虫) eggs.
• Clinical Uses
– Pinworm(蛲虫) infection
– Ascaris lumbricoides(蛔虫), Trichuris trichiura (鞭虫), Hookworm,
and Trichostrongylus(毛圆线虫)
– Other infections: intestinal capillariasis(毛细线虫病),
trichinosis(旋毛虫病), taeniasis(绦虫病), strongyloidiasis(类
圆线虫病), dracontiasis(麦地那丝虫病), et al.
• Adverse Effects and Cautions
– Low-dose: nearly free adverse effects.
– Diarrhea, abdominal pain is infrequent.
– High-dose: pruritus(瘙痒), rash, eosinophilia(嗜酸
性细胞增多), reversible neutropenia(嗜中性白血
球减少症), musculoskeletal pain(肌肉骨胳痛),
fever, transient liver function abnormalities,
alopecia(脱发), glomerulonephritis(肾小球肾炎),
agranulocytosis(粒细胞缺乏)
Albendazole
• A benzimidazole carbamate(氨基甲酸酯)
• A broad-spectrum oral anthelmintic for
treatment of hydatid(包虫囊) disease and
cysticercosis(囊虫病), pinworm infection,
ascariasis(蛔虫病), trichuriasis(鞭虫病),
strongyloidiasis(类圆线虫病), and infections
with both hookworm(钩虫) 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(蛔虫病), Trichuriasis(鞭虫病), and
Hookworm and Pinworm(蛲虫) infections.
2. Strongyloidiasis(类圆线虫病)
3. Hydatid(棘球蚴) Disease
4. Neurocysticercosis(神经猪囊尾蚴病）
5. Other infections: cutaneous larva migrans(幼虫迁
徙), gnathostomiasis(颚口线虫病)……
Piperazine
• Treatment of ascariasis(蛔虫病).
• No longer recommended for treatment of pinworm(蛲
虫) infection, because a 7-day couse of treatment is
required.
• Not useful in hookworm infection, trichuriasis(鞭虫病),
or strongyloidiasis(类圆线虫病).
• Causes flaccid(弛缓性) paralysis of ascaris by blocking
acetylcholine at the myoneural(肌神经的) junction.
• Neurotoxic adverse effects.
Levamizole
• A synthetic imidazothiazole(咪唑噻唑）
derivative and the L isomer of D,Ltetramisole(四咪唑).
• Highly effective in eradicating ascaris and
trichostrongylus(毛圆线虫属) and moderately
effective against both species of hookworm.
• Inhibiting succinic dehydrogenase(琥珀酸脱氢
酶) → energy↓ → flaccid paralysis
• Immunomodulating effect.
Pyrantel
• A tetrahydropyrimidine(四氢嘧啶) derivative.
• A broad-spectrum anthelmintic
• Highly effective for the treatment of pinworm(蛲虫), ascaris,
and Trichostrongylus orientalis(东方毛圆线虫属) infections.
• Moderately effective against both species of hookworm but less
so against N americanus.
• Not effective in trichuriasis(鞭虫病) or strongyloidiasis(类圆线
虫病).
• 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(卵).
• 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 Embonate
•
•
•
•
A dye.
Not absorb orally.
treatment of pinworm(蛲虫)
Selectively interfering energy metabolism
enzymatic system
• Inhibiting glucose-transporting enzymatic
system
• Red feces(粪便)
Niclosamide
• A salicylamide derivative
• Treatment of most tapeworm(绦虫) infection.
• Pharmacologic Effects
– Scoleces(头节) and segments of cestodes(绦虫) —
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 Uses
– Given 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 Cautions
– Infrequent, mild and transitory.
– Nausea, vomiting, diarrhea, and abdominal discomfort.
Praziquantel
• Effective in the treatment of schistosome(血吸
虫) infections of all species and most other
trematode(吸虫) and cestode(绦虫) infections,
including cysticercosis(囊虫病).
• A first choice in the treatment cestodiasis.