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
Mefloquine (Larium)
- prophylactic where high risk of chloroquine-resistant falciparum malaria
- rarely used for treatment due to potential serious neuropsychiatric reactions
insomnia
anxiety
psychosis
depression
suicide
long half life so symptoms can last a long time as it accumulates in acidic organelles
Chloroquine
cons:
- P. falciparum resistance
- Toxic if overdosed
- retinal toxicity: accumulation leads to blurred vision and blindness
pros:
- no neuropsychiatric reactions
- doesn’t readily bind to NT receptors in CNS
quinine
- widely used and effective as:
neutral form in plasma as its a zwitterion so easy to get into RBC or
less effective being pumped out by MDR - use with doxycycline to ensure eradication
- base trapping
quinine cons
- overdose
hypoglycaemia and coma
hyperinsulinemia as directly stimulated insulin secretion which plummets blood glucose level
acts like sulphonureas on KATP
doxycycline
- tetracycline antibiotic
- works on erythrocytic stages
- prophylaxis but not treatment?
- MOA too delayed for treatment
- can be used with quinine in treatment to ensure eradication
how does doxycycline work
- acts on merozoites in shizonts
- apicoplast in P. falciparum is vital for parasite survival: lipid metabolism/host cell invasion?
- doxycycline impairs progeny pf apicoplast genes; impaired invasion of subsequent new RBCs. Abnormal cell division
mechanisms of drug resistance
- combination of:
mutations in gene of target protein so decreased selectivity
increased production of target
decreased accumulation of drug - parasites with mutation or genetic polymorphisms evolve and confer resistance under drug pressure
monochemotherapy leads to rapid selection of resistant mutations as some organisms aren’t affected with lower dosage and survive and gain mutation, life cycle
simultaneous resistance - multiply mutations for multiple drugs at once
cross-resistance - resistance to same class of drugs ie all quinolines
new drugs
Artemisinin-based combo therapies (ACT)
- Artemisinin-derivate + another drug
mefloquine or chloroquine
the more targets, less likely to get resistance
- gold standard: Artemisinin mono therapy but leads to resistance
- fixed dose x3
- Artemisinin: multiple targets including haem disposal (>60 targets)
vaccine for malaria
Mosquirix (GSK)
