malaria

• malaria is the world's most serious infectious disease

  in 2020 there was 241 million malaria cases and 627,000 deaths

  • there has been a significant increase in past years due to disruption by pandemic
• malaria is caused by an animal protazoan with a unicellular level of organisation

  • they are motile at some stages of their life cycle due to locomotor organelles like cilia, flagella and pseudopodia
  • undergo both asexual and sexual reproduction
• protozoa divide by a process of fission, with 3 types:

  1. binary fission - 2 equal sized daughter cells (mitosis)
  2. budding - unequal daughter cells (mitosis)
  3. schizogony - multiple fission, numerous daughter cells (mitosis)
• protozoa commonly use encystment [similar to endospore] to combat adverse conditions

  • use heterotrophic nutrition
  • can be free-living or dependant on host
• there are more than 50 species of in the genus plasmodium

  • they have a 2 host life cycle - mosquito and vertebrate
  • they attack red blood cells and cause malaria
• humans are affected by 5 species of plasmodium:

  1. plasmodium falciparum - malignant tertian
  2. plasmodium vivax - benign tertian
  3. plasmodium ovale - benign tertian
  4. plasmodium malariae - benign quartan
  5. plasmodium knowlesi - unknown
• benign -> non-fatal

  malignant -> fatal

  tertian -> fevers every 48hrs (day 1 and 3)

  quartan -> fevers every 72hrs (day 1 and 4)
• plasmodia life cycle

  1. an infected female anopheline mosquito bites, and injects sporozoites from her salivary glands
• plasmodia life cycle

  2. sporozoites are taken into circulation to the liver which takes approximately 30 minutes

  • motile sporozoites penetrate the liver cells
• plasmodia life cycle

  3. in liver, asexual multiplication (schizogony) lasts 5 - 16 days
• plasmodia life cycle

  4. schizonts (mature sporozoites) rupture and release merozoites

  • these can reinfect liver cells and cause a secondary exoerythrocytic cycle
  • more often, they infect red blood cells and begin the erythrocytic cycle
• plasmodia life cycle

  5. asexual multiplication continues in red blood cells (erythrocytic schizogony) and more merozoites are released, which infect more red blood cells
• incubation period before clinical signs of malaria usually involves 2 exoerythrocytic cycles and 1-2 erythrocytic cycles

  • malarial fever is caused by toxins released by red blood cells burst (generally after 48 or 72 hours)
• plasmodia life cycle

  6. some merozoites produce sexual gametocytes which develop no further in erythrocytes
• plasmodia life cycle

  7. a non-infected anopheline mosquito takes infected blood and the gametocytes become mature male and female gametes in the stomach of the mosquito
• plasmodia life cycle

  8. the macrogamete (F) and microgamete (M) divide and after fertilisation, penetrate the stomach wall in the form of a motile zygote called an oökinete
• plasmodia life cycle

  9. the oökinete forms an oöcyst, which undergoes both meiotic and mitotic division (sporogony)
• plasmodia life cycle

  10. the oöcyst ruptures, releasing sporozoites which migrate to the salivary glands of the mosquito
• due to the abnormal shape of infected red blood cells, malaria can be diagnosed by a blood smear
• plasmodium vivax (43%)

  • benign tertian malaria (recurring fever every 48hrs)
  • symptoms relatively mild, but can be debilitating
  • if untreated, persistent reservoirs of infection remain due to dormancy stage
• plasmodium malariae (7%)

  • found around Tropics and Sub-Tropics
  • quartan benign malaria (recurring fevers every 72hrs)
  • benign in adults, nephrotoxic in kids
• plasmodium ovale (<1%)

  • benign tertian malaria
  • found in west africa
• plasmodium falciparum (50%)

  • malignant tertian malaria
  • infected RBCs have projection knobs, which stick to capillaries and cause obstruction, thrombosis and local ischaemia
  • complications result in cerebral malaria and blackwater fever
  • after CNS involvement, unarousable coma occurs
  • no secondary exoerythrocytic stage so no dormancy
  • fevers can last 36hrs, so attacks can overlap
• plasmodium knowlesi

  • malignant quotidian malaria
  • found in southeast asia
• malaria control in the past was mainly dependant on elimination of mosquito breeding places and involved water drainage programs, insecticide use and personal protection (nets, screens and repellent)

  • now, vector control and intermittent presumptive treatment is mainly used along with education and communication
• main targets for antimalarial drugs in humans:

  • tissue schizonts
  • blood schizonts (gametocytes and sporozoites)
• the ideal antimalarial drug would have:

  • potent activity against all plasmodium species
  • oral bioavailability
  • rapid speed of action
  • very strong safety profile
  • activity against all stages of malaria
• quinine is an alkaloid from a species of cinchona

  • 4-quinoline methanol was isolated in 1820
• quinine contains a quinoline ring and a quinuclidine ring

  • quinoline ring - flat, aromatic
  • quinuclidine ring - bridged, not aromatic
• quinine structure

  A) quinoline ring

  B) quinuclidine ring

  
• quinine has significant side effects including myocardial depression, vasodilation and haemolytic anaemia

  • quinine if effective against severe malaria however has no prophylaxis effects
• 4-aminoquinolines and derivatives are antimalarial drugs that attack the blood stage of malaria

  • it was developed from quinine by removing the quinucliside ring and by adding significant side chains at position 4 of the ring
• the quinoline ring is 2 6-membered aromatic rings connected by a double bond

  • nitrogen takes position 1 on the ring when naming
• structure of 4-aminoquinolines

  A) chain length c2 - c5

  B) quinoline ring

  C) must be trisubstituted

  D) amine group at position 4

  
• examples of 4-aminoquinolines:

  • chloroquine
  • hydroxychloroquine
  • mefloquine
  • halofantrine
• there was multiple proposed mechanisms of action for 4-aminoquinolines:

  1. DNA intercalation - need very high concentration for impact
  2. weak base - raise pH of lysosomes and impair haemoglobin digestion
  3. FPIX - drug binds to toxic byproduct of haemoglobin digestion and retains its toxicity
• pyrimethamine - sulfadoxine [fansidar]

  • targets metabolic pathways
  • developed for prevention and treatment of chloroquinine resistant malaria
  • combination of:

  1. pyrimethamine - inhibits plasmodial dihydrofolate reductase
  2. sulfadoxine - inhibits dihydropteroate synthase
• 8-aminoquinolines

  • prototype called pamaquine created in 1926 (now primaquine)
  • active against hepatic and tissue stages
  • given alongside chloroquine to eradicate all stages
  • gametocidal and hepatotoxic
• mechanism of action of 8-aminoquinolines:

  • interferes with cell redox system
  • undergoes multiple oxidations until incredibly reactive and toxic
  • causes cell death
• 8-aminoquinoline structure

  A) H

  B) OH

  C) OCH3

  D) O-alkyl

  E) second OCH3

  F) quinoline ring

  G) H

  H) any alkyl

  I) C2 - C6