Antiprotozoal Agents 1

• Antiprotozoal agents

  • Antimalarial chemotherapy
• Summary Epidemiology

  • endemic through tropics
  • 1.2 billion of approx 3.4 billion exposed worldwide annually at high risk
  • 198 mln symptomatic cases in 2013
  • 80% deaths occur in SSA
  • Deaths peaked at 1.82 million in 2004; fell to 1.24 mln in 2010
• Ruptured oocyst


  Stage in the life cycle of malaria
• Once plasmodia enter erythrocytic cycle they cannot reinvade liver
• Merozoites released from liver infect red blood cells
• Immature trophozoite

  Ring stage of malaria
• No parasites remain in liver once tissue schizonts burst in falciparum and malariae infections
• Periodicity of parasitaemia and fever

  • 48 hrs - falciparum, vivax ovale
  • 72 hrs - malariae
• Antimalarial drugs and prophylaxis

  • Causal prophylaxis
  • Suppressive prophylaxis
  • Terminal prophylaxis
• Causal prophylaxis

  Prevention of establishment of infection in the liver (inhibition of pre-erythrocytic schizogony)
• Suppressive prophylaxis

  Suppression of erythrocytic stage
• Drugs active against exoerythrocytic stage

  • primaquine
• Drugs active against erythrocytic stage

  • chloroquine
  • quinine
  • doxycycline
  • mefloquine
• Structural classification of antimalarial drugs

  • Cinchona alkaloids - quinine, quinidine
  • Synthetic quinoline derivatives
  • 4 aminoquinolines - chloroquine, amodiaquine, pyronaridine
  • 8 aminoquinolines - primaquine, tafenoquine
  • Quinolinemethanols - mefloquine, lumefantrine, halofantrine
  • Folate synthesis inhibitors
  • Biguanides - proguanil
  • Diaminopyrimidines - pyrimethamine
  • Sulphonamides - sulphadoxine
  • Sesquiterpene lactone endoperoxides - artemisinin & derivatives
  • Antimicrobials - doxycycline, clindamycin, atovaquone
• Structures and pathways targeted by antimalarial drugs

  • Haem metabolism
  • Electron transport
  • Folate metabolism
  • Protein translation
• Plasmodia have limited capacity for de-novo AA synthesis
• Plasmodia rely on AA released from digested host Hb for metabolism
• Chloroquine is a weak base
• Chloroquine mechanism of action

  Weak base that diffuses into parasite digestive vacuole; converted to protonated, membrane-impermeable form, trapped in the parasite
• Protonated chloroquine accumulates in vacuole, inhibits digestion of Hb by the parasite
• Chloroquine binds heme/FP to form a highly toxic complex
• Chloroquine is extraordinarily safe but has a narrow safety margin
• Chloroquine - clinical uses

  • Treatment of non-falciparum malaria
  • Chemoprophylaxis: vivax, ovale and malariae
  • Amoebic liver abscesses
  • Secondary (disease modifying) (RA, SLE etc)
  • Antiviral activity
• Chloroquine - adverse effects

  • Blurred vision
  • Pruritus
  • Cardiotoxicity
  • Ototoxicity
  • Retinopathy
  • Peripheral neuropathy
  • Severe hypotension
  • Respiratory and cardiac arrest
• Chloroquine resistance - basis

  • Chloroquine-resistant plasmodia accumulate less drug inside parasite food vacuole
  • Protonated amino acids are generated in parasite digestive vacuole as it degrades haemoglobin
  • Protonated amino acids exit lysosome via transmembrane protein (PFCRT)
  • pfcrt mutations associated with chloroquine resistance
• Quinine is a cinchona tree-derived alkaloid
• Quinine mechanism of action

  May be similar to chloroquine but concentrates to different extent in plasmodial digestive vacuole
• Quinine is administered orally or slow i.v. infusion
• Rare but serious side effects linked to CYP2C8 variant alleles when it come to amodiaquine
• CYP2C8*1

  WT allele (acceptable safety profile)
• CYP2C8*2, *3 and *4

  "poor metabolizer" phenotypes
• Poor metabolizers display lower treatment efficacy against malaria, as well as increased toxicity
• Quinine mechanism of action

  May be similar to CHQ; concentrates to different extent in plasmodial digestive vacuole
• Quinine may have alternative modes of action such as intercalation into DNA through hydrogen bonding, plasmodial transcription and replication
• Quinine is administered orally (7 day course!) or slow i.v. infusion
• Loading dose may be required but bolus i.v. administration is contraindicated due to cardiac dysrhythmia risk
• Quinine is readily absorbed and distributes into an apparent volume of approximately 1.5L/kg
• Quinine - PK characteristics

  • Plasma concentration higher among malaria patients
  • Apparent Vd and CL lower among malaria patients
  • T1/2 longer in severe malaria patients
• Quinidine

  Optical isomer with identical actions to Quinine
• Quinidine

  • Vd > Quinine
  • CL > Quinine
  • T½ elim < Quinine