antiprotozoal pcol 2
TRANSCRIPT
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Antiprotozoal Drugs
By: Dale Faith O. Dumalagan
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Trypanosomiasis
Human African trypanosomiasis, also known as sleeping sickness, is a vector-born parasitic disease.
They are transmitted to humans by tsetse fly (Glossina genus) bites which have acquired their infection from human beings or from animals harbouring human pathogenic parasites.
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Trypanosomiasis
Trypanosomiasis African sleeping
sickness -Trypanosoma brucei gambiense & Trypanosoma brucei rhodiense
American sleeping sickness (Chagas' disease) - Trypanosoma cruzi
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A. Melarsoprol derivatative of mersalyl oxide MOA: drug reacts with
sulfhydryl groups, including enzymes of organism and host
Resistance: decrease permeability of drug
Pharmacokinetic: slowly administered IV
DOC for T. brucei rhondesiense
has a very short half-life rapidly excreted in urine
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A. Melarsoprol
Adverse Effects:• CNS toxicity - encephalopathy• Hypersensitivity reactions - fever• GI disturbance - severe vomiting and
abdominal pain• Hemolytic anemia ( patient w/ glucose 6-
phosphate dehydrogenase deficiency)
Contraindication: Patients with influenza
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B. Pentamidine isethionate
• active against T. brucei gambiense• tx systemic blastomycosis (Blastomyces
dermatitidis) and infections (Pneumocystis jiroveci)
• DOC patients with pneumonia (P. jiroveci) who failed to respond to Trimetoprim-sulfamethoxazole and those allergic to sulfonamides
• chemotherapy in immunocompromised patients• alternative drug to Stibogluconate in tx of
Leishmaniasis
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B. Pentamidine isethionate
MOA:• T. brucei concentrates pentamine by an
energy-dependent, high affinity uptake system.
• Drug binds to parasite's DNA and interferes w/ synthesis of RNA, DNA, phospholipid and protein
Resistance:• Inability of trepanosome to concentrate the
drug
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B. Pentamidine isethionate
Pharmacokinetics: • Fresh solutions are
administered IM or aerosols
• concentrated and stored in liver and kidney for long period of time
• Ineffective against meningoencephalitic stage of trypanosomiasis
• Excreted slowly in urine• Half-life : 5 days
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B. Pentamidine isethionate
Adverse Effects:• Serious renal dysfunction• Hypotension• Dizziness• Rash• Toxicity to β cells of pancreas
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C. Nifurtimox
• tx of acute T. cruzi infections (Chagas disease)
• suppresive not curative
Moa: • undergoes reduction
and generates intracellular oxygen radicals (superoxide radicals & hydrogen peroxide)
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Figure 36.16Generation of toxic intermediates by Nifurtimox
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Pharmacokinetic:• administered orally• rapidly absorbed and
metabolized to unidentified products excreted in urine
Adverse Effects:• Anaphylaxis• dermatitis• icterus• GI problems - weight
loss• Peripheral neuropathy
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D. Suramin
• early treatment and prophylaxis of African trypanosomiasis
• inhibits glycerol phosphate dehydrogenase
• IV• binds to plasma for
long time, accumulating in liver and proximal tubular cells of the kidney
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Adverse Effects:• Nausea and vomiting• shock• loss of consciousness• acute urticaria• paresthesia, photophobia, palpebral
edema, hyperesthesia on hands and feet
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E. Benznidazole
• nitroimidazole derivative, inhibits protein synthesis and ribonucleic synthesis in T. cruzi cells
• alternative treatment of acute and indeterminate phases of Chagas Disease
• prophylaxis for preventing infections among hematopoietic stem cell transplant
• ADR: dermatitis, peripheral neuropathy, insomnia, anorexia
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Eflornithine • irreversible inhibitor of
ornithine decarboxylase • IV (first line tx second
stage African stage Trypanosomiasis)
• Topical (tx unwanted facial hair in women)
• short half life• ADR:
– anemia, seizure, temporary hearing loss
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Leishmaniasis
Leishmaniasis is caused by parasitic protozoa of the genus Leishmania. Humans are infected via the bite of phlebotomine sandflies, which breed in forest areas, caves, or the burrows of small rodents.
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There are four main types of the disease:1. In cutaneous forms, skin
ulcers usually form on exposed areas, such as the face, arms and legs. These usually heal within a few months, leaving scars.
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2. Diffuse cutaneous leishmaniasis produces disseminated and chronic skin lesions resembling those of lepromatous leprosy. It is difficult to treat.
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3. In mucocutaneous forms, the lesions can partially or totally destroy the mucous membranes of the nose, mouth and throat cavities and surrounding tissues.
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• Visceral leishmaniasis, also known as kala azar. • If left untreated, the disease can have a fatality rate as high as 1
00% within two years.
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Leishmaniasis
• it is transmitted from animals to humans (between humans) by a bite of infected sandflies.
• Diagnosis is establish by demonstrating the parasite in biopsy material and skin lesions
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Chemotheraphy for Leishmaniasis
• Sodium stibogluconate with Pentamidine and Amphotericin B• Allopurinol
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A. Life cycle of Leishmania species:
• Sandflies transfers the flagellated promastigote form of the protozoa, which is rapidly phagocytized by macrophage. In the macrophage, promastigotes rapidly change to nonflagellated amastigotes and multiplies, killing the cell. The newly released amastigotes are again phagocytized, and cycle continues
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B. Sodium stibogluconate
• MOA is not determined but evidence for inhibition of glycolysis in the parasite at the phosphofructokinase reaction8 has been found.
• Available parenterally distributed in extravascular compartment
• Minimal metabolism , excretion: Urine
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Adverse effects:• Pain at the injection site• Pancreatitis• elevated liver enzyme• athralgias• myalgias• Gastrointestinal upset• Cardiac arrhythmias
Renal and hepatic function should be monitored periodically
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C. Miltefosine (Impavido)• First orally active drug
for viceral Leishmaniasis• MOA: interfere with
phospholipids in parasitic cell membrane to induce apoptosis
• ADR: Nausea & vomiting
• Contraidicated to pregnacy because teratogenic
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VI. Taxoplasmosis
• Taxoplasma gondii • transmitted to humans when they consume raw or
inadequately cooked, infected meat • symptoms: flu-like symptoms but most people
affected never develop signs and symptoms (unaware); damage to the brain, eyes (reduced vision, blurred vision, pain (often with bright light), redness of the eye, and sometimes tearing), or other organsFor infants born to infected mothers and for people with weakened immune systems, toxoplasmosis can cause extremely serious complications.
• Cats - only shed oocysts
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Chemotheraphy for Taxoplasmosis
• Pyrimethamine - drug of choice
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Chemotheraphy for Taxoplasmosis
• Sulfadiazine and Pyrimethamine - DOC• Leucovorin - protect against folate
deficiency• Pyrimethamine w/ Clindamycin or
Trimethoprim and Sulfamethoxazole - tx immunocompromised patients
Leucovorin
At the first appearance of the rash, pyrimethamine should be discontinued because hypersensitivity of the drug is severe
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VII. Giardiasis Infection of the small intestine Giardia lamblia ingestion of contaminated drinking waterContaminated water can be in swimming pools, spas, and bodies of water, such as lakes. Sources of contamination include animal feces, diapers, and agricultural runoff.
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Symptoms: fatiguenauseadiarrhea or greasy stools loss of appetitevomitingbloating and abdominal
crampsweight lossexcessive gasheadachesabdominal pain
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• trophozoites exist in small intestine and divide by binary fission. Cysts are formed that pass out in the stool.
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Chemotheraphy of Giardiasis
• Metronidazole for 5 days - TOC
• Tinidazole 2g given once (alternative)
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• Nitazoxanide - 2 day shorter course of theraphytx Cryptosporidosis
•Albendazole •Paromomycin - for pregnant px