Artemisinin has a potency of _______ fold greater than other traditional class I agents and acts rapidly against which phase of the organism?
10-100; Asexual erythrocytic (no effect on liver stage organism)
_________ within the parasite catalyzes cleavage of an ________ bridge in the artemisinin molecule.
Heme iron; endoperoxide
Once the endoperoxide bridge is cleaved in the artemisinin molecule, the rearrangement produces a ___________ radical that ________ parasitic macromolecules. Name one target of this.
Carbon-centered; alkylates; ortholog of sarco/endoplasmic reticulum Ca++-ATPase
In the body, artemisinin is converted to ________ which has anti-malarial activity.
Aretmisinin is indicated for the initial treatment of what type of infections?
What is ACT? Why is it used?
Artemisinin combination therapy; artemisinin is used to rapidly reduce (incompletely) the level of parasite burden while another agent is used to eliminate organisms at other phases. It will also help prevent resistance.
List examples of class II drugs.
Atovaquone and Proguanil
__________ is a highly lipophilic analog of ubiquinone.
Atovaquone is active against liver stage of P. falciparum, but not ___________ hypnozoites.
Atovaquone acts at the _____________________ of the malaria mitochondria to inhibit ____________ which collapses the mitochondrial membrane potential and stop _____ production.
Cytochrome bc1; electron transport; ATP
Atovaquone can be administered with a ________ to get a more complete collapse of membrane potential.
Biguanide (such as proguanil)
Resistance to Atovaquone can occur rapidly due to _________ in the _____________ gene.
Mutations; cytochrome b
Pyrimethamine is a class ___ drug based on its
I; Diaminopyrimidine ring
Although resistance is fairly widespread, pyrimethamine is used in combination with _______ helps to synergize its action.
Pyrimethamine works by inhibiting what type of activity? This activity takes place in humans, so why can it still be used?
Dihydrofolate reductase; It inhibits the dihydrofolate
reductase activity of plasmodia at concentrations far less than human enzymes.
Dihydrofolate reductase activity is present in the same
protein as _________ which will be suppressed as well.
What is the effect of adding a sulfonamide to pyrimethamine?
It blocks two steps in nucleotide biosynthesis
Describe the two steps in nucleotide biosynthesis blocked by giving a combination of pyrimethamine and sulfonamide.
Step one: sulfonamides inhibit dihydropteroic acid formation from p-aminobenzoate by dihydropteroate synthase. Step two: pyrimethamine inhibits dihydrofolate reductase reducing tetrahydrofolate formation. (Results in a late effect on plasmodial development to schizonts in the liver and erythrocytes)
Combination therapy of pyrimethamine and sulfonamide or sulfone is restricted to treatment of _________-resistant P. falciparum.
Proguanil is use for P. falciparum infections and controls which two stages?
Primary liver and asexual erythrocyte
What is the active metabolite of proguanil?
For proguanil, _________ selectively inhibits plasmoidial dihydrofolate reductase-thymidylate shynthetase causing ______ synthesis to be inhibited.
Triazine metabolite; DNA (along with folate cofactors)
Proguanil is metabolized by ______ to cycloguanil. About 20% of which two ethnicities are deficient in this oxidative activity?
CYP2C; Asians and Kenyans
Why is proguanil usually given in combination with
Due to rapid resistance development
What are the mainstay anti-malarial agents for the past 400 years?
Quinolines (chloroquine and hydroxycholroquine more widely used)
Chloroquine is very effective against _______ forms of all species of Plasmodium except for some strains of __________. They are the agents of choice for both prophylaxis and treatment of these infections.
Erythrocytic; P. falciparum
Describe the mechanism of action for chloroquine.
Plasmodium use hemoglobin as primary source of amino acids. Acts by concentrating in parasite food vacuoles, preventing the polymerization of heme (Ferriprotoporphyrin IX) into hemozoin and thus eliciting parasite toxicity due to buildup of free heme.
What is Crt?
Chloroquine resistance transporter. It may code for
a vacule transporter by which chloroquine enters.
What are the two active metabolites of chloroquine?
Desethylchloroquine and bisdesethlychloroquine
Chloroquine is used for prophylaxis and treatment for ________, _____, and ________ in non-resistant areas.
P. malariae, ovale and vivax
Chloroquine is used with primaquine because
chloroquine has no activity against what?
Liver plasmoidial forms
Other than malaria, what else is chloroquine indicated for?
When is toxicity seen with chloroquine and what results?
Too rapid IV infusion; extensive CNS toxicity
including convulsions and coma. Can also have cardiovascular toxicity.
Chloroquine is an inhibitor of CYP___.
The mechanism of action of quinine is the same as _________.
Quinine is _____ toxic and _____ effective than chloroquine.
Why can quinine be used for symptomatic relief of myotonia congenita?
It can antagonize tetanic stimulation of skeletal muscle.
Quinine is extensively metabolized by CYP____.
The active metabolite of quinine is ________ which can cause toxicity in ______________ patients.
3-hydroxyquinine; renally impaired.
Quinine is the treatment of choice for _________.
Drug-resistant P. falciparum
Quinine is available in the U.S. as _______ and, prior to 1995, was marketed to treat ________.
Quinidine; nocturnal leg cramps
Primaquine is effective against ______ forms of the
Primaquine is used for ___________ and _____ for P. vivax and P. ovale.
Terminal prophylaxis; cure
At high doses, primaquine can cause ________________ because it is an analog of methylene blue.
In patients with _____________________, primaquine can cause acute hemolysis and hemolytic anemia.
G6P dehydrogenase deficiency
____________ are slow-acting blood schizontocides used as monotherapy.
Tetracylcines are used for travelers going to which two
resistant endemic areas?
Chloroquine and methoquine
_________________ is equivalent to tetracycline action.
Malarial resistance to ___________/___________, ___________ and ________ has been found in Southeast Asia.
Sulfadoxine/pyrimethamine, mefloquine and halofantrine