Antiparasitic Drugs: Mechanisms and Uses

Learning Objectives

• Describe the general characteristics of common human parasites.
• Recall the common diseases caused by human parasites.
• List the major classes of antiprotozoal and anthelminthic drugs.
• List commonly used individual antiprotozoal and anthelmintic drugs.
• Explain the mechanisms of action of antiprotozoal and anthelmintic drugs.
• List the indications, major side effects, and contraindications of individual antiprotozoal and anthelmintic drugs.
• List drug interactions of antiprotozoal and anthelmintic drug classes and individual drugs.
• Explain possible causes and processes involved in drug resistance to antiprotozoal and anthelmintic classes.

Common Parasitic Diseases

• Malaria is a common parasitic disease.
• Amoebiasis is caused by a parasite.
• Helminthiasis is a common parasitic disease.
• Leishmaniasis is a parasitic disease.
• Filariasis is parasitic disease.

Malaria: Causative Organisms

• Causative organisms of Malaria:
  • Plasmodium falciparum causes the most serious disease.
  • P. vivax.
  • P. ovale.
  • P. malariae.
• Transmitted by Anopheles mosquito.
• Initial symptoms: Fever, chills, malaise, and vomiting.
• Cold phase: Severe pallor and cyanosis of the lips.
• Hot phase: Fever between 40.5°C (104.9°F) and 41°C (105.8°F).
• Sweating phase follows the hot phase by 2–6 hours.

Malaria Prophylaxis & Treatment

• Chemoprophylaxis for all species of Plasmodium includes chloroquine or hydroxychloroquine in areas with chloroquine-sensitive strains.
• In areas with chloroquine-resistant P. falciparum (CRPF) strains, travelers should receive:
  • Doxycycline (in all areas).
  • Atovaquone-proguanil (in all areas).
  • Tafenoquine (in all areas).
  • Mefloquine (in mefloquine-sensitive areas).
  • Primaquine (in areas where mainly P. vivax).
• For children and adults with uncomplicated P. falciparum malaria (except pregnant women in their first trimester), use artemisinin-based combination therapy (ACT).
• ACT drugs:
  • Artemether + lumefantrine.
  • Artesunate + amodiaquine.
  • Artesunate + mefloquine.

Chloroquine

• MOA: Binds to and inhibits DNA and RNA polymerase; interferes with metabolism and hemoglobin utilization.
• Chloroquine concentrates within parasite acid vesicles and raises internal pH, resulting in inhibited parasite growth.
• Blood schizonticide.
• Moderately effective gametocide against all species but falciparum.
• Indication: Used in prophylaxis and acute attacks by all chloroquine-sensitive species and off-label use in COVID-19 (mostly hydroxychloroquine).
• ADRs: Includes cardiomyopathy and QT prolongation.
• There is an increased risk of torsade type of ventricular arrhythmia, EKG changes, GI upset, and visual disturbances.

Mefloquine

• MOA: Unclear, destroys asexual blood forms of the malarial pathogens that affect humans (Plasmodium falciparum, P. vivax).
• Highly effective blood schizonticide with no activity against hepatic stages or mature gametocytes of P. falciparum or latent tissue forms of P. vivax.
• Indication: Treatment of mild-to-moderate acute malarial infections; Prevention of malaria caused by Plasmodium falciparum (including chloroquine-resistant strains) or P. vivax; Prophylaxis of Plasmodium falciparum and Plasmodium vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.
• ADRs: Fever, chills, headache, rash, GI upset, myalgia, tinnitus, and QT prolongation.
• DIs: Substrate of CYP3A4 (major) and inhibits P-glycoprotein with major interactions with several drugs.
• Boxed Warnings: May cause neuropsychiatric adverse effects that can persist after mefloquine has been discontinued.
• Do not prescribe it for prophylaxis in patients with major psychiatric disorders.

Primaquine

• MOA: Active against exoerythrocytic stages of Plasmodium ovale and P. vivax, and active against the primary exoerythrocytic stages of P. falciparum and gametocytes of Plasmodia.
• Disrupts mitochondria and binds to DNA.
• Indication: For the radical cure (prevention of relapse) of vivax malaria.
• ADRs: QT prolongation, hematologic abnormalities, and GI upset.
• DIs: Substrate of CYP2D6 and CYP3A4 that inhibits CYP1A2 and induces CYP1A2 (weak/moderate).
• Both primaquine and tafenoquine may cause hemolysis in G6PD-deficient patients, so G6PD testing should be done before use.

Tafenoquine

• MOA: An 8-aminoquinoline active against pre-erythrocytic (liver) forms (including hypnozoite) and erythrocytic (asexual) forms, as well as gametocytes of Plasmodium species, including P. falciparum and P. vivax.
• Indication: Radical cure (prevention of relapse) of Plasmodium vivax malaria in patients ≥16 years of age who are receiving chloroquine therapy for acute P. vivax infection.
• CDC guidelines recommend tafenoquine for radical cure (prevention of relapse) of malaria caused by Plasmodium ovale.
• It can also be used for the Prophylaxis of malaria in patients ≥18 years of age.
• Limitation of use: Not indicated for the treatment of acute P. vivax malaria, and concomitant use with antimalarials other than chloroquine is not recommended due to increased risk of recurrence of P. vivax malaria.
• ADRs: Diarrhea, headache, methemoglobinemia, back pain, and epithelial keratopathy.
• DIs: May increase the serum concentration of MATE1/2-K Substrates and OCT2 Substrates.
• Pregnancy is not advisable while taking it.

Doxycycline

• MOA: Inhibit ribosomal 30S subunit and inhibit protein synthesis in the organelles.
• Indications: Gram +ve and Gram -ve infections, prophylaxis of malaria in areas with chloroquine- and/or pyrimethamine-sulfadoxine-resistant strains.
• Warnings/Precautions/ADRs: Permanent discoloration of teeth (yellow, gray, brown) can occur in children following in utero exposure and is more likely to occur following long-term or repeated exposure.
• Other ADRs include intracranial hypertension, tissue hyperpigmentation, and photosensitivity.
• DIs: Antacids, bacterial vaccines, and dairy products.

Artesunate

• Artesunate is an important drug in artemisinin-based combination therapy (ACT).
• It is a semisynthetic derivative of artemisinin.
• MOA: Prodrug converted to dihydroartemisinin (DHA active against all erythrocytic stages that inhibits parasite metabolism and enhances the clearance of infected erythrocytes).
• Proposed MOA involves cleavage of the Fe2+ of endoperoxide bridge causing free radical and damages parasite protein.
• Inhibits calcium adenosine triphosphatase (cATP) of the sarcoplasmic endoplasmic reticulum and impairs parasite protein folding.
• Indication: used in combination (ACT) malaria infections.
• It is the first-line treatment of severe malaria as IV.

Antiamebic Drugs

• These treat infection with amoeba.

Amebiasis

• Major causative organism in amebiasis is Entamoeba histolytica.
• It inhabits the colon, causes abdominal discomfort, and bloody diarrhea.
• Can migrate to the liver and to the lung and brain.
• 50 million cases worldwide, leading to over 100,000 deaths.
• 1% of the general U.S. population.
• More common in institutionalized mentally retarded patients, sexually active homosexuals, patients with AIDS, and new immigrants from endemic areas.

Drugs Used in Amebiasis

• Tissue-acting agents:
  • Metronidazole.
  • Tinidazole.
• Luminal agents:
  • Paromomycin.

Metronidazole (Flagyl®)

• MOA: Interacts with DNA to cause a loss of helical DNA structure and strand breakage resulting in inhibition of protein synthesis and cell death in susceptible organisms.
• Indication: Treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess, and other anerobic bacterial infections.
• ADRs: Flattened T-wave on ECG, local thrombophlebitis (IV), headache, metallic taste, nausea, vaginitis, genital pruritus.
• DI: Alcohol consumption can cause unpleasant side effects such as headaches, stomach cramps, nausea, vomiting, and flushing.
• Boxed warning: Possibly carcinogenic based on animal data.

Anthelminthic Drugs

• These treat worms.

Helminthes

• Usually seen in people from Southeast Asia, the Caribbean, Mexico, and Central America.
• Also seen in institutionalized patients (both young and elderly), preschool children in daycare centers, residents of Indian reservations, and homosexual individuals.

Nematodes & Approved Drugs

• Ancylostoma duodenale or Necator americanus (hook worm): Mebendazole.
• Ascaris lumbricoides (round worm): Mebendazole, alternative is albendazole.
• Enterobius vermicularis (pin worm): Mebendazole, pyrantel pamoate.
• Taenia solium (tape worm): Praziquantel, alternative albendazole.

Albendazole (Albenza®)

• MOA: Active metabolite, albendazole sulfoxide, causes selective degeneration of cytoplasmic microtubules in intestinal and tegmental cells of intestinal helminths and larvae.
• Glycogen is depleted, glucose uptake and cholinesterase secretion are impaired, and desecratory substances accumulate intracellularly.
• ATP production decreases causing energy depletion, immobilization, and worm death.
• Indication: Anthelminthic including Taenia solium (tape worm).
• ADRs: Headache and increase in LFTs.

Mebendazole (Vermox®)

• MOA: Inhibits the formation of helminth microtubules and selectively and irreversibly blocks glucose uptake and other nutrients in susceptible adult intestine-dwelling helminths.
• Indications: Broad spectrum anthelminthic except Taenia solium.
• ADRs: hepatitis and Gl upset.
• Dis: Increase the toxicity of metronidazole.

Pyrantel Pamoate (Pamix®)

• MOA: Causes the release of acetylcholine and inhibits cholinesterase and acts as a depolarizing neuromuscular blocker, paralyzing the helminths.
• Indication: Alternative therapy for pinworms caused by Enterobius vermicularis.
• ADRs: Dizziness, headache, and Gl upset.

Anti-lice Agents

• Pediculus humanus capitis (head louse).
• Pediculus humanus corporis (body louse).
• Drugs of choice:
  • Permethrin that inhibits sodium ion influx through nerve cell membrane channels in parasites resulting in delayed repolarization and thus paralysis and death of the pest.
• Alternate Drugs:
  • Malathion – organophosphate compound (pesticide).
  • Benzyl alcohol - Inhibits respiration of lice by obstructing respiratory spiracles, causing lice asphyxiation.