INF2 - F. ANTIMALARIAL DRUGS-COVERED Flashcards
only therapy today is in what form
oral
where do folate inhibitors and anti-mitochondrial target
- hepatic stages as uses mitochondria for energy
where do quinolines target
- erythrocytic stages as uses glycolysis for generation of energy
Malarone
- acts on hepatic stages of P. falciparum
- treatment and prophylaxis of P. falciparum of malaria
- combination of atovaquone and proguanil hydrochloride
how does atovaquone work
- a napthoquinone
- effective against sporozoites in hepatic stages (and hypnozoites)
- analogue of ubiquinone (Q)
- acts on mitochondrial ETC
- interacts with cytochrome bc1 complex (complex 3)
- hence blocks mitochondrial function and ATP synthesis
why doesn’t atavaquone affect man
- binds to ubiquinol oxidation pocket of cyto bc1 complex (ie - complex 3) and has less affinity for our complex 3 (1000x more potent for parasite)
- ubiquinone binding sites divergent from those of other species
- erythrocytic stages parasite don’t use mitochondria for energy ie the RBCs so only targets hepatic stage
- atavaquone resistance arises due to mutations in bc1 ubiquinol binding pocket
PK of atovaquone
Prophylaxis
- active against liver stages: sporozoites and hypnozoites
Treatment
- parasite death slower than with artemisinin or chloroquine as mitochondria are deep in parasite
general properties of mitochondrial-acting antimalarials
- trophozoite/shizont mainly glycolytic
- drugs lipophilic therefore slow uptake
- parasite resistance can occur
how does proguanil work
- a chloroguanide
- effective against sporozoites
- antifolate or
- synergistic with atavaquone - maybe impairs respiration of parasite
proguanil as an antifolate
- prodrug: proguanil converted to cycloguanil by our own cytochromes
- cycloguanil inhibits dihydrofolate reductase, DHFR which catalyses formation of dihydrofolate to tetrahydrofolate required for purine base (DNA synthesis) and some aa synthesis
- inhibits cell proliferation and growth in parasite
high hypnozoite turnover
high rate of replication
folate synthesis needed by rapidly dividing cells
proguanil as an antimitochondrial
- in humans with polymorphism P450, can’t metabolise proguanil but it still works (even on cycloguanil resistant parasites - point mutation in DHFR)
- therefore proguanil has alternative target to DHFR
- affect mitochondria (synergistically ie - needs to be with atovaquone)
- lower dose of atovaquone required
malarone contraindications
will get reduced absorption of drug if:
- nausea
- diarrhoea
- vomiting
side effects:
- dizziness
- depression
- insomnia
avoid in breastfeeding women
avoid use of machinery as affects psychomotor performance as affects CNS
ADME
- kidney problems, excretion higher so might need very high levels of drug
- drug-drug interactions
ie: those that act on cytochrome p450 enzyme
ie: interfere with prodrug metabolism to cycloquanil (eg - warfarin, tetracycline, artemisinin)
where do quinolines target (chloroquine and mefloquine - analogues of quinine)
- red blood stage: erythrocytic stage
how do quinolines work
- parasite crystallises haem to haemozoin and disables haem from its toxin effects
- the weak bases accumulate in acidic digestive vacuole of parasite (food vacuole)
- prevents haemozoin formation
- haem toxic (cytolytic, ROS production which are poisonous)
- toxic to parasite
base-trapping?
quinoline resistance
- multiple genes
- decreased drug accumulation due to accelerated drug efflux
- expresion of ATP-dependent P-glycoprotein in food vacuole membrane
PfMDR1 and PfMDR2 - P. falciparum MDR 1 and 2 proteins: pump out drugs - quinolines from food vacuole or food vacuole membrane and won’t accumulate
PfMDR1 contributes to CQ resistance
reduced uptake of CQ
PfCRT gene product:
- Chloroquine resistant transporter
- anion channel expressed in FV membrane
- selective for pumping out CQ from FV or FVW
- mutations of gene product increase resistance
