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• Malaria


  Caused by a Plasmodium parasite and transmitted to humans by the Anopheles mosquito

  
• Plasmodium species


  • Plasmodium falciparum
  • Plasmodium vivax
  • Plasmodium malariae
  • Plasmodium ovale
• Plasmodium falciparum


  • Causes the most severe form of malaria
  • Infects up to 65% of the patients erythrocytes

  
• Plasmodium vivax


  • Second most common species
  • Can be very chronic in recurrence because it can reinfect liver cells
• Plasmodium malariae

  • Although causing only 10% of all malarial cases, relapses are very common

  
• Plasmodium ovale


  • The least common species
• Malaria (history)


  • Derived from "mala aria" or bad area
  • Also called ague, intermittent fever, marsh fever and The Fever

  
• Anopheles Mosquito


  • A nocturnal feeder
  • Should prevent contact between humans and the insect
  • Can be eliminated by using insecticides (Ex. Dichlorodiphenyltrichloroethane/ DDT)

  
• Human Mutations that Protect Against Malaria

  • Sickling disease (sickle cell anemia)
  • G6PD patients
  • Hemoglobin C
  • Thalassemia
  • Increased production of NO
  • Pyruvate kinase deficiency
• Antimalarial Drugs


  • Kill the sporozoites injected by the mosquito and/or prevent the sporozoites from entering the liver
  • Kill the schizonts residing in hepatocytes and/or prevent them from becoming merozoites
  • Kill the merozoites in the blood and/or prevent them from developing into gametocytes
  • Kill the gametocytes before they can enter the mosquito and reproduce into zygotes
• Structure-Activity Relationship (SAR)


  Have one common structural feature - a quinoline ring, or a "quinoline with an additional benzene" (an acridine ring)
• Cinchona Alkaloids


  • Derived from Cinchona tree (Cinchona succirubra & Cinchona calisaya)
  • Has quinuclidine ring
• Quinine


  • Reserved for malarial strains resistant to other agents
  • Used for Chloroquine-resistant P. falciparum
  • Used in nocturnal leg cramps
  • Category X (abortifacient)
• Quinine Mechanism of Action

  Inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum and can bind with hemazoin in parasitized erythrocytes
• Quinidine


  • Not indicated for malaria, but a more potent agent than quinine
  • More toxic
  • Used for cardiac arrythmias
• Cinchonism


  • A syndrome causing nausea and vomiting, tinnitus and vertigo
  • Can proceed to involvement of GI tract, nervous and cardiovascular system, and the skin
• 1. Chloro-4-Aminoquinolines


  • Closest antimalarials that are bases on quinine structure
  • Substituted at the same position 4 as quinine and have assymetric carbon equivalent to quinine's C9 position
• Chloroquine


  • DOC in the treatment of erythrocytic falciparum malaria
  • Used for both prophylaxis and treatmant of P. ovale, P. vivax and P. malariae infections
  • MOA: unknown
  • Not effective against exoerythrocytic parasites
  • Does not prevent relapses of P. vivax and P. ovale
  • Also indicated for the treatment of extraintestinal amebiasis
  • Anti-inflammatory action explains its occasional use in RA and discoid lupus erythematosus
  • S/E: Retinopathy, hemolysis in patients with G6PD deficiency, muscular weakness, exacerbation of psoriasis and impaired liver function
• Hydroxychloroquine


  • Remains in the body for over a month
  • Prophylactic dosing is once weekly
• Amodiaquine


  • Highly suppressive in P. vivax and P. falciparum
  • Has curative activity against P. falciparum
  • S/E: hepatitis, agranulocytosis
• Mefloquine


  • Effective single agent for suppressing and curing multi-drug resistant forms of P. falciparum
  • CI: patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia and other major psychiatric disorders
• 1. Aminoquinolines


  All can cause hemolytic anemia in G6PD deficient patients
• Primaquine


  • Effective only against the exoerythrocytic stages of malaria
  • Only agent that can lead to radical cures of P. vivax and P. ovale malarias (dormant stages in the liver)
  • Gametocidal for all four plasmodia species, transmission of the disease can be prevented
  • Not used as prophylaxis
  • MOA: disrupt the parasites mitochondria

  
• Quinacrine


  • Primarily used in the treatment of Giardiasis but is also effective against tapeworm and malaria, and topically against leishmaniasis
  • Should not be given with primaquine because of increased toxicity
• Doxycycline


  • MOA: inhibits the pathogen's protein synthesis by reversibly inhibiting the 30S ribosomal subunit
  • Use for malaria is limited to prophylaxis against strains of P. falciparum resistant to chloroquine and sulfadoxine-pyrimethamine
• Halofantrine


  • Is a schizonticide
  • MOA: unknown
• Artemisinin


  A natural product from the dry leaves of Artemisia annua (sweet wormwood)
• Sulfadoxine & Pyrimethamine


  • Schizonticide
  • Sulfadoxine - interferes with the parasites ability to synthesize folic acid
  • Pyrimethamine - inhibits the reduction of folic acid to its active tetrahydrofolate coenzyme form
  • Indicated for the prophylaxis and treatment of chloroquine-resistant P. falciparum
  • Active against all the asexual erythrocytic forms
• Atovaquone & Proguanil


  • Proguanil - metabolized to cycloguanil
  • Combination is against both erythrocytic and exoerythrocytic Plasmodium
  • Indicated for malaria resistant to chloroquine, halofantrine, mefloquine and amodiaquine
• Artemether + Lumefantrine


  These two interfere with heme metabolism, thereby stopping development of the parasite in the erythrocyte states