Block 4: antimalarial drugs
Terms
undefined, object
copy deck
- malaria afflicts __ people and causes more than __ deaths per year
-
500 million people
2 million deaths - why has malarial incidence been on the rise since the 1960's
- removal of DDT from world market
- form of malaria that is highly fatal but not chronic
- p. falciparum
- form of malaria that is uncommonly fatal but has a chronic recurrent stage
- p. vivax
- describe 3 categorical uses of antimalarial drugs;
-
1. prevention of DISEASE (not infection)
2. treatment- reduce blood stage parasite numbers until the patient is well
3. eradication- after return from exposure (not for endemic populations) - what type of prophylaxis (prevention) kills parasite at liver stage
- causal
- what type of of prophylaxis kills or suppresses parasites in the early erythroyctic stage
- suppressive
-
3% p. falciparum parasitemia
organ failure
HCT <20 - complicated malaria- medical emergency
-
quinine
QUINIDINE
MEFLOQUINE
halofantrine
MOA? -
aryl-amino-alcohols
rapidly kill blood stage p. falciparum - DOC for acute severe disease- cardiotoxicity
- quinidine
- DOC for most p. falciparum regions- neuropsychiatric concerns
- mefloquine
-
CHLOROQUINE
amodiaquine
mepacrine
pyronaridine
MOA? -
4-aminoquinolines
kills blood stage parasites - DOC for Rx and Px for non-p. falciparum malaria
- chloroquine
-
primaquine
tafenoquine
MOA? -
8-aminoquinolines
non-growing parasite stages- hypnozoites in liver
terminal prophylaxis - contraindcated in G6PD def and pregnancy
- 8-aminoquinolines
-
doxycycline
clindamycin
floroquinolones
MOA? -
antibiotics, (I should know that, right?)
blood stage RX
slow acting but effective - DOC for prophylaxis in mefloquine resistant p. falciparum areas
- doxycycline
-
MALARONE
fansidar
maloprim - combination chemicals
-
NEW drug for uncomplicated MDR p. falciparum
concerns of development of proguanil resistance - malarone (proquanil and atovaquone)
- remote Rx in Africa
- fansidar (sulfadoxine and pyrimethamine)
- given to europeans in Africa
- maloprim (dapsone and pyrimethamine)
-
artemisinin and derivatives
MOA?
FDA approved? -
endoperoxides
quin hao plant
rapid killing blood stage parasites
not FDA approved - the primary regimen used to tx uncomplicated falciparum malaria in the US
- oral quinine w/ doxycycline
- diastereomers isolated from the bark of cinchona spp tree
- quinine and quinidine
- what else is quinine often used for
- tx of leg cramps
- quinidine was originally used as
- an antiarrhythmic drug
- why is quinidine the only treatment for malaria requiring parenteral therapy
- i.v. quinine is not available in the US
- what else is needed when giving quinidine i.v.
- ICU environment- electrocardiogram and cardiovascular parameters need to be continuously monitored
-
quinine and quinidine are both metabolized by...
quinidine is a potent inhibitor of... -
CYP450
CYP2D6 - what does severe malaria do to the pharmacokinetics of cinchonal alkaloids
-
1. clearance and volume of distribution are decreased
2. both drugs bind a-1-acid glycoproteins that are greatly increased during infection -> reduces the free drug fraction -> decreased efficacy and toxicity -
tinnitus
blurred vision
headache
nausea and
dysphoria from quinine and quinidine -
cinchonism
('si[ng]-k&-"ni-z&m) - what does quinidine do to QTc
- prolongation
- in what patient population is hypoglycemia from stimulation of insulin secretion from quinine and quinidine more likely
- pregnant women and severe malaria patients
- MCC of drug induced ITP
- quinine
-
massive hemolysis
hemoglobinemia
AND
hemoglobninuria -
blackwater fever
(from quinine and quinidine) - treatment of non falciparum malaria and treatment of autoimmune diseases
- chloroquine
- chloroquine MOA
- accumulates in acidic food vacuole of parasite -> becomes protonated and entrapped -> interferes w/ heme polymerase -> inhibits polymerization of toxic heme -> accumulates to levels that kill parasite
- what is the chloroquine active metabolite
- desethylchlorquine
- fansidar MOA
-
pyrimethamine (a benzylpyrimadine)- inhibits dihydrofolate reductase
sulfadoxine (a sulfonamide)- inhibits conversion of PABA by dihydropteroate synthetase
-> impacts THF synthesis - what happens when fansidar is used widespread
- resistance develops rapidly
- why isn't fansidar a prophylactic drug
- sulfonamide induced blood dyscrasias- hypersensitivity reax- hepatitis, vasculitis, exfoliative dermatitis (Steven's Johnson)
- drug developed to replace chloroquine; widespread publicity for associated neuropsychiatric disorders
- mefloquine
- uses of mefloquine
-
1. first line for MDR malaria prophylaxis
2. second line for MDR uncomplicated malaria -
contraindicated in patients w/ hx of seizure disorders, or neuropsychiatric disturbances
sinus bradycardia
QTc prolongation - mefloquine
- mefloquine resistance is widespread in ...
- Thailand (mechanism is an efflux pump)
- why isn't it recommend that halofantrine be given with food, even though absorption is significantly increased in the presence of dietary lipid
-
cardiotoxicity
prolongation of QTc and arrhythmia assoc death - patients on halofantrine previously treated w/ ___, are more likely to have their QT interval prolonged
- mefloquine
- why can't doxycylcine and tetracycline be used as single agents for tx
- slow acting!
- when does doxycycline compliance become most difficult
- when it must be given for 4 weeks after leaving the endemic area (not causally prophylactic- doesn't kill liver stage)
- doxycycline MOA
- inhibits protein synthesis by binding 30S and inhibits binding of aminoacyl-t-RNA
- why are tetracylcines contraindicated in pregnant women and children
- tooth and bone problems
- an old drug used for the radical curative treatment of hypnozoites during or following treatment of relapsing malaria
- primaquine
- how is primaquine unique
-
it affects all species of plasmodia
is causally prophylactic (kills liver stages)- so doesn't need to be taken long after leaving endemic area) - what special screening is needed before giving primaquine
- G6PD screening
- what dosing regimen of primaquine is needed for the p.vivax Chesson strain of the Southwest Pacific
- twice the dose
- weekly dosing regimens possible but only in phase III/IV trials
- tafenoquine
- proguanil (in atovaquone-proguanil = Malarone) must be metabolized to what active metabolite?
- cycloguanil
- is malarone causally prophylactic?
- yes- both agents
- tx and prevention of PCP and toxo
- atovaquone alone
- atovaquone MOA
-
inhibits mitochondrial electron transport at level of cytochrome bc1 complex
-> plasmodia have pyrimidine biosynthesis obligatorily coupled to electron transport, humans have a salvage pathway - proguanil MOA
-
enhances the ability of atovaquone to collapse mito membrane potential
cycloguanil inhibits parasite dihydrofolate reductase - what metabolizes proguanil to cycloguanil
-
CYP2C19
->10% of Caucasians are poor metabolizers - resistance to atoquavone
- point mutations in mito cytochrome B gene (Tyr268Asn mutation from Nigeria)
- cycloguanil resistance
- single point mutation in DHFR gene
- artemether and artesunate
- two artemisinin drugs used in Asia
- most rapidly acting of all antimalarials
- artemisinin derivatives
- why is water solubility of artemisinin derivatives handy
- can be administered by any route- even rectally