OrgMed Lec

• Malaria


  • One of the most widespread diseases in the world
  • "Mala" and "aria" - bad air
  • Also known as intermittent fever, marsh fever, and the fever
  • Caused by Plasmodium parasite, transmitted through a mosquito called Anopheles
• Plasmodium falciparum


  • Estimated to cause approximately 50% of all malaria, causing the most severe form of the disease and because patients feel ill between acute attacks, this is a devastating form of the disease
  • Infects up to 65% of the patient's erythrocytes
  • Characterized by a fever which occurs every 48 hours (malignant tertian malaria)
• Plasmodium vivax


  • 2nd most common specie causing about 40% of all malarial cases
  • Can be very chronic and recurrent because it can re-infect the liver cells
  • Together with Plasmodium ovale, they cause benign tertian malaria since it still occurs every 48 hours (also same with relapsing fever)
  • Comparing to falciparum, more and most fatal among the Plasmodium species
• Plasmodium ovale


  • Least common
• Plasmodium malariae


  • Only causes 10% of all the malarial cases and usually, the relapses are very common, known as benign quartan malaria since the fever occurs every 72 hours
• Plasmodium knowlesi


  • Occurs every 24 hours (quotidian malaria)
  • Parasite that causes malaria usually found in the Southeast Asia; particularly, it is the most common cause of human malaria in Malaysia
• Complications of malaria


  • Hemolytic anemia
  • Hepatosplenomegaly
  • Capillary obstruction
  • Death
  • Chronic repeated CNS infection: impaired consciousness with specific fever, generalized convulsion, and comatose that persist for 24-72 hours
• Malaria life cycle


  1. Infected female Anopheles mosquito injects sporozoites into the skin while feeding

  2. Sporozoites enter the blood stream and are carried to the liver where they infect liver cells

  3. Within liver cells, the parasites develop into schizonts

  4. Schizonts rupture, releasing thousands of individual merozoites into the bloodstream

  5. Merozoites infect red blood cells

  6. Some parasites change into male and female forms called gametocytes

  7. When the mosquito feeds, gametocytes are ingested into its stomach

  8. The gametocytes emerge from the infected red blood cells, becoming gametes

  9. The male gamete fuses with the female gamete, producing a zygote

  10. The zygotes elongate into ookinetes, which move through the stomach wall

  11. The ookinetes develop into oocysts

  12. The oocysts grow and rupture, releasing sporozoites

  13. The sporozoites migrate to the salivary glands, ready to be injected and renew the cycle
• Exoerythrocytic (hepatic stage or the pre-erythrocytic stage)

  Stage where the parasites localize in the liver and the patient is still asymptomatic
• Erythrocytic form

  Stage where the parasites invade the RBCs and here, the patients develop fever cycle
• Gametocytic form


  Stage where the female mosquito picks up gametocytes from an infected human. The sexual cycle occurs in the mosquito where sporozoites are formed.
• Drugs used to prevent and treat malaria

  • 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
• Common structural feature of antimalarial drugs

  A "quinoline ring" or a quinoline with an additional benzene added - "acridine ring"
• Cinchona alkaloids


  • Quinine
  • Quinidine
  • Quinuclidine ring
  • Cinchonidine
  • Cinchonine
• Quinine


  • Used for "fevers" in South America since 1600s; isolated in 1820 (first antimalarial agent)
  • Effective against all Plasmodium schizonts and gametocytes from P. vivax and P. malariae
  • Still used today, especially for malaria caused by P. falciparum resistant to other agents
  • Mechanism of action: Ferriprotoporphyrin IX (hematin) hypotheses - Plasmodium utilizes hemoglobin as a source of amino acid producing hematin as a byproduct, which is considered toxic in the Plasmodium
• Structure-activity relationship (SAR) of quinine


  • Stereochemical centers at C3, C4, C8, C9 are all important
  • Modification of C9 alcohol will reduce activity
  • Tertiary amine of C8 is essential for activity
• Quinidine


  • Stereoisomer of quinine
  • Limited use to treat severe malarial infection
  • Commonly used as an antiarrhythmic agent rather than an antimalarial
  • Effective as quinine, but more likely to be toxic
• 1. aminoquinolines


  • Closest of the antimalarials that are based on the quinine structure
  • Substituted at the same position as quinine and have a symmetric carbon equivalent to quinine C9 position
  • In general, chloroquine and other 4-aminoquinolines are not effective against exoerythrocytic parasites
• Metabolite


  If hematin is not converted into hemozoin, hematin will be produced in the Plasmodium, causing cell lysis or death of the parasite
• Stereochemical centers


  • At C3, C4, C8, C9 are all important
• Modification of C9 alcohol

  Will reduce activity
• Tertiary amine of C8


  Is essential for activity
• Quinidine


  Stereoisomer of quinine
• Quinidine


  • Limited use to treat severe malarial infection
  • Commonly used as an antiarrhythmic agent rather than an antimalarial
  • Effective as quinine, but more likely to be toxic
• 1. aminoquinolines


  • Closest of the antimalarials that are based on the quinine structure
  • This group is substituted at the same position as quinine and have a symmetric carbon equivalent to quinine C9 position
  • In general, chloroquine and other 4-aminoquinolines are not effective against exoerythrocytic parasites
• Chloroquine


  • Main antimalarial drug used both for prophylaxis and treatment of malaria
  • Indicated for P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum
  • S/E (orally): GI effects, mild headache, visual disturbance and urticaria
  • A/E: retinopathy, hemolysis in patients with G6PD deficiency, muscular weakness, exacerbation of psoriasis and porphyria, and impaired liver function
  • Has substitution on the position 4 as quinine and mechanism of chloroquine is not known, however, it is almost the same with quinine
  • Also indicated for the treatment of extraintestinal amoebiasis
• Chloroquine SAR


  • Chlorine at position C7 improves activity
  • C3 or C8 alkyl groups reduce activity (modification)
  • Hydroxylation of the N-ethyl group does not significantly affect activity
• Hydroxychloroquine


  • Parallels chloroquine
  • Differs in that it has a hydroxyl moiety on the N-ethyl group
  • Remains in the body for over a month
  • Prophylaxis is one a week dosing
• Amodiaquine


  • No longer marketed in the US, but available in Africa
  • Similar to chloroquine; used as prophylaxis
  • Higher incidence of hepatitis and agranulocytosis than chloroquine (chloroquine is safer to use than amodiaquine)
• Mefloquine


  • Newest 4-aminoquinoline
  • Differs in that it has two trifluoromethyl moieties at 2' and 8'
  • Schizonticide
  • S/E: neuropsychiatric which may pose suicidal tendencies and seizures, GI (nausea, vomiting, and diarrhea), dermatologic (rashes, pruritus, and urticaria), cardiovascular (bradycardia, arrhythmia, extrasystoles)
• 1. aminoquinolines


  • The other major group of antimalarial drugs based on the cinchona alkaloid quinoline moiety is the substituted 8-aminoquinolines
  • Substitution at the 8th position
• Pamaquine


  • First compound to be introduced in this series
  • Active against latent tissue forms of P. vivax and P. ovale and active against hepatic stage of P. falciparum
  • DOC: treatment of relapsing vivax and ovale form
  • MOA is unknown
  • Used together with chloroquine to eradicate the erythrocytic stage
  • Only primaquine is in use today after the Korean War since all of the other 8-aminoquinolines were found to cause hemolytic anemia in erythrocytic G6PD deficient patients (common genetic trait found in populations living in areas endemic in malaria, which provides some resistance to the parasite)
• Primaquine


  • Only 8-aminoquinoline currently in use for the treatment of malaria
  • One of the narrowest spectrum of activity since it is used for exoerythrocytic and gametocytic stages of malaria
  • Radical cure for malaria
  • Only drug that kills liver parasite
  • To cure a patient with P. vivax malaria, a radical treatment is needed to target both the blood stage and the liver stage (only primaquine can do this)
• Polycyclic antimalarials


  • There are three antimalarial drugs that have in common polycyclic ring system: tetracycline (doxycycline), halofantrine, and quinacrine (discontinued agent)
• Doxycycline


  • Inhibits protein synthesis
  • Prophylaxis against P. falciparum resistant to chloroquine and sulfadoxine-pyrimethamine
  • S/E: photosensitivity, interfere development of teeth
  • Tetracycline: targets 30s subunit
  • Precaution: should not exceed 4 months taking it
• Halofantrine


  • Trifluoromethyl moiety
  • Schizonticide; no effect on sporozoite, gametocyte or hepatic stages
  • Affect nerve conduction in cardiac tissue
• Lumefantrine


  • MOA is poorly understood
  • Very lipophilic
  • Marketed in combination with artemether
• Quinacrine HCl


  • No longer available in US; most toxic among antimalarial drugs
  • Tumorigenic (capable of causing tumors) and mutagenic (altering DNA, causing damage to the cell)
  • Sclerosing agent (acts by irritation of the venous initial epithelium, specifically those of the varicose veins)
  • An acridine dye which can cause yellow discoloration of skin and urine
  • Once a commonly used drug
• Artemisinin


  • Newest of the antimalarial drugs which are structurally unique
  • Natural product extracted from the leaves of Artemisia annua (sweet wormwood or Qinghaosu)
  • Structure: 7 asymmetric centers (stars), Trioxane ring, Endoperoxide (O-O)
  • SAR: Oxygen group will be converted into alcoholic group, which can be alkylated (methyl or ethyl group)
  • Dihydroartemisinin, artemether, arteether, and the sodium artesunate are all more active than artemisinin, hence, the lactone carbonyl group is not crucial to its antimalarial activity
  • Undergoes esterification which can convert carboxylic acid to an ester group using an alcohol and an acid
• Artemisinin analogues


  • Deoxyartemisinin – one oxygen only, not a peroxide, 300-1000 less fold active
  • Deoxodeoxyartemisinin – one oxygen only, not a peroxide, and the double bond oxygen was removed, poorly active
  • Deoxoartemisinin – double bond oxygen was removed, similar activity to arteether