Pharm - Antiprotozoal Drugs Flashcards
true or false
malaria is linked to bacteria
FALSE - linked to parasites
what parasite accounts for the majority of malaria cases in africa
plasmodium falciparum
explain the life cycle of malaria
when do symptoms start?
infected FEMALE mosquito bites the human and the parasite infects cells within organs, such as the liver (gets into hepatocytes via cell surface receptors)
For around a week, they asexually reproduce in the liver (called exoerythrocyte stage) – called SCHOZONTS
the hepatocytes will rupture eventually (may take a long time - even like a month - but will rupture eventually) and the merozoites will go into systemic circulation. The parasite within the RBCs asexually reproduce (THIS IS WHERE SYMPTOMS START) and can cause the RBC to rupture, and more and more RBC can be infected
if another mosquito bites this infected human, it can ingest a gametocyte and cause infection within that mosquito, and when that mosquito bites ANOTHER human, that human will be infected too
what is the “erythrocytic” parasite
when the parasite is in the blood and causing RBC rupture
what is the hepatic parasite
when hepatocytes are being infected
in pharmacotherapy for malaria, what TWO PARASITE STAGES need to be eradicated?
BOTH the erythrocytic and hepatic parasite
in which 3 continents is prophylactic therapy for malaria given
if traveling to asia, south america, or africa
name 4 categories of antimalarial drugs
(based on the STAGES that they target)
tissue schizonticides - kill the liver forms
blood schizonticides - kill the erythrocyte forms
gametocide - affects the sexual stage and prevents transmission to mosquito
prophylactic drugs
5 CLASSES of antimalarials
artemisinins
quinolones/quinine/quinidines
folate synthesis inhibitors
antibiotics (tetracycline)
lumefantrine
name 2 folate synthesis inhibitors for malaria
proguanil
pyrimethamine
which 2 anti malaria drugs target BOTH erythrocytic and hepatocyte schizonts?
atovaquone and proguanil
which anti malaria drugs targets the primary and latent liver stage, as well as gametocytes?
primaquine
MOST antimalarial drugs affect which stage of the life cycle?
erythrocyte schizonts
name 8 drugs that are erythrocyte schizonts
artemisinins
chloroquine
mefloquine
quinine
quinidine
pyrimethamine
sulfadoxine
tetracycline
for which anti malaria drug is resistance VERY COMMON
for which 2 strains?
chloroquine
mainly falciparum, but also vivax
true or false
artemisinin is a good drug for malaria prophylaxis
FALSE
what is the only area that seems to have no chloroquine resistance
central america
structurally, what is the key structural component of artemisinins
the endoperoxide bridge
active form of artemisinin
dihydroartemisinin
STRUCTURALLY, what is artemisinins
a sesquiterpene lactone ENDOPEROXIDE
what is the MOA of artemisinins
are healthy human cells affected
generates ROS (free radicals) – alters the cell redox cycle
these ROS’s kill both the parasite AND the RBC
HOWEVER, healthy RBC’s are not affected. this is because RBCS that are infected have their heme portion compromised and iron is exposed. this iron portion DIRECTLY REACTS with the peroxide part of the drug which generates ROS. HEALTHY RBCs DO NOT HAVE THEIR IRON FROM THE HEME EXPOSED!!! SO THEY’RE NOT AFFECTED BY THE DRUG!!!!
which stage(s) does artemisinins affect? how can you remember this?
ONLY THE ERYTHROCYTIC STAGE
does NOT affect the hepatic stage because hepatocytes do not have heme/iron to react with the endoperoxide bridge
are artemisinins good for prevention of malaria??
why or why not
NO
has a very short half life of 1-3 hours
any DDI concern with artemisinins?
yes – inducer of CYP2BD and 3A4
is resistance common for atemisinins
not really
it just generates free radicals – hard to develop resistance to that
with continued administration of atermisinins, what can happen to drug levels?
they can drop
how much does artemisins concentration build in the blood?
only nanograms but still works well
***3 rare but serious adverse effects of artemisinins
neutropenia
anemia
hemolysis
**when is artemisinins contraindicated and why
in pregnancy
causes congenital defects and stillbirths in the 1st trimester
WHO DOES recommend in the 2nd and 3rd trimester tho
NOT for children that weigh less than 5kg
explain the role of heme in malaria
protease enzymes from parasities break down hemoglobin into heme (Fe 2+) for “food”
heme dimerizes and becomes hematin (Fe3+)
BOTH heme and hematin are toxic to parasites and will kill them
however, if hematin assembles into crystals to become HEMOZOIN (Fe 3+) – this is not toxic to parasites and they can SURVIVE
we have drugs that inhibit this crystal assembly (SUCH AS CHLOROQUINE)
explain the MOA of chloroquine
in general - prevents the detoxification of heme by inhibiting crystal assembly into hemozoin (Hz)
the drug accumulates in lysosomes in a food vacuole as a charged molecule. it binds heme and changes the osmotic properties of the lysosome to PREVENT HEME DETOXIFICATION
chloroquine is _______, meaning that it can easily pass the cell membrane and accumulate in lysosomes as a charged molecule
lysosmotropic
2 mechanisms of chloroquine drug resistance
induction of MDR1 pump to pump drug out
pfcrt expression (also efflux)
how is chloroquine administered
orally - it is completely absorbed
can also be given by IV slow infusion
is the half life of chloroquine long or short and why
LONG (3-5 days) bc it gets deposited in tissues
which stage(s) of the malaria life cycle is chloroquine active against and why?
NOT ACTIVE AGAINST THE LIVER STAGE —- only blood and gametocide. bc MOA is related to prevention of HEME detoxicification within the RBC
true or false
both artemisinins and chloroquine are contraindicated in the 1st trimester of pregnancy
FALSE - only artemisinins
chloroquine is safe in pregnancy
***3 major toxicities of chloroquine
retinopathy
hemolysis in G6PDH deficiency
cardiac toxicity - arrhythmias, cardiac arrest
why is chloroquine given SLOWLY by IV
fast infusion can lead to toxicities
chronically administering chloroquine for RA leads to…
IRREVERSIBLE ototoxicity, retinopathy, and myopathy
when given with other drugs like amiodarone and halofantrine, chloroquine can cause increased risk of ________
arrythmia
chloroquine is CONTRAINDICATED in patients with what 4 things
psoriasis
myopathy
retinopathy
porphyria
chloroquine should not be administered with _____ because the absorption of chloroquine will be blocked
antacids
bc the drug is basic
chloroquine is an inhibitor of what CYP and thus has a DDI concern
CYP2D6
chlroquine opposes the action of what class of medication
anticonvulsants
what is the name of the drug that is similar to chloroquine?? Is it ever administered in combination?
amodiaquine
administered in combination FOR CHLOROQUINE RESISTANT MALARIA
quinine and quinidine are natural/synthetic?
natural
explain MOA of quinine/quinidine
it’s not well understood
similar to chloroquine in that it causes heme toxicity and death of the parasite
used as BLOOD schizonticide vs all 4 strains and gametocidal in 2
true or false
quinine/quinidine are NOT active against the hepatic stage
TRUE
quinine/quinidine resistance is attributed to what efflux pump
PfMDR1
quinine/quinidine are ____ toxic and ____ effective than chloroquine
more toxic and less effective
biggest toxicity concern for quinine/quinidine
MORE CARDIOTOXIC THAN THE OTHERS
causes lot of CV issues like QT prolongation, hematologic abnormalities like hemolysis and leukopenia
also can cause hypersensitivity reactions
which antimalaria drug can cause blackwater fever
(hemolysis, hemogloburia)
QUININE/QUINIDINE
MOA mefloquine
similar to chloroquine - associated with intra-erythrocytic hemozoin
A BLOOD SCHIZONTICIDAL
NOT active vs hepatic or gametocyte stages
how is mefloquine administerd and why
ORALLY
not given parenteral bc it will cause severe irritation
resistance to mefloquine is associated with what efflux pump
PfMDR1
what is the relative half life of mefloquine and what is the concern with this
VERY LONG - like 20 days
may be much more prone to resistance bc it’s in the body for a long ass time
is mefloquine recommended for chemoprophylaxis of malaria??
why or why not?
what about in areas of chloroquine resistance
YES
bc it has a very long half life
YES
**BLACK BOX WARNING MEFLOQUINE, and 1 other toxicity (not BBW)
and who is it thus contraindicated in?
has neurologic and psychiatric effects – vivid dreams, etc
not BBW = cardac abnormalities like arrythmia and condution
thus contraindicated in pts with psychiatric conditions and cardiac conduction issues
mefloquine should NOT be coadministered with which 3 drugs and why
quinine
quinidine
halofantrine
CARDIAC ISSUES
