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233 FINAL > Antimicrobial 4: Malaria > Flashcards

Antimicrobial 4: Malaria Flashcards

1
Q

Vast majority of malaria cases arise from what?

A
  • Infection from a mosquito belonging to the Anopheles
    genus (Greek for “useless”)
  • Affects a quarter of a billion people and induces
    ~900,000 deaths/year
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2
Q

List the 5 Plasmodium genus of protozoan parasites:

A
  • Plasmodium falciparum

Fever, followed by headache and chills
Organ failure
Lower pyretic threshold - lower number of parasites required to cause fever

  • Plasmodium vivax
  • Plasmodium ovale
  • Plasmodium malariae
  • Plasmodium knowlesi
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3
Q

Most malarial infections worldwide are due to

infection with either Plasmodium ___ or ___

A

Plasmodium falciparum or vivax

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4
Q

Plasmodium ____ causes the most severe form

of the disease (organ failure and death)

A

Plasmodium falciparum

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5
Q

Only Plasmodium ___ and ___ are capable of producing hypnozoites that can lead to recurrent 4
infections

A

Plasmodium vivax and ovale

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6
Q

Biology of the Malarial Infection:

See slide 5 picture for details!

cannot prevent as no drugs target sporocytes

A

• Sporozoites are injected into the bloodstream from
the salivary gland of the mosquito (no treatment
available that targets sporozoites)

  • In the hepatocytes the parasites form thousands of merozoites that are then released into the bloodstream In P.vivax and P.ovale the liver forms persist and differentiate into dormant hypnozoites (asymptomatic)
  • The merozoites infect the erythrocytes and develop into trophozoites and then multinucleated schizonts

• Schizonts divide into new merozoites that infect new erythrocytes
- this stage causes fever, symptoms

• After several cycles some merozoites develop into
female and male gametocytes and fuse together
forming a zygote when they reach the stomach of a
new mosquito

• The zygote colonizes the mosquito stomach wall,
where it grows forming thousands of new sporozoites.
These migrate to and colonize the mosquito salivary
glands

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7
Q

3 classes of antimalarial agents:

A

• Drugs for suppressive prophylaxis (Class I):
– Target the asexual red cell forms
- prevent the symptoms of malaria by targeting RBC stage

• Drugs for causal prophylaxis (Class II):
– Treatment of the initial hepatic stages

• Drugs for terminal prophylaxis and radical cure (Class III):
– Eradication of hypnozoites (only plasmodium vivax or ovale)

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8
Q

Class I antimalarial agents

Drugs

A
  • Arteminsinins
  • Chloroquine
  • Mefloquine
  • Quinine, Quinidine
  • Pyrimethamine
  • Sulfadoxine
  • Tetracyclines

most class 1 inhibit at RBC asexual stage

Some drugs prevent formation of gametocytes
Prevent transmission of mosquitoes, stop spread

Pyrimethamine and sulfadoxine combo promotes the gametocyte pdtn

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9
Q

Class II antimalarial agents

Drugs

A
  • Atovaquone
  • Proguanil

Class 2 drug - can get off of therapy faster after travel, getting both

primary liver stages and asexual RBC stage

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10
Q

Class III antimalarial agents

Drugs

A
  • Primaquine

primary liver, hypnozoite, gametocyte stages

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11
Q

Quinolines and Related Compounds

Heterocyclic aromatic compounds derived from
quinoline, also know as ?

A

1-benzazine or benzopyridine

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12
Q

Name most commonly used quinolines in the

treatment of protozoal infections: (4)

A
  • Cinchona alkaloids (quinine and quinidine)
  • chloroquine
  • mefloquine
  • primaquine
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13
Q

Quinoline

MOA

A

• Malaria parasites use the host’s hemoglobin and breaks it down as the
prime source for amino acids

• Heme is detoxified by polymerization into inert crystalline material called “hemozoin”, toxic

• Accumulation of chloroquine (and other quinolines, CQ) into the food vacuole causes:
– Inhibition of heme polymerization (via heme
polymerase) and generation of free radicals (ROS), buildup of heme, leads to damage to parasite membrane/proteins
– Increased vacuole pH and block of hemoglobin proteolysis

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14
Q

Development of Quinoline Resistance

How?

A

– Mutations in CQ transporters (Chloroquine resistance
transporter (CRT))
- pumps chloroquine out of vacuole

– Mutations in the plasmodium multidrug resistance protein (MDR)
• Resistance to other quinolines (quinine and
quinidine) may be determined by similar factors
• Resistance to mefloquine is often associated with
increased sensitivity to chloroquine and vice versa
- independent MOA

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15
Q

Cinchona Alkaloids - Quinine & Quinidine

Characteristics

A

• Quinoline methanol derivatives isolated from the
natural cinchona bark.

• They contain a quinuclidine ring attached to the
quinoline group

both are less effective and more toxic than chloroquine

• Quinine is a mixture of the d- and l-isomers
– Quinidine is the pure d-isomer and is more
effective as an antimalarial agent.

• Quinine and Quinidine are still used to fight
chloroquine-resistant P.falciparum or the erythrocytic
stages of the other malarias

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16
Q

Cinchona Alkaloids - Quinine & Quinidine

Pharmacology

A

• Quinine and quinidine acts primarily against
erythrocytic forms.
- Quinine is still one of the primary treatments of
choice for drug-resistant P. falciparum . It is also
gametocidal for P. vivax and P. malarie , but not for P.
falciparum .

• Generally not used for prophylaxis due to their
toxicity and short half-life.

• Curare-like effect on motor endplate of skeletal
muscle (used in the past for night cramps)

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17
Q

Cinchona Alkaloids - Quinine & Quinidine

AE

A

• * Cinchonism (tinnitus, high-tone deafness, visual
disturbances, headache, nausea & vomiting,
abdominal pain & diarrhea)
- visual, ear toxicity, GI fx

• * Hypoglycemia (due to insulin secretion)
- direct action on beta cells to release insulin

• * Blackwater fever

• Hypotension (rapid IV infusion)
• Cardiac dysrhythmias and fibrillation (acute over 
   dosage)
• Hypersensitivity
• Thrombocytopenia
18
Q

Cinchona Alkaloids - Quinine & Quinidine

Contraindication/Precautions

A

• Patients with optic neuritis, cardiac dysrhythmias, or
G6PD deficiency

• Should not be administered with mefloquine
(additive effects), toxicities

19
Q

Chloroquine

Pharmacology

A

• 4-aminoquinoline compound. The chlorine atom
attached to position 7 of the quinoline ring confers the
greatest antimalarial activity

• Highly active against erythrocytic forms of P.vivax , P.
ovale , P. malariae , and sensitive strains of P.
falciparum . Prophylaxis and treatment of choice with
these organisms. Also active on gametocytes of
P.vivax , P. ovale and P. malariae but not P. falciparum .
No activity against hypnozoites.

• Rapid activity. The erythrocytic forms of the parasite
can be eradicated in 48-72 hrs.

• Safely administered to children and pregnant women

20
Q

Chloroquine

AE

A

• * Bleaching of hair and discoloration of mucus
membranes

• GI upset
• Headache
• Visual disturbances
• Urticaria
• Convulsions
• Hypotension, vasodilation, cardiac arrhythmias (rapid 
   parental injection)
21
Q

Mefloquine

Pharmacology

A

• 4-quinoline-methanol compound structurally related
to quinine and developed to combat new strains of
drug-resistant P. falciparum

• Highly effective on erythrocytic forms of the parasite.
No activity against other stages

• Mainly used for prophylaxis and treatment of
chloroquine-resistant malaria caused by P. falciparum
and P. vivax

22
Q

Mefloquine

AE

A

• * Neuropsychiatric effects

• * Severe but reversible CNS toxicity (seizures,
confusion, psychosis, dysphoria, insomnia, vertigo) in
0.5% of patients

• * Aberrant atrioventricular conduction
- before not for pregant women due to still birth, now shown to be ok

  • GI disturbances (Vomiting)
  • Dizziness
23
Q

Mefloquine

Contraindication/Precautions

A
  • Seizures or neuropsychiatric disturbances

* Avoid co-administration with quinine or chloroquine

24
Q

Primaquine

Characteristics

A

• Effective against hepatic stages, latent tissue forms
and gametocytes of malaria parasites

• Mainly used for terminal prophylaxis and radical cure
of P. vivax and P. ovale malarias. Usually administered
in combination with drugs such as chloroquine that
will target the erythrocytic stages
- can be used with a class 1

25
Q

Primaquine

MOA

A

• Not fully understood, may generate reactive oxygen species and interfere with electron transport in the parasite
- increases oxidative stress

26
Q

Primaquine

AE

A
    • Acute hemolysis (in people with G6PD deficiency)

* Methemoglobinemia

27
Q

Primaquine

Contraindication/Precautions

G6PD deficiency

A
  • People with G6PD deficiency ( enzyme that helps protect red blood cells)
  • Patients with granulocytopenia
  • Pregnancy

G6PD important in pentosephosphate pathway for blood cells and lipids to form NADPH –> reduces glutathione reductase needed for antioxidants

  • If low G6PD, then low NADPH (up to ~45-fold), then low GSH to act as a buffer to keep proteins reduced.
  • Membrane proteins in the red blood cell become more readily oxidized, leading to increased fragility, and lysis when the cells deform as they go through the spleen and capillaries
28
Q

Artemisinins

Artemisinin ( Qinghaosu ) – sesquiterpene lactone endoperoxide derived from the weed qing hao (Artemisia annua )

Name the 4 drugs:

A

– Artemisinin
– Dihydroartemisinin
– Artemether
– Artesunate

29
Q

Artemisinins

Characteristics

A

USED ONLY FOR ACTIVE INFECTION NOT PROPHYLAXIS

• Potent, fast-acting, no major clinical evidence of
resistance, key role in combination therapies. Has
been recommended by WHO as first-line treatment
since 2006

• Work rapidly against asexual RBC stages

• Always provided in combination therapies (often with
mefloquine or lumefantrine) for most part now to
reduce the risk for parasite resistance (certain
regions in Asia are starting to show signs of
resistance)

30
Q

Artemisinins

MOA

A

• Endoperoxide bridge is believed to be critical to anti-
malarial activity, they all contain it

• Transported to the food vacuole of parasite, interacts
with Fe 2+ (from heme) and converts to free radical, increase oxidative stress

• Irreversibly inhibits – calcium-dependent ATPase in 
   the ER (PfATP6)
31
Q

Artemisinins

AE

A
    • Transient heart block
    • Decrease in blood neutrophils

• Fever
• Neurotoxicity (brain stem nuclei regulating auditory f unction)???
Neurotoxicity (brain stem nuclei regulating auditory function)???

32
Q

Folic Acid Antagonists (Sulfadoxine + Pyrimethamine)

Malaria parasites depend on what?

MOA

AE

A
  • Malaria parasites depend on folate metabolism for purine and pyrimidine synthesis
  • Sulfonamides (sulfadoxine) and pyrimethamine inhibit two adjacent reactions in the folate biosynthetic pathway
  • Pyrimethamine = 2,4-diaminopyrimidine efficient against the liver and erythrocytic stages of P. falciparumAlso used against Toxoplasma gondii and other related protozoa
  • sulfa inhibits DHPS (dihydropteroate synthase) and pyrimethamine inhibits DHFR (dihydrofolate reductase)

AE
- may cause SJS
• **Not safe during 1st trimester of pregnancy (neural tube defects)

33
Q

Folic Acid Antagonists (Proguanil + Atovaquone)

What is Proguanil & Atovaquone?

AE?

A

• Proguanil is chemically related to pyrimethamine and
the active form is the triazine metabolite cycloguanil

• Atovaquone (hydroxynapthoquinone) is a lipophilic
analog of ubiquinone, highly selective for active
asexual blood stage

  • Nausea and vomiting
  • Abdominal pain & diarrhea
34
Q

Folic Acid Antagonists (Proguanil + Atovaquone)

MOA

A

• Inhibitor of dihydrofolate reductase (proguanil)

• Atovaquone acts on mitochondrial cytochrome bc 1
complex to inhibit ETC and decrease mitochondrial
membrane potential (ubiquinone is essential for
dihydroorotate dehydrogenase activity)

• The drug combination acts synergistically
resistance may occur, so combo used

35
Q

Antibiotics for malaria

Which 2 antibiotics are useful to treat malaria?

A

*Tetracycline and *doxycycline

36
Q

Antibiotics for malaria

*Tetracycline and *doxycycline
MOA

A

• Slow-acting toward blood stage – short term
chemoprophylaxis – chloroquine/mefloquine resistant
areas

• Inhibit protein translation in the parasite plasmid –
delayed death of progeny (same mechanism
discussed in antibacterial pharmacology)

• Slow mode of action makes these drugs ineffective as
single treatments (given in combination with quinine,
quinidine or artesunate)

37
Q

Vast majority of malaria cases arise from infection
from a mosquito belonging to the Anopheles genus

– Most infections due to Plasmodium ___ or ___

  • Only Plasmodium ___ and ___ are capable of
    producing hypnozoites that can lead to recurrent
    infections
A
  • Plasmodium falciparum or vivax

- Plasmodium vivax and ovale

38
Q

Name 3 classes of antimalarial agents

A

– Target the asexual red cell forms (Class I)

– Treatment of the initial hepatic stages (Class II)

– Eradication of hypnozoites (Class III)

39
Q

____ based drugs prevent heme detoxification in the parasite

– but many strains of Plasmodium falciparum or vivax
are now resistant to chloroquine

A

Quinoline

40
Q

____ is the only agent that targets the hypnozoite form of Plasmodium vivax and ovale

– Mechanism of action not fully understood, may
generate reactive oxygen species and interfere with
electron transport in the parasite

A

Primaquine

41
Q

____ are the most rapidly acting antimalarials against the asexual RBC stage

– Converted in the liver to the active metabolite
dihydroartemisinin and its endoperoxide bridge is
believed to be critical to anti-malarial activity

A

Artemisinins

42
Q

____ can also be used to treat malaria

– Sulfadoxine-pyrimethamine combination no longer
used as frequently

– Proguanil-atovaquone act synergistically with a
better overall safety profile and less risk for
resistance

A

Folic acid antagonists

233 FINAL (15 decks)

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