Antimalarials Flashcards
Chloroquine
- Drug of choice for both treatment & prophylaxis of all P. vivax and P. ovale malaria infections
- Use severely compromised by drug resistance
Clinical Applications
• Drug of choice in the treatment of non-falciparum and sensitive uncomplicated falciparum malaria
• Preferred chemoprophylactic agent in areas without resistant falciparum malaria
MOA
• Concentrates in parasite food vacuoles
• Prevents biocrystallization of hemoglobin breakdown product heme to non-toxic hemozoin
PK
• Oral
• t1/2 = 3-5 days
Resistance
• P. falciparum: mutations in putative transporter, PfCRT are common
Chloroquine PK, resistance, SE, CI
PK
• Oral
• t1/2 = 3-5 days
RESISTANCE
• P. falciparum: mutations in putative transporter, PfCRT are common
SE
• Generally well tolerated (at therapeutic doses)
• Pruritus (common in Africans)
• Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, urticaria (uncommon)
• Hemolysis (G6PD-deficient people)
• Can cause electrocardiographic changes
CI Patients with: • psoriasis or porphyria (may precipitate attacks) • retinal or visual field abnormalities SAFE IN PREGNANCY & YOUNG CHILDREN
Quinine, Quinidine
- First-line therapies for severe falciparum disease • Resistance is uncommon but increasing
- Derived from cinchona tree bark
- Quinidine (stereoisomer of quinine)
Clinical Applications
• Parenteral treatment of severe falciparum malaria (Quinidine)
• Oral treatment of falciparum malaria (alternative in chloroquine-resistant areas) (Quinine)
MOA
• Depresses O2 uptake and carbohydrate metabolism
• Intercalates into DNA, disrupting parasite’s replication and transcription
Quinine, Quinidine PK, resistance, SE, CI
PK
• Quinine: oral treatment of uncomplicated malaria • Quinidine: IV treatment for severe malaria
RESISTANCE
• Likely to be increasing problem
• Already common in some areas of South-east Asia
SE
• Cinchonism: tinnitus, headache, nausea, dizziness, flushing & visual disturbances
• Hypersensitivity: skin rashes, urticaria, angioedema, bronchospasm
• Hematologic abnormalities: hemolysis (G6PD deficiency), leukopenia, agranulocytosis, thrombocytopenia
• Hypoglycemia: stimulation of insulin release
• Uterine contractions: still drug of choice for severe falciparum malaria in pregnancy
• Severe hypotension: too rapid IV infusion
• ECG abnormalities: QT prolongation
• Blackwater fever: hemolysis & hemoglobinuria (likely hypersensitivity reaction)
Discontinue if signs of:
• severe cinchonism
• hemolysis
• hypersensitivity
Avoid if possible in patients with:
• visual or auditory problems
Use with caution in patients with:
• underlying cardiac abnormalities
- Do not use concurrently with mefloquine
- Can raise plasma levels of warfarin & digoxin
- Reduce dose in renal insufficiency
Pregnancy
• FDA Category C (however benefits do often outweigh risks in complicated malaria)
Mefloquine
- Effective against many chloroquine-resistant strains
- Chemically related to quinine
MOA
• Destruction of the asexual blood forms of malarial pathogens. Details unknown.
USES
• Chemoprophylaxis: effective against most strains of P. falciparum
• Currently only medication recommended for chemoprophylaxis in pregnant women in chloroquine-resistant areas
• Treatment : not appropriate for treating severe or complicated malaria
• Mefloquine + artesunate used in treatment of uncomplicated malaria in regions of Southeast Asia
Mefloquine PK, resistance, SE, CI
PK
• Oral only
• Elimination t1/2 = 20 days (weekly prophylactic dosing)
RESISTANCE
• Uncommon but has been reported
• Associated with resistance to quinine but not chloroquine
SE
Weekly dosing:
Nausea, vomiting, dizziness, sleep & behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash
Higher treatment doses:
Leukocytosis, thrombocytopenia, aminotransferase
elevations, arrhythmias, bradycardia
• Serious neuropsychiatric toxicities (depression,
confusion, acute psychosis, or seizures) = < 1 in 1000
CI
• Patients with history of:
Epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects, sensitivity to related drugs
• DO NOT coadminister with quinine, quinidine or halofantrine
• Considered safe in young children & pregnancy
Primaquine
- Drug of choice for eradication of dormant liver forms of P. vivax and P. ovale
- Also used for chemoprophylaxis (all strains)
USES
• Therapy of acute vivax and ovale malaria
• Terminal prophylaxis of vivax and ovale malaria
• Chemoprophylaxis: protection against falciparum & vivax (toxicities are a concern – reserved for when other drugs cannot be used
MOA
• Not completely understood (primaquine metabolites believed to act as oxidants, disrupting mitochondria and binding to DNA)
Primaquine PK, resistance, SE, CI
PK
• Oral
• Metabolites have less antimalarial activity but more potential for inducing hemolysis
RESISTANCE
• Resistant strains may require therapy to be repeated & dose to be increased
SE
• Generally well tolerated
• Infrequent (nausea, epigastric pain, abdominal cramps,
headache)
• Rare (leukopenia, agranulocytosis, leukocytosis, cardiac arrhythmias)
• Hemolysis or methemoglobinemia (especially in G6PD deficient patients)
• Patients should be tested for G6PD deficiency before primaquine is prescribed.
• For severely G6PD deficient patients withhold therapy & treat relapses
CI
• G6PD deficiency
• Pregnancy: fetus is relatively G6PD deficient (FDA category not yet assigned). DO NOT use during pregnancy
Malarone (atovaquone + proguanil)
Clinical Applications
• Treatment & prophylaxis of P. falciparum
Antimalarial Action
• Active against tissue & erythrocytic schizonts
• Chemoprophylaxis can be discontinued 1 week after exposure
MOA
• Disrupts mitochondrial electron transport
PK
• Oral only
SE
• Generally well tolerated
• Abdominal pain, nausea, vomiting, diarrhea, headache, rash
• Safety in pregnancy = Category C
Pyrimethamine, Proguanil, Sulfadoxine
• Inhibitors of folate synthesis
Clinical Applications
• Chemoprophylaxis: only in combination. Proguanil + chloroquine = no longer recommended
• Intermittent Preventive Therapy: high-risk patients receive intermittent therapy regardless of infection status
• Treatment of chloroquine-resistant falciparum malaria : pyrimethamine-sulfadoxine commonly used. DO NOT use for severe malaria
• Pyrimethamine + proguanil
Act slowly against erythrocytic forms of all
malaria species. Inhibit plasmodial dihydrofolate reductase
• Proguanil
Some activity against hepatic forms
• Sulfonamides
Weakly active against erythrocytic schizonts. Inhibit dihydropteroate synthase
Pyrimethamine, Proguanil, Sulfadoxine PK, resistance, SE, CI
PK
• Oral
Resistance
• Relatively common for P. falciparum
SE
• Well tolerated (GI problems, rashes, itching)
• Proguanil (mouth ulcers, alopecia = rare)
• Pyrimethamine-Sulfadoxine (erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis)
• Sulfadoxine (hematologic, GI, CNS, dermatologic & renal toxicity)
Pregnancy
• Proguanil = safe
• Pyrimethamine-sulfadoxine = safe
Doxycycline
- Doxycycline + quinine = treatment of severe falciparum malaria
- Used to complete treatment course after severe malaria is treated with quinine, quinidine or artesunate
SE
• GI, candidal vaginitis, photosensitivity
• Discoloration & hypoplasia of teeth, stunting of
growth
• Fatal hepatotoxicity (in pregnancy)
• DO NOT use in pregnancy or children < 8y (FDA Category D)
Artemisinin
- Artesunate : oral, IV, IM & rectal admin
- Artemether: oral, IM & rectal admin
- Dihydroartemisinin: oral admin
- Coartem = artemether + lumefantrine
- Treatment of severe falciparum malaria (given IV)
- NO effect on hepatic stages
- Should not (in general) be used as single agent to protect against resistance
MOA
• Appears to act by binding iron, breaking down peroxide bridges leading to generation of free radicals that damage parasite proteins.
Artemisinin PK, SE
PK
• Very short t1/2 (IV therapy must be followed by a longer- acting agent once patient is able to tolerate oral therapy)
• If used alone, artesunate must be administered 5-7 days (otherwise recurrent parasitemia results)
SE
• Overall remarkably safe (nausea, vomiting, diarrhea)
• Very high doses: neurotoxicity, QT prolongation
• More evidence for use in 2nd and 3rd trimesters of pregnancy
• In 1st trimester can be used for treatment of severe malaria
Clindamycin, Halofantrine, Lumefantrine
Clindamycin
• Can be used as an alternative to doxycycline
Halofantrine
• Effective against erythrocytic stages of all parasites
• Use is limited by irregular absorption & cardiac toxicity
• Teratogenic
Lumefantrine
• Effective against erythrocytic stages of all parasites
• Available only as fixed-dose combination with artemether
• Causes minor QT prolongation (clinically insignificant)
• Well tolerated
