Antimalarial Drugs

Malaria, a vector-borne parasitic disease caused by Plasmodium spp., is transmitted via injection of sporozoites or immature forms of the parasite into a person’s bloodstream. Sporozoites then infect the hepatocytes and differentiate into schizonts, which subsequently rupture, and merozoites invade red blood cells. As such, pharmacotherapy for malaria targets exoerythrocytic and erythrocytic forms of schizonts. Collectively, these agents are classified as schizonticides.

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Plasmodia Life Cycle and Prophylaxis

Plasmodium Life Cycle Antimalarial Drugs

Plasmodium life cycle

Image by Lecturio.

The treatment of malaria is targeted at different stages of the Plasmodium life cycle:

  • Human liver stage: targeted with tissue schizonticides
  • Human blood stage: targeted with blood schizonticides
  • Gametocyte stage: targeted with gametocides 
  • Human liver dormant stages: Hypnozoites can form in P. ovale and P. vivax infections and are targeted with primaquine or tafenoquine.

Treatment consists of 3 steps:

  1. Identification of the infecting Plasmodium species
    • P. falciparum is the most severe; can cause anemia and cerebral malaria
  2. Identification of drug susceptibility of the infecting Plasmodium
    • Determined by geographic origin of infection
  3. Patient’s clinical status
    • Avoid the same drug for treatment if it was used prophylactically

Malaria prophylaxis and prevention

  • Centers for Disease Control and Prevention (CDC) prophylactic regimens are based on a traveler’s geographic region.
  • Travelers should consult local guidelines (will vary from country to country and with seasons)
  • Principles of prevention
    • Chloroquine: first choice in areas without resistant P. falciparum
    • Mefloquine: first choice in areas with chloroquine-resistant P. falciparum
    • Doxycycline or Malarone® (atovaquone + proguanil): in areas with multidrug-resistant malaria
    • Primaquine: in terminal prophylaxis of P. vivax and P. ovale

Blood Schizonticides, Tissue Schizonticides, and Gametocides

Blood schizonticides

  • Chloroquine
    • Mechanism of action: prevents polymerization of heme and intracellular heme is toxic to the parasite
    • Mechanism of resistance:
      • Plasmodia develop membrane transporters to eject intracellular heme.
      • P. falciparum develops a transporter for chloroquine itself, coded by the P. falciparum chloroquine transporter (pfcrt) gene.
    • Side effects at low doses:
      • Gastrointestinal (GI) disturbances (nausea, cramping, diarrhea)
      • Skin rash
      • Headaches
    • Side effects at high doses:
      • Severe skin reactions
      • Peripheral neuropathies, toxic psychosis, retinal and auditory damage
      • Myocardial depression
      • May precipitate porphyria attacks
  • Quinine
    • Mechanism of action: combines with dsDNA, prevents strand separation, blocks replication and transcription
    • Used in chloroquine-resistant P. falciparum
    • Often combined with doxycycline or clindamycin, used to shorten the duration and limit toxicity
    • Toxicity:
      • Cinchonism (GI distress, headache, vertigo, blurred vision, tinnitus)
      • Hemolysis in G6PD deficient patients
      • Blackwater fever (intravascular hemolysis)
  • Mefloquine
    • Chemically related to quinine
    • Mechanism of action: creates toxic heme particles in food vacuoles
    • First-line agent: taken weekly (4 weeks before and 1 week after)
    • Toxicity:
      • GI distress, skin rash, headache, dizziness
      • Nightmares
      • May cause cardiac conduction defects and seizures at high doses

Tissue schizonticides

  • Primaquine  
    • Tissue schizonticide and gametocide
    • Used in conjunction with a blood schizonticide
    • Mechanism of action: forms quinoline-quinone metabolites that act as oxidants
    • Eliminates dormant liver stages (hypnozoites) of P. vivax and P. ovale
    • Toxicity:
      • GI distress, headaches
      • Methemoglobinemia, toxicity in G6PD-deficient patients (hemolysis)
      • Contraindicated in pregnancy

Gametocides

  • Kill sexual stages and prevent transmission to mosquitoes

Gametocidal + schizonticidal:

  • Quinine: gametocidal against P. vivax and ovale 
  • Primaquine: gametocidal against P. falciparum, malariae, ovale, and vivax

Artemisinins and Antifolate Drugs

Artemisinins

  • Blood schizonticides
  • Not used as monotherapy to prevent resistance
  • Only drugs effective against quinine-resistant strains
  • Mechanism of action: accumulate in protozoan food vacuoles, and once metabolized, release toxic free radicals
    • Rare adverse effects of nausea, vomiting, and diarrhea
    • No increase in congenital problems or stillbirths in women taking these drugs
  • Short half-lives and not used for malaria prophylaxis
  • Artesunate IV: treatment of severe malaria
  • Artemether-lumefantrine: CDC recommended for uncomplicated malaria treatment in adults and children weighing ≥ 5kg
    • Not to be used in patients on mefloquine prophylaxis  
  • Halofantrine: Active against all 4 plasmodium malarial species
    • Not available in the United States
    • Not recommended by the CDC due to adverse cardiac events
    • Contraindicated in pregnancy
  • Dihydroartemisinin-piperaquine: not available in the United States and not recommended by the CDC due to widespread resistance

Antifolate drugs

  • Prophylaxis and treatment for multidrug-resistant P. falciparum 
  • Mechanism of action: antimetabolites, block folic acid synthesis
  • Proguanil
    • Inhibits protozoan dihydrofolate reductase (DHFR)
    • Used in combination with atovaquone
  • Pyrimethamine
    • Inhibits DHFR
    • Combination with sulfadoxine (Fansidar®) inhibits both dihydrofolate reductase and dihydropteroate synthase 
    • Not used in the United States
  • Sulfonamides
    • Mechanism of action: inhibit dihydropteroate synthase
    • Adverse reactions: skin rashes, GI upset, hemolysis, kidney damage
    • Sulfadoxine-pyrimethamine: not used in the United States
    • Dapsone: rarely used
  • May combine pyrimethamine and sulfadoxine: synergistic effects through a sequential blockade
  • Toxicity:
    • Skin rash, GI distress
    • Contraindicated in pregnancy

Erythrocides and Miscellaneous Drugs

Erythrocides

  • Atovaquone
    • Malarone® (atovaquone + proguanil)
    • Used as treatment and as once-daily prophylaxis
    • Is an alternative treatment for P. jiroveci infection
    • Mechanism of action: disrupt mitochondrial electron transport
    • Toxicity:
      • Abdominal pains
      • GI effects
  • Halofantrine
    • Active against erythrocytic forms of all 4 malarial organisms
    • Not used as a chemoprophylactic agent
    • High potential for cardiotoxicity: prolonged QT interval
    • Embryotoxic: contraindicated in pregnancy

Miscellaneous drugs

  • Doxycycline
    • Used for chemoprophylaxis for travelers
    • Unknown mechanism
  • Amodiaquine
    • Inexpensive
    • Used extensively in the developing world
    • Used in fixed dosing with artesunate
    • Toxicity:
      • Agranulocytosis and aplastic anemia

Adverse Effects

DrugAdverse effects
Artemether-lumefantrine (Coartem®)Headache, dizziness, anorexia, nausea/vomiting, weakness, arthralgia, myalgia
ArtesunateHeadache, dizziness, anorexia, nausea/vomiting
Atovaquone-proguanil (Malarone®)Abdominal pain, nausea/vomiting, headache, cough in children
Chloroquine
  • GI upset, headache, exacerbation of psoriasis, retinal toxicity, visual impairment
  • Blue-gray skin pigmentation with long-term use
  • Cardiomyopathy and QT prolongation have been seen with long-term therapy
HydroxychloroquineGI upset, headache, rash, visual changes
DoxycyclinePhotosensitivity, GI upset (mitigated by taking with food), permanent tooth discoloration in children < 8 years
Mefloquine
  • GI upset, skin rash, headache, dizziness
  • Psychiatric effects: nightmares, anxiety, depression
  • Cardiac conduction defects
  • Seizures at high doses
PrimaquineGI upset, headaches, methemoglobinemia, hemolysis (due to G6PD deficiency)
Quinidine
  • Hemolysis (G6PD deficiency)
  • Cinchonism (syndrome of nausea, vomiting, tinnitus, and vertigo)
  • Hypoglycemia (quinine-induced insulin release)
  • Blackwater fever: uncommon anemia of massive hemolysis with “Coca-Cola”-colored urine
Tafenoquine
  • Dizziness, nausea/vomiting, headache
  • Psychiatric effects are rarely seen (in ≤ 3% of patients): somnolence, anxiety, abnormal dreams, depression

Overview

DrugClassificationMechanism of actionUsageContraindications
Artemether-lumefantrine (Coartem®)
  • Blood schizonticide
  • Artemisinin-aryl alcohol combination
Metabolized in plasmodial food vacuole to toxic free radicals
  • Treatment of uncomplicated P. falciparum malaria in patients weighing ≥ 5 kg
  • Treatment of severe malaria after the administration of IV artesunate
  • Strong CYP3A4 inducers
  • Known hypersensitivity to artemisinins
Artesunate
  • Blood schizonticide
  • Artemisinin
Metabolized in plasmodial food vacuole to toxic free radicals
  • First-line treatment for severe malaria in the United Sates (CDC recommended, not FDA approved)
  • 3-day treatment of 4 equal IV doses of 2.4 mg/kg
  • Followed by 1 of the following PO:
    1. Artemether-lumefantrine
    2. Atovaquone-proguanil
    3. Doxycycline
    4. Clindamycin
    5. Mefloquine (if no other options)
Known hypersensitivity to artemisinins
Atovaquone-proguanil (Malarone®)
  • Blood schizonticide
  • Tissue schizonticide
  • Quinone-folate antagonist
  • Atovaquone inhibits the plasmodial electron transport chain
  • Proguanil inhibits DHFR and blocks plasmodial DNA synthesis
  • Prophylaxis in all areas
  • Taken with milk or fatty meal to aid absorption
Severe renal impairment (CrCl < 30 mL/minute)
Chloroquine
  • Blood schizonticide
  • 4-Aminoquinoline
Enters the food vacuoles of Plasmodia and disrupts heme polymerizationProphylaxis in areas with chloroquine-sensitive malaria
  • Retinal or visual changes
  • Caution in patients with porphyrias, psoriasis, seizures, pre-existing hearing impairment
HydroxychloroquineBlood schizonticideKnown hypersensitivity to 4-aminoquinolone derivatives
Doxycycline
  • Tetracycline
  • Blood schizonticide
Inhibits protein synthesis in the plasmodial apicoplast
  • Prophylaxis in all areas
  • Treatment with quinine
  • Children < 8 years old
  • Pregnancy or breastfeeding
Mefloquine
  • Blood schizonticide
  • Quinoline methanol
Enters the food vacuoles of Plasmodia and disrupts heme polymerizationProphylaxis in areas with chloroquine-sensitive malaria or chloroquine-resistant areas
  • History of seizures
  • Psychiatric disorders
Primaquine
  • Tissue schizonticide, including hypnozoites
  • 8-Aminoquinoline
  • Forms quinoline-quinone metabolites that act as oxidants
  • Gametocidal against P. falciparum, malariae, ovale, and vivax
Prophylaxis in P. vivax predominant areas
  • Treatment for presumptive antirelapse therapy of P. ovale and P. vivax
  • In conjunction with chloroquine (blood schizonticide)
  • Taken for 14 days after departing malaria area
  • G6PD deficiency
  • Lupus erythematosus
  • Rheumatoid arthritis
  • Pregnancy and breastfeeding
Quinidine IV
  • Blood schizonticide
  • Quinoline methanol
Interferes with heme polymerizationDiscontinued in the United States
Quinine
  • Blood schizonticide
  • Quinoline methanol
  • Interferes with heme polymerization
  • Gametocidal against P. vivax and P. ovale
  • Treatment of uncomplicated chloroquine-sensitive malaria
  • Quinine sulfate oral PLUS either:
    • Doxycycline
    • Tetracycline
    • Clindamycin (preferred in first trimester of pregnancy)
  • Prolonged QT interval
  • Myasthenia gravis
  • Optic neuritis
Tafenoquine
  • Tissue and blood schizonticide, including hypnozoites
  • Gametocide
  • 8-Aminoquinoline derivative
Interferes with heme polymerizationProphylaxis in all areas
  • Treatment of presumptive antirelapse therapy of P. ovale and P. vivax
  • Administered as a single dose after departing malaria area
  • G6PD deficiency
  • Pregnancy and breastfeeding
  • Children < 16 years old
  • History of or active psychotic disorder

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