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41 Cards in this Set
- Front
- Back
Parasite Life Cycle - P. Falciparum and P. malariae
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- one cycle of liver cell invasion
- liver infections ceases in less than 4 wks - only erythrocytic parasites have to be eliminated |
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Parasite Life Cycle - P. vivax and P. ovale
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- have dormant hepatic stage
- erythrocytic AND hepatic parasites have to be eliminated |
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P. falciparum - sx and signs
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- most severe disease (microvascular effects) and can be fatal if untreated
- cerebral malaria (irritability --> seizures --> coma) |
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Major Antimalarial Drugs
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Chloroquine
Quinine and Quinidine Mefloquine Primaquine Atovaquone Sulfadoxine-pyrimethamine Doxycycline Artemisinins |
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Chloroquine
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DOC for BOTH TX AND PROPHYLAXIS OF MALARIA
- use is severely compromised by drug resistance - antimalarial action = highly effective blood schizonticide; NOT active against liver stage parasites |
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Chloroquine - MOA / PK
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- concentrates in parasite food vacuoles
- prevents biocrystallization of Hb breakdown product heme --> non-toxic hemozoin PK: oral; excreted in urine |
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Chloroquine - Resistance/Clinical app/ AE
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Resistance: P. falciparum - mutations in putative transporter, PfCRT
Clinical app: DOC in tx of NON-FALCIPARUM and SENSITIVE FALCIPARUM MALARIA; Preferred chemoprophylactic in areas w/o resistant falciparum |
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Chloroquine - AE / CI
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AE: pruritus (Africans), Hemolysis in G6PD def people, can cause electrocardioographic changes
CI: pts w/ PSORIASIS or PORPHYRIA; RETINAL or VISUAL FIELD ABNORMALITIES SAFE IN PREGNANCY AND YOUNG CHILDREN |
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Quinine and Quinidine
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- FIRST-LINE THERAPIES FOR SEVERE FALCIPARUM DISEASE
- resistance uncommon but inc - derived from cinchona tree bark - quinidine is a stereoisomer of quinine - Antimalarial action: rapidly-acting, highly effective blood schizonticide |
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Quinine and Quinidine - MOA / PK
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MOA - not fully resolved (maybe similar to chloroquine - acc of toxic free heme)
PK - quinine: rapidly abs orally and well dist; IV admin for severe infections |
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Quinine and Quinidine - Resistance and Clinical Applications
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Resistance: inc problem; already common in some areas of SE Asia
Clinical App: - PARENTERAL tx of SEVERE FALCIPARUM MALARIA - ORAL tx of FALCIPARUM MALARIA (alt in chloroquine-resistant areas) |
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Quinine and Quinidine - AE
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- Cinchonism - tinnitus, headache, nausea, dizziness, flushing, visual dist
- HS - skin rashes, urticaria, angioedema, bronchospasm - Hematologic abnormalities - hemolysis (G6PD def), leukopenia, agranulocytosis, thrombocytopenia - Hypoglycemia - stimulation of insulin release - Uterine contractions - but still DOC for severe falciparum malaria in pregnancy - Severe Hypotension - too rapid IV infusion - ECG abnormalities - QT prolongation - Blackwater fever - hemolysis and hemoglobinuria (likely HS rxn) |
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Quinine and Quinidine - CI
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- Discontinue if signs of severe cinchonism, hemolysis, HS
- Avoid if possible in pts w/ visual or auditory problems - Use w/ caution in pts w/ underlying cardiac abnormalities - DONT use w/ mefloquine - can raise plasma levels of warfarin and digoxin - reduce dose in renal insuff. |
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Mefloquine
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- Effective against many CHLOROQUINE-RESISTANT strains
- Chemically related to quinine - MOA unknown - PK: oral only; highly protein bound, ext dist, and eliminated slowly --> single dose tx |
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Mefloquine - Resistance / Clinical App
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Resistance - uncommon; assoc w/ resistance quinine but not chloroquine
Clinical App - Chemoprophylaxis - against most strains of P falciparum - Treatment - NOT appropriate for tx severe or complicated malaria - Mefloquine + artesunate = uncomplicated malaria in regions of SE Asia |
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Mefloquine - AE
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Weekly dosing - nausea, vomiting, dizziness, sleep, behav dist, epigastric pain, diarrhea, abd pain, headache, rash
Higher treatment doses - Leukocytosis, thrombocytopenia, aminostransferase elevations, arrhythmias, bradycardia SERIOUS NEUROPSYCHIATRIC TOXICITIES (depression, confusion, acute psychosis, or seizures) in <1/1000 |
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Mefloquine - CI
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- pts w/ history of epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects, sensitivity to related drugs
DO NOT COADMIN QUININE, QUINIDINE, or HALOFANTRINE safe in young children and pregnancy |
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Primaquine
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DOC for ERADICATION OF DORMANT LIVER FORMS OF P. VIVAX and P. OVALE
ALSO CHEMOPROPHYLAXIS (ALL STRAINS) antimalarial action - only agent against dormant liver forms of p vivax and p ovale |
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Primaquine - MOA / PK
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MOA: not sure; metabolites act as oxidants possibly
PK - oral; rapidly met and excreted in urine; metabolites = less antimalarial activity but more potential for inducing hemolysis |
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Primaquine - Resistance / Clinical App
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Resistance - exists; may require therapy to be repeated or dose increased
Clinical app: - THERAPY OF ACUTE VIVAX AND OVALE MALARIA - terminal prophylaxis of vivaz and ovale malaria - Chemoprophylaxis - protection against falciparum and vivax (when other drugs cant be used) |
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Primaquine - AE / CI
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AE - well tolerated
- infrequent (nausea, epigastric pain, abd cramps, headache) - rare (leukopenia, agranulocytosis, leukocytosis, cardiac arrhythmias) - hemolysis or methemoglobinemia (esp G6PD def) - CI - G6PD DEFICIENCY, PREGNANCY |
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Primaquine and G6PD Def
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- should test for def before giving primaquine
- severely G6PD def pts = w/hold therapy and treat relapses |
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Atovaquone
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Malarone = atovaquone + proguanil
Antimalarial action - active against tissue and erythrocytic schizonts - Chemoprophylaxis can be discontinued 1 wk after exposure MOA - disrupts mitochondrial electron transport chain |
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Atovaquone - PK / Clinical App / AE
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PK: oral (inc w/ fatty food)
Clinical App: Malarone = tx and prophylaxis of P. falciparum AE: well tolerated Safety in pregnancy = Category C |
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Inhibitors of Folate Synthesis
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- used in combination regimens
- Include Pyrimethamine, Proguanil, Sulfadoxine - Antimalarial action ~ Pyrimethanine + proguanil = act slowly against erythrocytic forms of all malaria species ~ Proguanil = SOME activity against hepatic forms ~ Sulfonamides = weakly active against erythrocytic schizonts |
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Inhibitors of Folate Synthesis - MOA / PK
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Pyrimethamine and proguanil = inhibit plamodial dihydrofolate reductase
Sulfonamides = inhibit dihydropterate synthases PK = oral; pyrimethamine has longest half-life (3-5 days) |
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Inhibitors of Folate Synthesis - Resistance / Clinical App
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Resistance: relatively common for P falciparum
Clinical App: - Chemoprophylaxis - only in combination; Proguanil + chloroquine = no longer rec. - Intermittent Preventive Therapy - high risk pts receive intermittent therapy regardless of infection status - Tx of Chloroquine-resistant falciparum malaria - pyrimethamine-sulfadoxine commonly used (DO NOT USE FOR SEVERE MALARIA) |
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Inhibitors of Folate Synthesis - AE
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- well tolerated
- proguanil - mouth ulcers, alopecia - pyrimethanine-sulfadoxine - erythema multiforme, Steven Johnson syn, toxic epidermal necrolysis - sulfadoxine - hematologic, GI, CNS, derm and renal toxicity - Pregnancy: PROGUANIL = SAFE PYRIMETHANINE-SULFADOXINE = SAFE |
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Doxycycline / Tetracyclines
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- Active against ERYTHROCYTIC SCHIZONTS OF ALL HUMAN MALARIA PARASITES
- NOT active against liver stage Clinical app: Doxy + quinine = tx of falciparum malaria used to complete tx course after severe malaria tx w/ quinine, quinidinee, or artesunate |
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Doxycycline / Tetracylcine - AE
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GI, candidal vaginitis, photosensitivity, discoloration, hypoplasia of teeth, stunting of growth, fatal hepatotoxicity (in pregnancy)
DO NOT USE IN PREGNANCY OR CHILDREN LESS THAN 8 |
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Artemisinin
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- Derived from Qinghaosu plant
- Artesunate - oral, IV, IM, and rectal - Artemether - oral, IM, and rectal - Dihydroartemisinin - oral MOA - prod of free radicals w/in plasmodium food vacuole, following iron-catalyzed cleavage of drugs endoperoxide bridge by heme iron; or inhibition of parasitic calcium ATPase |
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Artemisinin - Clinical App / AE
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Clinical App: tx of severe, MDR falciparum malaria
- NO effect on hepatic stages AE: safe; very high doses - neurotoxicity, QT prolongation Can be used in trimesters 2 and 3 of pregnancy |
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Other Antimalarials
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Clindamycin
- can be used as alt to doxycycline Halofantrine - against erythrocytic stages of all parasites - use limited by irregular abs and cardiac toxicity - TERATOGENIC Lumefantrine - against erythrocytic stages of all parasites - avail only as fixed-dose comb w/ artemether - causes minor QT prolong |
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CDC Malarial Guidelines
- Uncomplicated Malaria / P. Falciparum - Chloroquine Resistant or unknown |
- Atovaquone-proguanil
- Artemether-lumefantrine - Quinine + doxycycline - Mefloquine |
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CDC Malarial Guidelines
- Uncomplicated Malaria / P. Falciparum - Chloroquine Sensitive |
- Chloroquine / hydrochloroquine
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CDC Malarial Guidelines
- Uncomplicated Malaria / P. malariae |
- Chloroquine / hydrochloroquine
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CDC Malarial Guidelines
- Uncomplicated Malaria / P. vivax or P. ovale |
- Chloroquine + Primaquine
- Hydroxychloroquine + Primaquine |
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CDC Malarial Guidelines
- Uncomplicated Malaria / P. vivax - Chloroquine Resistant |
- Quinine + doxycycline + primaquine
- Atovaquone-proguanil + primaquine - Mefloquine + primaquine |
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CDC Malarial Guidelines PREGNANCY
- Uncomplicated Malaria |
Chloroquine sensitive: Chloroquine/hydrochloroquine
Chloroquine resistant P. falciparum - Quinine + clindamycin Chloroquine resistant P. vivax - Quinine |
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CDC Malarial Guidelines
- Severe Malaria |
- Quinidine + doxycycline or clindamycin
- investigational new drug: Artesunate + atovaquone-proguanil; Doxycycline, or mefloquine |
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Malaria Chemoprophylaxis
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Chloroquine-sensitive: Chloroquine
Chloqoruine-resistant: Mefloquine |