Antimalarials Flashcards
Five human malaria parasites
Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae Plasmodium knowlesi
Which malaria parasite is responsible for the most malaria deaths?
Plasmodium falciparum
Which malaria parasites cause relapsing malaria?
Plasmodium vivax
Plasmodium ovale
Which malaria parasite has a 24 h life cycle?
Plasmodium knowlesi
Which malaria parasite is predominant in the tropics
Plasmodium falciparum
Which malaria parasite is common in subtropics and temperate regions?
Plasmodium vivax
Which malaria parasite is found in West Africa?
Plasmodium ovale
Which malaria parasites have 48 h life cycles in the blood?
P. falciparum
P. vivax
P. ovale
Which malaria parasite has a 72 h life cycle in the blood?
P. malariae
Which malaria parasite do you always treat with Primaquine because of hypnozoites in the liver?
P. vivax and P. ovale
What’s the name of the mosquito that does malaria?
anopheles mosquito
Classic symptoms of uncomplicated malaria?
cold stage, hot stage, sweating stage, fever and flu-like symptoms (chills, headache, myalgias, and malaise)
anemia and jaundice
Symptoms of severe malaria?
serious organ failure, including kidney cerebral malaria severe anemia and hemoglobinuria acute respiratory distress syndrome placental malaria
Describe cerebral malaria
abnormal behavior, impairment of consciousness, seizures, coma or other neurologic abnormalitites
Describe placental malaria
Happens especially during first pregnancy
Causes low birth weight and miscarriage
Tissue schizonticides
kills liver stage parasites
Blood schizonticides
kills erythrocytic forms
Gametocytocides
Kills sexual stages
Blocks transmission
Factors to consider with malaria chemoprophylaxis
species present
level and type of drug resistance
lead time before travel
Malarone
Atovaquone + Proguanil
All areas
Start 1-2 d prior and continue 7 d after
daily admin + short pretreatment
Doxycycline
All areas
Start 1-2 d prior and continue 4 weeks
Chloroquine
Aralen and generic
Chloroquine sensitive areas (Central/South America)
start 1-2 wk prior and continue 4 wk after leave area
Mefloquine
Lariam and generic
Mefloquine sensitive areas
start >2 wk early and continue 4 wks
toxicity issues
Primaquine
if >90 P. vivax in area
start 1-2 d prior and continue 7 d after
Considerations for malaria treatment
type (species) of the infecting parasite
area where the infection was acquired and its drug-resistance status
clinical status of the patient
Treatment of uncomplicated malaria infection with P. vivax or P. ovale (hypnozoites in liver) in a CQ sensitive area?
- Chloroquine [Aralen and generic] or
2. Hydroxychloroquine sulfate [Plaquenil] + primaquine (14d)
Treatment of uncomplicated malaria infection with P vivax or P ovale in a CQ resistant area?
- Quinine sulfate + Doxycycline/Tetracycline + Primaquine OR
- Atovaquone + Proguanil [Malarone] + Primaquine OR
- Mefloquine [Lariam and generic] + Primaquine
Treatment of uncomplicated malaria with P. malariae or P. knowlesi?
- Chloroquine [Aralen and generic] OR
2. Hydroxychloroquine sulfate [Plaquenil]
In general, what do you use in chloroquine sensitive areas for uncomplicated/unidentified species?
Chloroquine [Aralen] and Hydroxychloroquine sulfate [Plaquenil]
In general, what do you use in chloroquine resistant areas for an uncomplicated/unidentified malaria infection?
- Malarone [Atovaquone + Proguanil]
- Coartem [Artemether + lumefantrine]
- Quinine sulfate + Doxycycline/Tetracycline/Clindamycin
- Lariam [Mefloquine]
Complicated (severe) malaria
impaired consciousness/coma, severe monocytic anemia, renal failure, pulmonary edema
Treatment for complicated (severe) malaria?
Quinindine glyconate (IV) + doxycycline/tetracycline/clindamycin
What should you monitor in severe/complicated malaria?
blood pressure (hypotension) cardiac function (widening of QRS complex and/or lengthening of the QTc interval) blood glucose (hypoglycemia)
Treatment of complicated/severe malaria if quinidine gluconate not available or not tolerated?
Artesunate followed by malarone, doxycycline/clindamycine, or mefloquine
Artemisinin
Sesquiterpene lactone endoperoxide
endoperoxide is the active group
Mechanism of action for artemisinin?
must be activated likely via heme-iron
activated artemisinin may form free radicals (target parasite proteins and lipids)
Mechanism of resistance for artemisinin?
mutations in Kelch 13 gene
delays progress through the life cycle and may alter stress response
Why is artemisinin not appropriate for chemoprophylaxsis?
It has a short half-life (1-2 h) and recrudescence rate is high after short course of treatment
Where in the body does artemisinin act?
rapidly acting blood schizonticide (no effect on liver stages)
What is artemisinin commonly paired with?
Mefloquine or lumefantrine
Semisynthetic artemisinins that have an oral route of administration?
dihydroartemisinin
artesunate
artemether
Semisynthetic artemisinins that have an intramuscular route of administration?
artesunate
artemether
Semisynthetic artemisinin that has an intravenous route of administration?
artesunate (available in US via CDC for treatment of severe malaria)
Semisynthetic artemisinin that has a rectal route of administration?
artesunate
What kind of drugs are artemisinin derivatives paired with?
paired with longer half-life drugs
Common artemisinin combination therapies?
Lumefantrine [Coartem]
amodiaquine
mefloquine
Piperaquine
Artemisinin adverse effects
well tolerated
nausea, vomiting, diarrhea, and dizziness
embryotoxic in animal studies (not recommended in 1st trimester for uncomplicated malaria)
4-aminoquinolines
Quinine
Chloroquine [Aralen]
Mefloquine [Lariam]
What does chloroquine do to hemoglobin metabolism?
chloroquine accumulates in food vacuoles and inhibits heme polymerization
How do 4-substituted quinolines work?
interfere with heme polymerization
Initial and terminal half lives of chloroquine?
Initial half-life: 3 - 5 days
Terminal half-life: 1 - 2 months
Contraindications for chloroquine
psoriasis or porphyria
retina or visual field abnormalities
potential for hemolysis in G6PD deficient patients
Which drugs can interfere with the absorption of chloroquine?
Kaolin (antidiarrheal agent) and antacids
Adverse effects of Chloroquine?
usually well tolerated
pruritus is common, especially in people of African descent
G6PD deficiency patients
Primary mechanism of chloroquine resistance?
mutations in PfCRT1
localized to food vacuole
causes reduced accumulation of chloroquine
over-expression of PfMDR1 (drug transporter)
What kind of drug is quinine?
Blood schizonticide
When is quinine the treatment of choice?
- Chloroquine-resistant falciparum malaria (quinine sulfate - oral)
- Severe falciparum malaria (quinidine gluconate - IV)
Why is quinine inappropriate for chemoprophylaxsis?
short half-life and toxicity
Adverse effects of quinine?
- cinchonism: tinnitis, headache, nausea, dizziness, flushing and visual disturbances
- can stimulate uterine contractions
- hemolysis (G6PD deficiency)
- blackwater fever - severe, rare, marked by hemoglobinuria
What can occur from too-rapid infusion of quinine?
severe hypotension
What is Mefloquine [Lariam] effective against?
erythrocytic forms of P. falciparum and P. vivax
Adverse effects of Mefloquine [Lariam]
Neuropsychiatric toxicity: seizures, toxic psychosis, sleep disturbance
Name the other chloroquine-related compounds
Lumefantrine
Piperaquine
Amodiaquine
Halofantrine
What is primaquine metabolized by?
CYP2D6
metabolism required for activity and may involve free radicals
What is the drug of choice for liver stages of P. vivax and P. ovale (in combination with chloroquine)?
Primaquine
Which antimalarial drug is gametocidal aginst all four malaria parasites?
Primaquine
Contraindications for primaquine?
G6PD deficiency (hemolytic anemia)
pregnancy
breast feeding
What stages does malarone kill?
kills liver and blood stages (but NOT hypnozoites)
Which two drugs is malarone made of?
proguanil and atavaquone
What is atavaquone also used to treat?
Toxoplasma gondii and Pneumocystis jiroveci
What is atavaquone a selective inhibitor of?
selective inhibitor of malaria mitochondrial cytochrome bc1 complex (inhibits electron transport, mitochondrial membrane potential collapses)
What is the main role for mitochondrial electron transport in P. falciparum?
regenerate ubiquinone
What is atavaquone an analog of?
ubiquinone analog
electron acceptor for parasite dihydroorotate deydrogenase - essential for pyrimidine biosynthesis in the parasite
What is proguanil converted to?
cycloguanil
What is proguanil a selective inhibitor of?
selective inhibitor of the bifunctional plasmodial dihydrofolate reductase-thymidylate synthetase (crucial for parasite purine and pyrimidine synthesis)
What does proguanil do when paired with atavaquone?
enhances mitochondrial toxicity of atavaquone
What does Pyrimethamine-Sulfadoxine [Fansidar] inhibit?
folate synthesis inhibitor
slow acting erythrocytic schizonticide
What does Pyrimethamine specifically inhibit?
inhibits plasmodia DHF-reductase (1000-fold selectivity for Plasmodium)
First-line therapy for toxoplasmosis?
pyrimethamine + sulfadiazine (can be replaced with clindamycin)
First-line therapy for pneumocystis?
trimethoprim + sulfamethoxazole
What type of antimalarial drugs are tetracycline/doxycycline/clindamycin?
blood schizonticides
What do antibiotics as antimalarial drugs target?
target components of the apicoplast (plant-like organelle that carries out many biochemical processes)
What is doxycycline commonly paired with?
Commonly paired with quinine or quinidine for treatment of falciparum malaria
