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
[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.
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