Antimalarials Flashcards
What are the five falciparum spp.? (not really five anymore fyi)
Beyonce, not a circle, obvious, Chris’s worst one, vivacious
vivax malariae ovale knowlesi falciparum
What are the five falciparum spp? No prompts
vivax knowlesi malariae falciparum ovale
When we think of immune evasion, what stage of infection are we thinking of?
Internalisation within RBCs.
The life cycle form of parasites exiting from ruptures hepatocytes are called?
Merozoites.
In RBCs, the merozoites develops into uninucleate…
… ring trophozoite.
Uninucleate ring trophozoites develop into multinucleate X through asexual nuclear divisions.
Schizonts
Still in the RBC, multinucleate schizonts release numerous mononucleate…
… merozoites [again].
What stage of the malaria life cycle brings on the characteristic acute symptoms?
Emergence of merozoites from erythrocytes (also releases toxins).
What are the little green wormies and where do they come from?
SPOROZOITES and they come from nuclear divisions within the oocysts sitting on the outer wall of the mosquito GI lining.
What are three stages of the life cycle where the parasites undergo nuclear divisions?
Hepatic sporozoites -> merozoites
Erythrocytic ring trophozoites -> schizonts
Oocyts -> sporozoites
Malaria has historically killed M many people per year. In 2015 it was half that.
1 million.
P% of malaria deaths are in children under Q.
78%; <5yo
J is the most virulent plasmodium sp. but K is the most common.
falciparum; vivax.
Think dormant liver stage relapsing weeks (or even years) later?
[what are they called, which spp. do it?]
They’re called hypnozoites, and it’s VIVAX and OVALE.
Targeting hypnozoites is the idea of a new “radical cure” primaquine.
Uncomplicated clinical malaria presentation is non-specific and flu-like/febrile. Describe the stages of characteristic malaria attacks.
Easy to remember since it’s what happened to me in iso.
CYCLICAL - recur every two days or so (internal life cycle)
- cold stage
- hot stage
- sweaty stage.
What spp. would we use primaquine for and why?
Ovale and vivax - they’re hypnozoites and that what primaquine targets.
Are quinolines used for prophylaxis or intervention?
BOTH. They’re main use is intervention but they are still used as a typical prophylactic.
But NB only MEFLOQUINE that’s used as a prophylactic.
Quinine was originally purified from Cinchona bark extract. What is the side effects’ grouped term?
What are the five effects to remember?
Head, tummy, senses, skin, blood
Cinchonism.
GI upset, rashes, tinnitus & blurred vision, dizziness and rare thrombocytopaenia.
What are the five symptoms of Cinchonism (quinine side effects)? No prompts
GI upset, dizziness, blurred vision & tinnitus, rashes, rare thrombocytopaenia.
What kind of quinolone is the radical cure that kills hypnozoiteic ovale and vivax?
Primaquine is an 8-aminoquinolone.
Quinolones act by preventing the conversion of S to the non-toxic form T. They accumulate in the acidic food vacuoles because they are weak bases.
Ferric heme; haemozoin.
How have are chloroquine resistant parasites resistant?
They have evolved a way to EXCLUDE quinolines from the food vacuole.
Think poor absorption and obligatory fat ingestion for absorption? Also 99% protein bound.
Atovaquone.
Why does atovaquone have such an exessively long half life? 66-70h
Enterohepatic recycling.
Think inhibition of cytochrome electron transport, think…
… atovaquone.
Name 3 special properties of atovaquone.
- inhibits intrahepatic development
- inhibits oocyst development
- broad spectrum, against all plasmodia.
Bonus: mechanism is cytochrome electron transport inhibition.
Folate is made by M, and its immediate precursor is made by N.
Two-headed hydra eat horse babies thus reducing the population.
Archeopteryx loved electronic music.
Dihydrofolate reductase (DHFR); dihydropteroate synthase (DHPS).
Folate is made by M, and its immediate precursor is made by N. No prompt.
Dihydrofolate reductase
Dihypriopteroate synthase.
Antifolate is a popular prophylaxis. T or F?
FALSE. Antifolates are for acute attacks.
Oh no - the patient has chloroquine-resistant AND cerebral malaria? X to the rescue!
Artemisinin.
Artemisinin and antifolates are both blood schizonticides. T or F?
True.
Think PfPI3K, think…
Mechanism of artemisinin resistance.
Also a theorised artemisinin target.
Why was there a push for semisynthetic artemisinins?
I.e. DIHYDROARTERMISININ
Because natural artemisinin is so poorly water soluble.
What are the three (sorta four) drugs used for prophylaxis?
- Mefloquine
- Atovaquone + proguanil
- Doxycycline
Bonus: chloroquine in susceptible areas (i.e. Central America).
What are two pros of doxycycline?
Good lipid solubility
Once daily oral dose (long half life).
What four drugs have the biggest problems with resistance?
Chloroquine, mefloquine, antifolates, artemisinin.
What is the one drug whose mechanism of resistance isn’t just a mutation in the [putative] target?
Chloroquine - efflux mechanism preventing it from reaching ferric heme.
What’s, like, the last place you’d wanna get a malaria infection resistance-wise?
Thai-Cambodian border.
So this 6months-pregnant Danyelluh wants to go to Laos. You’ve told her not to because Malaria, but she’s just watched Eat Pray Love and has decided she “just needs this”. Chloroquine would be safest but there’s resistance in Laos. What would you give her?
What WOULDN’T you give her?
Give her mefloquine.
DON’T give her primaquine, A:P or doxycycline.
Danyelluh comes back, she’s 9 weeks pregnant and wants to a heavily chloroquine-resistant region. You tell her she doesn’t want prophylaxis with mefloquine because…
It’s not recommended in the first trimester.
What are four drugs with anti-gametocyte effects?
Chloroquine, primaquine, quinine, artemisinin.
What are FIVE challenges to a malaria vaccine (aside from $$).
Power rangers, rabbits, PA (anthrax), testing, form-fitting genes are complicated to find.
- they are really complex (genetically and in terms of life cycle) - heterogenous forms.
- there are no good correlates to test protective immunity.
- There are a lot of protein polymorphisms (hard to get a broadly representative antigen)
- they replicate so quickly - it’s hard for adaptive response to keep up anyway.
- we don’t understand Pf protective antigen very well.
What are FIVE challenges to a malaria vaccine (aside from $$).
No prompts
- Genetic complexity and heterogenous life cycle forms.
- Such rapid replication
- Protective antigen not understood well (immune evasion)
- many protein polymorphisms - hard to nail down a universal antigen
- No good correlates to test success of vaccination.
