• PLasmodium vivax (most common and widely distributed)- relapsing malaria
• P. falciparum (tropical regions)- medical emergency especially in kids, pregnant women
• P. malariae (limited entirely to subtropical areas)
• P ovale (usually in Africa)
• P knowlesi

Obligate intracellular protazoan parasites transmitted by mosquitoes

Malaria: clincial manifestations

• fever- hallmark of malaria (RBC ruptures, merozoites and pyrogen released)
  • leads to vasodilation
• anemia (RBC destroyed)
  • results from increased phagocytosis of RBC's, capillary hemorrhage, thrombosis, decreased marrow function
  • most anemia asssoc. w/ P. falciparum
• pigmentation of organs- malarial pigment, hemozoin ingested by phagocytes
  • spleen
  • liver
  • bone marrow
  • lymphoid tissue
• hepatomegaly and splenomegaly
  • due to dilation of sinuses and increase number of macrophages
• capillary inclusions- parasitized RBC's involved in immune complexes occulde capillaries
  • cause local hemorrhaging and anoxia
  • most severly effects brain
• intravascular hemolysis in kidney- hemoglobinemia and hemoglobinuria results in dark urine (Blackwater fever)

1. sporozoites- the infective form trnasmitted during blood meal feeding of femal Anopheles mosquito on human
   • invade, reside in hepatocytes where they increase in numbers
2. merozoites- several days after initial infection, progeny in liver enter bloodstream and infect RBC's (ring cell stage)
3. erythrocyte stages
   • merozoites infect RBC's (feed on Hb)
   • parasites attach to RBC receptors and are endocytosed
   • asexual reproduction cause the rupture of RBC and release up to 25

• anemia
• hyperthermia
• diarrhea
• hypoglycemia
• acidosis
• cerebral malaria
• renal failure
• pulmonary edema
• splenomegaly

1. incubation period of two weeks or longer with a brief prodromal period
2. cold stage (shaking chill)
3. fever stage lasts 24 hrs (41-42)
4. wet stage
   • several hrs after fever, body temp drops quickly to normal
   • this leads to profuse sweating beginning
   • patient exhausted by well until next cycle of paroxysms begins

• bening tertian (vivax, ovale)- fever every 3rd day
• bening quartan (malariae)- fever every 4th day
• malignant tertian (falciparum)

• cold stage less pronounced
• fever stage prolonged, intensified, out of synchrony
• fever continous or only briefly remittent
• no wet stage
• DANGEROUS- comlications of capillary blockage
• dark colored urine

• quinine sulfate
• mefloquine
• Atovaquone-Proguanil

• kills all different malarial merozoites
• kills most gametocytes
• does NOT kill P falciparum gametocytes
• does NOT kill dormant sporozoites of vivax or ovale

• mechanism- w/chloroquine eliminate sporozoites in liver and falciparum gametocytes; for "radical cure"
• adverse effects- anemia (CI: G6PDH deficiency)

• "quines"
• artemether
• Pyr/Sulfa
• Doxycyclin
• Clindamycin

1. accumulates in acidic food vacuole of parasite
2. binds to heme and forms a heme-chloroquine complex
3. inhibits the heme polymerase, thereby disrupting concersion to hemmazoin polymer
4. complex will incorperate into hemazoin polyer to terminate chain extension, blocking further incorperation of toxic heme
5. eventually will cause inhibition of parasite protease activity and digestion of hemoglobin
6. Net result of block in parasite replication

• impaired drug concentration mechanism via mutation of P glycoprotein
• increased drug efflux via mut. of PfCRT

• unknown, but may be highly redox active (explains toxicity in G6PDH deficiency)

• atovoquuone- selective inh. of parasite mit. electron transport
• proguanil- metabolized to cycloguanil, which acts as dihydrofolate reductase inhibitor, which stops deoxythymidylate synthesis

• aremether- met. to DHA (active metabolite), containing a endoperoxide moiety which with iron will produce reactive oxygen species
• lumefantrine- not well defined, but we believe it inhibits beta hematoin by forming a complex with hemin

• only effective agains erythrocytic forms
  • acute attacks of P vivax
  • chloroquine resistant and multidrug resistant strains of P falciparum and chloroquine resistant strains of P vivax

• well absorbed after oral administration
  • if attacks severe, IV infusion until patient well enough for oral therapy
• extensively metabolized
• excreted primarily in urine
• plasma life: 12 hrs

IV quinidine may be used in place of IV quinine

• cinchonism
  • tinnitus
  • headache
  • nausea
  • abdominal pain
  • visual disturbances
• occasional
  • hemolytic anemia
  • photosensitivity reactions
  • hypoglycemia
  • arrhythmias
  • hypotension
• CI: IV use requires cardiac monitoring due to widening of QT interval

• erythrocytic forms
  • P. falciparum or vivax acute attacks

Increasing resistance requires it being replaced with quinidine more often.

• well absorbed after oral administration
• for parenteral administration, give intramuscular injection
• accumulates in tissue greatly esp:
  • liver
  • spleen
  • kidney
  • lungs
  • leukocytes
• met. in liver
• excreted in urine (metabolites and unchanged drug)

OCCASIONAL

• pruritis
• confusion
• depigmentation of hair
• skin eruptions
• corneal opacity
• weight loss
• partial alopecia
• extraocular muscle palsies
• exacerbate dermatoses
• myalgias

• only against erythrocytic forms
  • useful tx, px of multidrug resistant P. falciparum and P vivax

• well absorbed after oral administration
• persists in tissues
• elimination half life is 2-4 weeks
• excreted in feces
• once per week dosing

• frequent
  • CNS effects
    • vertigo
    • lightheadedness
    • nightmares
    • visual disturbances
    • headache
  • GI disturbances
• occasional- confusion, can prolong cardiac conduction

CI

• pregnancy
• h/o depression, anxiety, psychosis, schizo
• drugs that prolong or alter cardiac conduction
  • quinine/quinidine
  • beta blockers
  • calcium channel blockers

• for eradication of persisting exoerythrocyte liver forms of P. vivax
• used in combo with chloroquine to result in radical cure and thereby prevent relapse

• well absorbed from GI tract after oral admin.
• extensively met.
• excreted primarily in urine
• half life of 3-6 hrs

• frequently
  • hemolytic anemia in G6PDH deficiency
• occasional
  • neutropenia
  • GI disturbance
  • methemoglobinemia in G6PDH deficiency

• acute attacks of chloroquine resistant P. flaciparum when given as Pyr/Sulfa+quinine
• also useful against chloroquine resistant P. vivax
• suppressive px as PYR/SULFA + Chloroquine + Primaquine with risk of chloroquine resistance

• slow but complete absorption in GI
• excreted as parent compound and metabolites mainly in urine

• occasional
  • blood dyscrasias
  • folic acid deficiency

• blood dyscrasias
• folic acid deficiency
• stomach pain
• nausea
• insomnia
• mouth sores

• generally well tolerated
• insomnia
• joint and muscle stiffness

• mosquito control, insecticide treating mosquito netting
• chloroquine px in chloroquine sensitive endemic areas
• primaquine good when leaving endemic areas
• vaccines against P vivax and P falciparum being developed

• P faliciparum: chloroquine or hydroxychloroquine
• P vivax or ovale: chloroquine + primaquine

• P vivax: 3 options
  • quinine + doxycycline + primaquine
  • atovoquone-proguanil + primaquine
  • mefloquine + primaquine
• P falciparum (4 options)
  • Atovoquone-proguanil
  • artemether-lumfantrine
  • quinine + doxycycline + clindamycin
  • mefloquine

1. ingestion of feces contaminated water or food
2. form trophozoites
3. penetrate intestinal wall
4. multiplication within colon wall
5. systemic invasion
6. cysts discarded w/feces

• direct chemotherapy of invasive amebic
• tx of luminal amoeba
• general antibiotics to decrease intestinal flora (optional)

• metronidazole- drug of choice for active infections esp. if advanced to liver abscess
  • reduced to electrophilic intermediate via metabolism
  • binds to critical macromolecules (DNA, RNA, proteins) and causes cell death
• diloxanide furoate
  • hydrolyzed and activated in intestinal mucosa
  • 90% absorbed, but is ACTIVE UNABSORBED
  • mechanism of killing unknonw

• adverse effects
  • flatulence
  • itchiness
  • dry mouth
• alternative anti amebics
  • systemic: emetine
  • luminal: paromomycin

• rapidly and completely absorbed
• metabolized by P450
• accumulates in patients with hepatic disease
  • CAUTION: hepatic disease

• reddish brown urine
• yeast infections of mouth
• metalic tast
• disulfiram like rxn with alcohol

• first line- SULFA/TMP
• pentamiiidine
• atovaquone

• mechaniism- unknown, but probably interferes with syn. of DNA, RNA, phospholipids
• PK- administered in aerosol, IM
  • very long half life
  • poor CNS penetration
• adverse effects
  • renal dysfunction
  • possibly toxic to pancreatic beta cells

• blood smears: thick and thin (Wright or Giemsa)
• malaria specific Ab
• serological tests- agar diffusion, passive hemagglutination, immunofluorescence, ELISA
• detect carriers of P. vivax and malariae in blood used for transfusion