Malaria is a protozoan infection. Malaria is caused by the bite of female Anopheles mosquito. In this article, we will study the various antimalarial drugs, mechanism of action, adverse effects/toxicity and drugs of choice in detail. Important therapeutic aspects of individual drugs will also be studied.
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anopheles stephensi

Image: “Anopheles stephensi.” by Jim Gathany – This media comes from the Centers for Disease Control and Prevention’s Public Health Image Library (PHIL), with identification number #5814. License: Public Domain


Malaria

Malaria is caused by four different species of the protozoan parasite Plasmodium: P. falciparum, P. malariae, P. ovale and P. vivax. These are transmitted by the bite of female Anopheles mosquitoes. Malaria caused by the P. falciparum species is severe in nature; it can cause severe anemia and cerebral malaria.

malaria

Image: “Malarial sporozoites develop inside oocysts and are released in large numbers into the hemocoel of Anopheles stephensi mosquitoes.” Image by Ute Frevert; False Color by Margaret Shear – http://biology.plosjournals.org/perlserv/?request=get-toc&issn=1545-7885&volume=3&issue=6. License: CC BY 2.5

Important: P. falciparum species is most dangerous with high mortality rates.

This parasite has a complex life cycle, and it is active in both the blood (erythrocytic schizonts) and in the tissues, mainly the liver (exoerythrocytic forms of schizonts).

Treatment against malaria is directed towards killing the schizonts by one or more mechanisms.

Resistance develops when the parasite develops mechanisms that reduce the effect of the antimalarials or bypasses the mechanisms interrupted by the drug. Resistance is a major problem in some parts of the world, e.g., Africa and South East Asia; therefore, newer drugs are tried, and their monotherapy should be avoided to prevent resistance against them.

Classifications of Antimalarial Drugs

Chemical classification of antimalarials

4–Aminoquinoline derivatives Chloroquine
4–Quinoline derivatives Mefloquine
8–Aminoquinoline derivatives Primaquine, Bulaquine
Cinchona alkaloid Quinine, Quinidine
Biguanides Proguanil
Diaminopyrimidines Pyrimethamine
Sulfonamides and sulfones Sulfadoxine, Dapsone
Sesquiterpene lactones Artemisinin derivatives

Functional classification of antimalarials

  • Schizonticide: a drug that selectively kills schizonts of a sporozoan parasite (in this case, the malarial parasite)
    • Tissue schizonticides kill exoerythrocytic forms of schizonts, such as those in the liver (e.g., primaquine).
    • Blood schizonticides kill schizonts only in the erythrocyte (e.g., chloroquine, quinine).
  • Sporonticide: a drug that prevents sporogony and multiplication in the mosquito (e.g., proguanil, pyrimethamine).

Individual Antimalarial Drugs

Chloroquine

  • Rapidly and completely absorbed following oral administration
  • Concentrates in erythrocytes, liver, spleen, kidney and lung, and melanin-containing tissues, and leukocytes; also penetrates the central nervous system (CNS) and crosses the placenta.

Mechanism of Action

red blood cells infected with malaria

Image: “Electron micrograph of a Plasmodium falciparum-infected red blood cell (center), illustrating adhesion protein “knobs”.” by Rick Fairhurst and Jordan Zuspann, National Institute of Allergy and Infectious Diseases, National Institutes of Health – https://www.flickr.com/photos/nihgov/25534997493/in/photolist-EUrx8t-CvR53a-B3Ad52-ydGygr-wZzPff-C5BN5H. License: CC BY 2.0

The free heme is generated by the parasite while digesting the host cell’s hemoglobin. The parasite polymerizes the heme to hemozoin to avoid the toxic effects of free heme. However, chloroquine accumulates in the food vacuoles of plasmodia and prevents polymerization of heme. Consequently, free heme cause the lysis of parasite along with the RBC.

Note: Free heme is a cytotoxic agent. It causes damage to proteins, DNA, cell membranes, cell organelles via oxidation and lipid peroxidation.

Clinical uses Drug of choice for treatment and prophylaxis of all forms of malaria:

  • Non-resistant P. falciparum malaria prophylaxis and treatment
  • Vivax malaria treatment
  • Ovale malaria treatment.
Adverse effects/toxicity GI symptoms: nausea, vomiting; pruritus (mostly in African population, lasts for 48-72 hours), headaches, blurred vision; prolongs QT interval

Resistance: when parasite develops membrane pumps to flush out heme and a transporter to flush out chloroquine. Mutation in the gene encoding for chloroquine resistance transporter protein (PfCRT) has a role in resistance development by plasmodium.

Severe adverse effects are rare.

Drug interactions Antacids may decrease oral absorption of chloroquine.
Contraindications
  • Presence of psoriasis and porphyrias
  • Avoided concomitantly with other drugs that prolong QT interval

Mefloquine

  • Long half-life (20 days)
Mechanism of action Unknown
Clinical uses
  • Resistant P. falciparum treatment
  • Falciparum malaria prophylaxis (once weekly)
Adverse effects/toxicity
  • (At high doses) nausea, vomiting, dizziness, disorientation, hallucinations, and depression
  • Prolongs QT interval and can precipitate Torsade de Pointes
  • Rare: pneumonitis
Drug interactions
  • Resistance to mefloquine confers cross resistance to quinine and halofantrine
  • ECG abnormalities and cardiac arrest can occur when taken with quinine or quinidine
Contraindications
  • Neurologic and psychiatric disorders
  • Family history of seizures

Artemisinin Derivatives

Artesunate, Artemether and Arteether are artemisinin derivatives. These blood schizonticides are considered a superior antimalarial drug to quinine. Artemisinin clears the parasitic load in lesser time as compared to other antimalarial drugs. It kills young parasites before they enter into the deep microvasculature.

Artemisinin derivatives should not be used as monotherapy to prevent the development of resistance. Possible combinations: artemether with lumefantrine; artesunate with mefloquine, clindamycin, etc.

The drugs have short half-lives; therefore, they cannot be used for prophylaxis. They are available as intravenous preparations.

Mechanism of action
  • Accumulate in food vacuole and get metabolized to release toxic free radicals
  • Additional possible action includes binding to and damaging certain parasite proteins
Clinical uses
  • Artemether + lumefantrine: acute, uncomplicated malaria infections in adults and children > 5 kg
  • Multidrug-resistant P. falciparum treatment (they are the only drugs effective against quinine-resistant strains).
  • Severe malaria: sometimes intravenous artesunate is used instead of quinine; this is available for the treatment of severe malaria in the United States; drug of choice in low-transmission areas and in the second and third trimesters of pregnancy
Adverse effects/toxicity
  • Usually mild GI symptoms such as nausea, vomiting, and diarrhea
  • Prolong QT interval
  • Hypersensitivity reactions and rash

Quinine

This blood schizonticide is usually administered as a combination with clindamycin, doxycycline, or tetracycline. It is available as oral and intravenous formulation.

Mechanism of action Same as chloroquine; interferes with heme polymerization
Clinical uses
  • Multidrug-resistant malaria treatment
  • Severe malaria, including cerebral malaria – intravenous quinine has been the drug of choice
  • Quinidine, a stereoisomer of quinine, is the only non-oral drug approved by the US FDA for the treatment of severe malaria
  • Quinine should not be given for prophylaxis to avoid resistance development.
Adverse effects/toxicity
  • Quinine is a cardiotoxic drug causing ventricular tachycardia, arrhythmia, hypotension, etc.
  • Prolongs QT interval and can precipitate Torsade de Pointes
  • Cinchonism – a syndrome of nausea, vomiting, tinnitus, and vertigo; however, this is reversible so therapy need not be stopped
  • Hemolysis (blackwater fever) is rare and it can lead to hemolytic anemia, hemoglobinuria and renal damage
Drug interactions
  • Enhances the activity of neuromuscular blockers
  • Elevation of digoxin levels
  • Antacids that contain aluminum hydroxide reduce quinine absorption
Contraindications
  • Known hypersensitivity
  • Pregnancy

Primaquine

This tissue schizonticide and gametocide is the only agent that prevents the relapse of P. vivax and P. ovale malaria. It is not effective against blood schizonts.

Mechanism of action Forms quinoline–quinone metabolites, which act as cellular oxidants. Its mechanism of action is not clearly understood; however, it is postulated that it damages the DNA structure and mitochondrial membranes.
Clinical uses
  • Eradication of liver schizonts (liver hypnozoites)
  • Prophylaxis of P. vivax and P. ovale malaria
Adverse effects/toxicity
  • Usually well tolerated
  • GI distress symptoms, pruritus, headache, methemoglobinemia
  • Methemoglobinemia due to excessive hemolysis
Contraindications
  • G6PD deficiency, leads to hemolysis
  • Pregnancy

Antifolate Drugs

Proguanil, Pyrimethamine, Sulfadoxine and Dapsone are blood schizonticides; Pyrimethamine has a sporonticide action as well. Proguanil has a shorter half-life (12–16 h) than others (>100 h).

Mechanism of action
  • Proguanil (prodrug, biotransformed to cycloguanil) and pyrimethamine inhibit protozoan dihydrofolate reductases, which is needed for the synthesis of tetrahydrofolate, a cofactor that plays a role in the synthesis of nucleic acids
  • Sulfonamides (sulfadoxine and dapsone) block folic acid synthesis by inhibiting dihydropteroate synthase
  • Pyrimethamine and sulfadoxine (Fansidar): act by both mechanisms, thereby leading to a synergistic effect
Clinical uses
  • Multidrug-resistant P. falciparum prophylaxis and treatment
  • Pyrimethamine and sulfadoxine (Fansidar): chloroquine-resistant P. falciparum treatment and toxoplasmosis
  • Proguanil with atovaquone (Malarone): chloroquine- and mefloquine-resistant P. falciparum prophylaxis
  • Dapsone is used in the treatment of leprosy. In combination with trimethoprim, it is also used in pneumocystis pneumonia.
Adverse effects/toxicity
  • Pyrimethamine: folic acid deficiency in high doses; megaloblastic anemia (can be reversed with leucovorin)
  • Sulfonamides: skin rashes, GI symptoms, hemolysis and kidney damage
Drug interactions
Carbamazepine increases doxycycline metabolism

Doxycycline

  • Blood schizonticide
Mechanism of action Inhibits protein synthesis in the bacteria; this is achieved by interfering with the binding of aminoacyl-tRNA molecules to bacterial ribosomes
Clinical uses
  • P. falciparum malaria (even chloroquine-, mefloquine-, or multidrug-resistant malaria) prophylaxis
  • P. falciparum malaria treatment, in combination with quinine
  • Many other clinical uses: gonorrhea, community-acquired pneumonia, Lyme disease, amebiasis, etc.
Adverse effects/toxicity
  • Dizziness and vertigo: these are dose-dependent and reversible
  • Candidal vaginitis, photosensitivity
Drug interactions
  • Carbamazepine increases doxycycline metabolism
  • Barbiturates increases its metabolism
  • Phenytoin decreases doxycycline levels by stimulating its metabolism
Contraindications Younger children and pregnant women

Amodiaquine

This drug is similar to chloroquine but less metallic/bitter in taste and somewhat faster acting than chloroquine.

Mechanism of action Similar to chloroquine
Clinical uses
  • Uncomplicated P. falciparum malaria treatment
  • Not for prophylaxis
Adverse effects/toxicity
  • Similar to chloroquine
  • Neutropenia in the pediatric age group
Drug interactions Similar to chloroquine
Contraindications Similar to chloroquine

Atovaquone

  • Rapidly acting blood schizonticide
Mechanism of action
  • Inhibits mitochondrial electron transport—interrupts ATP production and breaks down mitochondrial membranes
  • May also interfere with folate metabolism
Clinical uses
  • Mild to moderate pneumocystis pneumonia
  • Falciparum malaria prophylaxis and treatment, in combination with proguanil (malarone)
  • Can also be used for toxoplasmosis (including as a second-line drug in AIDS patients).
Adverse effects/toxicity Coughing, rash, GI symptoms: nausea, vomiting, diarrhea
Contraindications (presence or history of) cardiac conduction defects, psychiatric disorders, or seizures

Halofantrine and Lumefantrine

  • Blood schizonticides
Halofantrine Lumefantrine
Mechanism of action Unknown
Clinical uses Not used anymore for malaria prophylaxis (effective against all 4 species) because of QT prolongation In combination with artemether: acute, uncomplicated malaria infections in adults and children > 5 kg
Adverse effects/toxicity GI symptoms: abdominal pain, diarrhea, vomiting; coughing, rash, headache, pruritus; prolongs QT interval and can precipitate Torsade de Pointes Extremely well tolerated, very mild GI symptoms, headache, etc. may rarely be seen.
Drug interactions Prior mefloquine therapy worsens QT interval prolongation
Contraindications Cardiac conduction defects

Drugs for Prophylaxis of Malaria in Travelers

Type of malaria Therapy
Chloroquine – sensitive P. falciparum Chloroquine or mefloquine (weekly)
Chloroquine – resistant P. falciparum Mefloquine (weekly)
Mefloquine – or multidrug-resistant malaria Doxycycline or Malarone (daily)
P. vivax and P. ovale Primaquine (daily for 14 days)

Antimalarial Drug Treatment in Severe Malaria

  • Approved by US FDA: i.v. quinidine
  • Recommended by WHO, CDC, and other sources: i.v. quinine or i.v. artesunate
  • After initial treatment with one of these drugs, a 1-week course of doxycycline is administered. If doxycycline is contraindicated, e.g., in the pediatric age group, clindamycin can be used.

Review Questions on Antimalarial Drugs

The correct answers can be found below the references.

  1. Which of the following is the only non-oral drug approved by the US FDA for the treatment of severe P. falciparum malaria?
    1. Quinine
    2. Quinidine
    3. Artesunate
    4. Mefloquine
    5. Proguanil
  2. A 35-year-old Belgian man is planning to travel to an Asian country endemic to P. falciparum malaria but where malaria resistance has not developed. He is a known case of bipolar disorder type 2. Which of the following prophylactic drugs, or drug combinations, is contraindicated in this patient?
    1. Mefloquine
    2. Chloroquine
    3. Doxycycline
    4. Malarone
    5. Primaquine
  3. Which of the following drugs kills the hypnozoites?
    1. Quinine
    2. Chloroquine
    3. Doxycycline
    4. Malarone
    5. Primaquine

 

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