Malaria Flashcards

1
Q

What is a hypnozoite?

A

A dormant form of the parasite that stays in the liver, found in relapsing malaria.

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2
Q

Describe the key stages of Plasmodium in the mosquito.

A
  1. Male and female gametocytes ingested during blood meal.
  2. Microgametes penetrates macrogametes to form diploid zygotes.
  3. Zygote becomes motile and elongated (ookinete), invades midgut wall and develops into oocyst.
  4. Oocyst ruptures, sporozoites move to salivary glands.
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3
Q

Describe key stages of Plasmodium in human liver cells.

A
  1. Sporozoites invade the liver (2 mins of bite).
  2. They mature into schizonts.
  3. Schizonts rupture to release merozoites.
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4
Q

Describe key stages of Plasmodium in human red blood cells.

A
  1. Merozoites invade RBC.
  2. Parasite digests haemoglobin (needs space to grow) and forms haemozoin.
  3. Schizonts rupture releasing merozoites. Cycle continues.
  4. Some parasites develop into gametocytes and are taken back up by the mosquito.
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5
Q

Why are only ring parasites of falciparum found in the blood?

A

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.

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6
Q

What is haemozoin?

A

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.

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7
Q

name the malaria vaccine in trials and what stage does it target?

A

RTS-S, targets the pre-erythrocytic stage in the liver

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8
Q

What are the targets for chemotherapy for malaria?

A

Erythrocytic cycle in blood to relieve clinical symptoms.
Liver stage for prophylaxis.
Gametocytes to reduce transmission.

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9
Q

What is the extrinsic incubation period?

A

The time taken for the parasite to develop in the mosquito. This is shorter when it is warmer.

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10
Q

What is meant by the term vectorial capacity?

A

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)

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11
Q

How do you calculate vectorial capacity?

A
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
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12
Q

What new solutions are there to resistance of insecticides?

A
  1. new insecticides for IRS (bendiocarb)
  2. Add synergists to bed nets (PBO) which blocks resistance causing enzymes in mosquitoes.
  3. larval source management (insecticides, predatory fish, biodegradable films that suffocate larvae, toxic bacteria, drainage)
  4. zooprophylaxis
  5. attractive targeted sugar baits (but will kill all pollinators)
  6. Screening houses
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13
Q

What are the malaria chemotherapy targets?

A
  1. Liver stages- prophylaxis
  2. Intraerythrocytic cycle - relieve clinical symptoms
  3. Gametocytes- prevent transmission
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14
Q

Define drug resistance

A

The ability of an organism to multiply and survive in the presence of concentrations of drug that normally destroy it or prevent its multiplication.

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15
Q

Define treatment failure

A

Inability to clear malarial parasitemia or resolve clinical symptoms despite administration os an antimalarial medicine.

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16
Q

What factors does resistance to antimalarials depend on?

A

Mutation rate
Pharmacodynamics
Pharmacokinetics

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17
Q

What is pharmacodynamics?

A

The effects of drugs and the mechanism of their action

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18
Q

If IC50 range for a drug is high, what does this mean in terms of resistance?

A

Parasites have greater chance of becoming resistant to the drug when the sub-lethal drug concentration range is high.

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19
Q

How can you reduce the spread of resistant parasites when designing a new drug

A

Target gametocytes, reduces transmission of resistant parasites

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20
Q

Define pharmacokinetics

A

What the body does to a drug

  • absorption
  • bioavailability
  • distribution
  • metabolism
  • excretion
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21
Q

What is the ideal therapeutic half life of an antimalarial?

A

-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

22
Q

What are the 5 categories of drug resistance mechanisms?

A
  1. altered drug transport
  2. alternative target
  3. drug metabolism
  4. cellular repair mechanisms
  5. substrate competition
23
Q

What mechanisms of altered drug transport resistance are there?

A

Increased efflux
Decreased uptake
Re-distribution to a non-target site

24
Q

What does chloroquine target? What are the resistance mechanisms against it?

A

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.

25
Q

Describe the mode of action of artemisinin

A

They have endoperoxide bridges that are activated by a source of iron to generate toxic radicals.

26
Q

What parasite resistance mechanisms have been seen against artemisinins?

A

Parasites remain dormant at ring stage for up to 20 days following Artemisinin exposure.

27
Q

What is G6PD

A

Glucose-6-phosphate dehydrogenase found on RBC which prevents chemicals from damaging RBC

28
Q

What happens if you are G6PD deficient?

A

Increase in oxidative stress in RBC which may negatively effect parasite. Provides some protection against malaria.
Genetically inherited on female chromosome.

29
Q

What is haemozoin

A

Parasite feeds on RBC, breaks down haemoglobin, haeme is toxic to parasite so converts it to inert form (crystals)

30
Q

What are pyrogens

A

Released when schizonts rupture, cause fever.

31
Q

What are the two types of cytoadherence in P.falciparum?

A
  1. Rosetting- infect RBC sticks to other non-infected RBCs and hides itself from the immune system.
  2. Sequesteration- adheres to endothelial cells of blood vessels
32
Q

What is the principle behind antimalarial mechanism?

A

Bind to haeme, which stops formation of haemozoin, therefore build up of toxicity

33
Q

define sporogony

A

parasites multiplication in the mosquito (sporozoite formation)

34
Q

define schizogony

A

asexual reproduction of parasite characterized by multiple divisions of nucleus and cell

35
Q

difference between acquired immunity and innate immunity

A

acquired: living in endemic area
innate: not exactly known… G6PD deficiency, RBC surface components, sickle cell haemoglobin, reactive oxygen species

36
Q

Microscopy is gold standard but what other diagnostic methods

A

QBC
PCR
ELISA
RDTs

37
Q

malaria vaccine:
name
target
protein it contains

A

RTS-S
Liver stage
Circum sporozoite protein

38
Q

What do aminoquinoline antimalarials target

A

hemozoin formation

they inhibit crystallistion

39
Q

What do antifolates target

A

enzymes in the folate pathway of parasite which is essential for making dna

40
Q

What does atovaquone target

A

bc1 complex of mitochondria

41
Q

What are the last line of defence drugs

A

Artemisinin-based Combination Therapy

42
Q

How do artemisinins work

A

Have endoperoxide bridges that are activated by a source of iron, producing free radicals which can attack parasite

43
Q

Why is it important to match the PK of two drugs

A

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.

44
Q

Antimalarial for uncomplicated vivax, ovale, malariae

A

Chloroquine
Primaquine
Amodiaquine

45
Q

Antimalarial of uncomplicated falciparum

A
ACT
Artesunate + lumefantrine
Artesunate + amodiaquine
Artesunate + mefloquine
Atovaquone + proguanil (malarone)
46
Q

Antimalarial of severe falciparum

A

Artesunate/ Artemether/ Quinine intravenous

47
Q

What potential drug targets are there for new antimalarials?

A
kinases
food vacuole
mitochondria
plastid
transporters
48
Q

If someone is G6PD deficient what should they be treated with?

A

low dose primaquine

49
Q

community based vector control methods for malaria

A

IRS, ITN, larvicidal control, remove mosquito breeding sites, education, intermittent preventative chemotherapy of pregnant women, trials for RTS-S vaccine

50
Q

what is the advantage to relapsing malaria of it having hypnozoites

A

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

51
Q

what drug is needed to kill hypnozoites

A

primaquine

52
Q

treatment of g6pd deficiency

A

treat with lower doses of primaquine