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Antimalarial agent, life cycle of malaria
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9/2/2012
1
© 2010 Delmar, Cengage Learning1
By- Jitendra Bhangale
Assistant Professor & Head,
Department of Pharmacology,
Smt N. M. Padalia Pharmacy College,
Ahmedabad
© 2010 Delmar, Cengage Learning2
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
9/2/2012
2
© 2010 Delmar, Cengage Learning3
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
Plasmodium vivax (tertian)
Plasmodium ovale (tertian)
Plasmodium falciparum (tertian)
Plasmodium malariae (quartian)
© 2010 Delmar, Cengage Learning4
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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.
9/2/2012
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© 2010 Delmar, Cengage Learning5
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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.
© 2010 Delmar, Cengage Learning6
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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.
9/2/2012
4
© 2010 Delmar, Cengage Learning7
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
Exo-erythrocytic(hepatic) cycle
Sporozoites
Mosquito Salivary Gland
Gametocytes
Oocyst
Erythrocytic Cycle
Zygote
Schizogony
Sporogony
Hypnozoites(for P. vivaxand P. ovale)
© 2010 Delmar, Cengage Learning8
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
9/2/2012
5
© 2010 Delmar, Cengage Learning9
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
© 2010 Delmar, Cengage Learning10
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
9/2/2012
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© 2010 Delmar, Cengage Learning11
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
© 2010 Delmar, Cengage Learning12
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
9/2/2012
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© 2010 Delmar, Cengage Learning13
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
© 2010 Delmar, Cengage Learning14
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
9/2/2012
8
© 2010 Delmar, Cengage Learning15
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
© 2010 Delmar, Cengage Learning16
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
Early symptoms
Headache
Malaise
Fatigue
Nausea
Muscular pains
Slight diarrhea
Slight fever, usually not intermittent
Could mistake for influenza or gastrointestinal
infection
9/2/2012
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© 2010 Delmar, Cengage Learning17
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
Infection is by mosquito bite
Infects liver, then blood cells
© 2010 Delmar, Cengage Learning18
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
9/2/2012
10
© 2010 Delmar, Cengage Learning19
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
4-AminoquinolinesChloroquineAmodiaquinePiperaquine
Quinoline-methanolMefloquine.
Cinchona alkaloid QuinineQuinidine
BiguanidesProguanil(Chloroguanide)Chlorproguanil
DiaminopyrimidinesPyrimethamine
8-AminoquinolinePrimaquineBulaquine
Sulfonamides and sulfoneSulfadoxineSulfamethopyrazineDapsone
TetracyclinesTetracyclineDoxycycline
Sesquiterpine lactonesArtesunateArtemetherArteether
Amino alcoholsHalofantrineLumefantrine
Mannich basePyronaridine
NaphthoquinoneAtovaquone
© 2010 Delmar, Cengage Learning20
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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.
9/2/2012
11
© 2010 Delmar, Cengage Learning21
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
© 2010 Delmar, Cengage Learning22
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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.
9/2/2012
12
© 2010 Delmar, Cengage Learning23
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
© 2010 Delmar, Cengage Learning24
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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.
9/2/2012
13
© 2010 Delmar, Cengage Learning25
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
© 2010 Delmar, Cengage Learning26
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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.
9/2/2012
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© 2010 Delmar, Cengage Learning27
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
© 2010 Delmar, Cengage Learning28
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
9/2/2012
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© 2010 Delmar, Cengage Learning29
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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.
© 2010 Delmar, Cengage Learning30
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
9/2/2012
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© 2010 Delmar, Cengage Learning31
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
Pyrimethamine is combined with dapsone for
prophylaxis of Plasmodium falciparum malaria.
Adverse effects
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis
© 2010 Delmar, Cengage Learning32
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
9/2/2012
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© 2010 Delmar, Cengage Learning33
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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.
© 2010 Delmar, Cengage Learning34
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
9/2/2012
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© 2010 Delmar, Cengage Learning35
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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
© 2010 Delmar, Cengage Learning36
By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad
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.
9/2/2012
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© 2010 Delmar, Cengage Learning37
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
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