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Pharmacology > Antimalarials > Flashcards

Antimalarials Flashcards

1
Q

Plasmodium species?

A 
Four species of plasmodium typically cause human
malaria:
• Plasmodium falciparum
• Plasmodium vivax
• Plasmodium malariae
• Plasmodium ovale
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2
Q

Parasite Life Cycle of:

P. falciparum & P. malariae?

P. vivax & P. ovale?

A

P. falciparum & P. malariae
• only one cycle of liver cell invasion
• liver infections ceases in < 4 weeks
• only erythrocytic parasites have to be eliminated

P. Vivax and P. ovale:
• have a dormant hepatic stage
• erythrocytic and hepatic parasites have to be
eliminated

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3
Q

Incubation Period?

A
  • P. vivax: 2 →17 days
  • P. falciparum: 9 →14 days
  • P. ovale: 16 →18 days
  • P. malariae: 18 →40 days (can be years)
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4
Q

Symptoms?

A

• Malarial paroxysm (fever, anemia, jaundice, splenomegaly, hepatomegaly)
• In established infections, malarial paroxysms typically
occur about every 2-3 days

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5
Q

Overview P. falciparum?

A

• Most severe disease (microvascular effects)
• Only species likely to cause fatal disease if untreated
• Cerebral malaria (irritability → seizures → coma)
• Symptoms: eg, respiratory distress syndrome, diarrhea,
severe thrombocytopenia, spontaneous abortion,
hypoglycemia

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6
Q

Infecting Plasmodium species distinctive treatment points?

A

(a) P. falciparum can cause rapidly progressive severe
illness or death (in other species is very rare)
(b) P. vivax and P. ovale infections require treatment for
the hypnozoite forms dormant in the liver
(c) P. falciparum and P. vivax have different resistance
patterns in different geographic areas

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7
Q

How to treat Uncomplicated Malaria?

A

• Treat with oral antimalarials

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8
Q

Define complicated malaria?

A

Complicated Malaria
• One or more of following: impaired
consciousness /coma, severe normocytic anemia,
renal failure, pulmonary edema, acute respiratory
distress syndrome, circulatory shock,
disseminated intravascular coagulation,
spontaneous bleeding, acidosis, hemoglobinuria,
repeated generalized convulsions, and/or
parasitemia of >5%)
• Treat aggressively with parenteral
antimalarials

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9
Q

Major antimalarial drugs?

A
  • Chloroquine
  • Quinine and Quinidine
  • Mefloquine
  • Primaquine
  • Atovaquone
  • Sulfadoxine-pyrimethamine
  • Doxycycline
  • Artemisinins
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10
Q

Overview and applications of Chloroquine?

A

• Drug of choice for both treatment & prophylaxis of all P.
vivax and P. ovale malaria infections since 1940’s
• Use severely compromised by drug resistance
Clinical Applications
• Drug of choice in the treatment of non-falciparum and
sensitive uncomplicated falciparum malaria
• Preferred chemoprophylactic agent in areas without
resistant falciparum malaria

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11
Q

Chloroquine antimalarial action and MOA?

A

Antimalarial Action
• Highly effective against blood parasites
• NOT active against liver stage parasites
MOA
• Concentrates in parasite food vacuoles
• Prevents biocrystallization of hemoglobin breakdown
product heme to non-toxic hemozoin

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12
Q

Chloroquine PK and Resistance?

A

Pharmacokinetics
• Oral
• t1/2 = 3-5 days (only need to take once weekly)
Resistance
• P. falciparum: mutations in putative transporter, PfCRT are
common

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13
Q

Chloroquine AE?

A

• Generally well tolerated (at therapeutic doses)
• Pruritus (common in Africans)
• Nausea, vomiting, abdominal pain, headache, anorexia,
malaise, blurring of vision, urticaria (uncommon)
• Hemolysis (G6PD-deficient people)
• Can cause electrocardiographic changes

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14
Q

Chloroquine contraindications?

A

Patients with:
• psoriasis or porphyria (may precipitate attacks)
• retinal or visual field abnormalities
SAFE IN PREGNANCY & YOUNG CHILDREN

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15
Q

Quinine and Quinidine overview and clinical applications?

A

• Derived from cinchona tree bark
• First-line therapies for severe falciparum disease
• Resistance is uncommon but increasing
• Quinidine (stereoisomer of quinine)
Clinical Applications
• Parenteral treatment of severe falciparum malaria
(Quinidine)
• Oral treatment of falciparum malaria (alternative in
chloroquine-resistant areas) (Quinine)

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16
Q

Quinine and Quinidine antimalarial action and MOA?

A

Antimalarial Action
• Rapidly-acting, highly effective against blood parasites
• NOT active against liver stage parasites
MOA
• Depresses O2 uptake and carbohydrate metabolism
• Intercalates into DNA, disrupting parasite’s replication and
transcription

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17
Q

Quinine and Quinidine PK and Resistance?

A

Pharmacokinetics
• Quinine: oral treatment of uncomplicated malaria
• Quinidine: IV treatment for severe malaria
Resistance
• Likely to be increasing problem
• Already common in some areas of South-east Asia

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18
Q

Quinine and Quinidine AE?

A

• Cinchonism: tinnitus, headache, nausea, dizziness,
flushing & visual disturbances
• Hypersensitivity: skin rashes, urticaria, angioedema,
bronchospasm
• Hematologic abnormalities: hemolysis (G6PD
deficiency), leukopenia, agranulocytosis,
thrombocytopenia
• Hypoglycemia: stimulation of insulin release
• Uterine contractions: still used in treatment of severe
falciparum malaria in pregnancy
• Severe hypotension: too rapid IV infusion
• ECG abnormalities: QT prolongation
• Blackwater fever: hemolysis & hemoglobinuria (likely
hypersensitivity reaction)

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19
Q

Quinine and Quinidine Contraindications?

A

Discontinue if signs of:
• severe cinchonism
• hemolysis
• hypersensitivity

Avoid if possible in patients with:
• visual or auditory problems

Use with caution in patients with:
• underlying cardiac abnormalities

• Do not use concurrently with mefloquine
• Can raise plasma levels of warfarin & digoxin
• Reduce dose in renal insufficiency
Pregnancy
• FDA Category C (however benefits do often outweigh
risks in complicated malaria)

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20
Q

Mefloquine overview and MOA?

A

• Effective against many chloroquine-resistant strains
• Chemically related to quinine
MOA
• Destruction of the asexual blood forms of malarial
pathogens. Details unknown.

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21
Q

Mefloquine Clinical Applications?

A

• Chemoprophylaxis: effective against most strains of P.
falciparum and P.vivax
• Currently only medication recommended for
chemoprophylaxis in pregnant women in
chloroquine-resistant areas
• Treatment : can be used to treat mild to moderate acute
malaria caused by P.falciparum and P.vivax
• Mefloquine + artesunate used in treatment of
uncomplicated malaria in regions of Southeast Asia

22
Q

Mefloquine PK and Resistance?

A

Pharmacokinetics
• Oral only
• Elimination t1/2 = 20 days (weekly prophylactic dosing)
Resistance
• Uncommon but has been reported
• Associated with resistance to quinine but not chloroquine

23
Q

Mefloquine AE?

A

Serious neurological and psychiatric toxicities:
Dizziness, loss of balance, ringing in the ears, anxiety, depression, hallucinations

Weekly dosing:
Nausea, vomiting, diarrhea, dizziness, sleep & behavioral disturbances,rash

Higher treatment doses:
Leukocytosis, thrombocytopenia, aminotransferase elevations, arrhythmias, bradycardia

24
Q

Mefloquine Contraindications?

A

• Patients with history of:
Epilepsy, psychiatric disorders, arrhythmia,
cardiac conduction defects, sensitivity to related
drugs
• DO NOT coadminister with quinine, quinidine or
halofantrine
• Considered safe in young children & pregnancy

25
Q

Primaquine overview and Clinical applications?

A
  • Drug of choice for eradication of dormant liver forms of P. vivax and P. ovale
  • Also used for chemoprophylaxis (all strains)

Clinical Applications
• Therapy of acute vivax and ovale malaria
• Terminal prophylaxis of vivax and ovale malaria
• Chemoprophylaxis: protection against falciparum & vivax (toxicities are a concern – reserved for when other drugs cannot be used)

26
Q

Primaquine antimalarial action and MOA?

A

Antimalarial Action
• Only available agent active against dormant liver
forms of P. vivax and P. ovale

MOA
• Not completely understood (primaquine metabolites
believed to act as oxidants, disrupting mitochondria and
binding to DNA)

27
Q

Primaquine PK and Resistance?

A

Pharmacokinetics
• Oral
• Metabolites have less antimalarial activity but more
potential for inducing hemolysis

Resistance
• Resistant strains may require therapy to be repeated & dose to be increased

28
Q

Primaquine AE?

A
  • Generally well tolerated
  • Infrequent (nausea, epigastric pain, abdominal cramps, headache)
  • Rare (leukopenia, agranulocytosis, leukocytosis, cardiac arrhythmias)
  • Hemolysis or methemoglobinemia (especially in G6PD deficient patients)
29
Q

Primaquine G6PD Deficiency?

A
  • G6PD deficiency results in a decrease in NADPH and GSH synthesis, making the cell more sensitive to oxidative agents. This
    causes hemolysis.
    ** Primaquine oxidizes GSH to GSSG. Therefore, less GSH is available to neutralize toxic
    compounds.
    • Patients should be tested for G6PD deficiency before
    primaquine is prescribed.
    • For severely G6PD deficient patients withhold therapy & treat relapses
30
Q

Primaquine contraindications?

A
  • G6PD deficiency

* Pregnancy: fetus is relatively G6PD deficient (FDA category not yet assigned). DO NOT use during pregnancy

31
Q

Malarone components, clinical applications, antimalarial actions?

A

Malarone = atovaquone + proguanil

Clinical Applications
• Treatment & prophylaxis of P. falciparum

Antimalarial Action
• Active against tissue & erythrocytic schizonts
• Chemoprophylaxis can be started 1-2 days before travel
and discontinued 1 week after exposure

32
Q

Malarone MOA, PK, and AE?

A

MOA
• Disrupts mitochondrial electron transport

Pharmacokinetics
• Oral only

Adverse Effects
• Generally well tolerated
• Abdominal pain, nausea, vomiting, diarrhea, headache,
rash
• Do not use in pregnancy
33
Q

Inhibitors of Folate synthesis?

A

Used generally in combination regimens:
• Pyrimethamine
• Proguanil
• Sulfadoxine

34
Q

Inhibitors of folate synthesis clinical applications?

A

Clinical Applications
• Chemoprophylaxis: only in combination. Proguanil +
chloroquine = no longer recommended

• Intermittent Preventive Therapy: high-risk patients
receive intermittent therapy regardless of infection status

• Treatment of chloroquine-resistant falciparum malaria
: pyrimethamine-sulfadoxine commonly used. DO NOT
use for severe malaria

35
Q

Inhibitors of folate synthesis antimalarial action?

A 
Antimalarial Action
• Pyrimethamine + proguanil
Act slowly against erythrocytic forms of all
malaria species
• Proguanil
Some activity against hepatic forms
• Sulfonamides
Weakly active against erythrocytic schizonts
36
Q

Inhibitors of folate synthesis MOA?

A
  • Pyrimethamine + proguanil = inhibit plasmodial dihydrofolate reductase
  • Sulfonamides = inhibit dihydropteroate synthase
37
Q

Inhibitors of folate synthesis PK and resistance?

A

Pharmacokinetics
• Oral
Resistance
• Relatively common for P. falciparum

38
Q

Inhibitors of folate synthesis AE?

A

• Well tolerated (GI problems, rashes, itching)
• Proguanil (mouth ulcers, alopecia = rare)
• Pyrimethamine-Sulfadoxine (erythema multiforme,
Steven-Johnson syndrome, toxic epidermal necrolysis)
• Sulfadoxine (hematologic, GI, CNS, dermatologic & renal toxicity)
Pregnancy
• Proguanil = safe
• Pyrimethamine-sulfadoxine = safe

39
Q

Doxycycline overview and clinical applications?

A
  • Active against erythocytic schizonts of all human malaria parasites
  • NOT active against liver stage

Clinical Applications
• Used to complete treatment for severe falciparum
malaria (given along with quinine) after initial
treatment with quinine, quinidine or artesunate
• Chemoprophylaxis against most forms: must be
taken daily

40
Q

Doxycycline AE?

A

• GI, candidal vaginitis, photosensitivity
• Discoloration & hypoplasia of teeth, stunting of growth
• Fatal hepatotoxicity (in pregnancy)
• DO NOT use in pregnancy or children < 8y (FDA
Category D)

41
Q

Artemisinin four drugs route of administration?

A

Derived from qinghaosu plant
• Artesunate : oral, IV, IM & rectal admin
• Artemether: oral, IM & rectal admin
• Dihydroartemisinin: oral admin
• Coartem = artemether + lumefantrine

42
Q

Artemisinin clinical applications?

A

Clinical Applications
• Treatment of severe falciparum malaria (given IV)
• NO effect on hepatic stages
• Should not (in general) be used as single agent to protect against resistance

43
Q

Artemisinin MOA and PK?

A

MOA
• Appears to act by binding iron, breaking down peroxide
bridges leading to generation of free radicals that damage
parasite proteins.

Pharmacokinetics
• Very short t1/2 (IV therapy must be followed by a longer acting agent once patient is able to tolerate oral therapy)
• If used alone, artesunate must be administered 5-7 days (otherwise recurrent parasitemia results)

44
Q

Artemisinin AE?

A

• Overall remarkably safe (nausea, vomiting, diarrhea)
• Very high doses: neurotoxicity, QT prolongation
• More evidence for use in 2nd and 3rd trimesters of
pregnancy
• In 1st trimester can be used for treatment of severe
malaria

45
Q

Other Antimalarials?

A

Clindamycin
• Can be used as an alternative to doxycycline

Halofantrine
• Effective against erythrocytic stages of all parasites
• Use is limited by irregular absorption & cardiac toxicity
• Teratogenic

Lumefantrine
• Effective against erythrocytic stages of all parasites
• Available only as fixed-dose combination with artemether
• Causes minor QT prolongation (clinically insignificant)
• Well tolerated

46
Q

Malarial Chemoprophylactic for pregnant women:

Chloroquine-sensitive:

Chloroquine resistant

A

Chloroquine-sensitive:
Chloroquine

Chloroquine resistant:
Mefloquine

47
Q

Malarial Chemoprophylaxis:

Chloroquine-sensitive:

Chloroquine resistant

A

Chloroquine-sensitive:
Chloroquine

Chloroquine resistant:
Mefloquine, Doxycycline,
Primaquine

48
Q

Severe malaria in Pregnancy?

1st trimester and 2nd/3rd trimester?

A

1st trimester: Quinidine or artesunate

2nd and 3rd trimester?
First option = artesunate
Second option = artemether

49
Q

Severe Malaria recommended IV drug for all resistance and all species?(2 guideline recommendations)

A 
Quinidine + doxycycline
or clindamycin (can progress to oral quinine
\+ doxycycline)

Artesunate followed by
atovaquone-proguanil,
clindamycin, or
mefloquine

50
Q

Uncomplicated Malaria in Pregnancy by resistance:

Chloroquine sensitive-
Chloroquine resistant P.falciparum
Chloroquine resistant P.vivax

A

Chloroquine sensitive- Chloroquine / hydrochloroquine

Chloroquine resistant P.falciparum - 1. Mefloquine
2. Quinine + clindamycin

Chloroquine resistant P.vivax- Mefloquine

51
Q

Uncomplicated Malaria:
P.vivax chloroquine resistant:
P.vivax and P.ovale all regions(little resistance reported):

A 
P.vivax and P.ovale all regions(little resistance reported):
1. Chloroquine +
primaquine
2. Hydroxychloroquine +
primaquine
P.vivax chloroquine resistant:
1. Quinine + doxycycline
\+ primaquine
2. Atovaquone-proguanil(Malarone)
\+ primaquine
3. Mefloquine +
primaquine
52
Q

Uncomplicated Malaria:
P.falciparum:
P.falciparum(Chloroquine-resistant or unknown):
P.malariae(All regions (no known resistance):

A

P.falciparum: Chloroquine or
hydroxychloroquine

P.falciparum(Chloroquine-resistant or unknown):1. Atovaquoneproguanil
(Malarone)
2. Artemetherlumefantrine
(coartem)
3. Quinine +
doxycycline
4. Mefloquine

P.malariae(All regions (no known resistance):
Chloroquine /
hydroxychloroquine

Pharmacology (49 decks)

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