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Chapter 36: Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections

INTRODUCTION

This chapter will be most useful after having a basic understanding of the material in Chapter 50, Chemotherapy of Protozoal Infections in Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition. In addition to the material presented here, the 12th Edition contains:

  • A detailed discussion of protozoal infections, including amebiasis, giardiasis, toxoplasmosis, trichomoniasis, cryptosporidiosis, trypanosomiasis, leishmaniasis, babesiosis, balantidiasis, Isospora belli, and microsporidia

LEARNING OBJECTIVES

  • Understand the most common protozoal infections, the clinical symptoms, and the mainstays of therapy.

  • Describe the mechanisms of action of antiprotozoal drugs.

  • Understand the treatment of giardiasis, amebiasis, and cryptosporidiosis.

  • Identify the therapeutic uses of antiprotozoal drugs.

  • Describe the toxicities and precautions to the use of antiprotozoal drugs.

DRUGS INCLUDED IN THIS CHAPTER

Amphotericin B (see Chapter 43)

Eflornithine (ORNIDYL)

Fumagillin (FUMIDIL)

8-Hydroxyquinolines (iodoquinol; YODOXIN)

Melarsoprol

Metronidazole (FLAGYL)

Miltefosine (IMPAVIDO)

Nitazoxanide (ALINA)

Nifurtimox (LAMPIT)

Benznidazole (ROCHAGAN)

Paromomycin

Pentamidine

Sodium stibogluconate

Suramin

PROTOZOAL INFECTIONS DISCUSSED IN THIS CHAPTER

Amebiasis

Giardiasis

Cryptosporidiosis

MECHANISMS OF ACTION AND RESISTANCE OF ANTI-PROTOZOAL DRUGS
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MECHANISMS OF ACTION AND RESISTANCE OF ANTI-PROTOZOAL DRUGS
DRUG MECHANISM OF ACTION MECHANISM OF RESISTANCE
Amphotericin Binds ergosterol in protozoal membranes to form pores and increase membrane permeability No significant protozoal resistance
Eflornithine Inhibition of ornithine decarboxylase Mutations in ornithine decarboxylase
Fumagillin Inhibition of methionine-aminopeptidase-2
Melarsoprol Inhibition of many enzymes Mutations in drug transporters
Metronidazole

Forms highly reactive nitro radical anion that targets DNA and other vital biomolecules

Interferes with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron-transfer reaction, which is essential to anaerobic metabolism in protozoan and bacterial species

Impaired O2 scavenging capabilities leading to higher local O2 concentrations and decreased activation of metronidazole

Also mutations in nitroreductase
Miltefosine Not completely known Point mutations in transporter which leads to decreased drug uptake
Nitazoxanide Nitazoxanide (like metronidazole) interferes with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron-transfer reaction, which is essential to anaerobic metabolism in protozoan and bacterial species Resistance to nitazoxanide has been induced in Giardia in vitro, but resistant clinical isolates have not been reported
Nifurtimox Nifurtimox is activated by an NADH-dependent mitochondrial nitroreductase, leading to the intracellular generation of nitro radical anions that are thought to account for trypanocidal effects; these radicals form covalent attachments to macromolecules leading to cellular damage that kills the parasites Reduced nitroreductase expression
Benznidazole Same as nifurtimox Same as nifurtimox
Paromomycin Paromomycin binds to the 30S ribosomal subunit similar to neomycin and kanamycin (see Chapter 40) and shares their spectrum of antibacterial activity
Pentamidine In Trypanosoma brucei pentamidine is concentrated via an energy-dependent high-affinity uptake system in cells where it is thought to react with a variety of negatively charged intracellular targets Although failure to concentrate pentamidine is the usual cause of resistance, other mechanisms also may be involved
Sodium Stibogluconate Pentavalent antimonials act as prodrugs being reduced to ...

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