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67 Cards in this Set

  • Front
  • Back
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