Living Textbook MC610

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Antiparasitic Agents

Parasitic Diseases:

A wide variety of diseases that afflict three billion people annually, mostly in developing countries where the conditions are prime for such infections. The major parasitic diseases include Malaria, Amebiasis, Giardiasis, Pneumocystis, Lieshmaniasis and Trypanosomiasis

Malaria:

There are around 300 million cases annually, with sub-Saharan Africa accounting for nearly 75% of all cases. In the US, there are around 1,000 cases annually, typically acquired abroad. Overall, there are one million deaths world-wide from Malaria.

The main carrier of the parasite is the Female Anopheles mosquitoes. It results from either the more common Plasmodium Vivax or the less common Plasmodium Falciparum infection. The disease has an incubation period that ranges from one to three weeks, and results in a number of symptoms that are typical of infectious diseases.

The life cycle of the parasite starts when the sporozytes is injected into the human host and proceeds to invade the liver, which starts the extraerythrocytic stage. The parasite proceeds to replicate and transform to the merozytes (pre-erythrocytic stage) or to hypnozoites (aggregation of merozoites that lay dormant in liver). The former is eventually released from liver, and infects the RBCs, which starts the erythrocytic stage and forms the schizont that can transform to more merozoites leading to RBC lysis, further infection of other RBCs and release of pyrogens. Relapse occurs when dormant merozoites from hypnozoites are released.

Drug Therapy of Malaria:

1. Chloroquine (Aralen®)

The most common drug used for both treatment and prophylaxis.

Mechanism of Action: Not well understood, but seems to concentrate in the food vacuole in parasites present in the RBCs. It prevents the parasitic conversion of Heme into Hemozoin, leading to accumulation of heme, which is poisonous to the parasite and leads to cell lysis of both the parasite and the infected RBC.

Clinical Uses: Treatment and prophylaxis of erythrocytic stage of malarial infections resulting from both Plasmodium strains.

Route of Administration: Oral.

Adverse Effects: GI effects that include discomfort, nausea and diarrhea and may be severe. Other effects include visual disturbances, pruritus and headache.

Resistance: A serious problem with this drug, possibly due to overuse for prophylaxis. Multidrug resistant strains have been observed.

2. Primaquine:

An agent related to Chloroquine. It is only effective in hepatic infections caused by Plasmodium Vivax. It is used as a prophylactic agent or to prevent relapse due to dormant infections in the liver. A major drawback is the massive hemolysis in patients with G6PD deficiency.

Primaquine is also used in patients with Pneumocystis pneumonia.

3. Quinoline Alkaloids:

Two drugs belong to this class; Quinine and its d-isomer Quinidine. The major ingredient, Quinine, was first isolated from the Cinchona tree in 1820 and was the first anti-malarial drug used, although the actual bark has been actually used for more than 500 years.

Mechanism of Action: It accumulates in the food vacuoles, raises pH in the vacuoles, inhibits enzymes important for digestion and may intercalate into parasite DNA, inhibit DNA/RNA biosynthesis.

Clinical Uses: Useful for chloroquine-resistant or multi-drug-resistant strains. It is sometimes used in combinations such as Quinine with Mefloquine (Lariam®). Quinidine is the only drug approved in US for parenteral malaria therapy.

Adverse Effects: Cinchonism, ventricular arrhythmias and cardiotoxicity (especially quinidine, an antiarrhythmic drug). They can also cause primaquine-like hemolysis in patients with G6PD deficiency.

4. Artemisinin-based Drugs:

Artemisinin and its derivatives are a group of drugs that possess rapid action against Malarial infections. They are used in combination with other traditional antimalarial agents. These combinations are both effective and well tolerated in patients. Artemisinin itself is a natural product isolated from a Chinese herb. The use of the drug by itself as a monotherapy is discouraged.

Mechanism of Action: These drugs are prodrugs that must be metabolized to the dihydro derivative, which appear to control the infection by generating highly reactive oxygen radicals that can lead to malarial parasite death. An alternative theory is that the active drug may disrupt the parasitic redox cycle.

Clinical Uses: The current standard treatment of Malaria is a combination of an artemisinin derivative with a conventional antimalarial drug (ACTs).

Adverse Effects: Generally well tolerated, with mild symptoms such as nausea and vomiting and dizziness, with some rare serious side effects.

Amebiasis:

The causative organism for amoebic dysentery is the Entamoeba histolytica. Symptoms include dysentery, fever, chills and intestinal bleeding occur in the intestinal disease and are relatively easy to treat. It may also cause liver or lung abscesses or reach the brain, which are all difficult to treat and are usually fatal.

The life cycle of the parasite starts with the ingestion of the mature cysts in contaminated food, water, or hands. Excystation occurs in the small intestine, where trophozoites are released. They multiply by binary fission and produce cysts.

There are different types of infections:

  • Non-invasive infection involve in asymptomatic carriers, where they may pass cysts in their stool.
  • Intestinal disease, where trophozoites invade the intestinal mucosa
  • Extra-intestinal disease, where trophozoites invade extraintestinal sites such as the liver, brain, and lungs through the bloodstream, with resulting pathologic manifestations.

Usual treatment for nonsystemic infection involves the use of Metronidazole (Flagyl®), followed by Iodoquinol (Yodoxin®).

Giardiasis:

The causative organism for water-borne diarrhea.

Usual treatment involves the use of Metronidazole (Flagyl®).

Pneumocystis:

The causative organism of pneumonia in AIDS patients.

Usual treatment is the use of Trimethoprim and Sulfamethoxazole (Bactrim ®).

Trypanosomiasis:

Involves two different diseases:

The first is the African sleeping sickness affects 30,000 annually, mostly in Africa. It is transmitted by the tsetse fly.

There are two phases of infection, the hemolymphatic stage, which involves itching, fever and lymphadenopathy and the meningoencephalitic stage, where it invades the CNS, causing headaches, somnolence and abnormal behavior, that eventually leads to loss of consciousness and coma.

Usual treatment for initial stage is Suramin sodium, while for the second stage Melarsoprol is used. Pentamidine which is used for Pneumocystis carinii can also be used.

The second is Chagas’ Disease caused by Trypanosoma cruzi and affects 16–18 million people annually with 50,000 deaths. The major affected areas are Central and South America, particularly Brazil.

There are two phases of infection, the acute phase, is asymptomatic for many adults, but can be fatal to children and the chronic phase, which occurs ten to twenty years later, where the parasites attack the heart, leading to irreversible damage and heart failure.

Usual treatment includes Nifurtimox (Lampit®), which is effective only against the acute phase of the disease, but unfortunately there is no therapy that can be used in chronic phases.
Control of disease transmission by blood screening and vector control has been highly effective, leading to 72% reduction in the incidence of infection in South American countries.

Leishmaniasis:

The causative organisms are several protozoa of the genus Leishmania. They are transmitted by the female phlebotomine sandflies. Symptoms include open sores that can be mild or very disfiguring. One or more cutaneous lesions appear and can change in size and appearance over time. A scab covers some sores and swollen glands can occur (in the armpit if the sores are on the arm or hand). Severe visceral forms can be fatal. In addition, abdominal discomfort from enlarged spleen is observed and death can occur due to severe diarrhea, pneumonia, and GI bleeding.

Usual treatment involves the use of Stibogluconate sodium (Pentostam®).

Trichomoniasis:

Probably the most common protozoal infection worldwide. Symptoms include vaginitis in women and UTI in both sexes. The infection spreads mainly by sexual contact or contact with contaminated items.

Usual treatment involves the use of Metronidazole (Flagyl®).

Helminth Diseases:

A number of different worm-infections that include:

Nematodes (roundworms)

Ascariasis; Few symptoms that include abdominal pain and intestinal obstruction, and can proceed to the lung phase that may give rise to cough or shortness of breath.

Usual treatment involves the use of Mebendazole (Vermox®) and Albendazole (Zental®).

Dracunculiasis (Guinea Worm Infection); The life cycle starts when contaminated water infected with small crustaceans that contain the parasite are consumed by the patient. The crustaceans are killed in the digestive track, and larvae are released, penetrate GI walls and after maturation, males die and females migrate to subcutaneous tissue. After one year, a blister forms and ruptures, and females emerge, released into water and ingested by crustaceans and the cycle begins again.

Only treatment is cleaning wound and applying local antibiotic to avoid secondary infection.

Ancylostomiasis (Hookworms); The larvae penetrate the skin, usually through the feet and are carried through the veins to the lungs. They penetrate the pulmonary alveolae, ascend the bronchial tree to the pharynx, and are swallowed. Symptoms include anemia and GI disturbances.

Usual treatment includes Mebendazole, Albendazole (Albenza®) and Pyrantel (Pamix®).

Trichinosis (Trichinosis); Arises from the ingestion of undercooked pork. Symptoms include GI symptoms (diarrhea, abdominal pain, vomiting), with facial swelling, conjunctivitis, fever, muscular weakness, capillary rupture and rash.

Usual treatment with Thiabendazole or Mebendazole.

Onchocerciasis (River Blindness) infects 18 million people, mostly in Africa. The infection is transmitted by the blackfly, common to fertile riverbeds. The parasite lives for around 12 years in the human body and the worm can reach 24 inches in length. Symptoms include rashes, lesions, intense itching, depigmentation of the skin, serious visual impairments, including blindness and inflammation of the lymph nodes, leading to elephantiasis

Usual treatment with Ivermectin (Mectizan®), but it only kills microfilariae, not adult parasite

Cestodes (tapeworms)

Taeniasis is caused by tapeworms, where humans are the only definitive hosts that attach to the intestinal wall and feed on blood and diet.

Usual treatment is with Praziquantel (Biltricide®).