Pharmacology- Malaria

Question 1

What percentage of malaria fatalities are from P. falciparum?

Answer 1

90% of fatalities are from P. falciparum.

Question 2

Disadvantages of oral therapy for malaria?

Answer 2

only cover oral therapy, excluding vaccines, severe or complicated cases, intravenous therapy, cerebral malaria, and pregnancy.

Question 3

On what basis should an antimalarial drug be selected?

Answer 3

A drug should be selected based on its ability to exploit phenotypic differences between the host and the parasite, ensuring selective toxicity.

Question 4

What is Malarone used for?

Answer 4

Malarone is used for the treatment and prophylaxis of uncomplicated P. falciparum malaria and is a combination of atovaquone and proguanil hydrochloride.

Question 5

How does atovaquone work against malaria?

Answer 5

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.

Question 6

Why doesn’t atovaquone affect humans in the same way as the malaria parasite?

Answer 6

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.

Question 7

How does proguanil work as an antimalarial?

Answer 7

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.

Question 8

What is the role of proguanil in malaria treatment?

Answer 8

Proguanil is converted to cycloguanil, which inhibits the dihydrofolate reductase enzyme, crucial for DNA synthesis in the malaria parasite.

Question 9

How can malaria parasites develop resistance to atovaquone?

Answer 9

Resistance can develop through point mutations in the bc1 ubiquinol binding pocket, which decrease the drug’s efficacy.

Question 10

At which stage of the Plasmodium life cycle is atovaquone effective?

Answer 10

Atovaquone is effective against the sporozoites in the hepatic stage.

Question 11

Why are atovaquone and proguanil hydrochloride combined in Malarone?

Answer 11

The combination is used to treat and prevent uncomplicated malaria caused by P. falciparum, leveraging their different mechanisms of action for a synergistic effect.

Question 12

How does atovaquone interfere with malaria parasites?

Answer 12

Atovaquone acts as an analogue of ubiquinone and disrupts the mitochondrial electron transport chain in parasites, impeding ATP synthesis.

Question 13

What makes atovaquone a selective antimalarial drug?

Answer 13

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.

Question 14

What is the mechanism of action of proguanil in antimalarial therapy?

Answer 14

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.

Question 15

Why can proguanil be effective even in individuals with certain polymorphisms in the P450 enzyme system?

Answer 15

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.

Question 16

What is the rationale behind using a combination of atovaquone and proguanil (Malarone) for malaria?

Answer 16

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.

Question 17

How does chloroquine work to treat malaria?

Answer 17

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.

Question 18

In what context is mefloquine commonly used?

Answer 18

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.

Question 19

What factors contribute to chloroquine resistance in malaria parasites?

Answer 19

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.

Question 20

Why is atovaquone a good choice for both treatment and prophylaxis of malaria?

Answer 20

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.

Question 21

How does quinine act against the malaria parasite?

Answer 21

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.

Question 22

What are the mechanisms by which malaria parasites develop resistance to quinoline medications like chloroquine?

Answer 22

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.

Question 23

What are some common side effects associated with the antimalarial drug Malarone?

Answer 23

Side effects may include nausea, diarrhea or vomiting (which can reduce the absorption of atovaquone), dizziness, depression, and insomnia.

Question 24

What are some of the adverse effects associated with quinine use?

Answer 24

Quinine can cause hypoglycemia, as it stimulates insulin secretion. Overdosing on quinine can lead to hyperinsulinemia and potentially severe hypoglycemia.

Question 25

How does the malaria parasite Plasmodium falciparum develop resistance to multiple antimalarial drugs?

Answer 25

The parasite can express genes like PfMDR1 that lead to multidrug resistance, similar to mechanisms observed in tumor cells, allowing the parasite to survive a range of antimalarial agents.

Question 26

What happens when quinoline-containing compounds like chloroquine accumulate in the parasite’s food vacuole?

Answer 26

The accumulation of these weak base drugs in the parasite’s acidic food vacuole impairs the digestion of hemoglobin and the disposal of heme, leading to the buildup of toxic heme derivatives that are lethal to the parasite.

Question 27

How do genetic mutations contribute to quinoline drug resistance in malaria parasites?

Answer 27

Mutations in genes such as PfCRT (chloroquine resistance transporter) and PfMDR1 (multidrug resistance protein 1) can alter the function of proteins that transport the drug, leading to decreased intracellular drug concentration and resistance.

Question 28

What serious side effects have been associated with the use of mefloquine (Lariam)?

Answer 28

Mefloquine has been linked to potentially serious neuropsychiatric reactions, including insomnia, anxiety, psychosis, depression, suicidal ideation, and suicide.

Question 29

What are the pros and cons of using chloroquine in malaria treatment?

Answer 29

Chloroquine is widely used and effective with resistance being less prevalent even after 200 years of usage. However, P. falciparum resistance and toxicity if overdosed are significant drawbacks.

Question 30

What are the side effects of quinine overdose?

Answer 30

Overdose of quinine can lead to hypoglycemia due to increased insulin secretion, and hyperinsulinemia can result from direct stimulation of insulin release from the pancreas.

Question 31

What are the main mechanisms by which malaria parasites develop drug resistance?

Answer 31

The main mechanisms include mutations in the gene of target proteins, decreased drug accumulation due to increased efflux or decreased uptake, and parasites with mutations once exposed to drug pressure.

Question 32

What are Artemisinin-based combination therapies and why are they important?

Answer 32

ACTs are treatments combining an artemisinin derivative with another drug (like mefloquine or chloroquine) to improve efficacy and delay resistance development. They target multiple life stages and biological processes of the malaria parasite.

Question 33

What strategies are being used to eradicate malaria?

Answer 33

Strategies include the prevention of transmission by screening the whole population and treating infected individuals, targeting new proteins specific to Plasmodium, and the development of vaccines like Mosquirix.

Question 34

How are natural products contributing to malaria treatment?

Answer 34

Herbal and fungal products, often traditional medicines, are being explored for antimalarial properties, providing a vast source of potential new treatments.

Question 35

What is the proposed mechanism of action for the drug imatinib in malaria treatment?

Answer 35

Imatinib prevents schizont rupture by inhibiting red blood cell tyrosine kinase, which is activated by P. falciparum, and is RBC-specific, potentially preventing the parasite from evolving resistance.

Question 36

What contributes to the development of antimalarial drug resistance?

Answer 36

Resistance can develop through a combination of genetic mutations, polypharmacy pressures, and the use of monotherapies, leading to simultaneous resistance and cross-resistance to multiple drugs.

Question 37

What are some prospective strategies for tackling malaria?

Answer 37

Strategies include eradication efforts by screening and treating the entire population, discovering new drug targets specific to the Plasmodium species, and utilizing natural products for their antimalarial properties.

Question 38

What is a recent development in malaria vaccines?

Answer 38

The Mosquirix vaccine (GSK) is a recent advancement, representing a significant step forward in preventing malaria through immunization.

Question 39

How could imatinib be used in malaria treatment, and why is it a promising candidate?

Answer 39

Imatinib, by inhibiting RBC tyrosine kinase activated by P. falciparum, could prevent schizont rupture and the subsequent release of parasites, offering a new method of treatment that the parasite may not easily develop resistance against.