antimalarials MT1 Flashcards
if a mosquito is infected with __________ it will inject elongated sporozoites into the blood stream of the human
Plasmodium
sporozoites travel to the liver where they enter liver cells and rapidly divide asexually. this asexual division called schizogony generates the next life cycle form called __________
merozoites
the released merozoites invade other liver cells and enter the hosts bloodstream where they evade __________
erythrocytes
once inside the erythrocyte, the merozoite begins to enlarge as a uninucleate cell called a ____________
Ring trophozoite
the trophozoites nucleus then divided asexually to produce a _______ which contains several nuclei
shizont
the shizont then divides and produced mono nucleated ________
merozoites
the erythrocyte ruptures and releases toxins throughout the body of the host bringing about the well-known cycle of fever and chills that is a characteristic of __________
malaria
Plasmodium enters a sexual phase when some merozoites in the erythrocytes develop into to gametocytes, cells capable of producing both male and female gametes. true or false: erythrocytes containing gametocytes rupture
false
what are the main symptoms of malaria
- headache
- nausea
- muscular pain
- high fever
how long does each malarial attack last
6-10 hrs
explain the three stages of a malarial attack
- cold stage: very cold and shivering
- hot stage: high fever, fast respiration and heart beat
- sweating stage: due to profuse sweating temperature goes down to normal
malaria secondarily causes enlargement of what organs
spleen and liver
true or false: there is no antimalarial agent that kills at the sporozoite level
true
all antimalarials target the liver stages besides these two which can target both the blood and liver stages
Atovaquone/Proguanil and Primaquine/Tefenoquine
this is a 4-quinolinemethanol derivative which is very bitter which re-emerged as the DOC for chloroquine-resistant strains of Plasmodium falciparum in recent years
Quinine
this was synthesized from 9-aminoacridine, a known antibacterial agent. it is a weak anti-malarial agent
Quinacrine
these two substituted quinolones are 4-aminoquinolones that have similar structures to the right half of Quinacrine
chloroquine and hydroxychloroquine
these two substituted quinolones are Quinolone-4-methanols. they have structures similar to the quinolinemethanol portion of Quinine
Mefloquine and Halofantrine
these two substituted quinolones are 8-aminoquinolones where the methoxyquinoline nucleus of Quinine and Quinacrine are retained
Pamaquine and Primaquine
explain the MOA of 4-substituted quinolones (4Q) e.g. chloroquine, hydroxychloroquine, Mefloquine, Halofantrine
- Hemoglobin degradation waste theory
- as we know, plasmodium uses host hemoglobin as a source of AA. this causes a waste product (hemozoin) that contains FPIX.
- when FPIX is combined with a 4Q, it is complex towards the erythrocytes and parasites which causes lysis of these cells - Weak base hypothesis
- being weak bases, 4Qs accumulate in the acidic lysosomes of the parasites
- an increase of pH of the lysosomes decreases the ability of lysosomal proteases to digest the hemoglobin and therefore there is less AA for the parasites
explain the MOA of 8-substituted quinolones (8Q) e.g. Palaquine and Primaquine
Likely due to the ability to generate reactive oxygen species (e.g. hydroxyl radicals)
How many chiral centers does Quinine have?
4
what is Quinine’s (+) isomer
Quinidine
these antimalarials are the most effective; they are well absorbed at GI and widely distributed in many tissues; tightly bound; slowly eliminated
chloroquine and derivates
chloroquines and its derivatives are metabolized by this process
N-dealkylation
true or false: the level of metabolism is correlated to the degree of resistance in chloroquine’s and their derivatives
true
if there is resistance to chloroquines & derivatives, what agent may be used
Amodiaquine (an artemisinin based combination therapy)
this is a derivative of chloroquine.
- structurally related to Amodiaquine
- well tolerated and content against P. falciparum and P. vivax
- an ACT partner drug
Pyronaridine
this derivate of chloroquine.
- well tolerated and potent
- bisquinolone structurally related to chloroquine
- an ACT partner drug
Piperaquine
what are the three pharmacological actions of chloroquine
- antimalarial activity
- other parasitic infections
- direct relaxant effect on vascular smooth muscle, anti-inflammatory, antihistamine
how does chloroquine resistance develop?
- efflux mechanism
- accelerated metabolism (dealkylation)
what is the half-life of chloroquine
3-10 days
true or false: chloroquine is concentrated in the retina
false - concentrated in liver, spleen, kidney, lungs and leukocytes. SELECTIVE ACCUMULATION in retina which may cause ocular toxicity if used for long periods of time at high doses
what are some ADRs of chloroquine
- N/V
- anorexia
- skin rashes
- photosensitivity
- ocular toxicity (at high doses for long time)
- long term may cause bleaching of hair
- insomnia
- depression seizures
- decrease in BP
- ST & T wave abnormalities
- cardiac arrest in children
this anti-malarial drug has CF3 blocked sites for metabolism (hydroxylation).
it is slowly metabolized to its inactive form but most of the parent drug excreted is in its unchanged form which decreases resistance
this is active against chloroquine-resistant strain
oral medication that is well absorbed
Mefloquine
true or false: the metabolite (Desbutylhalofantrine) of Halofantrine is less active than the parent compound
false - more active!!!!
true or false: Halofantrine has poor oral absorption
true - too lipophillic
this is an 8-aminoquinolone deriative
replacement of Pamaquine
99% metabolized
longer half life
Primaquine and Tafenoquine
this is used for multi-drug resistant strains of falciparum malaria. a key chemical feature of this is the presence of an endoperoxide. it is a highly effective antimalarial
artemisinins
this artemisinin semi-synthetic derivative is water soluble: for oral, rectal, IM or IV use. it must always be given with another antimalarial such as Mefloquine or Amodiquine to avoid development of resistance
Artesunate
this artemisinin semi-synthetic derivative is lipid soluble for oral, rectal or IM use. it is used to treat multi-drug resistant stains of P. falciparum malaria
Artemether
this artemisinin semi-synthetic derivative is a fast-acting blood schizontocide (against blood stage parasites). it is used for chloroquine-resistant P. falciparum malaria and cerebral malaria cases
Artemotil
what is the MOA of artemisinins
- artemisinins is first activated by intraparasitic heme-iron which catalyzes the cleavage of the endoperoxide
- a resulting free radical intermediate may then kill the parasite by alkylating and poisoning one or more of the essential malarial proteins
what is the first line for P. falciparum in regions where Chloroquine-resistance, that are often combined with other agents in order to decrease resistance
artemisinins and 3 derivatives
3 derivatives (DHA, artesunate and artemether)
true/false: artemisinins is commonly used for chemoprophylaxis
false - should not be used for chemoprophylaxis
what is the half life of artemisinins
only 1-2 hrs
what are some contraindications and toxicity concerns in artemisinins
- may cause neurological changes for young patients
- may cause decrease in some cell counts (e.g. neutrophils); this is reversible
- allergic rxn may occur (rare)
- should not be used in first trimester of pregnancy or for the tx of children 5kg or less
mono therapy of artemisinin would have to be extended beyond disappearance of parasites to prevent recrudescence. how can this be prevented?
artmesinin based combination therapy (ACT)
- combining a 3-5 day regimen of artemisinin compounds with one long acting drug like Mefloquine
what are some advantages of ACT (combination therapy)
- rapid parasitological cure
- high cure rates
- absence of resistance
- good tolerability profile
do ACT partner drugs have shorter or longer half life than arteminisin
longer! from 2-3 days up to 5 weeks!
whereas arteminisn is only 1-2 hrs
__________ is crucial for parasite de novo purine synthesis.
tetrahydrofolate (THF)
these are selective inhibitors of dihydrofolste reductase of plasmodium. they are used for the treatment and prevention of chloroquine-resistant strains. they are slowly absorbed, 90% protein bound and have a half-life of 85-100hrs
Pyrimethamine and Sulfadoxine
what enzyme in THF acid synthesis does Sulfadoxine inhibit
Pteridine synthase
what enzyme in THF acid synthesis does Pyrimethamine inhibit
dihydrofolate reductase
this is a lipophilic analog of ubiquinone
- the electron acceptor for parasites cytbc1 complex inhibits parasite dihydroorotate dehydrogenase, an essential enzyme for pyrimidine synthesis, inhibits electron transport, collapse mitochondrial membrane potential, inhibits regeneration of ubiquinone
- has two peaks after single
- having with a fatty meal increases absorption
Atoavaquone
this is structurally related to pyrimethamine.
selectively inhibits plasmodium dihydrofolate reductase-thymidylate synthetase that is crucial for parasite de novo purine and pyrimidine biosynthesis
Proguanil
therapeutic uses of this include:
- a 3 day regimen for treating mild to moderate attacks of chloroquine or Fansidar (Pyrimethamine and Sulfadoxine) resistant P. falciparum malaria
- the same 3-day regimen followed by a primaquine course for treating P. vivax malaria
Atoavaquone and Proguanil (Malerone)
this combination therapy is I.V. and can be used for severe malaria patients unable to take oral medications
quinidine +
- tetracycline
- doxycycline
- clindamycin
what is the recommended duration for prophylaxis of malaria
1-2 weeks before traveling or 4 weeks after returning form a endemic area
what tx options can be used for chloroquine sensitive malaria
chloroquine and hydroxychloroquine
what options can be used for chloroquine resistant malaria
mefloquine
doxycycline
atovaquone + proguanil
what option should be used if travelling to an area that has mainly P. vivax
Primaquine (8Q)
