Antimalarials Flashcards
General tx of uncomplicated malaria?
Oral antimalarias
What is complicated malaria and very general tx?
Is there anything making the pt unstable and this needs to be treated with parenteral antimalarials.
Chloroquine?
DOC - tx and prophylaxis of P. vivax and P. ovale malaria [non-falciparum unless it is sensitive uncomplicated falciparum]. It is the preferred chemoprophylactic agent in areas without resistant falciparum malaria.
Resistance is frequently an issue - P. falciparum mutation in putative transporter (PfCRT) is common.
Effective against drug parasites and not the liver stage.
MOA - concentrates in parasite food vacuoles and prevents biocystallization of Hb breakdown product heme to non-toxic hemozoin [accumulation of heme (toxic) leads to death of RBC and parasite]
Oral administration with a long half-life so need to take it one a week
AE - generally well tolerated but may result in pruritis (esp in africans), Hemolysis (G6PD def people), deadly at high doses as it is a medication commonly used to commit suicide.
Contraindications - pts with psoriasis or porphyria or retinal/visual field abnormalities
**safe in pregnancy and young children
Quinine and Quinidine?
1st line therapy for severe falciparum disease. Resistance is uncommon - but is becoming an increasing problem esp in SE Asia. Derived from cinchona tree bark.
Quinidine (parentally) is a stereoisomer of Quinine (oral).
Medications are rapidly-acting, highly effective against BLOOD parasite. It is NOT effective against LIVER STAGES of parasite.
MOA - depresses O2 uptake and carb metabolism and intercalates into DNA, disrupting parasite’s replication and transcription.
AE - cinchonism, HSN rxn, Hematologic abnormalities, hypoglycemia (stimulates insulin release), uterine contractions, severe hypotension, ECG abnormalities (QT prolongation), Blackwater fever (hemolysis and hemoglobinuria)
Contraindications - discontinue with AE and do not use in pts with cardiac, visual or auditory problems, do not use if pt takes Mefloquine, may raise plasma levels of warfarin and digoxin, reduce dose in renal insufficiency, category C for pregnancy but benefits usually outweigh risk in complicated malaria
Mefloquine?
Effective against many Chloroquine-resistant strains and is chemically related to quinine.
MOA - destruction of asexual blood forms of malarial pathogens [details unknown]
Application…
- chemoprophylaxis - effective against P. falciparum and P. vivax strains
- tx of mild to moderate acute malaria caused by falciparum and vivax
- Mefloquine+artesunate = SE Asia tx of uncomplicated malaria
Oral administration that has a 20 day half-life and is given weekly as a prophylaxis.
Resistance - increasing, but fairly uncommon, associated with resistance to quinine
AE - serious neurological and psychiatric toxicities, weekly dosing (mild GI, behavioral disturbance, rash), higher dose (leukocytosis, thrombocytopenia, aminotransferase elevations, arrhythmias, bradycardia)
Contraindications: pts wtih epilepsy, psych disorders, arrhythmias, DO NOT coadminister with quinine, quinidine or halofantrine
*safe in young children and pregnancy
Primaquine?
DOC - eradication of dormant liver forms of vivax and ovale [can also be used for chemoprophylaxis of all strains]
Clincal application
- therapy of acute vivax and ovale
- terminal prophylaxis of vivax and ovale malaria
- chemoprophylaxis - protection against falciparum and vivax
Animalarial action - ONLY agent that is active against dormant liver forms of vivax and ovale
MOA - not understood but may relate to primaquine metabolites acting as oxidants by disrupting mitochondria and binding to DNA
Oral administration with metabolites having little antimalarial activity but increased hemolysis risk.
Resistance - strains may require therapy to be repeated and dose to be increased
AE - generally well tolerated, hemolysis of methemoglobinemia (esp in G6PD pts)
With hemolysis - Primaquine oxidizes GSH to GSSG decreasing amt of GSH to neutralize toxic compounds.
Contraindications - G6PD def, pregnancy as fetus is relatively G6PD deficient
Malarone?
Malarone = atovaquone + proguanil
Tx and prophylaxis of blood forms of Falciparum.
Action against malaria - active against tissue and erythrocytic schizonts and can be started 1-2 days before travel and discontinued 1 week after exposure
MOA - disrupts mitochondrial electron transport
Oral administration
AE - well tolerated, mild GI effects, do not use in pregnancy
Folate synthesis inhibitors for malaria?
Pyrimethamine, Proguanil, Sulfadoxine
**not used for complicated form of malaria
Clinical application..
- Chemoprophylaxis only in combination, Proguanil+chloroquine no longer recommended
- Intermittent preventive therapy - high risk pts receive intermittent therapy regardless of infection status
- Tx of chloroquine-resistant falciparum malaria - pyrimethamine-sulfadoxine is most commonly used
Antimalarial Action
• Pyrimethamine + proguanil [inhibit plasmodial dihydrofolate reductase]
Act slowly against erythrocytic forms of all
malaria species
• Proguanil
Some activity against hepatic forms Some activity against hepatic forms
• Sulfonamides [inhibit dihydropteroate synthase]
Weakly active against erythrocytic schizonts
Oral administration, resistance common with P. falciparum
AE - well tolerated (GI problems, rashes, itching), proguanil (mouth ulcers and alopecia), Pyrimethamine-sulfadozine *erythema multiforme, steven-johnson syndrome, toxic epidermal necrolysis), Sulfadoxine (hematologic, GI, CNS, dermatologic, renal toxicity)
Pregnancy - proguanil AND pyrimethamine-sulfadoxineare safe
Doxycycline for malaria?
Active against erythrocytic schizonts of all human malaria parasites. It is not active against liver stages. It is used to complete tx for severe falciparum malaria after intial tx with quinine, quinidine or artesunate. Chemoprophylaxis against most forms of malaria need to be taken daily.
AE - GI, candidal vaginitis, photosensitivity, discoloration, hypoplasia of teeth, stunting of growth, fetal hepatotoxicity
**DO NOT use in pregnancy or children under 8 years old
Artemisinin?
Derived from qinghaosu plant
- Artesuate: ora, IV, IM & rectal admin
- Artemether: oral, IM & rectal admin
- Dihydroartemisinin: oral admin
- Coartem = artemether + lumefantrine
Only alternative to tx quinine/quinidine of complicated malaria tx. Only treats blood stage, no tx of liver stage.
MOA - binds iron breaking down peroxide bridges leading to generation of free radicals that damage parasite proteins
Very short half-life, if used alone, artesunate must be administered 5-7days??
AE - relatively safe, nigh dose leads to neurotoxicity and QT prolongation, do not use in 1st trimester of pregnancy unless malaria is severe, it can be used in 2nd and 3rd trimester
Clindamycin for malaria?
May be used as alternative to doxycycline
Halofantrin for malaria?
Effective against erythrocytic stages of ALL parasites. Use is limited by irregular absorption and cardiac toxicity and they are teratogenic.
Lumefantrine for malaria?
Effective against erythrocytic stages of all parasites. Available only as fixed-dose combination with artemether. May cause minor QT prolongation which is clinically insignificant.
