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Pharm > 2: Antiparasitics - Antimalarials > Flashcards

2: Antiparasitics - Antimalarials Flashcards

1
Q

which malaria is responsible for the most deaths?

A

plasmodium falciparum

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2
Q

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

A

tropics: falciparum

subtropics/temp: vivax

west africa: ovale

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3
Q

which malarias can be relapsing? why?

A

vivax and ovale - hypnozoites in the liver

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4
Q

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

A
  • falciparum
  • vivax
  • ovale
  • malariae
  • knowlesi
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5
Q

why is vivax generally less severe?

A

it is limited ti reticulocytes, whereas falciparum is not

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6
Q

what is important about the lifecycle of knowlesi?

A

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

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7
Q

describe the life cycle times for each malaria parasite?

A

liver stage ~7d

  • falciparum, vivax, ovale: 48h cycles in blood
  • malariae: 72h cycles in blood
  • knowlesi: 24h cycles in blood
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8
Q

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

A

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

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9
Q

what are the classic symptoms of uncomplicated malaria?

A
  • cold stage
  • hot stage
  • sweating stage
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10
Q

what are the more usual symptoms of uncomplicated malaria?

A
  • fever and flu-like symptoms: chills, headache, myalgias, malaise
  • anemia and jaundice
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11
Q

what are the symptoms of severe malaria?

A
  • 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)
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12
Q

what are the types of drugs used for malaria?

A
  • tissue schizonticides (kill liver stage)
  • blood schizonticides (kill erythrocytic forms)
  • gametocytocides (kill sexual stage, block transmission)
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13
Q

what is the only drug to kill malaria hypnozoites?

A

primaquine

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14
Q

what stage do all drugs work on?

A

asexual blood stages

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15
Q

when should you take malaria chemoprophylaxis?

A

before, during, and after travel

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16
Q

list 5 malaria chemoprophylaxis drugs

A
  • atovaquone + proguanil (malarone)
  • doxycycline
  • chloroquine
  • mefloquine
  • primaquine
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17
Q

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?

A
  1. atovaquone + proguanil
  2. all areas
  3. start 1-2d prior, end 7d after
  4. daily admin + short pretreatment
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18
Q

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

A
  1. all areas

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

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19
Q

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

A
  1. Aralen and generic
  2. chloroquine sensitive areas (mostly C and parts of S Am)
  3. start 1-2w prior, end 4w after
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20
Q

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

A
  1. Lariam and generic
  2. mefloquine sensitive areas
  3. start >2w prior, end 4w after
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21
Q

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

A
  1. if >90 vivax in area

2. start 1-2d prior, end 7d after

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22
Q

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

A

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

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23
Q

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

A

chloroquine (aralen) and hydroxychloroquine sulfate (plaquenil)

add primaquine if find out ovale/vivax

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24
Q

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

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

add primaquine if find out ovale/vivax

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25
Q

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

A
  • 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
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26
Q

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

A

artesunate - IV only

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

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27
Q

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

A

artemisinin

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28
Q

what type of chemical is artemisinin?

A

blood schizonticide

-sesquiterpene lactone endoperoxide (endoperoxide is active group)

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29
Q

artemisinin: mechanism of action

A

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

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30
Q

artemisinin: mechanism of resistance

A
  • mutations in Kelch 13 gene
  • delays progress through life cycle
  • may alter stress response
31
Q

why is artemisinin not appropriate for chemoprophylaxis?

A

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

32
Q

what other drugs is artemisinin commonly paired with?

A

mefloquine or lumefantrine

33
Q

how must artemisinin be administered and why?

A

orally b/c insoluble - low bioavailability

34
Q

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

A

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

35
Q

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

A

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

36
Q

what is the purpose of combining artemisinin with other therapies?

A
  • artemisinin provides rapid knockdown

- others with longer half-lives eliminate remaining parasites

37
Q

what are some common combination therapies with artemisinin?

A
  • most common = coartem (artemisinin + lumefantrine)
  • amodiaquine
  • mefloquine
  • piperaquine
38
Q

artemisinin AE

A
  • generally well tolerated
  • nausea
  • vomit
  • diarrhea
  • dizziness
  • not recommended in first trimester for uncomplicated malaria
39
Q

describe hemoglobin metabolism by malaria parasites

A

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
Q

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

A

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
Q

describe the pharmacokinetics of chloroquine

A
  • well absorbed
  • very large Vd - slowly released from tissues
  • initial half-life = 3-5d
  • terminal half-life = 1-2mo
42
Q

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

A

slow release over time

43
Q

chloroquine AE

A
  • 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
Q

primary mechanism of chloroquine resistance

A

mutations in PfCRT1

  • localized to food vacuole
  • causes reduced accumulation of chloroquine
  • no cross-resistance w/ mefloquine or quinine
45
Q

other mechanism of chloroquine resistance

A

-over-expression of PfMDR1 (drug transporter)

46
Q

what drink contains quinine?

A

gin and tonic (tonic water)

47
Q

what kind of drug is quinine?

A
  • blood schizonticide
  • think mechanism is similar to chloroquine
  • resistance rare but increasing
48
Q

what is quinine the treatment of choice for?

A
  • chloroquine-resistance falciparum (quinine sulfate p.o.)

- severe falciparum (quinidine gluconate i.v. w/ cardiac monitoring)

49
Q

why is quinine inappropriate for chemoprophylaxis?

A
  • shorter half-life

- toxicity

50
Q

quinine AE

A
  • 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
Q

what is cinchonism?

A
  • tinnitus
  • headache
  • nausea
  • dizziness
  • flushing
  • visual disturbances
52
Q

mefloquine: prophylaxis or treatment?

A

both - effective against against falciparum and vivax

-resistance increasing

53
Q

mefloquine AE

A

neuropsychiatric toxicity:

  • seizures
  • toxic psychosis
  • sleep disturbance
54
Q

list 4 other chloroquine-related compounds

A
  • lumefantrine
  • piperaquine
  • amodiaquine
  • halofantrine
55
Q

what is the structure of primaquine? type of antimalarial?

A

8-aminoquinoline - gametocytocide

56
Q

what metabolizes primaquine?

A

CYP2D6 - metabolism required for activity***

-mechanism may involve free radicals

57
Q

contraindications of primaquine

A
  • G6PD deficiency
  • pregnancy
  • breast feeding
58
Q

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

A

tafenoquine

59
Q

what is malarone a combination of?

A

proguanil and atavaquone

60
Q

why is malarone given as a combo?

A

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

61
Q

what type of drug is malarone?

A

kills liver and blood stages, but not hypnozoites

62
Q

what is malarone effective for?

A

treatment for uncomplicated malaria and chemoprophylaxis

63
Q

what is atavaquone also used to treat?

A

Toxoplasma gondii

Pneumocystis jiroveci

64
Q

mechanism of action of atavaquone

A

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

65
Q

what is the main role for mitochondrial electron transport in falciparum

A

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

66
Q

mechanism of action of proguanil

A

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
Q

mechanism of action of pyrimethamine-sulfadoxine (fansidar)

A
  • 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
Q

other uses of antifolates

A
  • toxoplasmosis: pyrimethamine + sulfadiazine/clindamycin

- pneumocystis: TMX or atavaquone

69
Q

is use of single antifolates recommended?

A

no, b/c resistance develops easily

-synergistic effect allows 20-fold reduction in dose of each component

70
Q

why was the combination of pyrimethamine and sulfadoxine chosen?

A

both have long half-lives:

  • pyrimethamine: 90h
  • sulfadoxine: 170h
71
Q

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

A

blood schizonticides:

-tetra, doxy, clinda

72
Q

what do antimalarial antibiotics target?

A

target components of the apicoplast

73
Q

what is doxy commonly paired with for treatment of falciparum?

A

quinine or quinidine

74
Q

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

A

doxy

Pharm (19 decks)

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