Antiprotozoal Drugs

By: Dale Faith O. Dumalagan

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.

Trypanosomiasis

Trypanosomiasis African sleeping

sickness -Trypanosoma brucei gambiense & Trypanosoma brucei rhodiense

American sleeping sickness (Chagas' disease) - Trypanosoma cruzi

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

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

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

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

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

B. Pentamidine isethionate

Adverse Effects:• Serious renal dysfunction• Hypotension• Dizziness• Rash• Toxicity to β cells of pancreas

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)

Figure 36.16Generation of toxic intermediates by Nifurtimox

Pharmacokinetic:• administered orally• rapidly absorbed and

metabolized to unidentified products excreted in urine

Adverse Effects:• Anaphylaxis• dermatitis• icterus• GI problems - weight

loss• Peripheral neuropathy

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

Adverse Effects:• Nausea and vomiting• shock• loss of consciousness• acute urticaria• paresthesia, photophobia, palpebral

edema, hyperesthesia on hands and feet

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

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

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.

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.

2. Diffuse cutaneous leishmaniasis produces disseminated and chronic skin lesions resembling those of lepromatous leprosy. It is difficult to treat.

3. In mucocutaneous forms, the lesions can partially or totally destroy the mucous membranes of the nose, mouth and throat cavities and surrounding tissues.

• 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.

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

Chemotheraphy for Leishmaniasis

• Sodium stibogluconate with Pentamidine and Amphotericin B• Allopurinol

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

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

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

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

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

Chemotheraphy for Taxoplasmosis

• Pyrimethamine - drug of choice

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

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.

Symptoms: fatiguenauseadiarrhea or greasy stools loss of appetitevomitingbloating and abdominal

crampsweight lossexcessive gasheadachesabdominal pain

• trophozoites exist in small intestine and divide by binary fission. Cysts are formed that pass out in the stool.

Chemotheraphy of Giardiasis

• Metronidazole for 5 days - TOC

• Tinidazole 2g given once (alternative)

• Nitazoxanide - 2 day shorter course of theraphytx Cryptosporidosis

•Albendazole •Paromomycin - for pregnant px