Pharmacotherapy/Treatment Of Malaria

Malaria is an endemic disease that affects people all over the world. It is more severe in children, pregnant women, non immune immigrants and immunocompromised persons. Very few countries have been able to eliminate malaria. A country that does not record any case of malaria over a period of two years is considered to have eliminated malaria. The United States of America (USA) is not on the list. This is because the majority of those infected in the USA are travellers coming from endemic areas.

Mosquito

Cause Of Malaria

Malaria is caused by plasmodium parasites. There are five species of plasmodium parasites responsible for malaria. They are plasmodium ovale, plasmodium falciparum, plasmodium vivax, plasmodium malariae and plasmodium knowlesi which is the newest among them.

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Plasmodium falciparum and plasmodium vivax pose the greatest threat. Plasmodium falciparum accounts for 99.7 percent of malaria in Africa, 50 percent in South East Asia, 71 percent in eastern Mediterranean coast and 65 percent in western Pacific. Plasmodium vivax is common in America with about 75 percent prevalence.

Plasmodium falciparum is common in the tropics and sub Africa region and not in the temperate regions. Africa has more malaria cases generally with 93 percent prevalence and 94 percent death recorded. A 2019 estimate places the number of cases at 228 million worldwide. Death toll in 2018 was 205000. Six countries accounted for more than half of all malaria cases in 2018 worldwide.

Nigeria topped the chart with 25 percent share of all new cases followed by democratic Republic of Congo having 12 percent. Uganda followed with 5 percent, côte d'Ivoire, Mozambique and Niger had 4 percent each. 67 percent (272000) of deaths occurred in under 5 years old children.

Mode Of Transmission

It is spread by the bite of an infected female anopheles mosquito. There are over 400 species of anopheles mosquito 30 of which are known to be responsible for transmitting malaria. They bite from dawn to dust. They suck blood to nourish their egg which they lay in stagnant water. The egg hatch into larva and then into adult.

The anopheles mosquito in Africa prefers human blood to those of animals. They also have a longer lifespan giving them the advantage of spreading a series of malaria before they die. Malaria is common during the rainy seasons due to the fact that female mosquitoes are more active laying eggs in stagnant water.

Other means of contracting malaria are blood transfusion, from mother to child (congenital malaria) and sharing needles. It is not spread by sex or contact.

A couple of conditions have been found to offer protection against some of the plasmodium parasite species. Hemoglobin S, thalassemia, hemoglobin C and glucose-6-phosphate dehydrogenase deficiency protect against plasmodium falciparum. Hemoglobin E has offered protection against plasmodium vivax.

Life Cycle Of Plasmodium Parasites

Following the bite of an infected anopheles mosquito, sporozoites enter the bloodstream and migrate to the liver (hypnozoites). After some days, it enters the bloodstream as merozoite. These merozoites enter the red blood cells (RBC) and develop into trophozoites. They multiply and rupture the RBC releasing many schizonts and few gametophytes. The schizonts reinfect other RBC while the gametophyte is sucked up by a feeding mosquito. The schizonts spend about a week inside the mosquito as oocysts, migrate to the mosquito salivary gland as sporozoites to complete the life cycle.

Classification Of Malaria

1. Complicated malaria

2. Uncomplicated malaria

Symptoms

Symptoms appear within a space of 7 days up to 1 year from the day of the infection depending on the species of the malaria. Plasmodium falciparum normally shows symptoms from 7 to 15 days but plasmodium vivax and plasmodium ovale can remain dormant in the liver up to one year before symptoms appear. However, they show similar symptoms with differences in severity. Malaria symptoms usually come in waves of 12 hours interval coinciding with when the RBC ruptures.

Uncomplicated

1. Fever (39°c)

2. Nausea and vomiting

3. Muscle pain

4. Fatigue

5. Headache

6. Chills

7. Sweating

8. Cough

Complicated

1. Severe anaemia

2. Kidney failure

3. Cerebral malaria (seizures, unconsciousness, abnormal behaviour or confusion)

4. cardiovascular collapse

5. hypoglycemia

Symptoms In Children

1. Severe anaemia

2. Respiratory distress in relation to metabolic acidosis or cerebral malaria

Complications

1. Hemoglobinuria

2. Lactic acidosis

3. Hemolysis

4. Noncardiogenic pulmonary edema

5. Multi organ failure

Diagnosis

Parasite based diagnostic testing is the microscopic examination of the parasite from blood smear under a light microscope used to count the number of parasites seen in a smear and identify the species. Rapid diagnostic tests use antigens and can be done at home using a home test kit. Result takes less than 30 minutes.

Pharmacotherapy/Treatment Of Malaria

Treatment depends on the type of parasite, severity, age of the person, medical history and pregnancy status. There are several antimalarials available. Majority are no longer effective especially in Africa as malaria parasites have developed resistance. However, some of those drugs are still being used in some countries where resistance has not been recorded. That is why you may find several articles on the use of these drugs. In Nigeria and Africa, the world health organisation (WHO) has recommended that artemisinin based combination therapy (ACT) be used for all malaria cases. They warn against the use of artemether base monotherapy (AMT) as resistance has also been recorded.

Complicated malaria is treated with injection. This happens when the patient has gotten to a state where swallowing drugs is not feasible.

Classification Of Antimalarial

There are two classification of antimalarials. They are based on activity and structure. This post will focus on classification based on activity.

Tissue schizonticides (prophylaxis): these drugs act on the primary tissue form of the plasmodium in the liver e.g pyrimethamine and primaquine.

Tissue schizonticides (relapse): they act in hypnozoites of plasmodium vivax and plasmodium ovale in the liver e.g pyrimethamine and primaquine.

Blood schizonticides: they act on the blood form e.g chloroquine, mefloquine, halofantrine, pyrimethamine, sulfadoxine, quinine, tetracycline, sulphadoxine, etc.

Gametocytes: these drugs destroy the sexual form of the parasite in the blood preventing transmission of the parasite into the mosquito during blood meal e.g chloroquine and quinine (plasmodium vivax and plasmodium malariae but not plasmodium falciparum) while primaquine works against all forms of malaria.

Sporontocides: they prevent the development of oocysts in the mosquito which abort the transmission e.g primaquine and chloroguanide.

Artemisinin based combination therapy (ACT)

Artemisinin is gotten from a tree called artemisia annua (sweet wormwood)

1. Artemether + lumefantrine

2. Dyhydroquinine + piperaquine

3. Artesunate + mefloquine

4. Artesunate + amodiaquine

Treatment Of Complicated Malaria

Artemether: Available as 80mg/ml injection and 40mg per capsule

Injection: 3.2 mg/kg intramuscularly as a loading dose, followed by 1.6 mg/kg daily until oral therapy.

Oral: 4mg/kg on the first day followed by 2mg/kg.

Arteether: Available as 150mg per 2 ml ampoule

Dose: 3 mg/kg once a day for 3 days, as deep intramuscular injection.

Artesunate: In India it is available as 50mg tablets and 60mg/ml injection. In China it is also available as 100mg suppository and in Switzerland is available as 200mg rectocap

Oral: 4 mg/kg.

Parenteral: Loading dose of 2.4 mg/kg followed by 2.4mg/kg after 12 hours, 24 hours and once daily thereafter.

Treatment of Uncomplicated Malaria

Artesunate + Amodiaquine

Dose: Artesunate 4mg/kg and amodiaquine 10mg base/ kg once a day 3 days

Artesunate + Mefloquine

Dose: Artesunate (4mg/kg once daily) for 3 days + mefloquine (25mg base/kg) as a split dose of 15mg/kg on day 2 and 10mg/kg on day 3. (Alternatively 8mg/kg mefloquine daily for three days)

Artesunate + sulfadoxine + pyrimethamine (SP)

Dose: Artesunate 4mg/kg once daily for 3 days and SP single dose of 25mg/kg and 1.25mg/kg respectively

Artemether + lumefantrine 

Dose: Artemether 1.5mg/kg and lumefantrine 9mg/kg at 0, 8, 24, 36, 48 and 60 hours

Dihydroartemisinin (DHA) + piperaquine (PPQ)

Dose: Child 5 to < 25 kg: 2.5 to 10 mg/kg daily of DHA + 20 to 32 mg/kg daily of PPQ

Child 25 kg and over and adult: 2 to 10 mg/kg daily of DHA + 16 to 27 mg/kg daily of PPQ

Non Artemisinin Based Combination Therapy

Sulfadoxine + pyrimethamine (SP)

Dose: Sulfadoxine 25mg/kg and pyrimethamine 1.25mg/kg as single dose

SP + amodiaquine

Arterolane + piperaquine (newly introduced)

Arterolane is one of the first fully synthetic non-artemisinin antimalarial compounds with rapid schizontocidal activity. Each tablet of fix dose combination consists of arterolane (150 mg) and piperaquine (750 mg). The recommended regimen is a 3-dose treatment schedule given as a single dose on diagnosis, followed with subsequent doses at 24 and 48 h after the first dose.

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Parasite Specific Treatment

Plasmodium falciparum and plasmodium knowlesi is best treated with quinine sulphate (quinidine) + doxycycline or clindamycin or sulfadoxine + pyrimethamine. Another alternative is to use artemether + lumefantrine, atovaquone + proguanil or mefloquine or chloroquine.

Plasmodium ovale and plasmodium vivax respond well to chloroquine + primaquine or primaquine + dihydroartemisinin + piperaquine. Primaquine is active against the dormant strain in the liver.

Prevention

Malaria can be prevented and should be prevented in high risk individuals. High risk individuals include travellers from malaria eliminated areas to malaria endemic zones. Others are pregnant women, weakened immune system persons like in human immunodeficiency virus (HIV), sickle cell anemia and children.

Research has shown that sickle cell patients don't fall easily to malaria infection. But malaria infection in sickle cell patients can be fatal.

Malaria In Pregnancy

Malaria in pregnancy can be complicated. It is recommended to prevent using prophylaxis. The use of sulfadoxine + pyrimethamine after the first trimester and for every three months until delivery is recommended. Also, proguanil can be used 200mg once daily.

The choice of a suitable drug for treating malaria in pregnant women has been long debated. This is because of the ethical considerations in organising clinical trials in pregnant women. Very limited data is available out there. Most of the data are pulled from individual practical approaches and not from research work.

The first trimester has been the major cause of concern. The recommended drugs are the use of chloroquine phosphate, atovaquone + proguanil, mefloquine or quinine sulphate + clindamycin. But if none of the above is available, artemether + lumefantrine combination can be used. Artemether + lumefantrine combination can be used both in the second and third trimester also.

Malaria In Sickle Cell Patient

Malaria prophylaxis is recommended for sickle cell disease patients. In Nigeria, daily proguanil or weekly pyrimethamine are the most commonly prescribed regimens individuals who are carriers for the sickle cell disease (with one sickle gene and one normal hemoglobin gene, also known as sickle cell trait) have some protective advantage against malaria. Treatment is the use of any suitable ACT.

Vaccine

RTS,S/ASOI is the first and only vaccine for malaria. It is effective against plasmodium falciparum. Four doses are given. There are several other vaccines undergoing clinical trials currently.

Malaria can be prevented without the use of drugs. Target is to break vector-human contact as much as possible. The WHO recommends sleeping under mosquito treated nets. Others are the use of insecticide, mosquito repellent creams applied to expose part of the body at night, long sleeves and trousers to cover as much body part as possible and remove all stagnant water and bush. Mosquito repellent creams can last up to 12 hours if it is made of 95 percent DEET or 6 hours if it is 35 percent DEET. Children should use those with 35 percent DEET. Some are also made from picaridin.

List Of Other Drugs

There are so many drugs that are active against malaria. Majority are not approved in Nigeria due to lack of efficacy or development of resistance to it.

1. Atovaquone + proguanil is given for prevention using a tablet daily. Drug is started two days before travelling to endemic areas and continued seven days after returning. It is contraindicated in pregnancy and breastfeeding women with children less than 5kg.

2. Quinine sulphate + doxycycline

3. Hydroxychloroquine is given once a week for prevention

4. Primaquine phosphate can be use daily for two weeks for dormant strains

5. Tenoquine is an adult drug use for relapse in plasmodium vivax

6. Clindamycin + proguanil for prophylaxis in pregnant women resistant to chloroquine