Antimalarial Drugs

ANTI-MALARIAL DRUGS
S.RAVINDRA BABU
ASSOCIATE PROFESSOR
• Human malaria is causes by four species of
Plasmodia.
• Plasmodium falciparum
• Plasmodium vivax
• Plasmodium malariae
• Plasmodium ovale
P falciparum is responsible for the majority
of serious complications and deaths. Drug
resistance is most notably with P
falciparum.
1) A female Anopheles mosquito injects the parasites
in the form of sporozoites into the bloodstream.
The sporozoites travel to the liver and invade liver
cells.
2) Over 5-16 days*, the sporozoites grow, divide,
and produce tens of thousands of merozoites.
Some malaria parasite species remain dormant for
extended periods in the liver, causing relapses
weeks or months later.
3) The merozoites exit the liver cells and re-enter the
bloodstream, beginning a cycle of invasion of red
blood cells, asexual replication, and release of
newly formed merozoites from the red blood cells
repeatedly over 1-3 days*. This multiplication can
result in thousands of parasite-infected cells in the
bloodstream, leading to illness and complications of
malaria .
4) Some of the merozoite-infected blood cells leave
the cycle and develop into sexual forms of the
parasite, called male and female gametocytes, that
circulate in the bloodstream.
5) When a mosquito bites an infected human, it ingests the
gametocytes. In the mosquito gut, the infected human
blood cells burst, releasing the gametocytes, which
develop into mature sex cells called gametes. Male and
female gametes fuse to form zygotes, which develop into
ookinetes into the mosquito gut wall and form oocysts.
6) Growth and division of each oocyst produces thousands of

active sporozoites. After 8-15 days*, the oocyst bursts,
releasing sporozoites into the body cavity of the mosquito,
from which they travel and invade the mosquito salivary
glands. The cycle of human infection re-starts when the
mosquito takes a blood meal, injecting the sporozoites
from its salivary glands into the human bloodstream .
CHLOROQUINE
• Highly effective blood schizonticide.
• controls most clinical attacks in 1-2 days with

disappearance of parasites from blood in 1-3 days.
• The mechanism of action of chloroquine is not

completely known.
• It is also moderately effective against gametocytes of P

vivax, P.ovale, and P.malariae but not against those
of P. falciparum.
ADVERSE EFFECTS
• hypotension, cardiac depression, arrhythmias and
CNS toxicity including convulsions (more likely
in children).
• high doses may cause loss of vision due to retinal

damage.
• Loss of hearing, rashes, photoallergy, mental

disturbances, myopathy and graying of hair can
occur on long-term use
contraindications
• liver damage, severe g.i., neurological and

haematological diseases. Attacks of seizures.
USES
1) Chloroquine is the drug of choice for all types of
malaria, except caused by resistant P. falciparum.
2) Extraintestinal amoebiasis
3) Rheumatoid arthritis
4) Discoid lupus erythematosus-very effective; less
valuable in systemic LE.
5) Lepra reactions.
• Other actions
1 Entamoeba histolytica and Giardia Iamblia also.
2 It has antiinflammatory, local irritant and local
anaesthetic (on injection)
Pharmacokinetics
• Oral absorption of chloroquine is excellent.
• About 50% gets bound in the plasma.
• Concentrated in liver, spleen, kidney, lungs (several

hundred-fold), skin, leucocytes and some other tissues.
• Accumulation in retina is responsible for the ocular

toxicity seen with prolonged use.
• Chloroquine is partly metabolized by liver and slowly

excreted in urine.
• Plasma t1/2 varies from 3-10 days.

Quinine &Quinidine
• Quinine is derived from the bark of the

cinchona tree.
• Quinine is a rapid-acting, highly effective

blood schizonticide against the four species
of parasites.
• The drug is gametocidal against P vivax

and P ovale but not P falciparum.
Adverse Effects
• Tinnitus, headache, nausea, dizziness, flushing,
and visual disturbances(cinchonism)
• Severe symptoms, include more visual and
auditory abnormalities, vomiting, diarrhea, and
abdominal pain.
• Hematologic abnormalities include hemolysis
leukopenia, agranulocytosis, and
thrombocytopenia.
• Thrombophlebitis, Severe hypotension
Contraindications & Cautions
• Cinchonism, hemolysis, or hypersensitivity occur.
• Visual or auditory problems.
• Cardiac abnormalities.
D.I
• Absorption may be blocked by aluminum
containing antacids.
• Quinine can raise plasma levels of warfarin and
digoxin.
Uses
Malaria: Quinine is used orally for uncomplicated
chloroquine-resistant malaria, and i.v. for
complicated/ cerebral malaria.
Adverse effects
• Mefloquine is bitter in taste;
• Common reaction is dizziness, nausea, vomiting,
diarrhoea, abdominal pain and sinus bradycardia.
• Major : neuropsychiatric reactions (disturbed

sense of balance, ataxia, errors in operating
machinery, strange dreams, anxiety,
hallucinations, rarely convulsions)
• Rare : haematological, hepatic and cutaneous

toxicity.
Interactions
• Halofantrine or quinidine/ quinine given to
patients who have received mefloquine
cause QTc lengthening--cardiac arrests are
reported.
use
• Effective drug for resistant P. falciparum.
• The combination of artesunate plus mefloquine is

now recommended by the WHO for the treatment
of uncomplicated falciparum malaria.
Pharmacokinetics
• It can only be given orally
• It is well absorbed, and peak plasma

concentrations are reached in about 18 hours.
• Mefloquine is highly protein-bound,
• The half-life is about 20 days,allowing weekly

dosing for prophylaxis.
• metabolites of the drug are slowly excreted,
mainly in the feces.
PRIMAQUINE
• Primaquine is active against hepatic stages of all
malaria parasites.
• It is the only available agent active against the dormant

liver stages of P vivax and P ovale.
• Primaquine is also gametocidal against the four human

malaria species.
• Primaquine acts against erythrocytic stage parasites, but

this activity is too weak.
• The mechanism of antimalarial action is unknown.

Adverse Effects
• nausea, epigastric pain, abdominal cramps,
and headache, with higher dosages and when
the drug is taken on an empty stomach.
• More serious but rare adverse effects are

leukopenia, agranulocytosis, leukocytosis,
and cardiac arrhythmias.
• hemolysis
USES
1) The primary use is for radical cure of relapsing
(vivax) malaria
2 Pneumocystis jiroveci Infection:
3 Gametocidal action
Artemisinin
• Artemisinin is isolated from the plant Artemisia
annua.
• These compunds have endoperoxide bridge
• Artemisinins exert their antimalarial action by free

radical formation that depends on their endoperoxide
bridge.
• Endoperoxide bridge interact with heme in parasite.

The iron of the heme cleaves this endoperoxide
bridge, generating oxygen free radicals which
damages the parasite and lead to its death
• Artemisinin monotherapy is now discouraged.
• Combination therapies are recommended to

improve efficacy and prevent resistant parasites.
• Artemisinin and its analogs are rapidly acting

blood schizonticides against all human malaria
parasites.
Interactions
• administration of artemisinin
compounds with terfenadine, asternizole,
antiarrhythmics, tricyclic antidepressants
and phenothiazines may increase the risk of
cardiac conduction defects.
Adverse effects
• Mild:
nausea, vomiting, abdominal pain, itching
and drug fever.
Abnormal bleeding, dark urine, S-T segment
changes, Q-T prolongation, first degree A-
Vblock, and leucopenia have been noted but
subside when the drug is stopped.
Clinical Uses
• Artemisinin-based combination therapy is
now for the treatment of uncomplicated
falciparum malaria.
• The WHO recommends five artemisinin-
based combinations for the treatment of
uncomplicated falciparum malaria .
• Their gametocidal action cuts down
transmission and spread of resistant P.
falciparum.
Clinical Uses
• Severe and complicated falciparum malaria:
Parenteral artemisinins are higly effective.
i.v. artesunate offers several advantages:
1) It causes faster parasite clearance than i.v
quinine.
2) It is safer and better tolerated than i.v.
quinine.
3) Its dosing schedule is simpler.
4) Recent evidence indicates higher efficacy
and lower mortality.
PYRIMETHAMINE
• It is a inhibitor of plasmoidal DHFRase.
• Selective antimalarial action depends on high

affinity for plasmodial enzyme (2000 times
greater than for the mammalian enzyme).
• At high doses, it inhibits Toxoplasmagondii.
• It is a slowly acting erythrocytic schizontocide.
• If used alone resistance develops.

•
Adverse effects
• Occasional nausea and rashes.
• Folate deficiency is rare; megaloblastic anaemia
and granulocytopenia may occur with higher
doses.
• This can be treated by folinic acid.
USES
• Use Pyrimethamine is used only in combination
• with a sulfonamide (S/P) or dapsone for treatment
of falciparum malaria.
SULFONAMIDE-PYRIMETHAMINE (S/P)
COMBINATION
• Fansidar, is a combination of the sulfonamide-

sulfadoxine and pyrimethamine
• Effective blood schizonticide against P.

falciparum.
• prevent DHFR ase enzyme and block the

conversion of dihydrofolic acid to tetrahydrofolic
acid-thus inhibit DNA synthesis.
• By the addition of sulfonamide, development of
resistance to pyrimethamine is retarded.
• The combination has serious adverse effects

(exfoliative dermatitis, StevensJohnson syndrome,
etc.) due to the sulfonamide.
• The major importance of this combination is due

to its efficacy against chloroquine-resistant P.
falciparum.

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ANTI-MALARIAL DRUGS

6) Growth and division of each oocyst produces thousands of

• controls most clinical attacks in 1-2 days with

• The mechanism of action of chloroquine is not

• It is also moderately effective against gametocytes of P

• high doses may cause loss of vision due to retinal

• Loss of hearing, rashes, photoallergy, mental

• liver damage, severe g.i., neurological and

• About 50% gets bound in the plasma.

• Concentrated in liver, spleen, kidney, lungs (several

• Accumulation in retina is responsible for the ocular

• Chloroquine is partly metabolized by liver and slowly

• Plasma t1/2 varies from 3-10 days.

• Quinine is derived from the bark of the

• Quinine is a rapid-acting, highly effective

• The drug is gametocidal against P vivax

• Major : neuropsychiatric reactions (disturbed

• Rare : haematological, hepatic and cutaneous

• The combination of artesunate plus mefloquine is

• It is well absorbed, and peak plasma

• Mefloquine is highly protein-bound,

• The half-life is about 20 days,allowing weekly

• It is the only available agent active against the dormant

• Primaquine is also gametocidal against the four human

• Primaquine acts against erythrocytic stage parasites, but

• The mechanism of antimalarial action is unknown.

• More serious but rare adverse effects are

2 Pneumocystis jiroveci Infection:

• These compunds have endoperoxide bridge

• Artemisinins exert their antimalarial action by free

• Endoperoxide bridge interact with heme in parasite.

• Combination therapies are recommended to

• Artemisinin and its analogs are rapidly acting

• Selective antimalarial action depends on high

• At high doses, it inhibits Toxoplasmagondii.

• It is a slowly acting erythrocytic schizontocide.

• If used alone resistance develops.

• Fansidar, is a combination of the sulfonamide-

• Effective blood schizonticide against P.

• prevent DHFR ase enzyme and block the

• The combination has serious adverse effects

• The major importance of this combination is due

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