Malaria Flashcards
What is a hypnozoite?
A dormant form of the parasite that stays in the liver, found in relapsing malaria.
Describe the key stages of Plasmodium in the mosquito.
- Male and female gametocytes ingested during blood meal.
- Microgametes penetrates macrogametes to form diploid zygotes.
- Zygote becomes motile and elongated (ookinete), invades midgut wall and develops into oocyst.
- Oocyst ruptures, sporozoites move to salivary glands.
Describe key stages of Plasmodium in human liver cells.
- Sporozoites invade the liver (2 mins of bite).
- They mature into schizonts.
- Schizonts rupture to release merozoites.
Describe key stages of Plasmodium in human red blood cells.
- Merozoites invade RBC.
- Parasite digests haemoglobin (needs space to grow) and forms haemozoin.
- Schizonts rupture releasing merozoites. Cycle continues.
- Some parasites develop into gametocytes and are taken back up by the mosquito.
Why are only ring parasites of falciparum found in the blood?
Cytoadherence. Cell to cell adhesion to endothelial cells results in sequestration of parasites in capillaries. Escapes removal by spleen and can mature into a schizont.
What is haemozoin?
A by-product of parasites metabolic processes when it breaks down haemoglobin in the RBC. It is released when RBC ruptures and is taken up by the WBC.
name the malaria vaccine in trials and what stage does it target?
RTS-S, targets the pre-erythrocytic stage in the liver
What are the targets for chemotherapy for malaria?
Erythrocytic cycle in blood to relieve clinical symptoms.
Liver stage for prophylaxis.
Gametocytes to reduce transmission.
What is the extrinsic incubation period?
The time taken for the parasite to develop in the mosquito. This is shorter when it is warmer.
What is meant by the term vectorial capacity?
The total number of potentially infectious bites that would eventually arise from all the mosquitoes biting a single perfectly infectious human on a single day. (i.e. all mosquito bites=infection)
How do you calculate vectorial capacity?
ma^2p^n / -ln(p) m= vector:host ratio a= human biting rate p=mosquito survival through one day n= extrinsic incubation of parasite in days
What new solutions are there to resistance of insecticides?
- new insecticides for IRS (bendiocarb)
- Add synergists to bed nets (PBO) which blocks resistance causing enzymes in mosquitoes.
- larval source management (insecticides, predatory fish, biodegradable films that suffocate larvae, toxic bacteria, drainage)
- zooprophylaxis
- attractive targeted sugar baits (but will kill all pollinators)
- Screening houses
What are the malaria chemotherapy targets?
- Liver stages- prophylaxis
- Intraerythrocytic cycle - relieve clinical symptoms
- Gametocytes- prevent transmission
Define drug resistance
The ability of an organism to multiply and survive in the presence of concentrations of drug that normally destroy it or prevent its multiplication.
Define treatment failure
Inability to clear malarial parasitemia or resolve clinical symptoms despite administration os an antimalarial medicine.
What factors does resistance to antimalarials depend on?
Mutation rate
Pharmacodynamics
Pharmacokinetics
What is pharmacodynamics?
The effects of drugs and the mechanism of their action
If IC50 range for a drug is high, what does this mean in terms of resistance?
Parasites have greater chance of becoming resistant to the drug when the sub-lethal drug concentration range is high.
How can you reduce the spread of resistant parasites when designing a new drug
Target gametocytes, reduces transmission of resistant parasites
Define pharmacokinetics
What the body does to a drug
- absorption
- bioavailability
- distribution
- metabolism
- excretion
What is the ideal therapeutic half life of an antimalarial?
-Fast clearance time that reduces the exposure of the parasite to sub-lethal drug concentrations
BUT
- not too fast so that the drug has not had time to act
e.e. Artemisinins = 45mins
What are the 5 categories of drug resistance mechanisms?
- altered drug transport
- alternative target
- drug metabolism
- cellular repair mechanisms
- substrate competition
What mechanisms of altered drug transport resistance are there?
Increased efflux
Decreased uptake
Re-distribution to a non-target site
What does chloroquine target? What are the resistance mechanisms against it?
Binds haeme to stop parasite digesting haemoglobin.
Point mutation in transporter gene (PfCRT) which is found in membrane of digestive vacuole of parasite, preventing accumulation of the drug in the digestive vacuole of the pathogen.
Describe the mode of action of artemisinin
They have endoperoxide bridges that are activated by a source of iron to generate toxic radicals.
What parasite resistance mechanisms have been seen against artemisinins?
Parasites remain dormant at ring stage for up to 20 days following Artemisinin exposure.
What is G6PD
Glucose-6-phosphate dehydrogenase found on RBC which prevents chemicals from damaging RBC
What happens if you are G6PD deficient?
Increase in oxidative stress in RBC which may negatively effect parasite. Provides some protection against malaria.
Genetically inherited on female chromosome.
What is haemozoin
Parasite feeds on RBC, breaks down haemoglobin, haeme is toxic to parasite so converts it to inert form (crystals)
What are pyrogens
Released when schizonts rupture, cause fever.
What are the two types of cytoadherence in P.falciparum?
- Rosetting- infect RBC sticks to other non-infected RBCs and hides itself from the immune system.
- Sequesteration- adheres to endothelial cells of blood vessels
What is the principle behind antimalarial mechanism?
Bind to haeme, which stops formation of haemozoin, therefore build up of toxicity
define sporogony
parasites multiplication in the mosquito (sporozoite formation)
define schizogony
asexual reproduction of parasite characterized by multiple divisions of nucleus and cell
difference between acquired immunity and innate immunity
acquired: living in endemic area
innate: not exactly known… G6PD deficiency, RBC surface components, sickle cell haemoglobin, reactive oxygen species
Microscopy is gold standard but what other diagnostic methods
QBC
PCR
ELISA
RDTs
malaria vaccine:
name
target
protein it contains
RTS-S
Liver stage
Circum sporozoite protein
What do aminoquinoline antimalarials target
hemozoin formation
they inhibit crystallistion
What do antifolates target
enzymes in the folate pathway of parasite which is essential for making dna
What does atovaquone target
bc1 complex of mitochondria
What are the last line of defence drugs
Artemisinin-based Combination Therapy
How do artemisinins work
Have endoperoxide bridges that are activated by a source of iron, producing free radicals which can attack parasite
Why is it important to match the PK of two drugs
Resistance to one drug occurs just as quickly.
What is critical is the length of time the parasite lives at sub-lethal drug levels and are able to re-infect.
Antimalarial for uncomplicated vivax, ovale, malariae
Chloroquine
Primaquine
Amodiaquine
Antimalarial of uncomplicated falciparum
ACT Artesunate + lumefantrine Artesunate + amodiaquine Artesunate + mefloquine Atovaquone + proguanil (malarone)
Antimalarial of severe falciparum
Artesunate/ Artemether/ Quinine intravenous
What potential drug targets are there for new antimalarials?
kinases food vacuole mitochondria plastid transporters
If someone is G6PD deficient what should they be treated with?
low dose primaquine
community based vector control methods for malaria
IRS, ITN, larvicidal control, remove mosquito breeding sites, education, intermittent preventative chemotherapy of pregnant women, trials for RTS-S vaccine
what is the advantage to relapsing malaria of it having hypnozoites
forming hypnozoites enables vivax to be transmitted in more temperate areas as they reman dormant for weeks/mnths/yrs. useful adaptation for short transmission season
what drug is needed to kill hypnozoites
primaquine
treatment of g6pd deficiency
treat with lower doses of primaquine
