MALARIA

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1. Mal-aria (Bad air) till 1880

2. Tropical disease due to presence of sporozoa of

plasmodium

3. Transmitted to humans by the infected female

mosquito Anopheles

4. Malarial parasite is a single cell protozoa called

Plasmodium.

5. 300-500 millions cases of malaria detected out of

which 1.5-2.7 million death every year

6. Nine major species of anopheline mosquitoes

transmit malaria in India. In urban areas, malaria is

mainly transmitted by Anopheles stephensi

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• Malaria is caused by four species of protozoa

Plasmodium malariae.

P. falciparum. (more lethal)

P. vivax.

P. ovale (rare).

• The plasmodium transmitted to human by the bite of an infected female anopheles mosquito.

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• NMEP (National Malaria Eradication Program) in India

1958.

• Nearly complete eradication in due to

powerful insecticides.

• In 1970’s due to emergent of drug and

insecticides resistant all attempts failed.

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Life Cycle of Malarial Parasite

• Complex Sexual (in female mosquito) and asexual

Life cycle (in humans).

• Sexual Life Cycle: Fertilization takes place in

mosquito gut and Oocysts liberates matured

sporozoites which migrates and stay in

insects salivary glands.

• Asexual Life Cycle: These sporozoites then

passed to blood of another human to begin

asexual cycle

• NO AVAILABLE DRUGS ARE LETHAL TO

SPOROZOITES

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Zygote

Oocysts

Sporozoites

Sporozoites

Schizonts

Merozoites

Pre-erythrocyitc

state

Exo--

erythrocyitc

state

Merozoites

TropozoitesSchizogony

Asexual

Erythrocytic

stage

Blood

Schizonts

MerozoitesPyrogen + TNF-α+

Haem

Tropozoites

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Sporozoites hardly survived in blood hence get sheltered in Liver parenchymal cell

In Liver it divide and developed into multinucleated SCHIZONTS. Hosts are asymptomatic

(PRE-ERHTHROCYTIC STATE)

In Liver, Schizonts gets matured in 8-21 days to form mononucleated MEROZOITES liberated from liver and

released in blood stream

If the species is P.vivax / P.ovale,

some merozoites re-enters liver

cell and form dormant

HYPNOZOITES (Sleeping form, which may lasts for several month and

may get relapse)

If the species is P.

falciparum, merozoites bind

to erythrocytes and forms

TROPHOZOITES

EXO OR PARA

ERYTHROCYTIC

STATE

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•The malaria parasite life cycle involves 2 hosts. During a blood meal, a malaria-

infected female Anopheles mosquito inoculates sporozoites into the human host.

Sporozoites infect liver cells.

There, the sporozoites mature into schizonts.

The schizonts rupture and release merozoites. This initial replication in the liver is

called the exoerythrocytic cycle.

Merozoites infect RBCs. There, the parasite multiplies asexually (called the

erythrocytic cycle). The merozoites develop into ring-stage trophozoites.

Some then mature into schizonts.

The schizonts rupture, releasing merozoites.

Some trophozoites differentiate into gametocytes.

During a blood meal, an Anopheles mosquito ingests the male (microgametocytes)

and female (macrogametocytes), gametocytes beginning the sporogonic cycle.

In the mosquito's stomach, the microgametes penetrate the macrogametes,

producing zygotes.

The zygotes become motile and elongated, developing into ookinetes.

The ookinetes invade the midgut wall of the mosquito where they develop

into oocysts.

The oocysts grow, rupture, and release sporozoites, which travel to the mosquito's

salivary glands. Inoculation of the sporozoites into a new human host perpetuates

the malaria life cycle.10

• During merozoite maturation in RBC, host’s

Hb is digested and transported to parasites

food vacuole and provides amino acids

• Free haem which may be toxic to parasite is

polymerised to haemozoin by parasitic haem

polymerase

• RBCs infected with merozoite, ruptures and

releases thousands of merozoites along with

pyrogens, TNF- α and polymerised haem to

show symptoms of Malaria

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• P. vivax causes BENIGN TERTIAN MALARIA

– Benign as it is rarely fatal

– Tertian as fever is on every 3rd day (48 h)

– Relapse may occur because dormant hypnozoites reside in

liver

• P. ovale infection has periodicity and relapse similar

to P. vivax but is milder and can be cured

• P. malariae causes QUARTAN MALARIA

– It has 72 h cycles

– No exo-erythrocytic stage but relapse may occur

• P. falciparum causes MALIGNANT TERTIAN MALARIA

– Malignant as it is severe form of malaria

– Tertian as fever occurs every after 3rd day

– Infected RBCs forms clusters called ROSETTES. Such

rosettes may block capillaries of vital organs causing renal

failure and encephalopathy (Cerebral Malaria)12

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Clinical presentation

• Early symptoms– Headache

– Malaise

– Fatigue

– Nausea

– Muscular pains

– Slight diarrhea

– Slight fever, usually not intermittent

• Could mistake for influenza or gastrointestinal infection

Clinical presentation

• Acute febrile illness, may have periodic febrileparoxysms every 48 – 72 hours with

• Afebrile asymptomatic intervals

• Tendency to recrudesce or relapse overmonths to years

• Anemia, thrombocytopenia, jaundice,hepatosplenomegaly, respiratory distresssyndrome, renal dysfunction, hypoglycemia,mental status changes, tropical splenomegalysyndrome

Drugs used to treat Malaria-First group

1. 4-aminoquinolones: Eg. Chloroquine, Amodiaquine

2. Chincona alkaloids: Quinine

3. Quinoline methanol: Mefloquine

4. Acridine: Mepacrine, Quinacrine

5. 8-aminoquinolines: Primaquine, Bulaquine

6. Biguanides: Porguanil

7. Diaminopyrimidines: Pyrimethamine

8. Artemisinin derivative: Artesunate,Artemether, Arteether

9. Phenanthrene methanol: Halofantrine, Lumefantrine

10. Naphthoquinone: Atovaquone

11. Antibiotics: TTC, Doxycycline, Clindamycin

12. Sulfonamides and Sulfones: Sulfadoxine and Dapsone

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CLOROQUINE• Available as Chloroquine Phosphate

• p.o./i.m./slow i.v. infusion

• very high volume of distribution

• Metabolised in liver

• Excreted in urine (70% unionized and 30% metabolized)

• T1/2 is 3-4 days

• Terminal T1/2 is 1-2 months

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MOA

• Chloroquine accumulates in parasitized erythrocytes

• Diffuse into parasite lysosomes

• Inhibit peptide formation and reduces supply of amino acid which is necessary for parasite viability

• Also inhibit parasite haem polymerase and thus protects host’s haem to get converted into haemozoin.

• At high concentration it also inhibit RNA and DNA synthesis