Antiparasitic Drugs

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Antiparasitic Drugs

• Fen-Fei Gao

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Overview

1. Antimalarial drugs
2. Anti-amebiasis drugs and Anti-trichomoniasis
   drugs
3. Anti-schistosomiasis drugs and Anti-filariasis
   drugs
4. Anthelmintic drugs

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Malaria(??)

• Malaria 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

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Parasite(???) Life Cycle

• Asexual stage in human
• Primary exoerythrocytic(????) stage
  sporozoites(???) invade liver cells ?
  schizonts(???) incubation period
• Asexual erythrocytic stage merozoites(???)
  invade erythrocytes, trophozoites(???) ?
  schizonts, rupture host erythrocytes ? repeated
  cycles cause clinical illness
• Secondary exoerythrocytic stage In P vivax and P
  ovale infections, a dormant(???) hepatic stage,
  hypnozoite(?????) ? relapses(??)
• Sexual stage in anopheline mosquito
• Sexual stage gametocytes(???) also develop in
  erythrocytes before being taken up by mosquitoes,
  where they develop into infective sporozoites.

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Drug Classification

• Classified by their selective actions on
  different phases of the parasite life cycle
• Tissue schizonticides(???????) eliminate
  developing or dormant(??) liver forms.
• Blood schizonticides act on erythrocytic
  parasites.
• Gametocides(?????) kill sexual stages and
  prevent transmission to mosquitoes.
• No one available agent can reliably effect a
  radical cures.

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Chloroquine
Control symptoms

• 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.

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• Pharmacological Effects
• Antimalarial action ?highly effective blood
  schizonticide. ?Moderately effective against
  gametocytes of P vivax, P ovale, and P malariae
  but not against those of P falciparum. ? not
  active against liver stage parasites.
• Mechanism ? plasmodium aggregates chloroquine.
  ?chloroquine incorporated into DNA chain of
  plasmodium ? inhibit proliferation. ? chloroquine
  prevents the polymerization(????) of the
  hemoglobin(????) breakdown product, heme(???),
  into hemozoin(?????) and thus eliciting parasite
  toxicity due to the buildup of free heme. ?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

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• Clinical Uses
• 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.
• Chemoprophylaxis for without resistant
  falciparum malaria in malarious regions.
• Amebic liver abscess(??????) not effective in
  the treatment of intestinal or other extrahepatic
  amebiasis.

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• Adverse Effects and Cautions
• Usually 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

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Quinine
Control symptoms

• Quinine and quinidine remain first-line therapies
  for falciparum malariaespecially 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.

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• 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.

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• Clinical Uses mainly for chloroquine-resistant
  falciparum malaria, especially for cerebral
  malaria.
• Parenteral(????) treatment of severe falciparum
  malaria
• Oral treatment of falciparum malaria
• Malarial chemoprophylaxis
• Babesiosis(?????)

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• Adverse Effects and Cautions
• 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

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Mefloquine
Control symptoms

• 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.

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• Clinical Uses
• Chemoprophylaxis
• Treatment mainly for chloroquine-resistant
  falciparum malaria.
• Adverse Effects and Cautions
• Nausea, vomiting, diarrhea, abdominal
  paindose-dependent
• Neuropsychiatric toxicities dizziness, headache,
  behavioral disturbances, psychosis, seizures.

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Malaridine
Control symptoms

• Developed by China.
• blood schizonticidal activity.
• Treatment for all types malaria, including
  chloroquine-resistant falciparum malaria.
• Mechanism destroy parasite compound membrane and
  food vacuoles.

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Artemisinin
Control symptoms

• 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

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Control symptoms

• Artemether and Artesunate
• Dihydroartemisinin

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Primaquine
Control relapse and transmission

• 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.

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• 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(??????) infection
  clindamycin(????)primaquine ? mild to moderate
  pneumocystosis

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• Adverse Effects and Cautions
• Nausea, epigastric(????) pain, abdominal
  cramps(????), headache.
• Hemolysis or methemoglobinemia(????????),
  especially in persons with G6PD deficiency or
  other hereditary metabolic defects.

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Pyrimethamine
Etiological factor prophylaxis

• 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.

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• Adverse Effects and Cautions
• Gastrointestinal symptoms, skin rashes.
• Interfering folic acid metabolism in human ?
  megalocyte anemia, granulocytopenia.
• Acute intoxication
• Teratogenesis

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Sulfonamides and Sulfone
Etiological factor prophylaxis

• 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.

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Rational Use of Antimalarial Drugs

• 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
• Combination therapy
• chloroquine primaquine symptom stages
• pyrimethamine primaquine dormant hypnozoite
  stages
• Combination of drugs with different mechanisms
  therapeutic effect?, resistance?

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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)

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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
• Oral metronidazole is readily absorbed and
  permeates all tissues by simple diffusion.
• Protein binding is low (lt20)
• Through blood brain barrier
• Metabolizing in liver.
• Excreted mainly in the urine.

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• Pharmacological Effects and Clinical Uses
• 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.
• Anti-trichomoniasis(???)
• Anti-anaerobic bacteria(????)
• Anti-giardiasis(??????)

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• 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(??), seizures)drug
  withdrawal
• Has a disulfiram(???,????????)-like effect, so
  that nausea and vomiting can occur if alcohol is
  ingested during therapy.

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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(???).

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• 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(??) for the
  minimum period because of toxicity.
• Occasionally as alternative therapies for amebic
  liver abscess.

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• Mechanisms
• Inhibiting peptidyl-tRNA transposition ?
  inhibiting elongation of peptide chain ?
  inhibiting protein synthesis ? interfering
  cleavage and breeding of trophozoites

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• Adverse Effects and Cautions
• 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.

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Diloxanide

• 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(??).

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Paromomycin

• 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.

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Chloroquine

• Chloroquine reaches high liver concentrations ?
  treatment of amebic liver abscess.
• Not effective in the treatment of intestinal or
  other extrahepatic amebiasis.

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Anti-trichomoniasis Drugs

• Metronidazole
• Acetarsol (????)

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Anti-schistosomiasis Drugs

• Schistosoma 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.

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Praziquantel

• A 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.

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• Clinical Uses
• Schistosomiasis(????)
• Clonorchiasis(?????) and Opisthorchiasis(?????)
• Paragonimiasis(????)
• Taeniasis(???) and Diphyllobothriasis(?????)
• Neurocysticercosis(?????)
• Hydatid(???) disease
• Other parasites fasciolopsiasis(????),
  metagonimiasis(?????), heterophyiasis(?????)

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• Adverse Reactions
• Mild 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.

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Anti-filariasis Drugs

• Epidemic in China
• Wuchereria bancrofti(????, ????)
• Brugia malayi(????, ????)
• Parasitize in lymphatic system.

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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(???) (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.

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• Clinical Uses
• The drug should be taken after meals.
• Wuchereria bancrofti(????), Brugia malayi(????),
  Brugia timori, and Loa loa(????)
• 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.

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Anthelmintic Drugs

• Classification of Helminth
• Roundworms (nematodes) epidemic in China
• Tapeworms
• Flukes (trematodes)

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Mebendazole

• A synthetic benzimidazole(????) that has a wide
  spectrum of anthelmintic activity and a low
  incidence of adverse effects.
• Pharmacokinetics
• Oral absorption lt10
• First pass elimination is high.
• Protein-binding gt90
• 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.

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• 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
• Pinworm(??) infection
• Ascaris lumbricoides(??), Trichuris trichiura
  (??), Hookworm, and Trichostrongylus(????)
• Other infections intestinal capillariasis(?????),
  trichinosis(????), taeniasis(???),
  strongyloidiasis(?????), dracontiasis(??????), et
  al.

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• Adverse Effects and Cautions
• Low-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(?????)

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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.

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• Clinical Uses
• Administered on an empty stomach when used
  against intraluminal parasites but with a fatty
  meal when used against tissue parasites.
• Ascariasis(???), Trichuriasis(???), and Hookworm
  and Pinworm(??) infections.
• Strongyloidiasis(?????)
• Hydatid(???) Disease
• Neurocysticercosis(???????)
• Other infections cutaneous larva migrans(????),
  gnathostomiasis(?????)

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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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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.

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Pyrantel

• 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.

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• 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.

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Pyrvinium Embonate

• A dye.
• Not absorb orally.
• treatment of pinworm(??)
• Selectively interfering energy metabolism
  enzymatic system
• Inhibiting glucose-transporting enzymatic system
• Red feces(??)

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Niclosamide

• A salicylamide derivative
• Treatment of most tapeworm(??) infection.
• Pharmacologic Effects
• Scoleces(??) and segments of cestodes(??) but
  not ova are rapidly killed on contact with
  nicolsamide due to the drugs inhibition of
  oxidative phosphorylation or to its
  ATPase-stimulating property.
• With the death of the parasite, digestion of
  scoleces and segments begins.

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• 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.

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Praziquantel

• 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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