Antiparasitic Agents

INFODUMP INCOMING!!!

I haven't written very much about parasites on this blog, but there's an introduction to them here if you need one. This lecture jumped all over the place, but hopefully I'll be able to provide some kind of coherent structure.

Malaria

For more information on malaria, see here.

Malaria can be treated with a range of antimalarials, such as quinine, mefloquine and artemisinin derivatives such as artemether and artesunate. Artemesia annua has been used in Chinese medicine for years, and the active ingredient was eventually isolated, earning Tu Youyou a Nobel Prize. The actual mechanism of action is not quite clear, but it is thought to involve increasing mitochondria-targeting endoperoxides in parasites and altering calcium metabolism. It is a well-tolerated drug and can clear parasites quickly. To prevent parasites from surviving and developing resistance, artemisinin is always given in combination with another antimalarial with a longer half-life.

Enteric protozoa and trichomonas

Enteric protozoa include Entamoeba histolytica, Giardia lamblia and Cryptosporidium, which can cause fun symptoms such as dysentery. Trichomonas, which can cause yellow-green discharge, has been discussed in further detail here. They are discussed together because amoebic dysentery, Giardia and Trichomonas can all be treated with metronidazole or tinidazole. Dientamoeba (another enteric protozoan) can also be treated with metronidazole, as well as doxycycline. Some other enteric protozoa, such as Isospora, Cyclospora and Blastocystis can be treated with co-trimoxazole (another name for trimethoprim/sulfamoxazole), or with pyrimethamine plus ciprofloxacin.

Metronidazole and Tinidazole

Metronidazole and tinidazole, which are classified as nitroimidazoles, are antibacterial and antiprotozoal. They are pretty cheap (metronidazole is 10c per tablet), well-tolerated and can be used in pregnancy (though not when breastfeeding). They can also be applied orally, topically or intravenously. Metronidazole treatment takes longer than tinidazole treatment.

Nitazoxanide

Nitazoxanide is a thiazolide mainly used to treat Cryptosporidia and other opportunistic protozoan infections in AIDS patients. It can also be used against Giardia and some viruses, such as HBV, HCV, rotavirus, influenza A, coronavirus, RSV, adenovirus and HSV1. It interferes with pyruvate ferredoxin oxidoreductase (PFOR).

Paromomycin

Paromomycin is an aminoglycoside that is also able to inhibit protozoan protein synthesis. It is effective against a wide range of protozoa, such as Entamoeba, Giardia, Dientamoeba and Leishmania.

Toxoplasmosis

Toxoplasmosis is caused by Toxoplasma gondii, which is spread in cat faeces and contaminated meat. It can cause cysts that can remain dormant in the brain for a while, eventually leading to cerebral disease such as fever, confusion, headache and seizures. One of the treatments for toxoplasmosis is pyrimethamine, which inhibits dihydrofolate reductase and may have synergistic activity with sulfonamides. It is also effective against malaria. Pyrimethamine can be given with sulphadiazine for effective treatment of toxoplasmosis. HIV patients may need to take pyrimethamine for life.

Leishmaniasis

Leishmaniasis is caused by leishmania, which resides in macrophages and is spread by mosquitoes. The two main forms are visceral and cutaneous leishmaniasis, but there are also mucosal, diffuse and disseminated forms.

Of the two main forms, the cutaneous form is more mild. It can self-heal within 3 months to 3 years, though it normally leaves scars. It can also be treated topically with heat, cryo or laser therapy. Other treatments include intralesional pentavalent antimonials, imiquimod, paromomycin, amphotericin B or oral miltefosine. Visceral leishmaniasis is more severe and generally requires intravenous or intramuscular pentavalent antimonials and/or amphotericin.

Pentavalent antimonials

Pentavalent antimonials, such as sodium stibogluconate and meglumine antimoniate, are first-line treatments for leishmaniasis. They have inactive Sb^V (Sb is antimony) which is converted to active Sb^III. The possible mechanism of action is inhibition of ATP synthetase, but this is still uncertain. Pentavalent antimonials are quite toxic and are linked to cardiotoxicity, elevation of pancreatic enzymes and hepatitis. Furthermore, there is some resistance to these drugs, particularly in India, where resistance to pentavalent antimonials is around 70%.

Miltefosine

Miltefosine was originally an anti-cancer drug, but has been found to have antiprotozoal activity. It is the only oral drug for leishmaniasis. It is mostly effective at treating visceral leishmaniasis, but there is increasing evidence that it may be helpful in cutaneous leishmaniasis as well.

Trypanosomiasis

There are two main kinds of trypanosomiasis: Chagas' disease and African trypanosomiasis. I have already written about African trypanosomiasis here. Chagas' disease, which is spread by the triatomine bug, can cause the Romana's sign or Chagoma acutely (a quick Google search will give you some pictures), or cardiomegaly, megaoesophagus and/or megacolon chronically. Chagas' disease can only really be treated in the acute stage by either nifurtimox or benznidazole- there are no treatments for chronic Chagas' disease.

Nifurtimox

Nifurtimox is an anti-Chagas' drug that causes free radical production. Side-effects include anorexia and neuro-psychological reactions.

Benznidazole

Benznidazole is a nitroimidazole (like metronidazole and tinidazole) that can also be used to treat Chagas' disease. Side-effects include hypersensitivity, oedema and bone marrow suppression.

Pentamidine

Pentamidine, which can be used to treat early-stage Gambiense disease, can be given as a deep IM or slow IV injection. Side-effects include hypotension, shock and renal failure.

Eflornithine

Eflornithine, which was originally developed as an anti-cancer drug, can be used to treat late-stage Gambiense disease. It is given as an IV for 14 days, which can be a bit of a problem, given that many cases of Gambiense disease occur in countries with underdeveloped healthcare systems. Side effects include GI upset, seizures and bone marrow suppression.

Suramin

Suramin is used to treat early-stage Rhodesiense disease. Side-effects include allergic reactions, nausea, vomiting, renal impairment and fever.

Melarsoprol

Melarsoprol is used to treat late-stage Rhodesiense disease. It is an arsenical, which means it comes with some nasty side-effects, such as post-treatment reactive encephalopathy. The fatality rate from this drug is 5-10%, but unfortunately it's the best treatment available for late-stage Rhodesiense disease. (You gotta wonder what the other treatments are like...)

Onchocerciasis (and other types of filariasis)

Onchocerciasis is another name for "river blindness," which is caused by subcutaneous filariasis, as detailed here. Just like with other filarial diseases, treatments involve killing microfilaria, rather than the adult worms. Hence, repeat treatments are often required.

Ivermectin

Ivermectin blocks chloride channels, paralysing microfilaria. Unfortunately, this drug may have oncogenic (cancer-causing) and sterilising effects. Other side-effects include hypotension, headache and fever.

Doxycycline

Doxycycline is a tetracycline that is used to kill Wolbachia. As mentioned here, filarial worms require Wolbachia in order to survive.

Diethylcarbamazine (DEC)

DEC kills microfilaria, as well as some adult worms. It is thought to sensitise microfilaria to phagocytosis by the immune system. DEC also inhibits arachidonic acid metabolism.

Soil-transmitted helminths

Soil-transmitted helminths, such as Ascaris and Enterobius, are mainly treated with benzimidazoles such as albendazole and mebendazole. Benzimidazoles are broad-spectrum anti-helminthics that are usually single-dose as they generally reach their target pretty well with few side-effects.

Albendazole

Albendazole binds to intracellular tubulin, impairing absorptive functions of the worm. Side-effects include transient GI upset, dizziness, itch and dry mouth. Albendazole is also potentially teratogenic, but the benefits usually outweigh the risks.

Mebendazole

Mebendazole also binds to tubulin, preventing microtubule formation, cell division and glucose uptake, which in turn leads to increased glycogen utilisation by the worm. Side-effects of mebendazole are similar to those of albendazole.

Trematodes (flukes)

I've written more about trematodes here. The main treatment is praziquantel, but albendazole, triclabendazole, nitazoxanide and chloroquine may also be used. Praziquantel increases calcium permeability of parasite membranes, but may also result in neuromuscular paralysis (presumably via the same mechanism).

Hydatid disease

Hydatid disease, as described here, is caused by tissue tapeworms. It is characterised by the formation of cysts that may rupture, so surgical intervention may be required. Before surgery, the cyst is sterilised with scolicidal agents, such as benzimidazoles and ethanol.

Taenia species

I've already written about Taenia here. T. saginata and T. solium can both be treated with praziquantel. If cysticercosis occurs (formation of cysts due to ingesting the eggs of Taenia spp.), prolonged courses may be required, as well as high-dose steroids to suppress the "immune storm" that results when worms are killed.