Amebicides

Amebicides are drugs toxic to amoebas such as Entamoeba histolytica (the causative organism of amebiasis Amebiasis Amebiasis, or amoebic dysentery, is an infection caused by the parasite Entamoeba histolytica. Transmission is through the fecal-oral route or by consumption of contaminated food and water. Most patients infected with E. histolytica are asymptomatic, but about 10% may develop dysentery. Amebiasis). Parasites enter the GI tract where trophozoites can penetrate the intestinal wall and cause an invasive infection. Amebicides are classified based on where the drug is most effective: intestinal lumen or tissues. Intestinal-lumen amebicides include iodoquinol and paromomycin. Tissue amebicides include the nitroimidazole drug class (e.g., metronidazole, tinidazole). Treatment of symptomatic disease usually requires a combination of both classes.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Amebiasis

  • Also known as amoebic dysentery
  • Infection caused by the parasite Entamoeba histolytica
  • Transmission:
    • Fecal-to-oral route
    • Consumption of contaminated food and water
  • Invasive infection is characterized by:
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Fevers
    • Bloody diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Serious complications:
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver abscess
    • Intestinal fistulas
    • Fulminant colitis
Pathogenesis of entamoeba histolytica

The pathogenesis of invasive Entamoeba histolytica infection:
In 10% of cases, E. histolytica colonizes the large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix mucosa and invades via secretion of proteinases and lytic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes. This causes cellular necrosis and lysis of the membranes, respectively. This chain of events induces mucosal cell apoptosis and disrupts tight junctions between cells, allowing for flask-shaped ulcers, abscesses, and fistulas to form. Invasion may reach the portal venous system, through which E. histolytica can spread to other organs.

Image by Lecturio. License: CC BY-NC-SA 4.0

Classification of amebicides

A combination of tissue and luminal amebicides are prescribed to treat amebiasis Amebiasis Amebiasis, or amoebic dysentery, is an infection caused by the parasite Entamoeba histolytica. Transmission is through the fecal-oral route or by consumption of contaminated food and water. Most patients infected with E. histolytica are asymptomatic, but about 10% may develop dysentery. Amebiasis.

Luminal amebicides:

  • Destroy cysts and trophozoites in the intestinal lumen
  • Usually poorly absorbed (drug remains in the intestinal lumen)
  • Includes:
    • Iodoquinol
    • Paromomycin

Tissue amebicides:

  • Destroy trophozoites invading the tissues
  • Usually well absorbed (very little remains in the intestine)
  • Includes the nitroimidazoles Nitroimidazoles Nitroimidazoles are prodrugs composed of an imidazole ring with an attached nitro group. Nitroimidazoles are reduced within susceptible microorganisms, leading to free radical formation and disruption of DNA integrity. Nitroimidazoles:
    • Metronidazole
    • Tinidazole

Iodoquinol

Mechanism of action

  • Luminal amebicide
  • The mechanism of action is not fully understood.

Pharmacokinetics

  • Poorly absorbed (approximately 90% remains in the intestine)
  • Excreted in the feces

Indications

Iodoquinol is used to treat amebiasis Amebiasis Amebiasis, or amoebic dysentery, is an infection caused by the parasite Entamoeba histolytica. Transmission is through the fecal-oral route or by consumption of contaminated food and water. Most patients infected with E. histolytica are asymptomatic, but about 10% may develop dysentery. Amebiasis (limited availability in the United States): 

  • Action against cysts and trophozoites in the intestinal lumen 
  • Usually used in combination with a tissue amebicide for symptomatic infections
  • Can be used alone for asymptomatic infection

Adverse effects

  • Diarrhea
  • Anorexia
  • Nausea and vomiting
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Headache
  • Rash and pruritus
  • Peripheral neuropathy
  • Optic neuritis or atrophy

Contraindications

Iodoquinol is contraindicated in individuals with an allergy or intolerance to iodine.

Paromomycin

Mechanism of action

  • Luminal amebicide
  • Aminoglycoside 
  • Binds to the 30S ribosomal subunit → inhibits protein synthesis
Site of action for aminoglycosides amebicides

The site of action for aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides, which target the 30S ribosomal subunit
tRNA: transfer RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure
mRNA: messenger RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

  • Absorption:
    • Poor orally (most remains in the intestinal lumen)
    • A small amount is absorbed.
  • Excretion:
    • Mostly in feces
    • The absorbed drug is excreted in urine (unchanged).

Indications

  • Amebiasis: 
    • Action against cysts and trophozoites in the intestinal lumen 
    • Usually used in combination with a tissue amebicide for symptomatic infections
    • Can be used alone for asymptomatic infection
  • Giardiasis Giardiasis Giardiasis is caused by Giardia lamblia (G. lamblia), a flagellated protozoan that can infect the intestinal tract. The hallmark symptom of giardiasis is foul-smelling steatorrhea. Patients who develop chronic infections may experience weight loss, failure to thrive, and vitamin deficiencies as a result of malabsorption. Giardia/Giardiasis
  • Leishmaniasis Leishmaniasis Leishmania species are obligate intracellular parasites that are transmitted by an infected sandfly. The mildest form is cutaneous leishmaniasis (CL), characterized by painless skin ulcers. The mucocutaneous type involves more tissue destruction, causing deformities. Visceral leishmaniasis (VL), the most severe form, presents with hepatosplenomegaly, anemia, thrombocytopenia, and fever. Leishmania/Leishmaniasis

Adverse effects

  • Abdominal cramps
  • Nausea and vomiting
  • Diarrhea
  • Ototoxicity

Precautions

Caution should be used in individuals with:

  • Renal impairment → ↑ accumulation and toxicity
  • Bowel obstruction or ulcerative/inflammatory bowel disease → ↑ absorption

Nitroimidazoles

Members of the drug class

  • Metronidazole
  • Tinidazole

Mechanism of action

  • Tissue amebicide
  • Nitroimidazoles passively diffuse into the microbial cell. 
  • Nitroreductases (produced by susceptible organisms) → reduce the nitro group on the molecule
  • Results in the production of:
    • Free radicals
    • Cytotoxic metabolites → interact with host DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure → strand breakage and destabilization of the DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure helix
  • Cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
  • Effect:
    • Bactericidal against anaerobic bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
    • Antiprotozoal

Pharmacokinetics

  • Absorption:
    • Almost completely absorbed when given orally 
    • Bioavailability > 90%
  • Distribution:
    • Distributed widely in tissues
    • Low protein binding (< 20%)
    • Crosses the blood-brain barrier
  • Metabolism and excretion:
    • Extensively metabolized in the liver
    • Excreted mainly through the urine

Indications

In addition to anaerobic bacterial infections, nitroimidazoles Nitroimidazoles Nitroimidazoles are prodrugs composed of an imidazole ring with an attached nitro group. Nitroimidazoles are reduced within susceptible microorganisms, leading to free radical formation and disruption of DNA integrity. Nitroimidazoles can be used for:

  • Amebiasis:
    • Effective for intestinal wall and extraluminal trophozoites
    • Does not kill cysts
    • Usually used in combination with a luminal amebicide
  • Giardiasis Giardiasis Giardiasis is caused by Giardia lamblia (G. lamblia), a flagellated protozoan that can infect the intestinal tract. The hallmark symptom of giardiasis is foul-smelling steatorrhea. Patients who develop chronic infections may experience weight loss, failure to thrive, and vitamin deficiencies as a result of malabsorption. Giardia/Giardiasis
  • Trichomoniasis

Adverse effects

  • GI upset
  • Disulfiram-like reaction with alcohol (due to inhibition of aldehyde dehydrogenase)
  • Dysgeusia (metallic taste) 
  • Peripheral neuropathy 
  • Headache
  • Dizziness 
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Urine discoloration (red/brown color)

Contraindications

  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care (1st trimester)
  • Breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding 
  • Severe hepatic impairment

Drug interactions

  • Ethanol-containing elixirs:
    • Cough syrups
    • IV trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim-sulfamethoxazole
  • Disulfiram (can cause acute psychosis)
  • ↓ Elimination of:
    • Lithium
    • Ergot
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver metabolism of:
    • Phenytoin
    • Warfarin
    • Carbamazepine

References

  1. Rosenthal, P.J. (2012). Antiprotozoal drugs. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 915–936). https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf
  2. Weller, P.F. (2021). Antiprotozoal therapies. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved September 4, 2021, from https://www.uptodate.com/contents/antiprotozoal-therapies
  3. Uptodate Lexicomp. Retrieved September 4, 2021, from:
  4. Campbell, S., and Soman-Faulkner, K. (2020). Antiparasitic drugs. StatPearls. Retrieved September 4, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK544251/
  5. Dhawan, V.K., Cleveland, K.O., and Cantey, J.R. (2019). Amebiasis medication. In Bronze, M.S. (Ed.), Medscape. Retrieved September 4, 2021, from https://emedicine.medscape.com/article/212029-medication

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