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• Antiprotozoal agents cover topics from parasites to malaria, trypanosomiasis, and leishmaniasis

Parasites: Definition and Classification

• Parasites are organisms living in/on hosts, deriving their needs at the host’s expense
• The three main categories of human parasites are Protozoa, Helminths, and Ectoparasites
• Protozoa, Helminths, and Ectoparasites each have general properties and transmission routes
• Lab diagnosis is moving towards antigen-detection and PCR tests

Protozoa

• Protozoa are pathogenic to humans and classified based on movement
• Sarcodina use pseudopodia, and examples include Entamoeba, Dientamoeba, Naegleria, and Acanthamoeba.
• Mastigophora use flagella and includes Giardia, Trypanosoma, Leishmania, and Trichomonas
• Ciliophora uses cilia, for example Balantidium
• Sporozoa (apicomplexa) uses an apical complex and features non-motile adult stages with examples such as Plasmodium, Cryptosporidium, Babesia, Toxoplasma, Isospora, and Sarcocystis

Helminths

• Helminths have larval and adult Stages
• Nematodes (roundworms) reside in the GIT lumen, blood/lymphatics, or subcutaneous tissue
• Diseases caused by nematodes include enterobiasis, ascariasis, ancylostomiasis, strongyloidiasis, trichinosis, onchocerciasis, lymphatic filariasis, loiasis, toxocariasis
• Cestodes (flatworms/tapeworms) cause cysticercosis, echinococcosis, diphyllobothriasis, and hymenolepiasis
• Trematodes (flatworms/flukes) lead to schistosomiasis, fascioliasis, clonorchiasis, and paragonimiasis
• Acanthocephalins reside between nematodes and cestodes, with adult forms living in the GIT

Ectoparasites

• Located externally on the skin or its appendages
• Examples include mites, fleas, ticks, lice, and bedbugs
• Ectoparasites cause diseases like scabies, myiasis, pediculosis, and trombiculosis.

Specific Protozoal Infections

• Protozoa are single-celled eukaryotes

Intestinal Protozoa

• E. histolytica causes amebiasis and liver abscesses
• G. intestinalis causes giardiasis
• Cryptosporidium sp. is responsible for cryptosporidiosis
• Balantidium coli causes dysentery
• Isospora belli causes isosporosis

Urogenital Tract Protozoa

• T. vaginalis causes trichomoniasis

Blood and Tissue Protozoa

• Plasmodium sp. causes malaria.
• Trypanosoma sp. causes trypanosomiasis
• T. cruzi causes Chagas' disease
• T. b. gambiense and T. b. rhodensiense both cause sleeping sickness
• Leishmania species cause leishmaniasis, presenting as visceral (kala-azar), cutaneous (old and new world), or mucocutaneous forms
• Toxoplasma gondii causes toxoplasmosis
• Naegleria sp. and Acanthamoeba cause Meningoencephalitis
• Babesia microti causes Babesiosis _Pneumocystis jirovecii* causes pneumonia and is a fungi with protozoa-like behaviors and treatment responses

Amebiasis (E. histolytica)

• Presents with trophozoites and cysts
• Trophozoites can live in the lumen, invade the colon epithelium to cause ulceration/bleeding, or spread to other organs like the liver
• Trophozoites survive on gut bacteria; broad-spectrum antibiotics can deplete their food source
• The range of illness/symptoms includes asymptomatic carrier, mild intestinal infection (diarrhea), severe intestinal infection (dysentery), amoebic liver hepatitis/abscess, and amoeboma with extraintestinal infection

Anti-Amoebic Agents: Classification

• Classification is based on the global site of action

Luminal Amoebicides

• Luminal amoebicides consist: the amides, iodoquinol/clioquinol, and antibacterials
• The amides include Diloxanide furoate, Etofamide, and teclozan
• Iodoquinol and clioquinol are Halogenated hydroxyquinolines
• Antibacterials- Paramomycin, Tetracyclines, and Erythromycin

Extra Luminal/Tissue Amoebicides

• These drugs include Chloroquine, and Emetine/dihydroemetine
• Emetine and dihydroemetine are alkaloids with restricted use due to tissue toxicity

Luminal and Tissue Amoebicides

• Nitroimidazoles are effective in both the lumen and tissue, metronidazole, tinidazole, and secnidazole included

The AMIDES

• Examples are diloxanide furoate, etofamide, and teclozan; the mechanism isn't clear

Diloxanide Furoate

• Splits in the GIT to diloxanide and furoic acid and administered orally
• The body absorbs most of the diloxanide (90%), what is left is effective
• It causes flatulence, dry mouth, nausea, abdominal cramps, pruritus, and urticaria
• It should not be used during pregnancy or in children under 2yrs old
• Has been used to treat Luminal amoebiasis (rx asymptomatic or alongside tissue amebicide to eradicate infection)

PARAMOMYCINsulphate

• An Aminosidine; aminoglycoside that directly affects amoebae by interfering with cell membrane to cause leakage,
• This is antibacterial that reduces the food source for trophozoites
• Administered orally at 25 to 35 mg/kg/day in 3 divided doses for 5 -10 days however, absorption is insignificant
• It causes GIT irritation and/or diarrhea that can progress to superinfection
• Should be used with caution if the person has GIT ulcers or renal dysfxn
• It treats moderate intestinal (Luminal) amoebiasis, Giardiasis, Cryptosporidiosis (Rx for 21 days), and Hepatic coma (adjunctive)

Halogenated Hydroxyquinolines

• IODOQUINOL and clioquinol directly affects trophozoites in lumen
• Its MOA unclear, but binding of iodine to proteins acts as chelating agent to chelate ferrous ions, reducing them for protozoal metabolism
• Dose at 650 mg 3 times daily after meals for 20 days but has poor absorption of only 10%
• There are GIT distress, allergic rxn (skin), goiter, and neurotoxic (optic atrophy /neuritis) side effects:
• This increases protein binding of iodine, lowering iodine uptake by the thyroid
• Should not be used with caution in persons intolerant to iodine, renal impairment, optic neuropathy or thyroid/hepatic disease
• The drug is second line for luminal amebicide with added metronidazole for systemic infection, superficial fungal infections (e.g. Tinea pedis), Balantidium coli, and some skin conditions (topical)

NITROIMIDAZOLES

• Metronidazole, tinidazole, secnidazole, Ornidazole and nimorazole are examples
• These drugs produce toxic metabolites to DNA and proteins in trophozoites
• It depends on concentration and kills exhibit a concentration-dependent
• Adm: almost is 100% bioavailable, however, topical administration is also common
• Widely distributes into tissues including CNS, breast milk, & saliva

METRONIDAZOLE and TINIDAZOLE side effects

Include metallic taste, moniliasis/ glossitis/stomatitis, GIT irritation, Disulfiram-like rxn with alcohol, neurotoxicity, and mutagenesis in bacteria

Nitroimidazoles Uses

• Metronidazole is the DOC for almost all extra-intestinal amoebiasis, and amoebic dysentery, DOC for gardiasis, H. pylori, Anaerobic bacteria
• Additional drugs that could be used are chloroquine: hydroxychloroquine

Extra-Intestinal Protozoa

Chloroquine and Hydroxychloroquine

• Treats extra-intestinal amebiasis (alongside metronidazole and diloxanide), UV light protection, anti-inflammatory
• Emetine, and dihydroemetine could also be used
• Inhibits protein synthesis; Administered parenterally, Never administered Intravenously
• It produces serious S/E like arrhythmias, hypotension, CHF, and cardiotoxicity

FURAZOLIDONE

• It is active against anti bacterial, and antiprotozoal organisms
• Is active against G. lamblia
• Tablet or liquid; can cause itching, rash, low BP, & GIT distress, it inhibits MAO
• This is used for Giardiasis

NITAZOXANIDE

• It is a prodrug so it needs to be converted to its active metabolite tizoxanide
• Active agent against Cryptosporidium parvum, H. pylori, G. lamblia, and E. histolytica
• Orally delivered it causes GIT abdominal pain/diarrhea, vomiting, and headache
• Indicated in: Cryptosporidiosis

OIther Considerations

• Some antibacterials decrease lumen bacterial population

Antiprotazoal agents

• Many drugs can be used to treat protoza
• Treatment depends on the protoza for example:

GIARDIASIS

• Can be treated using tinidazole/ Metronidazole, Paramomycin, and/or Mepacrine

TOXOPLASMOSIS

• Can be treated using Pyrimethamine + combination drugs: Cotrimoxazole, Clindamycin, and/or Azithromycin,

Protozoa in BALANTIDIUM COLI

• Can be treated using tetracycline, metronidazole, and/or Iodoquinol

ISOSPORA BELLI Protozoa

• Can be treated using Co-trimoxazole, Pyrimethamine

BABESIOSIS Protozoa

• Can be treated using Quinine, and clindamycin

PROTOZOAL CRYPTOSPORIDIOSIS Protozoa

• Can be treated using Paramomycin Nitazoxanide, Spiramycin,and/or Azithromycin

TRICHOMONIASIS Protozoa

• Can be treated using Tinidazole or Metronidazole

Malaria

• Is a prevalent disease, a main source of Global and child Mortality: 0.3% - 2.2%
• Is caused by Agents with complicated life cycles
• Microscopically tests are used using stains; to be exact > 100parasites/µL of blood is needed
• To confirm it requires 3 tests

Anti-Malarial Agents

• Are chemicaly classified

Quinoline-methanols (Cinchona alkaloids)

• Are classified as anti-malarial
• In the category of blood Schiztonicdes, Gametocides, and Tissue Schizonticides

The life cycle of malaria

• Begins when a female mosquito picks up gametocytes when taking a blood meal from an infected individual
• Sporozoites migrate to the liver where they form merozoites
• Merozoites are then released to infect red blood cells
• The red blood cells then release merozoites which can infect other blood cells, and the cycle begins again

Malaria: Artemisinin and its Derivatives

• Artemisnin compounds are DOC for quinine infections.
• Can be active against quinine, and also inhibits fast movement, but should be paired with at least 2 anti malarial agents due to its resistance
• Not active against liver stages of the parasite
• Is also useful for leg cramps, but is an irritant
• Can prevent the bodies ability to clear metals in the system

Chloroquine and Quinine Malaria Drugs

• Resistance to quinine and halofantrine can lead to severe irritation
• GIT infections and sleeping disorders can accur
• Cardiac (conduction) defects occur because of the resistance

CHLOROQUINE and the Malaria parasite.

• Can be used in pregnancy except in the 1st TM
• Is used in Chemoprophylaxis but is only useful where Malaria is still sensitive

LUMEFANTRINE

• It is used to help stop quinine group infections
• Can create food build up, that will damage the malaria parasites

5. HALOFANTRINE

• Is variable, with or without food being available
• Causes GIT irritation, cardiac conditions, and headache
• Not effective against chemoprophylaxis

Agents Effective Against Malaria

• Actoavanone
• Piperaquine
• Atovaquone

Malaria S/E from 8. CHLOROQUINE

S/E includes : Hemolysis, CNS Damage, Irreversible ototoxicity, myopathy and peripheral neuropathy, cardio conditions

10. PRIMAQUINE & TAFENOQUINE

• Not effective against liver stages of the parasite
• Prevent malaria transmission via mosquitos
• Causes cardiac arrhythmias

Malaria Agents & uses

• Agents are available that can treat protozoal infections like Leishmaniasas, Trypansomasis, Giardiasis, etc

TRYPANOSOMIASIS

• Is mainly drug based when is treated
• Effective agents need to go after the parasite

1. SURAMIN

• Not stable
• Causes death, shock and edema

2 .PENTAMIDINE

• Is an alternative treatment for trypanisomiasis
• Causes toxicity, and liver damage
• Can treat Acanthanoeba and Visceral leishmaniasis but must be inhaled

3. MELARSOPROL

• Can treat trypanisomiasis
• but can cause toxic side effects
• can damage the CNS

EFLORNITHINE

• Can prevent nucleic aides. _ can cause seizures, but it mainly used to damage the CNA
• Combined with nifurtimox for effective treatment.

LEISHMANIASIS

• Can be treated with antimonials
• Can cause heart issues, fevers
• Administered via, Volume

1. SODIUM STIBOGLUCONATE

• Can cause pancreatitis and myocarditis
• Can not be used with resistance

2. MILTEFOSINE

• Side effect GIT, has shown to be harmful for the baby

3. AMPHOTERICIN B

• Should be used if patient is allergic
• is well absorbed by the body

Other agents for Leishmaniasis

These agents includes

• Pentoamidine
• Allopurinol.
• Interferons.

COMMON HELMINTHS

Can causes:

• Roundworms
• Hookwarsm
• Tapeworms

ANTHELMITICS

• target common parasitical infections

Albendazole, mebendazole, thiabendazole, triclabendazole

Have a broad spread Are absorbed for the bodies tissue Causes toxicity The antihelmitics can cause all kinds of irritation

LEVAMISOLE

• Can damage the nervous system

PYRANTEL PAMOATE

• Is poorly absorbed and causes insomnia.

PIPERAZINE

Blocks nerve functions, is toxic

• It reduces worm volume

IVM

• Can eliminate parasite

###IVERMECTIN

• Can damage the nervous system,

DIETHYLCARBAMAZINE

• Can cause swelling
• Lowers parasite volume, and prevents it from growing

7. NICLOSAMIDE

• Damages the worms organs
• Can cause GIT issues

8. PRAZIQUANTEL

• Causes more harm because it is hard for the body to retain it
• Can cause more side effects related to the antiemtic, analgesic functions
• Should not be combined with the drug Praziquatel

9. METRIFONATE

• damages the bladder, and immune system
• Causes GIT problems