2: Antiparasitics - Antimalarials Flashcards Preview

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Flashcards in 2: Antiparasitics - Antimalarials Deck (74):
1

which malaria is responsible for the most deaths?

plasmodium falciparum

2

which malaria is mostly in the tropics? what about the subtropics and temperate regions? west africa?

tropics: falciparum

subtropics/temp: vivax

west africa: ovale

3

which malarias can be relapsing? why?

vivax and ovale - hypnozoites in the liver

4

what are the 5 malaria parasites that cause disease in humans?

-falciparum
-vivax
-ovale
-malariae
-knowlesi

5

why is vivax generally less severe?

it is limited ti reticulocytes, whereas falciparum is not

6

what is important about the lifecycle of knowlesi?

24h life cycle - can increase in numbers very rapidly -> need treatment right away
-usually associated with zoonotic infections

7

describe the life cycle times for each malaria parasite?

liver stage ~7d

-falciparum, vivax, ovale: 48h cycles in blood
-malariae: 72h cycles in blood
-knowlesi: 24h cycles in blood

8

why is it a problem if a pregnant woman gets malaria?

malaria has receptors that bind chondroitin sulfate, which is prevalent in the placenta -> causes low birth weight and miscarriage

9

what are the classic symptoms of uncomplicated malaria?

-cold stage
-hot stage
-sweating stage

10

what are the more usual symptoms of uncomplicated malaria?

-fever and flu-like symptoms: chills, headache, myalgias, malaise
-anemia and jaundice

11

what are the symptoms of severe malaria?

-serious organ failures, including kidney
-cerebral malaria (abnormal behavior, impairment of consciousness, seizures, coma, etc.)
-severe anemia and hemoglobinuria due to hemolysis
-ARDS/ pulmonary edema
-placental malaria (especially during 1st pregnancy)

12

what are the types of drugs used for malaria?

-tissue schizonticides (kill liver stage)
-blood schizonticides (kill erythrocytic forms)
-gametocytocides (kill sexual stage, block transmission)

13

what is the only drug to kill malaria hypnozoites?

primaquine

14

what stage do all drugs work on?

asexual blood stages

15

when should you take malaria chemoprophylaxis?

before, during, and after travel

16

list 5 malaria chemoprophylaxis drugs

-atovaquone + proguanil (malarone)
-doxycycline
-chloroquine
-mefloquine
-primaquine

17

malarone:
1. what is it a combination of?
2. where is it useful?
3. when do you start/stop taking it?
4. how it is taken?

1. atovaquone + proguanil
2. all areas
3. start 1-2d prior, end 7d after
4. daily admin + short pretreatment

18

doxycycline:
1. where is it useful?
2. when do you start/stop taking it?

1. all areas
2. start 1-2d prior, end 4w after

19

chloroquine:
1. other names
2. where is it useful?
3. when do you start/stop taking it?

1. Aralen and generic
2. chloroquine sensitive areas (mostly C and parts of S Am)
3. start 1-2w prior, end 4w after

20

mefloquine:
1. other names
2. where is it useful?
3. when do you start/stop taking it?

1. Lariam and generic
2. mefloquine sensitive areas
3. start >2w prior, end 4w after

21

primaquine:
1. where is it useful?
2. when do you start/stop taking it?

1. if >90 vivax in area
2. start 1-2d prior, end 7d after

22

why do you start mefloquine so much earlier than the other malaria chemoprophylaxis drugs?

to determine if it gives you AE (it is associated with some toxicity), so then you can switch in time if need be

23

treatment for uncomplicated malaria or unidentified species in chloroquine sensitive areas?

chloroquine (aralen) and hydroxychloroquine sulfate (plaquenil)

add primaquine if find out ovale/vivax

24

treatment options for uncomplicated malaria or unidentified species in chloroquine resistant areas

-malarone (atovaquone + proguanil)
-coartem (artemether + lumefantrine)
-quinine sulfate + one of the following: doxy, tetra, clinda
-mefloquine (lariam)

add primaquine if find out ovale/vivax

25

treatment for complicated (severe) malaria: drug + what do you monitor?

-IV quinidine gluconate + doxy, tetra, or clinda
-consult cardiologist or experiences physician
-monitor BP (hypotension), cardiac fxn (widening of QRS or long QT), serum glucose (hypoglycemia)
-severe cardiac complications may warrant temporarily discontinuing treatment or decreasing infusion rate

26

what is an alternate treatment for complicated malaria if quinidine gluconate is not tolerated or not available?

artesunate - IV only
-followed by one of the following: malarone, doxy (clinda in preggers), or mefloquine

27

what is the first line treatment in most of the world except for the U.S.?

artemisinin

28

what type of chemical is artemisinin?

blood schizonticide
-sesquiterpene lactone endoperoxide (endoperoxide is active group)

29

artemisinin: mechanism of action

must be activated likely via heme-irione, and activated form may form free radicals that target parasite proteins/lipids
-potent and fast-acting (10,000-fold reduction in 48h)
-low toxicity

no effect on liver stages

30

artemisinin: mechanism of resistance

-mutations in Kelch 13 gene
-delays progress through life cycle
-may alter stress response

31

why is artemisinin not appropriate for chemoprophylaxis?

short half life - recrudescence rate is high after short course of treatment

32

what other drugs is artemisinin commonly paired with?

mefloquine or lumefantrine

33

how must artemisinin be administered and why?

orally b/c insoluble - low bioavailability

34

which semisynthetic artemisinins are administered by the following routes: oral, IM, IV, rectal?

oral: dihydroartemisinin, artesunate, artemether
IM: artesunate, artemether
IV: artesunate
rectal: artesunate

35

is artemisinin more effective in one large dose or slowly administered over time?

associated with Cmax - more effective if given in a large bolus than if given at a lower concentration steadily over time

36

what is the purpose of combining artemisinin with other therapies?

-artemisinin provides rapid knockdown
-others with longer half-lives eliminate remaining parasites

37

what are some common combination therapies with artemisinin?

-most common = coartem (artemisinin + lumefantrine)
-amodiaquine
-mefloquine
-piperaquine

38

artemisinin AE

-generally well tolerated
-nausea
-vomit
-diarrhea
-dizziness
-not recommended in first trimester for uncomplicated malaria

39

describe hemoglobin metabolism by malaria parasites

parasites ingest host Hb -> degrade it to free a.a. + free heme in food vacuole -> free heme is toxic, so parasite polymerizes heme into hemozin, which is nontoxic

40

how does chloroquine (aka 4-substituted quinolines) mess up Hb metabolism by malaria parasites?

chloroquine accumulates in food vacuoles and inhibits heme polymerization, keeping it in free form, which is toxic to the parasite

*resistance associated with lack of accumulation in food vacuole

41

describe the pharmacokinetics of chloroquine

-well absorbed
-very large Vd - slowly released from tissues
-initial half-life = 3-5d
-terminal half-life = 1-2mo

42

is chloroquine more effective as one large dose or administered steadily over time?

slow release over time

43

chloroquine AE

-usually very well tolerated
-pruritus, especially in Africans
-potential for hemolysis in G6PD deficient patients
-contraindicated for psoriasis/porphyria, retina or visual abnormalities, myopathy
-don't give with antidiarrheal agent kaolin or antacids (interfere with absorption)

44

primary mechanism of chloroquine resistance

mutations in PfCRT1
-localized to food vacuole
-causes reduced accumulation of chloroquine
-no cross-resistance w/ mefloquine or quinine

45

other mechanism of chloroquine resistance

-over-expression of PfMDR1 (drug transporter)

46

what drink contains quinine?

gin and tonic (tonic water)

47

what kind of drug is quinine?

-blood schizonticide
-think mechanism is similar to chloroquine
-resistance rare but increasing

48

what is quinine the treatment of choice for?

-chloroquine-resistance falciparum (quinine sulfate p.o.)
-severe falciparum (quinidine gluconate i.v. w/ cardiac monitoring)

49

why is quinine inappropriate for chemoprophylaxis?

-shorter half-life
-toxicity

50

quinine AE

-cinchonism
-can stimulate uterine contractions
-hemolysis in G6PD deficiency -> blackwater fever (hemoglobinuria)
-can raise levels of warfarin and digoxin since metabolized by CYP3A4
-severe hypotension if infused too rapidly

51

what is cinchonism?

-tinnitus
-headache
-nausea
-dizziness
-flushing
-visual disturbances

52

mefloquine: prophylaxis or treatment?

both - effective against against falciparum and vivax
-resistance increasing

53

mefloquine AE

neuropsychiatric toxicity:
-seizures
-toxic psychosis
-sleep disturbance

54

list 4 other chloroquine-related compounds

-lumefantrine
-piperaquine
-amodiaquine
-halofantrine

55

what is the structure of primaquine? type of antimalarial?

8-aminoquinoline - gametocytocide

56

what metabolizes primaquine?

CYP2D6 - metabolism required for activity***
-mechanism may involve free radicals

57

contraindications of primaquine

-G6PD deficiency
-pregnancy
-breast feeding

58

what is another compound related to primaquine with same spectrum of activity and toxicities?

tafenoquine

59

what is malarone a combination of?

proguanil and atavaquone

60

why is malarone given as a combo?

atavaquone failed as monotherapy - developed resistance rapidly
-combination is synergistic

61

what type of drug is malarone?

kills liver and blood stages, but not hypnozoites

62

what is malarone effective for?

treatment for uncomplicated malaria and chemoprophylaxis

63

what is atavaquone also used to treat?

Toxoplasma gondii
Pneumocystis jiroveci

64

mechanism of action of atavaquone

(ubiquinone analog) selective inhibitor of malaria mitochondrial cytochrome bc1 complex -> inhibits electron transport, and mitochondrial membrane potential collapses

65

what is the main role for mitochondrial electron transport in falciparum

to regenerate ubiquinone - electron acceptor for parasite dihydroorotate DH - essential for pyrimidine biosynthesis in the parasite

66

mechanism of action of proguanil

prodrug: converted to cycloguanil
-selective inhibitor of bifunctional plasmodial dihydrofolate reductase-thymidylate synthetase (which is crucial for parasite purine and pyrimidine synthesis)
-proguanil also has inherent antimalarial activity - enhances mitochondrial toxicity of atavaquone

67

mechanism of action of pyrimethamine-sulfadoxine (fansidar)

-folate synthesis inhibitors
-slow acting erythrocytic schizonticides
-similar combination used to treat toxoplasmosis
-pyrimethamine: inhibits plasmodia DHF-reductase (DHFR)
-sulfadoxine: inhibits dihydropteroate synthase (DHPS)

68

other uses of antifolates

-toxoplasmosis: pyrimethamine + sulfadiazine/clindamycin
-pneumocystis: TMX or atavaquone

69

is use of single antifolates recommended?

no, b/c resistance develops easily
-synergistic effect allows 20-fold reduction in dose of each component

70

why was the combination of pyrimethamine and sulfadoxine chosen?

both have long half-lives:
-pyrimethamine: 90h
-sulfadoxine: 170h

71

what antibiotics are used as antimalarials, and what type of drugs are they?

blood schizonticides:
-tetra, doxy, clinda

72

what do antimalarial antibiotics target?

target components of the apicoplast

73

what is doxy commonly paired with for treatment of falciparum?

quinine or quinidine

74

which antimalarial antibiotic is used for chemoprophylaxis in areas with high resistance to mefloquine?

doxy