Anti-protozoal drugs

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Anti-protozoal drugs

• The unicellular protozoa are eukaryotes and it is
  difficult to treat them compared to bacteria
  which are prokaryotes.
• Most of the protozoal infections are due to
  unhygienic conditions.

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Anti-protozoal drugs

• Trypanosomiasis Caused by Trypanosoma
  
• African sleeping sickness
• Tryp brucei gambiense slow to enter CNS
• Tryp brucei rhodesiense invade CNS early.
  
• American sleeping sickness
• Chagas disease -- tryp cruzi - cardiomyopathy

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Anti-protozoal drugs

• Suramin Trypanosomiasis
• Used in the early treatment and prophylaxis of
  African trypanosomiasis.
• It acts by inhibiting enzymes of energy
  metabolism including glycerol phosphate
  dehydrogenase for trypanocidal activity

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Anti-protozoal drugs

• Melarsoprol Trypanosomiasis
• Trivalent arsenical
• Mainly used to treat trypanosoma infections with
  CNS involvement.
• The drug acts by reacting with SH groups of
  various enzymes

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Anti-protozoal drugs

• Pentamidine Trypanosomiasis
• Active against
• Trypanosoma
• leshmaniasis
• fungus - pneumocystis jiroveci
• Pentamidine interfere with synthesis of RNA, DNA
  and proteins.
• Administered IV or aerosol
• Nephrotoxicity is the limitation.

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Anti-protozoal drugs

• Nifurtimox Trypanosomiasis Chagas disease
• Used in the treatment of Trypanosoma cruzi
  infection.
• It acts by generating superoxide and hydrogen
  peroxide radicals toxic as they lack catalase.
• Orally well absorbed

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Anti-protozoal drugs

• Leishmaniasis transmitted by the bite of
  sandflies
• Cutaneous
• Mucocutaneous
• Visceral ( Liver and Spleen) - Kala Azar

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Anti-protozoal drugs

• Leshmaniasis
• Antimonials - Sodium stibogluconate
• Pentamidine
• Amphotericin

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Anti-protozoal drugs

• Sodium stibogluconate Leshmaniasis
• It acts by inhibiting glycolysis and fatty acid
  oxidation
• It is administered i.m or i.v
• Cardiac arrhythmia and nephrotoxicity are adverse
  effects.

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Protozoal diseases Drugs
Trpanosomiasis Chagas disease Nifurtimox
T. gambiense African Sleeping sickness Suramin Pentamidine
T. rhodesiense - CNS African Sleeping sickness Melarsoprol
Leishmaniasis Stibogluconate
Toxoplasmosis Pyrimethamine and Sulfadiazine
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Anti - Ameobic Drugs

• E. histolytica is a water-borne pathogen
  transmitted by the fecal-oral route.
• E. histolytica exists in two forms
• Cysts Infective and can survive outside the
  body
• Trophozoites Non-infective and do not persists
  outside the body but invasive.

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Anti-amebic drugs

• A person becomes infected with E. histolytica as
  follows
  
• First, the cyst is ingested by the host.
  
• As it travels through the small intestine, E.
  histolytica excysts and divides into 8
  trophozoites.
• The trophozoites multiply and either invade and
  ulcerate the mucosa of the large intestine or
  feed on the intestinal bacteria.

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Anti - ameobic drugs

• The trophozoites are carried towards the rectum,
  where they return to the cyst form and are
  excreted in feces.
• Large amount of trophozoites within the colon can
  lead to systemic infection.
• The trophozoites descend into the intestine, they
  make a flask shaped abscess.

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Anti - ameobic drugs

• The trophozoites can also enter the blood stream
  and travel to other parts of the bodymost
  commonly the liver, but sometimes the lungs or
  brain and can cause abscesses.
• In tissues, only trophozoites are present.

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Anti - Ameobic Drugs

• METRONIDAZOLE Mixed amebicidal
• Broad spectrum cidal activity against ---
  Protozoa E. histolytica, T. vaginalis, G.
  lamblia
• Anaerobic bacteria B.fragilis, C.perfringes,
  H.pylori, Cl. difficile

G. lamblia
T. vaginalis
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Metronidazole
Mechanism of action

1. Nitroimidazoles (R-NO2) are activated by the
   parasite via a reduction to an anion radical.
2. This highly reactive anion radical will then
   damage DNA and proteins resulting in parasite
   death.
3. Metronidazole appears to be specifically reduced
   by ferredoxin in Giaridia, Entamoeba, and
   Trichomonas.

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• Pharmacokinetics
• Well absorbed from the intestine
• Widely distributed in the body secretions
  semen, saliva and CSF

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Anti - Ameobic Drugs

• Metronidazole adverse effects
• Nausea and metallic taste are most common
• Seizures at high dose
• Contra-indications
• First trimester of pregnancy
• Chronic alcoholism

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Anti - Ameobic Drugs

• MIXED LUMINAL / SYSTEMIC AMEBICIDAL DRUGS
• Metronidazole, Tinidazole, Secnidazole,
  Ornidazole
• Emetine
• SYSTEMIC AMEBICIDAL DRUGS
• Chloroquine
• LUMINAL AMEBICIDAL DRUGS
• Diloxanide furoate, Iodoquinol, Tetracycline,
  Paramomycin.

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• Metronidazole Uses
• Ameobiasis with luminal amebicidal
• Giardiasis
• Trichomonas vaginalis both partners !!
• Anaerobic infections
• Pseudo-membranous enterocolitis
• Ulcerative gingivitis
• Helicobacter pylori

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Emetine
ipecac root

• Inhibit protein synthesis by blocking chain
  elongation.
• It is administered by i.m injection.
• Adverse effects
• cardiotoxicity
• neuromuscular weakness.

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Iodoquinol

• Amebicidal against luminal trophozoites and cysts
• Adverse effects
• peripheral neuropathy
• optic neuritis

the inflammation of the optic nerve cause a
complete or partial loss of vision.
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Anti - Ameobic Drugs

• Diloxanide furoate
• Effective luminal ameobicidal kills
  trophozoites
• High cure rates in mild intestinal amoebiasis and
  asymptomatic cyst passers

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Anti - Ameobic Drugs

• Paromomycin
• Aminoglycosides which is not absorbed from GIT.
• Effective against luminal forms of E.
  Histolytica directly
• It acts indirectly by reducing the intestinal
  flora also.

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Asymptomatic cysts carriers Iodoquinol or Paromomycin or Diloxanide furoate
Diarrhea / Dysentery Metronidazole Iodoquinol or Diloxanide or Paramomycin
Amebic liver abcess Chloroquine Metronidazole
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Anti-malarial drugs

• Malaria is caused by the four species of protozoa
  Plasmodium
• Plasmodium vivax
• Plasmodium falciparum
• Plasmodium malariae
• Plasmodium ovale

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Anti-malarial drugs

• Chloroquine most common
• Quinine Chloroquine resistant
• Pyrimethamine / Sulfonamides
• Primaquine Radical cure
• New drugs - Mefloquine, Artimisinin, Halofantrine

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Anti-malarial drugs

• Drugs for the Exo-erythrocytic
• phase (liver) and gametocytes
• Primaquine
• Drugs to suppress erythrocytic phase /
  Schizontocides / Clinical cure
• Chloroquine, Quinine, Pyrimethamine, Mefloquine,
  Artemisinin

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Anti-malarial drugs

• Radical cure Exoerythrocytic phase
  (hypnozoites) with the clinical cure thus
  achieve total eradication of parasite
• Primaquine Chloroquine

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Chloroquine

• It is rapidly acting erythrocytic schizontocide
  against all species of plasmodium
• No effect on exo-erythrocytic phase
• It is concentrated by intraerythrocytic plasmodia
  
• Conversion of toxic heme to non-toxic hemozoin is
  inhibited.
• Heme damages plasmodia.

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Being alkaline, the drug reaches high
concentration within the food vacuoles of the
parasite and raises its pH. It is found to
induce rapid clumping of the pigment. Chloroquine
inhibits the parasitic enzyme heme polymerase
that converts the toxic heme into non-toxic
hemazoin, thereby resulting in the accumulation
of toxic heme within the parasite.
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• Chloroquine is active against entameoba
  histolytica and giardia lamblia
• It has anti-inflammatory and local irritant
• It is used for the treatment of malaria in
  pregnancy

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• Pharmacokinetics Chloroquine
• Oral absorption is excellent
• It has high affinity for melanin (retina) and
  concentrated in liver, spleen, kidney
• Metabolized by liver and excreted in urine
• Half life 3-10 days

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• Adverse effects Chloroquine
• Nausea , vomiting and epigastric pain
• Parenteral administration hypotension and
  cardiac arrhythmia, convulsions
• Prolonged treatment ( as in RA) causes retinal
  damage
• Loss of hearing, mental disturbances, rashes

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• Uses Chloroquine
• Clinical cure and prophylaxis in malaria
• Extra-intestinal ameobiasis
• Rheumatoid arthritis
• Lepra reactions

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Anti-malarial drugs

• Quinine
• It is a levo-rotatory alkaloid from cinchona bark
  ( dextro isomer Quinidine)
• It is an erythrocytic schizontocide
• It is basic and gets concentrated in acidic
  schizonts and kills by inhibiting heme polymerase

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Anti-malarial drugs

• Quinine
• It is orally well absorbed
• It has antipyretic action, affects hearing and
  vision at high dose
• High intravenous dose can cause hypotension and
  cardiac depression

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Anti-malarial drugs

• Quinine adverse effects
• Cinchonism ringing in ears, nausea , difficulty
  in hearing, visual defects
• Hypersensitivity reactions
• Hemolysis can result in hemoglobinuria

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Anti-malarial drugs

• Primaquine
• Primary indication is radical cure of malaria.
• It is more active against exo-erythrocytic phase
  of vivax and ovale.
• It is highly active against non-growing forms -
  gametocytes and hypnozoites.

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Anti-malarial drugs

• Primaquine adverse effects
• Dose limiting side effect is hemolysis,
  methemoglobinemia and cyanosis
  (dose gt 60 mg/day)
• Neutropenia rarely with large dose
• Avoided in pregnancy G6PD

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Anti-malarial drugs

• Mefloquine
• It is rapidly acting erythrocytic schizontocide
• Effective against even chloroquine resistant
  strains of plasmodia
• It appears to damage the plasmodia membranes

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Anti-malarial drugs

• Mefloquine
• Oral absorption is good
• Concentrated in liver, lungs and intestine
• Metabolized in liver and excreted in bile
• QT interval prolongation (arrhythmia) when given
  with halofantrine or quinine
• Seizures at high dose.

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Anti-malarial drugs

• Artemisinin derivatives Artemether / Arteether
  / Artesunate
• It is a potent and rapidly acting blood
  schizontocide and have peroxide configuration
  responsible for its action.
• ST segment and QT prolongation conduction defects

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Anti-malarial drugs

• Halofantrine
• It is highly active against P. falciparum
  resistant to chloroquine
• Prolonged QT interval and increased liver enzymes

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Novel Anti-protozoal Drugs

• Nitazoxanide

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Nitazoxanide

• Treatment for
• Intestinal protozoa
• Cryptosporidium
• Giardia
• Mechanism of Action
• Metabolized rapidly to active form tizoxanide
• May be due to interference with the pyruvate
  ferredoxin oxidoreductase enzyme-dependent
  electron transfer reaction essential for
  anaerobic metabolism

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• Pharmacokinetics
• 70 gt absorption with suspension vs. tablet
• gt99 protein bound
• Metabolism hepatic
• Excretion urine, bile and feces
• Adverse Events
• Common
• HA
• GI complaints (Abdominal pain, diarrhea,
  nausea, vomiting)
• Uncommon
• Allergy
• Increased ALT
• Anemia
• Anorexia

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Other Antimicrobials for Parasites

• Atovaquone
• Dapsone
• Pentamidine
• Others

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Atovaquone

• Treatment for
• Pneumocystis carinii pneumonia (PCP)
• Malaria
• Babesia
• Mechanism of Action
• Unclear
• May inhibit electron transport in mitochondria
  thus inhibiting metabolic enzymes

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Atovaquone

• Pharmacokinetics
• Poor oral absorption (23 in tablets, 47
  suspension)
• Improved with high fat meals
• gt99 protein bound
• Metabolism minimal
• Undergoes enterohepatic recirculation
• Excretion stool (94 as unchanged drug)

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• Adverse Events
• Common
• HA
• GI complaints
• Rash
• Uncommon
• Pruritis
• Hypoglycemia/natremia
• Anemia, neutropenia
• Increased LFTS

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Dapsone

• Treatment for
• PCP
• Possibly malaria
• Mechanism of Action
• Competitive antagonist of para-aminobenzoic
  acid (PABA) for folate synthesis

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• Pharmacokinetics
• Good oral absorption (gt75)
• 70-80 protein bound
• Metabolism hepatic
• CYP3A4 azole antifungals, clarithromycin, INH,
  rifamycin, phenobarbitol
• CYP2C9 phenytoin, rifampin, carbamazipime
• Excretion urine (85)

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• Adverse Events
• Major
• Hemolysis (G-6-PD)
• Methemoglobinemia
• Erythema multiforme
• Neuropathy
• Cholestatic jaundice

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Pentamidine

• Treatment for
• Leishmania
• Trypanosoma brucei
• Mechanism of Action
• Aromatic diamine synthesized in the late 1930s
• Inhibits synthesis of parasitic DNA by blocking
  thymidine synthase
• Fixation of transfer RNA

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• Pharmacokinetics
• Poor oral bioavailability so used by aerosol or
  IV
• Metabolism ?
• Excretion urine
• Adverse Events
• Major
• Immediate with IV hypotension, tachycardia,
  nausea, vomiting, syncope, etc.
• Urticaria
• Pancreatitis
• New onset DM
• Altered glucose metabolism
• Renal failure
• Cardiac dysrythmia
• Leukopenia
• Thrombocytopenia

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Other Antimicrobials for Parasites
SXT
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Anthelmintic Drugs
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Characteristics of and therapy for commonly
encountered Nematode infections
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Examples of Nematodes
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Benzimidazoles

• Albendazole
• Mebendazole
• Triclabendazole

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Albendazole

• Now the drug of choice for intestinal nematodes
• Better spectrum of activity
• Better pharmacokinetics
• Treatment for
• Ascaris lumbricoides
• Trichurius trichuria
• Hookworms
• Pinworm
• Cutaneous larva migrans
• Echinococcus
• Cystercercosis
• Certain filarial species

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• Mechanism of Action
• Binds to beta-tubulin
• Prevents microtubule assembly
• Beta-tubulin dependent glucose uptake
• Other potential mechanisms
• Inhibits fumarate reductase (parasite specific)
• Decreases levels of NADH
• Degradation of endoplasmic reticulum and
  mitochondria
• Decreased production of ATP

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• Pharmacokinetics
• Well absorbed with fatty meal
• Increases absorption by 4-5 times
• Serum half live 8-9 hours
• CSF 40 penetration
• Concurrent administration of steroids increase
  serum levels by 50 (and thus CSF concentration
  neurocystercercosis)
• Metabolized (1st pass) in liver to albendazole
  sulfoxide (excellent anti-helminthic activity)
• Elimination renal and feces

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• Adverse Events
• Embryotoxic in animals
• Occasional
• Abdominal pain
• Reversible alopecia
• Increased LFTs
• Rare
• Leukopenia (reversible)
• Fever
• Increased ICP
• Rash
• Renal toxicity

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Mebendazole

• Treatment for
• Intestinal helminths
• Trichinella spiralis
• Mechanism of Action
• Binds to beta-tubulin
• Prevents microtubule assembly
• Beta-tubulin dependent glucose uptake

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• Pharmacokinetics
• Minimally water soluble
• Poorly absorbed in GI tract
• Serum half life 2.5 to 5 hours
• Metabolized liver
• Excreted urine

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• Adverse Events
• Occasional
• Abdominal pain
• Diarrhea
• Reversible alopecia
• Increased LFTs
• Rare
• Leukopenia
• Agranulocytosis
• Hypospermia
• Seizure

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Piperazine

• MOA paralyzes Ascaris by acting as an agonist at
  GABA receptors.
• The paralyzed roundworms are expelled live by
  normal peristalsis.
• Clinical use an alternative drug for ascariasis.
  
• Adverse events
• Common mild gastrointestinal irritation side
  effect.
• Piperazine should not be used in patients with
  seizure disorders.

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Pyrantel Pamoate

• MOA
• Stimulates nicotinic receptors present at
  neuromuscular junctions of nematodes.
• Contraction of muscles occurs followed by a
  depolarization-induced paralysis.
• Clinical use
• Pyrantel pamoate is one of two drugs of choice
  (with mebendazole) for infections due to
  hookworm, pinworm, and roundworm
• The drug is poorly absorbed when given orally.
• Adverse events
• minor but include gastrointestinal distress,
• Headache
• weakness

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Ivermectin

• Treatment for
• Intestinal helminths
• Treatment of choice for
• Strongyloidiasis
• Onchocerciasis
• Ectoparasites
• Scabies
• Lice
• Has broad spectrum against helminths

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• Mechanism of Action
• Targets the parasite's glutamate-gated Cl-
  channel receptors.
• Chloride influx is enhanced, and
  hyperpolarization occurs, resulting in paralysis
  of the worm.

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• Pharmacokinetics
• Well absorbed in GI tract
• Serum half live 12 hours
• Highly protein bound
• Collects in adipose tissue
• Subject to enterohepatic recirculation
• Metabolized liver
• Eliminated stool

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• Adverse Events
• Common
• Itching
• Dizziness
• Occasional
• Mazzotti-type reaction in onchocerciasis
• Fever, pruritis, HA, joint pain
• Seizure
• Rare
• Hypotension

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Characteristics of and therapy for commonly
encountered trematode infections.
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P. westermani
Schistosoma
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Praziquantel

• Treatment for
• Cestodes (tapeworms)
• Taenia sp.
• Diphyllobothrium latum
• Echinococcus
• Trematodes (flukes)
• Schistosomiasis
• Chlonorchis sinensis
• Paragonimus westeramani
• Exception Fasciola hepatica
• Cystercercosis (second line)

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Praziquantel

• Mechanism of Action
• Tapeworms
• Release of Ca from endogenous stores
• Paralysis and expulsion of worm
• Schistosomes
• Damage to tegument (covering) resulting in
  intense vacuolation and increased permeability to
  Ca.
• Sequestered Ag exposed to parasite surface
  allowing for immune recognition

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• Pharmacokinetics
• Well Serum half absorbed in GI tract (80)
• live 4-6 hours
• Highly protein bound (80)
• Collects in adipose tissue
• CSF penetration 15-20
• Increased serum levels with cimetidine,
  ketoconazole, miconazole
• Metabolized liver
• Extensive 1st pass metabolism to inactive
  metabolites
• Eliminated urine (99 as metabolites)

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• Adverse Events
• Frequent
• Abdominal pain
• Diarrhea
• Malaise
• HA
• Dizziness

• Occasional
• Sedation
• Fever
• Sweating
• Nausea
• Eosinophilia
• Rare
• Pruritis
• Rash
• Edema
• Hiccups

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Bithionol

• Clinical use
• the DOC for treatment of fascioliasis (sheep
  liver fluke)
• alternative agent in paragonimiasis.
• MOA unknown.
• is orally effective
• eliminated in the urine.

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• Adverse events
• Common
• nausea and vomiting,
• diarrhea and abdominal cramps
• dizziness
• Headache
• phototoxicity
• Less frequent
• pyrexia
• tinnitus
• proteinuria
• leukopenia

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Metrifonate

• Metrifonate is an organophosphate prodrug that is
  converted in the body to the cholinesterase
  inhibitor dichlorvos.
• The active metabolite acts solely against
  Schistosoma haematobium (the cause of
  bilharziasis).
• Adverse events
• occur from excess cholinergic stimulation.

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Oxamniquine

• Oxamniquine is effective solely in Schistosoma
  mansoni infections
• Adverse events
• Common
• dizziness
• Headache
• gastrointestinal irritation
• pruritus
• Reactions to dying parasites include
  eosinophilia, urticaria, and pulmonary
  infiltrates.
• Contraindicated in pregnancy or in patients with
  a past history of seizure disorders.

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Triclabendazole

• Treatment for
• Fasciola hepatica
• Paragonimus sp.
• Mechanism of Action
• Binds to beta-tubulin
• Prevents microtubule assembly
• Beta-tubulin dependent glucose uptake
• Pharmacokinetics
• Bioavailability unquantified
• 99 Protein bound
• Metabolized liver
• Excreted urine

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• Other Uncommon Antiparasitic Drugs

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Filariasis

• DEC (Diethylcarbamazine)
• Treatment for
• Filaria infections
• Wuncheria bancrofti
• Brugia sp.
• Loa loa
• Mechanism of Action
• Effective against adult worms, not microfilaria
• Pharmacokinetics
• High bioavailability with oral administration
• Rapid absorption and peak drug levels
• Metabolism liver
• Excretion gt50 unchanged in urine, lt10 feces,
  urine is pH dependent

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• Adverse Events
• Major
• Mazzotti reaction
• Seizure
• Encephalitis
• Ocular lesions (due to worm death)
• Minor
• Anorexia
• Vomiting

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DRUGS THAT ACT AGAINST CESTODES (TAPEWORMS)

• Four medically important cestodes
• Taenia saginata (beef tapeworm)
• Taenia solium (pork tapeworm, which can cause
  cysticerci in the brain and the eyes)
• Diphyllobothrium latum (fish tape worm)
• Echinococcus granulosus (dog tapeworm, which can
  cause hydatid cysts in the liver, lungs, and
  brain).
• The primary drugs for treatment of cestode
  infections are praziquantel and niclosamide.

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Characteristics of and therapy for commonly
encountered cestode infections
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Niclosamide

• Mechanism Niclosamide may act by uncoupling
  oxidative phosphorylation or by activating
  ATPases.
• Clinical use Niclosamide is one of two drugs of
  choice (with praziquantel) for infections caused
  by beef, pork, and fish tapeworm infections.
  Scoleces and cestode segments are killed, but ova
  are not.
• Niclosamide is effective in the treatment of
  infections due to small and large intestinal
  flukes.

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• Adverse events
• gastrointestinal distress
• headache
• rash
• fever.
• Some of these effects may result from systemic
  absorption of antigens from disintegrating
  parasites.