Anti-Malarials

Question 1

Which parasites cause malaria?

Answer 1

Plasmodium falciparum, vivax, malariae, ovale.

Question 2

In 2015, how many deaths did malaria cause?

Answer 2

429,000.

Question 3

Which continent carries a disproportionately high share of the global malaria burden?

Answer 3

Africa.

Question 4

What agents are commonly used to treat or prevent malaria?

Answer 4

Chloroquine, mefloquine, primaquine, proguanil, pyrimethamine.

Question 5

What is chloroquine used for?

Answer 5

The prophylaxis of malaria in areas of the world where the risk of chloroquine-resistant falciparum malaria is still low.

Question 6

What is mefloquine used for?

Answer 6

Used for prophylaxis of malaria in areas of the world where there is a high risk of chloroquine-resistant falciparum malaria.

Question 7

What is primaquine used for?

Answer 7

Used to eliminate the liver stages of P. vivax or P. ovale following chloroquine treatment.

Question 8

What is proguanil used for?

Answer 8

Used (usually with chloroquine) for the prophylaxis of malaria.

Question 9

What is pyrimethamine used for?

Answer 9

It is used with sulfoxadine and shouldn’t be used alone.

Question 10

By what mechanisms do anti-malaria drugs work?

Answer 10

Interference with haem disposal mechanisms, inhibition of parasitic dihydrofolate reductase, free radical formation and alkylation, interfering with parasitic mitochondrial electron transport.

Question 11

Why are multiple mechanisms targeted in the treatment of malaria?

Answer 11

This improves the chance of defeating the disease and overcoming resistance.

Question 12

Which enantiomer of chloroquine is used in the prophylaxis/treatment of malaria?

Answer 12

Both, they both have pharmacological activity and neither are toxic.

Question 13

What are the consequences of parasitic haemoglobin metabolism? How does the malaria parasite combat this?

Answer 13

Haemoglobin is metabolised into heam which is toxic to the parasite, to combat this haem is cinverted into insoluble crystals of haemozoin through bio-crystalisation.

Question 14

Chloroquine is a basic drug; when it enters the parasitic digestive vacuole how does it change?

Answer 14

When chloroquine enters the parasitic digestive vacuole it becomes protonated so it can’t leave. Here it caps the growing crystal of haemozoin, preventing further crystallisation. This causes haem to build up to toxic levels, killing the parasite.

Question 15

How does chloroquine work to kill the malaria parasite?

Answer 15

It caps the growing crystal of haemozoin, preventing further crystallisation. This causes haem to build up to toxic levels, killing the parasite. It also forms a complex with haem which is highly toxic to the parasite by disrupting membrane function. These two effects lead to cell lysis and ultimately parasitic cell autodigestion.

Question 16

What other drugs work in the same way as chloroquine?

Answer 16

Mefloquine, primaquine, lumefantrine, quinine/

Question 17

What beverage has weak anti-malarial properties and why?

Answer 17

Tonic water as it contains a small concentration of quinine.

Question 18

Which anti-malarial drug’s use has been called into question based on serious negative side effects such as severe anxiety and paranoia?

Answer 18

Mefloquine (Lariam).

Question 19

What are the side effects of mefloquine (Lariam)?

Answer 19

Severe anxiety, paranoia, hallucinations, depression, feeling restless, unusual behaviour, feeling confused.

Question 20

What is the active metabolite of the anti-malarial drug proguanil?

Answer 20

Cycloguanil.

Question 21

How does the anti-malarial drug proguanil work?

Answer 21

Through inhibition of parasitic dihydrofolate reductase which prevents the formation of purines and pyrimidines, essential for the synthesis of DNA.

Question 22

What potential selectivity issue is there with proguanil? Is this of major concern?

Answer 22

The drug may potentially target mammalian DHFR however there is often enough difference between the enzymes for this to not be of concern.

Question 23

What is the major problem with proguanil?

Answer 23

Metabolism of proguanil to its active metabolite (cycloguanil) is carried out by CYP450 enzymes in the liver. Different races can have different levels of expression of these enzymes. African and Asian people usually have lower levels of the required enzymes, so do not produce enough of the active metabolite even after multiple doses. This is a problem as these peoples are often the most likely to be affected by malaria.

Question 24

How does pyrimethamine work in the treatment of malaria?

Answer 24

By inhibiting parasitic dihydrofolate reductase, preventing DNA synthesis.

Question 25

WHere did the anti-malarial drug artemisinin originate?

Answer 25

China.

Question 26

Why can't artemisinin be synthetically produced?

Answer 26

It is a very complex molecule, it must be derived from the herb.

Question 27

Although it can't be synthetically produced, can artemisinin be made into semi-synthetic forms? Name some.

Answer 27

Yes. Artesunate, artemether.

Question 28

What is the active metabolite of the anti-malarial drug artemether?

Answer 28

Dihydroartemisinin.

Question 29

How does artemether work to treat malaria?

Answer 29

It works against the erythrocytic stages of P. falciparum by inhibiting nucleic acid and protein synthesis. The full reaction isn't known however it is believed to involve a reaction with haem to produce cytotoxic free radicals.

Question 30

How does artemether provide rapid symptomatic relief for those suffering from malaria?

Answer 30

It has a rapid onset of action and is rapidly cleared from the body, possibly rapidly reducing the number of malaria parasites in the body.

Question 31

Artemether and lumefantrine are used in combination therapy for malaria; why is lumefantrine used?

Answer 31

It has a much longer half-life than artemether and is thought to clear residual parasites.

Question 32

How does atovaquone act to treat malaria?

Answer 32

It acts by selectively inhibiting mitochondrial electron transport and parallel processes such as ATP and pyrimidine synthesis.

Question 33

Why is atovaquone useful for patients who have undergone a bone marrow transplant and need treatment for malaria?

Answer 33

It does not cause myelosupression/bone marrow supression.

Question 34

What is myelosuppression/bone marrow suppression?

Answer 34

The decrease in the production of cells responsible for immunity (leukocytes), oxygen transport (erythrocytes), and normal blood clotting (thrombocytes).

Question 35

Recently, where has artemisinin resistance been seen?

Answer 35

Cambodia, Laos, Myanmar, Thailand, Vietnam.

Question 36

What drug is P. falciparum resistant to in most parts of the world?

Answer 36

Chloroquine.

Question 37

What drug regimens are used to treat P. falciparum?

Answer 37

Quinine, mefloquine, proguanil with atovaquone. Or artemether with lumefantrine.

Question 38

What drug regimens are used to treat unknown or mixed malaria?

Answer 38

Quinine, mefloquine, proguanil with atovaquone. Or artemether with lumefantrine.

Question 39

In malaria infections caused by P. vivax or P. ovale, what radical treatment is required?

Answer 39

Primaquine to destroy the parasites in the liver, preventing relapse.

Question 40

What is the drug of choice for the treatment of benign malaria?

Answer 40

Chloroquine.

Question 41

What is the most effective strategy for the prevention of mosquito bites, to prevent malaria?

Answer 41

Mosquito nets impregnated with permethrin.

Question 42

What non-pharmacological interventions can be used to prevent mosquito bites leading to malaria?

Answer 42

Mosquito nets, vapourised insecticides (coils, sprays), DEET lotions, wearing long sleeves and trousers at dusk.

Question 43

How long should mefloquine be used for prophylaxis of malaria?

Answer 43

One week before travel to the exposed area continued for the length of the trip then 4 weeks after returning.

Question 44

How long should atovaquone/proguanil be used for the prophylaxis of malaria?

Answer 44

1-2 days before travel to the exposed area continued for the length of the trip and then continued for one week after returning.