Malaria

Introduction:

Malaria is a life-threatening infectious disease caused by the Plasmodium parasite that is transmitted through the bites of infected Anopheles mosquitoes. The name "malaria" comes from the Italian words "mal" (bad) and "aria" (air), reflecting the belief that the disease was caused by the foul air emanating from swamps and marshes. [1]It is prevalent in tropical and subtropical regions, particularly in sub-Saharan Africa, where the majority of the world's malaria cases occur. According to the World Health Organization (WHO), malaria is a significant global health challenge, with an estimated 229 million cases and 409,000 deaths reported in 2019 alone [2].

The history of malaria can be traced back to ancient times, with the first recorded case found in the remains of a young child buried in Italy, dating back to 4500-1500 BC [3]. Malaria has had a significant impact on human history, with some scholars attributing its prevalence in sub-Saharan Africa to the underdevelopment of the region [4]. During the 19th century, malaria played a significant role in the colonization of Africa by European powers [5]. Despite significant advances in the prevention and treatment of malaria, it remains a significant public health concern. In recent years, there has been a growing concern about the emergence of drug-resistant strains of the parasite, which pose a significant challenge to malaria control efforts [6]. Additionally, the ongoing COVID-19 pandemic has had a significant impact on malaria control efforts, with disruptions to prevention and treatment services potentially leading to an increase in malaria cases and deaths [7]. Efforts to control and eliminate malaria have been ongoing for decades, with significant progress made in recent years. The WHO has developed a Global Technical Strategy for Malaria that aims to reduce the global malaria burden by 90% by 2030 [8]. New tools and technologies, such as long-lasting insecticidal nets, rapid diagnostic tests, and novel antimalarial drugs, have been developed to help combat the disease [9]. Preventative measures are crucial in the fight against malaria. The WHO recommends the use of insecticide-treated bed nets, indoor residual spraying, and early diagnosis and treatment to help control the spread of the disease [10]. Additionally, ongoing research and development efforts are focused on developing new tools and strategies to help eliminate malaria [11].

 

Species of Plasmodium parasite and their function

There are several species of Plasmodium that can infect humans, each with its own specific characteristics and effects. Here are some of the main species and their functions:

1. Plasmodium falciparum: This species is the most deadly and causes severe malaria. It can rapidly invade and destroy red blood cells, leading to organ failure and death if left untreated. [12]

2. Plasmodium vivax: This species causes less severe symptoms but can remain dormant in the liver and cause relapses of the disease months or years after the initial infection. [13]

3. Plasmodium malariae: This species causes a less severe form of malaria and has a longer incubation period than other species. It can persist in the bloodstream for several decades after the initial infection. [13]

4. Plasmodium ovale: This species is similar to P. vivax in that it can remain dormant in the liver and cause relapses of the disease. It is primarily found in West and Central Africa. [14]

5. Plasmodium knowlesi: This species is found in Southeast Asia and can infect both monkeys and humans. It is becoming an increasingly important cause of human malaria in the region. [15]

 

Life cycle of Plasmodium parasite

The life cycle of Plasmodium involves two hosts: a human host and a female Anopheles mosquito. The life cycle can be divided into two phases - the mosquito phase and the human phase.

Mosquito Phase:

1. Blood meal: A female Anopheles mosquito ingests the gametocytes (sexual stage of the parasite) of Plasmodium from an infected human host during a blood meal. [12]

2. Sexual Replication: The gametocytes mature and differentiate into male and female gametes within the mosquito's gut. [12]

3. Fertilization: The male and female gametes fuse to form a zygote, which develops into an ookinete. [12]

4. Penetration: The ookinete penetrates the midgut wall of the mosquito and forms an oocyst. [12]

5. Asexual Replication: The oocyst undergoes asexual replication, producing thousands of sporozoites (the infective stage of the parasite) inside it. [12]

6. Release of Sporozoites: The oocyst ruptures, releasing the sporozoites into the mosquito's body cavity, from where they migrate to the salivary glands. [12]

Human Phase:

1. Transmission: When the mosquito takes a blood meal, it injects the sporozoites along with its saliva into the human host. [12]

2. Invasion of Liver Cells: The sporozoites enter liver cells and replicate asexually, forming thousands of merozoites. [12]

3. Invasion of Red Blood Cells: The merozoites are released into the bloodstream, where they invade and replicate within red blood cells. [12]

4. Symptoms: The rupture of infected red blood cells leads to symptoms of malaria such as fever, chills, and anemia. [12]

5. Transmission to Another Host: When a mosquito bites an infected person, it ingests the gametocytes, completing the life cycle. [12]

Symptom of Malaria

Malaria is a potentially deadly disease caused by Plasmodium parasites transmitted by the bites of infected mosquitoes. The symptoms of malaria can vary depending on the severity of the infection, the species of Plasmodium involved, and other factors. Here are some common symptoms of malaria:

1. Fever: A high fever is one of the hallmark symptoms of malaria. It can come and go in cycles, depending on the species of Plasmodium involved. [16]

2. Chills and sweats: People with malaria often experience sudden, intense chills followed by profuse sweating as the fever breaks. [16]

3. Fatigue: Malaria can cause extreme fatigue and weakness, even in people who are otherwise healthy. [16]

4. Headache: Many people with malaria experience severe headaches, often accompanied by nausea and vomiting. [16]

5. Muscle and joint pain: Malaria can cause severe muscle and joint pain, which can make movement difficult. [17]

6. Anemia: Malaria can cause anemia, a condition in which the body doesn't have enough red blood cells to carry oxygen to the tissues. This can cause weakness, shortness of breath, and other symptoms. [17]

7. Jaundice: In severe cases, malaria can cause jaundice, a condition in which the skin and whites of the eyes turn yellow. This is a sign of liver damage. [17]

 

Anti-malarial drug [18]

Anti-malarial drugs are the agents that are used in the treatment of Malaria.

Classification of anti-malarial drugs

A.   Blood schizontocides: used for clinical & suppressive cure:

Ø Chloroquine (first choice)

1.     S-P combination (Fansidar)

S= Sulfonamides,P= Pyrimethamine.

Quinine or, Quinine + tetracycline

2.     M-S-P combination

M = Mefloquine , S = Sulfonamides, P Pyrimethamine

 

B.   Tissue schizontocides used for causal prophylaxis:

Ø Pyrimethamine

Ø Primaquine

C.   Tissue schizontocides used to prevent relapse:

Ø Pyrimethamine

Ø Primaquine

Ø Proguanil

D.   Gametocides:

Ø Primaquine.

E.   Sporontocides:

Ø Primaquine

Ø Chloroguanide

Mechanism of action of anti-malarial drugs [18]

Anti-malarial agents grossly divided into two groups.

First group: Drug form a complex with DNA that prevents DNA from acting as template for its own replication or transcription to RNA. Drug molecules are inserted between the base pairs of DNA double helix. This phenomenon results in the arrest of multiplication of malarial parasites.

-         Primaquine, Chloroquine and

-         Quinine act by this mechanism.

Second group: Folic requires conversion of tetra-hydro-folic acid for utilisation by the malarial parasites. This process of reduction requires dihydrofolic acid reductase. Drugs in this group either interfere incorporation of PABA into folic acid or bind to inhibit dihyrofolate reductase. Without folic acid cell division in the parasite is not achieved.

-         Chloroquine, Pyrimethamine, Sulfonamides and

-         Salfones act by this mechanism

 

Chloroquine [18]

Chloroquine is the most important member of 4-amino quinoline groups. The drug is very much active against the asexual erythrocytic form of all species of plasmodium

Pharmacological properties of chloroquine

                      I.            Chloroquine is a synthetic 4-amino-quinolone and is a highly effective blood schizonticide.

                   II.            Chloroquine may act by blocking the enzymatic synthesis of DNA and RNA in protozoal cells.

                III.            It has no effect on exoerythrocytic stages of plasmodia.

               IV.            It is rapidly and completely absorbed from the GIT.

                  V.            50%-60% of the drug is protein bound.

               VI.            Chlorogine has a very large apparent volume of distribution and the drug readily crosses the placenta.

            VII.            Chloroquine also has the properties of anti-inflammatory. extra-intestinal amoebicidal (liver) action.

Pharmacological action of Chloroquine [18]

A.   Anti-malarial effect: Blood schizonticidal against all four species. Remission of fever and parasitaemia occurs within 24-48 hours. No effects on sporozoites.

ü Mechanism:

Ø Causes fragmentation of parasite RNA.

Ø To be able to intercalate in the parasite DNA.

Ø Inhibit digestion of haemoglobin by the parasite and thus reduces the supply of amino acids necessary for parasite viability.

B.   Anti-amoebic effect: effective in amoebic liver abscess because it reaches a high concentration in the liver.

C.   Anti-inflammatory effect: particularly in the Rheumatoid arthritis, Discoid lupus erythematous and SLE.

ü Mechanism: chloroquine causes

Ø Inhibition of lymphocytes proliferation.

Ø Decreases leukocyte chemotaxis, lysosomal enzyme release. So prevent inflammatory response.

Ø Inhibit phospholipase A₂ and therefore reduces prostaglandin synthesis. So no inflammation.

D.   Anti-arrhythmic effect: acts as alternative drug to Quinidine.

ü Mechanism of anti-malarial action of chloroquine

Chloroquine is highly effective rapidly acting blood schizon- ticidal agent. The postulate mechanisms of anti-malarial action of chloroquine are as follows:

Ø Inhibition of plasma nucleic acid synthesis. Chloroquine acts by blocking the enzymatic synthesis of DNA and RNA in plasmodial cells by forming a complex with DNA that prevents replication or transcription of RNA.

Ø Inhibition of digestion f haemoglobin by parasite and thus reduces the supply of amino acids necessary for parasites viability.

 

Chloroquine

↓

Uptake by parasitized RBC

↓

Drug concentrates in lysosomal vacoules and causes alteration (raises) of lysosomal pH

↓

Interfere with lysosomal breakdown of haemoglobin.

 

Ø Interference with phospholipid metabolism within the parasite has also been proposed.

 

 

Pharmacokinetics of chloroquine [18]

Route of administration: oral, parenteral

Absorption: Rapid, complete from the gut.

Distribution: Large volume of distribution. Extensive tissue binding (heart, kidney, liver, spleen, retina and cornea)

Metabolism: Liver (metabolites have antimalarial activity)

Excretion: Urine

Plasma half-life: Five days.

 

Indication of Chloroquine

Ø Malaria (treatment and chemoprophylaxis)

Ø Extra-intestinal amoebiasis (Hepatic amoebiasis)

Ø Rheumatoid arthritis

Ø Discoid lupus erythematous

Ø Suppression of skin cancer induced by U-V light

 

Contraindication of Chloroquine

Ø Pregnancy

Ø Hepatic failure

Ø Psoriasis

Ø Retinal or visual field abnormality.

Ø Neurological and blood disorders.

 

Adverse effects of Chloroquine

Chief side effects

Ø Mild and transient headache

Ø Visual disturbance

Ø Abdominal discomfort.

Ø Discoloration of nail bed and mucous membrane

Ø Dizziness

Ø Haemolysis in G-6-PO, dehydrogenase deficient patient

 

 

References:

[1] World Health Organization. (2021). Malaria. https://www.who.int/news-room/fact-sheets/detail/malaria

[2] World Health Organization. (2021). Malaria. https://www.who.int/news-room/fact-sheets/detail/malaria

[3] Centers for Disease Control and Prevention. (2021). History of Malaria. https://www.cdc.gov/malaria/about/history/index.html

 

[4] Ghebreyesus, T. A. (2019). The history of malaria and its control. Advances in Experimental Medicine and Biology, 1149, 3-10. https://doi.org/10.1007/978-3-030-17950-1_1

[5] Packard, R. M. (2007). The making of a tropical disease: A short history of malaria. J

[6] World Health Organization. (2020). Global Technical Strategy for Malaria 2016-2030. https://www.who.int/publications/i/item/9789241564991

[7] World Health Organization. (2021). Malaria and the COVID-19 pandemic. https://www.who.int/publications-detail-redirect/malaria-and-the-covid-19-pandemic

[8] World Health Organization. (2020). Global technical strategy for malaria 2016-2030. https://www.who.int/publications/i/item/9789241564991

[9] WHO. (2021). Malaria. Retrieved April 29, 2023, from https://www.who.int/news-room/fact-sheets/detail/malaria

[10] WHO. (2022). Malaria prevention. Retrieved April 29, 2023, from https://www.who.int/news-room/q-a-detail/malaria-prevention

[11] WHO. (2021). Research and development for malaria. Retrieved April 29, 2023, from https://www.who.int/malaria/areas/research/en/

12. World Health Organization. (2020). Malaria. https://www.who.int/news-room/q-a-detail/malaria

13. Centers for Disease Control and Prevention. (2021). Malaria. https://www.cdc.gov/malaria/about/biology/index.html

14. Looareesuwan, S., Wilairatana, P., & Glanarongran, R. (1997). Malaria: clinical presentation and complications. In Malaria: Drugs, Disease and Post-genomic Biology (pp. 59-70). Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-2662-7_5

15. Singh, B., Daneshvar, C., & Vasudevan, A. (2016). Plasmodium knowlesi malaria in Malaysia. The Medical journal of Malaysia, 71(3), 117-124. [PubMed PMID: 27487649]

16. World Health Organization. (2020). Malaria. https://www.who.int/news-room/q-a-detail/malaria

17. Centers for Disease Control and Prevention. (2021). Malaria. https://www.cdc.gov/malaria/about/biology/symptoms.html

18. Yousuf, D. (2023). Apex Medical Pharmacology. Apex publication.