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79. Antiprotozoal drugs

Antimalarial drugs

Malaria is the most common disease in the world. It’s caused by the plasmodia species of parasites, which are spread by the Anopheles mosquito. Plasmodium vivax causes benign tertian malaria. Plasmodium falciparum causes malignant tertian malaria, which affects the CNS.

Compounds

  • Chloroquine
  • Primaquine
  • Artesunate
  • Quinine
  • Atovaquone
  • Proguanil
  • Pyrimethamine
  • Doxycycline
  • Clindamycin

Of all of the antimalarials the first four are the most important to know, according to prof. Pintér. The others need only be mentioned.

No single drug targets the whole life cycle of the parasite, which is why we often combine drugs. Some drugs are more effective at treating acute attacks while some are more effective at preventing infection.

Metronidazole is important in the treatment of protozoa like trichomonas, giardia and entamoeba, but metronidazole is described in topic 71.

Chloroquine

Indications

Chloroquine is the first choice for most cases of non-resistant malaria. It can also be used as prophylaxis in regions where chloroquine-resistance is not widespread.

In addition to having antimalarial effects chloroquine plays a small role in the treatment of autoimmune diseases like RA and SLE.

Mechanism of action

Plasmodium steals haemoglobin from RBCs. It then degrades the haemoglobin into heme and amino acids, which is the parasite’s source of amino acids. Heme however, is toxic to the parasite. It uses an enzyme called heme polymerase, which polymerizes heme into harmless haemozoin.

Chloroquine inhibits heme polymerase, causing heme to accumulate in the parasite.

Mechanism of resistance

P. falciparum is resistant to chloroquine in most parts of the world. This is the result of drug efflux due to mutated efflux pumps.

Pharmacokinetics

It is completely orally absorbed and concentrated in parasitized red blood cells. Due to its long half-life a loading dose is often necessary. It can also be given IV and IM in severe cases.

Chloroquine is uncharged at neutral pH and can therefore diffuse into the parasite lysosome. Inside the acid pH of the lysosome the drug is protonated, which “traps” it inside the lysosome.

It is metabolized in the liver and excreted in the urine, partially in unchanged form and partially as metabolized. It has a long half-life of 50 hours.

Adverse effects

  • Visual disturbances
  • GI symptoms

Primaquine

Indications

Primaquine has no effect against parasites in the blood (it has no schizontocidal effect), so it can not be used to treat acute malaria. It is the most effective antimalarial at preventing transmission of the parasite. It’s almost always combined with other drugs, usually chloroquine.

It’s also used to treat pneumonia caused by pneumocystis jirovecii

Mechanism of action

Active metabolites of primaquine inhibits the function of ubiquinone (coenzyme Q in the oxidative phosphorylation) and cause oxidative damage to the mitochondria of plasmodia.

Adverse effects

Primaquine can cause haemolysis is people with glucose 6-phosphate dehydrogenase deficiency. The drug depletes NADPH in RBCs. The RBCs of people with G6PD deficiency can’t regenerate NADPH, which causes haemolysis.

Artemisinin derivatives

These drugs are derivatives of artemisinin, a compound found in a plant called artemisia annua. This plant was used in traditional Chinese medicine to treat fever. In the 1970s a Chinese group discovered that it had antimalarial properties, which they received the Nobel Prize for in 2015. Artemisinin itself is no longer used as it has poor oral bioavailability, poor pharmacokinetics properties and is costly. Its derivatives are used instead.

These are the newest antimalarial drugs.

Compounds

  • Artesunate
  • Artemether

These drugs are always combined with other antimalarials, like lumefantrine.

Indications

Used to treat acute malaria. They’re one of the first-line drugs for falciparum malaria. No resistant strains are known. They’re not suitable for prophylaxis.

Mechanism of action

Not well known. They probably alkylate and damage malarial proteins and heme, preventing heme for being polymerized.

Pharmacokinetics

Can be given orally or IV.

Adverse effects

  • GI symptoms
  • Prolonged QT

Quinine

Quinine is an antimalarial drug, but it is an enantiomer of the class 1A antiarrhythmic drug quinidine. Quinidine is no longer used, though.

Indications

Quinine is a 2nd or 3rd line drug in treating acute malaria. It may be especially useful in chloroquine-resistant P. falciparum.

Mechanism of action

Same as for chloroquine.

Adverse effects

  • Negative heart effects
  • GI symptoms
  • Cinchonism
    • Tinnitus
    • Headache
    • Nausea
    • Visual disturbance

Quinine har a bitter taste, so oral compliance is often poor. It can also induce abortion as it has an oxytocin-like effect on the uterus.