2: Antiparasitics - Antimalarials Flashcards
which malaria is responsible for the most deaths?
plasmodium falciparum
which malaria is mostly in the tropics? what about the subtropics and temperate regions? west africa?
tropics: falciparum
subtropics/temp: vivax
west africa: ovale
which malarias can be relapsing? why?
vivax and ovale - hypnozoites in the liver
what are the 5 malaria parasites that cause disease in humans?
- falciparum
- vivax
- ovale
- malariae
- knowlesi
why is vivax generally less severe?
it is limited ti reticulocytes, whereas falciparum is not
what is important about the lifecycle of knowlesi?
24h life cycle - can increase in numbers very rapidly -> need treatment right away
-usually associated with zoonotic infections
describe the life cycle times for each malaria parasite?
liver stage ~7d
- falciparum, vivax, ovale: 48h cycles in blood
- malariae: 72h cycles in blood
- knowlesi: 24h cycles in blood
why is it a problem if a pregnant woman gets malaria?
malaria has receptors that bind chondroitin sulfate, which is prevalent in the placenta -> causes low birth weight and miscarriage
what are the classic symptoms of uncomplicated malaria?
- cold stage
- hot stage
- sweating stage
what are the more usual symptoms of uncomplicated malaria?
- fever and flu-like symptoms: chills, headache, myalgias, malaise
- anemia and jaundice
what are the symptoms of severe malaria?
- serious organ failures, including kidney
- cerebral malaria (abnormal behavior, impairment of consciousness, seizures, coma, etc.)
- severe anemia and hemoglobinuria due to hemolysis
- ARDS/ pulmonary edema
- placental malaria (especially during 1st pregnancy)
what are the types of drugs used for malaria?
- tissue schizonticides (kill liver stage)
- blood schizonticides (kill erythrocytic forms)
- gametocytocides (kill sexual stage, block transmission)
what is the only drug to kill malaria hypnozoites?
primaquine
what stage do all drugs work on?
asexual blood stages
when should you take malaria chemoprophylaxis?
before, during, and after travel
list 5 malaria chemoprophylaxis drugs
- atovaquone + proguanil (malarone)
- doxycycline
- chloroquine
- mefloquine
- primaquine
malarone:
1. what is it a combination of?
2. where is it useful?
3. when do you start/stop taking it?
4. how it is taken?
- atovaquone + proguanil
- all areas
- start 1-2d prior, end 7d after
- daily admin + short pretreatment
doxycycline:
1. where is it useful?
2. when do you start/stop taking it?
- all areas
2. start 1-2d prior, end 4w after
chloroquine:
1. other names
2. where is it useful?
3. when do you start/stop taking it?
- Aralen and generic
- chloroquine sensitive areas (mostly C and parts of S Am)
- start 1-2w prior, end 4w after
mefloquine:
1. other names
2. where is it useful?
3. when do you start/stop taking it?
- Lariam and generic
- mefloquine sensitive areas
- start >2w prior, end 4w after
primaquine:
1. where is it useful?
2. when do you start/stop taking it?
- if >90 vivax in area
2. start 1-2d prior, end 7d after
why do you start mefloquine so much earlier than the other malaria chemoprophylaxis drugs?
to determine if it gives you AE (it is associated with some toxicity), so then you can switch in time if need be
treatment for uncomplicated malaria or unidentified species in chloroquine sensitive areas?
chloroquine (aralen) and hydroxychloroquine sulfate (plaquenil)
add primaquine if find out ovale/vivax
treatment options for uncomplicated malaria or unidentified species in chloroquine resistant areas
- malarone (atovaquone + proguanil)
- coartem (artemether + lumefantrine)
- quinine sulfate + one of the following: doxy, tetra, clinda
- mefloquine (lariam)
add primaquine if find out ovale/vivax
treatment for complicated (severe) malaria: drug + what do you monitor?
- IV quinidine gluconate + doxy, tetra, or clinda
- consult cardiologist or experiences physician
- monitor BP (hypotension), cardiac fxn (widening of QRS or long QT), serum glucose (hypoglycemia)
- severe cardiac complications may warrant temporarily discontinuing treatment or decreasing infusion rate
what is an alternate treatment for complicated malaria if quinidine gluconate is not tolerated or not available?
artesunate - IV only
-followed by one of the following: malarone, doxy (clinda in preggers), or mefloquine
what is the first line treatment in most of the world except for the U.S.?
artemisinin
what type of chemical is artemisinin?
blood schizonticide
-sesquiterpene lactone endoperoxide (endoperoxide is active group)
artemisinin: mechanism of action
must be activated likely via heme-irione, and activated form may form free radicals that target parasite proteins/lipids
- potent and fast-acting (10,000-fold reduction in 48h)
- low toxicity
no effect on liver stages
artemisinin: mechanism of resistance
- mutations in Kelch 13 gene
- delays progress through life cycle
- may alter stress response
why is artemisinin not appropriate for chemoprophylaxis?
short half life - recrudescence rate is high after short course of treatment
what other drugs is artemisinin commonly paired with?
mefloquine or lumefantrine
how must artemisinin be administered and why?
orally b/c insoluble - low bioavailability
which semisynthetic artemisinins are administered by the following routes: oral, IM, IV, rectal?
oral: dihydroartemisinin, artesunate, artemether
IM: artesunate, artemether
IV: artesunate
rectal: artesunate
is artemisinin more effective in one large dose or slowly administered over time?
associated with Cmax - more effective if given in a large bolus than if given at a lower concentration steadily over time
what is the purpose of combining artemisinin with other therapies?
- artemisinin provides rapid knockdown
- others with longer half-lives eliminate remaining parasites
what are some common combination therapies with artemisinin?
- most common = coartem (artemisinin + lumefantrine)
- amodiaquine
- mefloquine
- piperaquine
artemisinin AE
- generally well tolerated
- nausea
- vomit
- diarrhea
- dizziness
- not recommended in first trimester for uncomplicated malaria
describe hemoglobin metabolism by malaria parasites
parasites ingest host Hb -> degrade it to free a.a. + free heme in food vacuole -> free heme is toxic, so parasite polymerizes heme into hemozin, which is nontoxic
how does chloroquine (aka 4-substituted quinolines) mess up Hb metabolism by malaria parasites?
chloroquine accumulates in food vacuoles and inhibits heme polymerization, keeping it in free form, which is toxic to the parasite
*resistance associated with lack of accumulation in food vacuole
describe the pharmacokinetics of chloroquine
- well absorbed
- very large Vd - slowly released from tissues
- initial half-life = 3-5d
- terminal half-life = 1-2mo
is chloroquine more effective as one large dose or administered steadily over time?
slow release over time
chloroquine AE
- usually very well tolerated
- pruritus, especially in Africans
- potential for hemolysis in G6PD deficient patients
- contraindicated for psoriasis/porphyria, retina or visual abnormalities, myopathy
- don’t give with antidiarrheal agent kaolin or antacids (interfere with absorption)
primary mechanism of chloroquine resistance
mutations in PfCRT1
- localized to food vacuole
- causes reduced accumulation of chloroquine
- no cross-resistance w/ mefloquine or quinine
other mechanism of chloroquine resistance
-over-expression of PfMDR1 (drug transporter)
what drink contains quinine?
gin and tonic (tonic water)
what kind of drug is quinine?
- blood schizonticide
- think mechanism is similar to chloroquine
- resistance rare but increasing
what is quinine the treatment of choice for?
- chloroquine-resistance falciparum (quinine sulfate p.o.)
- severe falciparum (quinidine gluconate i.v. w/ cardiac monitoring)
why is quinine inappropriate for chemoprophylaxis?
- shorter half-life
- toxicity
quinine AE
- cinchonism
- can stimulate uterine contractions
- hemolysis in G6PD deficiency -> blackwater fever (hemoglobinuria)
- can raise levels of warfarin and digoxin since metabolized by CYP3A4
- severe hypotension if infused too rapidly
what is cinchonism?
- tinnitus
- headache
- nausea
- dizziness
- flushing
- visual disturbances
mefloquine: prophylaxis or treatment?
both - effective against against falciparum and vivax
-resistance increasing
mefloquine AE
neuropsychiatric toxicity:
- seizures
- toxic psychosis
- sleep disturbance
list 4 other chloroquine-related compounds
- lumefantrine
- piperaquine
- amodiaquine
- halofantrine
what is the structure of primaquine? type of antimalarial?
8-aminoquinoline - gametocytocide
what metabolizes primaquine?
CYP2D6 - metabolism required for activity***
-mechanism may involve free radicals
contraindications of primaquine
- G6PD deficiency
- pregnancy
- breast feeding
what is another compound related to primaquine with same spectrum of activity and toxicities?
tafenoquine
what is malarone a combination of?
proguanil and atavaquone
why is malarone given as a combo?
atavaquone failed as monotherapy - developed resistance rapidly
-combination is synergistic
what type of drug is malarone?
kills liver and blood stages, but not hypnozoites
what is malarone effective for?
treatment for uncomplicated malaria and chemoprophylaxis
what is atavaquone also used to treat?
Toxoplasma gondii
Pneumocystis jiroveci
mechanism of action of atavaquone
(ubiquinone analog) selective inhibitor of malaria mitochondrial cytochrome bc1 complex -> inhibits electron transport, and mitochondrial membrane potential collapses
what is the main role for mitochondrial electron transport in falciparum
to regenerate ubiquinone - electron acceptor for parasite dihydroorotate DH - essential for pyrimidine biosynthesis in the parasite
mechanism of action of proguanil
prodrug: converted to cycloguanil
- selective inhibitor of bifunctional plasmodial dihydrofolate reductase-thymidylate synthetase (which is crucial for parasite purine and pyrimidine synthesis)
- proguanil also has inherent antimalarial activity - enhances mitochondrial toxicity of atavaquone
mechanism of action of pyrimethamine-sulfadoxine (fansidar)
- folate synthesis inhibitors
- slow acting erythrocytic schizonticides
- similar combination used to treat toxoplasmosis
- pyrimethamine: inhibits plasmodia DHF-reductase (DHFR)
- sulfadoxine: inhibits dihydropteroate synthase (DHPS)
other uses of antifolates
- toxoplasmosis: pyrimethamine + sulfadiazine/clindamycin
- pneumocystis: TMX or atavaquone
is use of single antifolates recommended?
no, b/c resistance develops easily
-synergistic effect allows 20-fold reduction in dose of each component
why was the combination of pyrimethamine and sulfadoxine chosen?
both have long half-lives:
- pyrimethamine: 90h
- sulfadoxine: 170h
what antibiotics are used as antimalarials, and what type of drugs are they?
blood schizonticides:
-tetra, doxy, clinda
what do antimalarial antibiotics target?
target components of the apicoplast
what is doxy commonly paired with for treatment of falciparum?
quinine or quinidine
which antimalarial antibiotic is used for chemoprophylaxis in areas with high resistance to mefloquine?
doxy
