Pharmacology- Malaria Flashcards
What percentage of malaria fatalities are from P. falciparum?
90% of fatalities are from P. falciparum.
Disadvantages of oral therapy for malaria?
only cover oral therapy, excluding vaccines, severe or complicated cases, intravenous therapy, cerebral malaria, and pregnancy.
On what basis should an antimalarial drug be selected?
A drug should be selected based on its ability to exploit phenotypic differences between the host and the parasite, ensuring selective toxicity.
What is Malarone used for?
Malarone is used for the treatment and prophylaxis of uncomplicated P. falciparum malaria and is a combination of atovaquone and proguanil hydrochloride.
How does atovaquone work against malaria?
Atovaquone is a naphthoquinone that is effective against sporozoites in the hepatic stage. It acts as an analogue of ubiquinone, interfering with the mitochondrial electron transport chain and blocking ATP synthesis.
Why doesn’t atovaquone affect humans in the same way as the malaria parasite?
Atovaquone has low mammalian toxicity due to the specificity for the parasite’s mitochondrial electron transport chain, which has a structurally different ubiquinone binding site compared to humans.
How does proguanil work as an antimalarial?
Proguanil works as an antifolate by being converted to cycloguanil, which inhibits dihydrofolate reductase (DHFR), a critical enzyme in the folate pathway necessary for DNA synthesis and replication in the parasite.
What is the role of proguanil in malaria treatment?
Proguanil is converted to cycloguanil, which inhibits the dihydrofolate reductase enzyme, crucial for DNA synthesis in the malaria parasite.
How can malaria parasites develop resistance to atovaquone?
Resistance can develop through point mutations in the bc1 ubiquinol binding pocket, which decrease the drug’s efficacy.
At which stage of the Plasmodium life cycle is atovaquone effective?
Atovaquone is effective against the sporozoites in the hepatic stage.
Why are atovaquone and proguanil hydrochloride combined in Malarone?
The combination is used to treat and prevent uncomplicated malaria caused by P. falciparum, leveraging their different mechanisms of action for a synergistic effect.
How does atovaquone interfere with malaria parasites?
Atovaquone acts as an analogue of ubiquinone and disrupts the mitochondrial electron transport chain in parasites, impeding ATP synthesis.
What makes atovaquone a selective antimalarial drug?
Atovaquone’s selectivity comes from its binding to a ubiquinol oxidation pocket of the cytochrome bc1 complex that is structurally different in the malaria parasite compared to humans.
What is the mechanism of action of proguanil in antimalarial therapy?
Proguanil is converted to cycloguanil, which inhibits dihydrofolate reductase, interfering with the synthesis of tetrahydrofolate necessary for purine and pyrimidine synthesis, which is vital for DNA replication in the malaria parasite.
Why can proguanil be effective even in individuals with certain polymorphisms in the P450 enzyme system?
While polymorphisms in P450 can affect drug metabolism, proguanil still works because it does not solely rely on P450 for activation and has alternative pathways or targets.
What is the rationale behind using a combination of atovaquone and proguanil (Malarone) for malaria?
The combination takes advantage of atovaquone’s ability to interfere with mitochondrial electron transport and proguanil’s inhibition of dihydrofolate reductase, offering a dual mechanism of action that is particularly effective against malaria parasites.
How does chloroquine work to treat malaria?
Chloroquine accumulates in the acidic digestive vacuole of the malaria parasite, interfering with hemoglobin digestion and haem detoxification, leading to the buildup of toxic heme and death of the parasite.
In what context is mefloquine commonly used?
Mefloquine is used as a prophylactic drug in areas with high risk of chloroquine-resistant falciparum malaria, but it’s rarely used for treatment due to potential severe neuropsychiatric side effects.
What factors contribute to chloroquine resistance in malaria parasites?
Chloroquine resistance can arise from multiple gene mutations that lead to decreased drug accumulation, such as changes in the drug transporter PfCRT on the parasite’s food vacuole membrane and the expression of ATP-dependent P-glycoprotein, which pumps chloroquine out of the food vacuole.
Why is atovaquone a good choice for both treatment and prophylaxis of malaria?
Atovaquone is active against liver stage sporozoites, making it useful as a prophylactic drug, and it also contributes to the treatment of malaria by targeting the mitochondrial electron transport chain of the parasite.
How does quinine act against the malaria parasite?
Quinine is thought to interfere with the parasite’s ability to detoxify heme, which is a byproduct of hemoglobin digestion, thereby poisoning the parasite with its own waste.
What are the mechanisms by which malaria parasites develop resistance to quinoline medications like chloroquine?
Resistance mechanisms include mutations that decrease drug accumulation in the parasite’s vacuole, such as changes to PfCRT (chloroquine resistance transporter) and increased activity of efflux pumps that remove the drug from the vacuole.
What are some common side effects associated with the antimalarial drug Malarone?
Side effects may include nausea, diarrhea or vomiting (which can reduce the absorption of atovaquone), dizziness, depression, and insomnia.
What are some of the adverse effects associated with quinine use?
Quinine can cause hypoglycemia, as it stimulates insulin secretion. Overdosing on quinine can lead to hyperinsulinemia and potentially severe hypoglycemia.
