malaria by jitendra bhangale

9/2/2012

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© 2010 Delmar, Cengage Learning1

By- Jitendra Bhangale

Assistant Professor & Head,

Department of Pharmacology,

Smt N. M. Padalia Pharmacy College,

Ahmedabad


By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad

Malaria is a parasite that enters the blood.

This parasite is a protozoan called plasmodium.

3 to 700 million people get malaria each year, but only

kills 1 to 2 million

40% of the worlds population lives in malaria zones

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Plasmodium vivax (tertian)

Plasmodium ovale (tertian)

Plasmodium falciparum (tertian)

Plasmodium malariae (quartian)



Falciparum: Almost 80% of cases and 90% of malaria

deaths. Primarily found in South America and

Africa.

Ovale: Rarest form. Found in West Africa. Can be up to

four years before and symptoms occur.

Malariae: Can infect other mammals. Found in Africa

and SE Asia.

Vivax: 20% of infections. Widest geographic

distribution.

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The life cycle of all species that infect humans is basically

the same.

There is an exogenous asexual phase in the mosquito called

sporogony during which the parasite multiplies.

There is also an endogenous asexual phase that takes place

in the vertebrate or human host that is called schizogeny.

This phase includes the parasite development that takes

place in the red blood cell, called the erythrocytic cycle.



Schizogeny phase includes the parasite development that

takes place in the red blood cell, called the erythrocytic

cycle and the phase that takes place in the parencymal

cells in the liver, called the exo-erythrocytic phase.

The exo-erthrocytic phase is also called the tissue phase.

The schizogeny that takes place here can occur without

delay during the primary infection or can be delayed in

the case of relapses of malaria.

I will focus on the development of the parasite in the human

host.

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Exo-erythrocytic(hepatic) cycle

Sporozoites

Mosquito Salivary Gland

Gametocytes

Oocyst

Erythrocytic Cycle

Zygote

Schizogony

Sporogony

Hypnozoites(for P. vivaxand P. ovale)



Parasite undergoes sexual reproduction in the mosquito

Some merozoites differentiate into male or female gametocyctes

Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts

Dormant liver stages (hypnozoites) of P. vivax and P. ovale

Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood

MOSQUITO HUMAN

Sporozoires injected into human host during blood meal

Parasites mature in mosquito midgut and migrate to salivary glands

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Blood is infected with sporozoites about 30 minutes

after the mosquito bite

The sporozoites are eaten by macrophages or enter the

liver cells where they multiply –

-pre-erythrocytic schizogeny

P. vivax and P. ovale sporozoites form parasites in the

liver called hypnozoites



P. malariae or P. falciparum sporozoites do not form

hypnozites, develop directly into pre-erythrocytic

schizonts in the liver

Pre-erythrocytic schizogeny takes 6-16 days post

infection

Schizonts rupture, releasing merozoites which invade

red blood cells (RBC) in liver

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P. vivax and P. ovale hypnozoites remain dormant for

months

They develop and undergoe pre-erythrocytic sporogeny

The schizonts rupture, releasing merozoites and

producing clinical relapse



Pre-patent period – interval between date of infection

and detection of parasites in peripheral blood

Incubation period – time between infection and first

appearance of clinical symptoms

Merozoites from liver invade peripheral (RBC) and

develop causing changes in the RBC

There is variability in all 3 of these features depending

on species of malaria

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Stages of parasite in RBC

Trophozoites are early stages with ring form the

youngest

Tropohozoite nucleus and cytoplasm divide forming a

schizont

Segmentation of schizont’s nucleus and cytoplasm

forms merozoites

Schizogeny complete when schizont ruptures, releasing

merozoites into blood stream, causing fever

These are asexual forms



Stages of parasite in RBC

Merozoites invade other RBCs and schizongeny is

repeated

Parasite density increases until host’s immune

response slows it down

Merozoites may develop into gametocytes, the sexual

forms of the parasite

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Schizogenic periodicity is length of asexual erythrocytic

phase

48 hours in P.f., P.v., and P.o. (tertian)

72 hours in P.m. (quartian)

Initially may not see characteristic fever pattern if

schizogeny not synchronous

With synchrony, periods of fever or febrile paroxsyms

assume a more definite 3 (tertian)- or 4 (quartian)- day

pattern



Early symptoms

Headache

Malaise

Fatigue

Nausea

Muscular pains

Slight diarrhea

Slight fever, usually not intermittent

Could mistake for influenza or gastrointestinal

infection

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Infection is by mosquito bite

Infects liver, then blood cells



Acute febrile illness, may have periodic febrile paroxysms

every 48 – 72 hours with

Tendency to recrudesce or relapse over months to years

Anemia, thrombocytopenia, jaundice, hepatosplenomegaly,

respiratory distress syndrome, renal dysfunction,

hypoglycemia, mental status changes, tropical splenomegaly

syndrome

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4-AminoquinolinesChloroquineAmodiaquinePiperaquine

Quinoline-methanolMefloquine.

Cinchona alkaloid QuinineQuinidine

BiguanidesProguanil(Chloroguanide)Chlorproguanil

DiaminopyrimidinesPyrimethamine

8-AminoquinolinePrimaquineBulaquine

Sulfonamides and sulfoneSulfadoxineSulfamethopyrazineDapsone

TetracyclinesTetracyclineDoxycycline

Sesquiterpine lactonesArtesunateArtemetherArteether

Amino alcoholsHalofantrineLumefantrine

Mannich basePyronaridine

NaphthoquinoneAtovaquone



Chloroquine is one of several 4-aminoquinolinederivatives that display antimalarial activity.

Chloroquine is particularly effective againstintraerythrocytic forms because it is concentratedwithin the parasitized erythrocyte.

This preferential drug accumulation appears to occur as aresult of specific uptake mechanisms in the parasite.

Chloroquine appears to work by intercalation with DNA,inhibition of heme polymerase or by interaction withCa–calmodulin mediated mechanisms.

It also accumulates in the parasite’s food vacuoles, where itinhibits peptide formation and phospholipases, leadingto parasite death.

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The drug is effective against all four types of malariawith the exception of chloroquine-resistant P.falciparum.

Chloroquine also can be used prophylactically in areaswhere resistance does not exist.

The absorption of chloroquine from the gastrointestinaltract is rapid and complete.

The drug is distributed widely and is extensively boundto body tissues.

Adverse effect:-

Dizziness, headache, itching (especially in darkskinnedpeople), skin rash, vomiting, and blurring of vision



Amodiaquine is another 4-aminoquinoline derivative

whose antimalarial spectrum and adverse

reactions are similar to those of chloroquine,

although chloroquine-resistant parasites may not

be amodiaquine- resistant to the same degree.

Prolonged treatment with amodiaquine may result in

pigmentation of the palate, nail beds, and skin.

There is a risk of agranulocytosis and hepatocellular

dysfunction when the drug is used

prophylactically.

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Mefloquine is a 4-quinolinemethanol derivative used

both prophylactically and acutely against resistant

P. falciparum malaria.

It is ineffective against the liver stage of P. vivax

malaria.

It is an effective blood schizonticide.

Adverse effect:-

Vertigo, visual alterations, vomiting, and such CNS

disturbances as psychosis, hallucinations, confusion,

anxiety, and depression



Quinine is the levo rotatory alkaloid obtained from

cinchona bark. Its d-isomer quinidine is used as an

antiarrhythmic.

Quinine is an erythrocytic schizontocide for all species

of plasmodia.

Like chloroquine, it is a weak base: gets concentrated

in the acidic vacuoles of the blood schizonts and causes

pigment changes; inhibits polymerization of haeme to

hemozoin; free haeme or haeme-quinine complex

damages parasite membranes and kills it.

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Quinine is used for the prevention and treatment of

nocturnal leg muscle cramps, especially those resulting

from arthritis, diabetes, thrombophlebitis,

arteriosclerosis, and varicose veins.

Adverse effect:-

sweating, ringing in the ears, impaired hearing, blurred

vision, nausea, vomiting, and diarrohea.

Quinine is a potent stimulus to insulin secretion and

irritates the gastrointestinal mucosa



Chloroguanide hydrochloride is activated to a triazine

metabolite, cycloguanil, which also interferes with

parasite folic acid synthesis.

It is a dihydrofolate reductase inhibitor that is used for

the prophylaxis of malaria caused by all

susceptible strains of plasmodia.

Chloroguanide is rapidly absorbed from the

gastrointestinal tract.

Adverse effect:-Mild abdominal upset, vomiting, occasional stomatitis,haematuria, rashes and transient loss of hair.

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It inhibit the parasite’s ability to synthesize folic acid.

Sulfonamides should always be coadministered with

pyrimethamine (or trimethoprim), since the combined

antimalarial activity of the two drugs is significantly

greater than when either drug is used alone.

Adverse effect:-

Anorexia, vomiting, anemia, leukopenia,

thrombocytopenia, and atrophic glossitis.

CNS stimulation, including convulsions, may follow an

acute overdose



Primaquine is the least toxic and most effective of the8- aminoquinoline antimalarial compounds.

Antimalarial effects is thought to be through aquinoline–quinone metabolite that inhibits thecoenzyme Q–mediated respiratory chain of theexoerythrocytic parasite.

Primaquine is an important antimalarial because it isessentially the only drug effective against the liver(exoerythrocytic) forms of the malarial parasite.

The drug also kills the gametocytes in all four speciesof human malaria.

Primaquine is relatively ineffective against the asexualerythrocyte forms.

Adverse effect:- G-6-PD deficiency, haemolysis,methaemoglobinaemia, tachypnoea and cyanosis

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Pyrimethamine inhibits plasmodial dihydrofolate

reductase, for which it has a high affinity. It is well

absorbed from the gastrointestinal tract and is

extensively metabolised.

Pregnant women should receive supplementary folic

acid when taking pyrimethamine.

Adverse effects

Anorexia, abdominal cramps, vomiting, ataxia, tremor,

seizures and megaloblastic anaemia.



Pyrimethamine acts synergistically with sulfadoxine to

inhibit folic acid metabolism

Sulfadoxine is excreted in the urine.

The combination is chiefly used with quinine to treat

acute attacks of malaria caused by susceptible strains of

Plasmodium falciparum; a single dose of pyrimethamine

75 mg plus sulfadoxine 1.5 g (3 tablets) usually suffices.

Adverse effects

Erythema multiforme, Stevens-Johnson syndrome and

toxic epidermal necrolysis

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Pyrimethamine is combined with dapsone for

prophylaxis of Plasmodium falciparum malaria.

Adverse effects

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis



Atovaquone is a naphthoquinone

Mechanism of actionIt inhibit the mitochondrial electron transport system in the

protozoa.

Malaria parasites depend on pyrimidine biosynthesisthrough dihydroorotate dehydrogenase coupled toelectron transport.

Atovaquone has good initial activity against the blood butnot the hepatic stage of P. vivax and P. ovale malariaparasites.

It is effective against erythrocytic and exoerythrocytic P.falciparum.

Adverse effect:-Nausea, vomiting, diarrhea, abdominal pain, headache, and

rash

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Artemisinin which is isolated from the leaves of the

Chinese herb qinghao (Artemisia annua).

They act against the blood, including sexual forms, of

plasmodia and may also reduce transmissibility

Artemisinins do not kill hypnozoites.

E.g. Artemether, Artesunate, Arteether

Artemisininis poorly soluble in water as well as oil.

Artemether is soluble in oil, while Artesunate (sod.) is

soluble in water.



Its sodium salt is water-soluble and administered by

oral, i m or i v. routes

After oral ingestion, absorption is incomplete.

It is rapidly converted to the active metabolite

dihydroartemisinin (DHA).

Adverse effect:-

Nausea, vomiting, abdominal pain, itching and drug

fever. Abnormal bleeding, dark urine, S-T segment

changes, Q-T prolongation, first degree A-V block

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It is lipid-soluble and is administered orally or i.m., but

not i.v

Oral absorption is slower taktng 24 hours, but is

enhanced by food.

It undergoes substantial first pass metabolism and is

converted to DHA.

Adverse effect:-

Nausea, vomiting, abdominal pain, itching and drug

fever. Abnormal bleeding, dark urine, S-T segment

changes, Q-T prolongation, first degree A-V block



Halofantrine is active against the erythrocytic forms of

all four Plasmodium species, especially

Plasmodium falciparum and Plasmodium vivax, and

at the schizont stage.

It is metabolised to an active metabolite and no

unchanged drug is recovered in the urine.

Halofantrine is used for the treatment of

uncomplicated chloroquine-resistant Plasmodium

falciparum and Plasmodium vivax malaria.

It should not be given for prophylaxis.

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By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad

malaria by jitendra bhangale

Education

padalia pharmacy college

cengage learningby

dept of pharmacology

department of pharmacology

cengage learningmalaria

exoerythrocytic phase

blood cells rbc

stages of parasite