Anti Malarial Drugs

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 Etiology
• Caused by the plasmodium protozoa.
• obligate intracellular protozoa of the genus
Plasmodium. Four different plasmodium species.
Pl. vivax Pl falciparum
Pl Malariae Pl ovale
• Cause: the bite of an infected adult mosquito.
• Can also be transmitted by infected individuals via
blood transfusion, congenitally, or via infected
needles by drug abusers.

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 Life Cycle of Plasmodia

Two Interdependent Life Cycles

• Sexual phase: in the mosquito
• Asexual phase: in the human
 Pre erythrocytic stage – no symptoms
 Erythrocytic stage- symptoms
 Exo- erythrocytic stage (only for vivax & ovale
species)- relapse
Drugs are only effective during the asexual
cycle.
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• Infection usually is transmitted by the bite of infected female Anopheline mosquitoes.
• Sporozoites rapidly enter the circulation and localize to hepatocytes, where they
transform, multiply, and develop into tissue schizonts
• This primary asymptomatic stage (pre-erythrocytic or exoerythrocytic) lasts for 5–15
days, depending on the Plasmodium species.
• Tissue schizonts then rupture, releasing merozoites that enter the circulation, invade
erythrocytes, and initiate the erythrocytic cycle.
• Once the tissue schizonts burst in P. falciparum and P. malariae infections, no parasites
remain in the liver.
• In P. vivax and P. ovale infections, tissue parasites (hypnozoites) persist and can
produce relapses years after the primary attack.
• Once plasmodia enter the erythrocytic cycle, they cannot reinvade the liver; thus,
there is no tissue stage of infection for malaria contracted by transfusion.
• In erythrocytes, most parasites undergo asexual development from young forms to
trophozoites and finally to mature schizonts.
• Schizont-containing erythrocytes rupture, producing febrile clinical attacks. The
merozoites invade more erythrocytes to continue the cycle.
• The periodicity of parasitemia and fever depends on the timing of generation of
erythrocytic parasites. For P. falciparum, P. vivax, and P. ovale, it takes ~48 hours to
complete this process; P. malariae requires ~72 hours.
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LIFE CYCLE OF MALARIAL PARASITE

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 Parasites and
Types of Malaria

• Plasmodium falciparum Malignant fever

Malignant because it is the most severe form
and can be fatal. No exoerythrocytic stage. If erythrocytic stage eradicated
relapses do not occur.

• P. vivex / ovale Benign Tertian fever

Every third day. Have exoerythrocytic stage

• P. malariae Quartan Malaria

Every fourth day. No exoerythrocytic stage
 Sites for antimalarial drug action
• 1. Primary tissue schizonticides.
Prophylactic

• 2. Secondary tissue schizonticides.

Radical cure

• 3. Blood schizonticides Clinical

cure

• 4. Sporonticides Prophylactic

• 5. Gametocyticides Infection control

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• Since none of the drugs kills
sporozoites, it is not truly
possible to prevent infection but
only to prevent the development
of symptomatic malaria caused
by the asexual erythrocytic
forms. Also,
• none of the antimalarials is
effective against all liver and red
cell stages of the life cycle that
may coexist in a patient.
• Complete cure therefore may
require more than one drug.
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 Treatment

Antimalarial drugs
For prophylaxis, treatment and prevention of
relapses of malaria

Classification
• Active against which stage of life cycle
• Therapeutic objective
• MOA
• Chemical structure
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 :CLASSIFICATION:
Cinchona alkaloid- Quinine, Quinidine
Quinolines
4-Aminoquinolines - Chloroquine, Amodiaquine, Piperaquine.
8-Aminoquinoline- Primaquine, Bulaquine
Quinoline-methanol - Mefloquine.
Antifolatee
Biguanides- Proguanil, Chlorproguanil
Diaminopyrimidines- Pyrimethamine
Sulfonamides and sulfone – Sulfadoxine Sulfamethopyrazine, Dapsone
Artemisinins- Artesunate, Artemether, Arteether
Antimicrobials-
Tetracyclines- Tetracycline, Doxycycline
Naphthoquinone- Atovaquone
Amino alcohols- Halofantrine, Lumefantrine
Mannich base – Pyronaridine
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 Classification

According to the stage (life cycle) of plasmodia

- Tissue schizonticides :
Primary (pre-erythrocytic)
Secondary (Exo-erythrocytic)

- Erythrocytic schizonticides : fast acting

slow acting

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 Classification

• Pre erythrocytic phase drugs: Primaquine,

proguanil
• Erythrocytic phase drugs:
Fast: chloroquine,quinine,mefloquine,
halofantrine, artemisinin, atovaquone
Slow: proguanil, pyrimethamine, sulfonamides,
tetracyclines
• Exoerythrocytic phase drug: primaquine,
bulaquine
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14
 Classification

According to the therapeutic objective

• Causal prophylactic
• Suppressive prophylactic
• Clinical cure
• Radical cure
• Gametocidal

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 Target of Existing therapies
Target Pathway/ Target Existing
location mechanism molecule therapies
Cytosol Folate DHF reductase Pyrimethamine
metabolism Proguanil

DHP Sulfadoxine
synthetase
Food vacuole Heme Hemozoin Quinolines
polymerization

Free radical Unknown Artemisinin

generation
Mitochondrion Electron transport Cyt. c Atovaquone
oxidoreductase 16
 :CLASSIFICATION:
Cinchona alkaloid- Quinine, Quinidine
Quinolines
4-Aminoquinolines - Chloroquine, Amodiaquine, Piperaquine.
8-Aminoquinoline- Primaquine, Bulaquine
Quinoline-methanol - Mefloquine.
Antifolatee
Biguanides- Proguanil, Chlorproguanil
Diaminopyrimidines- Pyrimethamine
Sulfonamides and sulfone – Sulfadoxine Sulfamethopyrazine, Dapsone
Artemisinins- Artesunate, Artemether, Arteether
Antimicrobials-
Tetracyclines- Tetracycline, Doxycycline
Naphthoquinone- Atovaquone
Amino alcohols- Halofantrine, Lumefantrine
Mannich base – Pyronaridine
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 Evolution of therapy

1940 1950 1960 1970 1980

Quinine Proguanil Primaquine Sulfadoxine Artemisinin

Mefloquine
Chloroquine Amodiaquine pyrimethamine pyrimethamine
Halofantrine
Artemether
artesunate

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 Chloroquine – 4 aminoquinoline
 Quinolines and related
compounds:
quinine, chloroquine,
amodiaquine, piperaquine

mefloquine, halofantrine,
lumefantrine, pyronaridine,


Heme
Food vacuoles polymerase

Inhibition by quonolines
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 Antimalarials: Quinolines
 Mechanism of action:
– Quinolines concentrate in the food vacuole of the
parasite,
– Vacuoles are acidic in nature, basic drug raises the pH
– where human hemoglobin is digested, which releases
heme
– Heme by itself kills the parasite through oxidative
damage to membranes,
– To prevent this, the toxic heme is sequestered as an
unreactive malarial pigment termed hemozoin to
prevent toxic side effects
 Spectrum-
 Asexual Erythrocytic forms
 Gametocidal except P. falciparum

 Prophylaxis or treatment of acute attacks

of malaria caused by P. vivax, P. ovale, and
P. malariae

 Chloroquine is active against Entamoeba

histolytica and Giardia Iamblia also. It has
antiinflammatory, local irritant and local
anaesthetic, antiarrhythmic properties

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CHLOROQUINE
 It is a rapidly acting erythrocytic schizontocide
against all species of plasmodia;
 but P. Falciparum has grown a large resistance.
 controls most clinical attacks in 1-2 days with
disappearance of parasites from peripheral blood in
1-3 days.
 Therapeutic plasma concentrations are in the range
of 15-30 ng/ml.
 However, it has no effect on pre- and exo-erythrocytic
phases of the parasite- does not prevent relapses in
vivax and ovale malaria.

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Resistance
 Chloroquine-resistance among [Link] has been
slow in developing.
 However, P. falciparum has acquired significant
resistance
 Some of these have also acquired resistance to
proguanil and S/P (multidrug resistant strains)
 emergence of such strains is the biggest threat to
the antimalaria programmes, and is the focus of
attention for current research efforts.
 Resistance in P. falciparum is associated with a
decreased ability of the parasite to accumulate
chloroquine.

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 P/K
 Oral absorption of chloroquine is excellent.
 It has high affinity for melanin & nuclear chromatin: gets
tightly bound to these tissue constituents
 concentrated in liver (Amoebiasis), spleen, kidney, lungs
(several hundred-fold), skin, leucocytes and some other
tissues.
 Its selective accumulation in retina is responsible for the
ocular toxicity seen with prolonged use. (irrveersible)
 Absorption after i.m. injection is also good.
 Chloroquine is partly metabolized by liver and slowly
excreted in urine.
 The early plasma t1/2 varies from 3-10 days.
 Because of tight tissue binding, small amounts persist in the
body with a terminal t1/2 of 1-2 months.

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 s/e
 GI- nausea, vomiting, anorexia, uncontrollable itching,
epigastric pain, uneasiness, difficulty in accommodation
and headache.
 Hypotension, cardiac depression, arrhythmias and CNS
toxicity including convulsions- parenteral
 Loss of vision due to retinal damage. Corneal deposits may
also occur and affect vision, Blue black pigmentation, loss
of accomodation
 Loss of hearing, rashes, photoallergy, mental disturbances,
myopathy and graying of hair can occur on long-term use.
 no abortifacient or teratogenic effects have been reported.
 Chloroquine should not be coadministered with
mefloquine, amiodarone and other antiarrhythmics.

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 Uses
1. Malaria- treatment
Chemoprophylaxis: one week before entering the
endemic area & 4 weeks after leaving.

2. Rheumatoid arthritis .
3. Extraintestinal amoebiasis – conc in liver. giardiasis
4. Discoid lupus erythematosus-very effective; less
valuable in systemic LE.
5. Lepra reactions .
6. Infectious mononucleosis:
7. Photogenic reactions.

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 DOSE
 600 mg base (4 tab.) then 300 mg after 6 h.
then 150 mg bid for two more days.
 10 tablets- bitter
 Parenteral- only in severe , falciparum
 As third choice to Quinine/ACT
 Slow IV infusion 10 mg/kg in dextrose

 Amodiaquine- once a day, hepatitis

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 QUININE
 Quinine is an erythrocytic schizontocide for all
species of plasmodia;
 less effective and more toxic than chloroquine.
 Resurgence of interest in quinine is due to the
fact that most chloroquine and multidrug-
resistant strains of [Link] still respond to it.
 Partial cross resistance between quinine and
mefloquine
 Quinidine is both somewhat more potent as an
antimalarial and more toxic than quinine.

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 Quinine:
• It is a levo-rotatory alkaloid from cinchona bark
• ( dextro isomer – Quinidine----antiarrythmic)
• It is an Rapidly acting erythrocytic schizontocide
effective in all species.
• Less effective & toxic than ChQ
• ChQ resistant strain respond to it.
• No effect on pre erythrocytic stage &
Hypnozoites
• Effective for acute attack but no radical cure
 Quinine:
• Mechanism of action:
– It is basic and gets concentrated in acidic vacuoles of
parasite and kills by inhibiting heme polymerase
• Other actions
– Local irritant & local anaesthetic
– Increased gastric secretion
– hypoglycemia
– Weak analgesic antipyretic
– Cardiodepressant
– - decrease contractile power of skeletal muscle
Quinine : pharmacokinetics
• It is orally well absorbed
• 70% bound to plasma protein
• Readily crosses BBB and placenta
• Metabolized in liver
• Half life 10-12 hr. Noncumulative
• It has antipyretic action, affects hearing and vision at
high dose
Quinine : adverse effects
 Toxicity of quinine is high and dose related
 Cinchonism - It consists of ringing in ears, nausea,
vomiting headache, mental confusion, vertigo,
difficulty in hearing and visual defects. Diarrhoea,
flushing and marked perspiration may also appear.
 The syndrome subsides completely if the drug is
stopped.
 Hypotension, cardiac arrhythmias develop only on
rapid i.v. injection
 causes haemolysis, resulting in haemoglobinuria
(black water fever) and kidney damage. (Massive
haemolysis with renal failure-black water fever)
 Hypoglycemia- release of insulin
 Hypersensitivity reactions
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Uses:
• Uncomplicated Chloroquine-resistant P. falciparum (orally). DOC in 1 st
trimester
• Complicated severe malaria including Cerebral malaria (i.v infusion 10
mg/kg over 4 h.). it could repeated at an intervals of 8-12 h. until patient can
take the drug orally.
• Replaced by faster acting, more effective, better tolerated, more convenient
for administration drug—ARTESUNATE
• Nocturnal cramp
• Varicose veins
• Diagnosis of myasthenia gravis
• Babeosis- clindamycin + quinine

Quinidine:
• It is the dextro-isomer of quinine. antiarrhythmic
 Primaquine :(8-aminoquinoline derivative)

• Primary indication is radical cure of malaria.

• It is poor erythrocytic schizonticide.
• It is more active against exo-erythrocytic phase of vivax
and ovale.
• It is highly active against non-growing forms -
gametocytes and hypnozoites

• MOA: unknown. It has a cellular oxidant activity and possibly

interferes with mitochondrial function. No resistance.

• P/K:
• half life 3-6 hr
• noncumulative.
Uses:
• Eradication of liver stages (hypnozoites) of [Link] &
[Link], after standard chloroquine therapy to prevent
relapse.
• Dose 15mg daily for 2 week.
• Falciparum: 45mg
• It should not be given if there is risk of reinfection.
A/E: GIT upset, pruritis, headache,
dose related hemolysis especially in G-6-PD.
methemoglobinemia, tachypnoea ,cyanosis
Dark colored urine
Not given in pregnancy : G6PD deficient
 Mefloquine
• It was developed during the Vietnam War to deal with problem of ChQ
resistant P. falciparum
• It is rapidly acting erythrocytic schizontocide, slower than Chq or Quinine
• No effect on exo erythrocytic, pre erythrocytic stage
• Effective against chloroquine sensitive & resistant strains of plasmodia
• It appears to damage the plasmodia membranes

• P/K
• Oral absorption is good
• Concentrated in liver, lungs and intestine
• Metabolized in liver and excreted in bile. Enterohepatic circulation.
• Half life-2-3 week
• Due to long half life-resistance
• Cross resistance with quinine & halofantrine
 Mefloquine
• Side effects
– nausea, vomiting, diarrhea, loss of appetite, abd pain,
– Neuropsychiatric symptoms- Ataxia , disturbed sense of balance, insomnia or
abnormal dreams, anxiety, convulsions
• QT interval prolongation (arrhythmia) when given with halofantrine or quinine
• Seizures at high dose.
• Uses
• Used as preventative and in the treatment of chloroquine-resistant falciparum malaria
• As a preventaive, take once a week, 1-3 weeks before traveling to malaria endemic
area, continuing 4 weeks after you return from the area.
• T/t-toxicity, cost, half life limited to endemic areas
• Used with Artesunate for uncomplicated ChQ & SP resistant malaria. Not used for
complicated malaria
•Current recommendation is to use it only along with the rapidly
acting drug artesunate, as ACT for uncomplicated chloroquine as
well as S/P resistant falciparum malaria.

•For vivax malaria, it should be used only in the rare case of the
parasite being both chloroquine and quinine + doxycycline
resistant.

•Mefloquine cannot be given parenterally and is not used in

complicated/cerebral malaria.

•For prophylaxis of malaria among travellers to areas with

multidrug resistance; 5 mg/kg (adults 250 mg) per week is started
preferably 2- 3 weeks before travel to assess side effects in the
individual.
•Not used in pregnancy.
 Halofantrine:
• Blood shizonticide
• Not active against hypnozoites, gametocytes
• Unknown mechanism of action.
• Used only by oral route in P. falciparum cerebral malaria.
• No parenteral preparation.
• Low & erratic absorption. 3 days.
• Not used for prophylaxis.
• Not used during pregnancy unless benefit outweighs the risk.
• Arrythmias, rash increase in liver enzymes
• Cross resistance with mefloquine
• Can be used for ChQ resistant S/P resistant [Link]
 Antifolates (sulfonamides &
sulfones):
Synergistic blockade of folic acid
synthesis
• PAS, Dapsone, Sulfonamide
inhibits dihydropteroate synthetase,
so inhibits folic acid synthesis.
• Methotrexate, Pyrimethamine and
proguanil inhibit dihydrofolate
reductase, so inhibit
tetrahydrofolate (folinic acid/
leucovorin ).
 PYRIMETHAMINE
 directly acting inhibitor of plasmoidal
DHFRase (does not require conversion to a
cyclic triazine, as is the case with
proguanil).
 Selective antimalarial action depends on
high affinity
 In contrast to trimethoprim, it has very poor
action on bacterial DHFRase.
 At high doses, it inhibits toxoplasma gondii

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 Pyrimethamine is more potent.
 It is a slowly acting erythrocytic schizontocide,
 It is not a radical curative,
 If used alone, resistance develops rather rapidly by
mutation in the DHFRase enzyme of the parasite.
 These organisms exhibit cross resistance to proguanil.
 Certain organs like liver, spleen, kidney and lungs
concentrate pyrimethamine.
 metabolized and excreted in urine with a t1/2 of 4 days.
 Prophylactic concentrations remain in blood for 2 weeks.
 Nausea and rashes. Folate deficiency is rare;
megaloblastic anaemia and granulocytopenia
 Pyrimethamine is used only in combination with a
sulfonamide (S/P) or dapsone

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 Sulfadoxine + Pyrimethamine
• Sulfonamides do not give a complete cure- given with
other antimalarials
• It is a combination of sulfadoxin and pyrimethamine.
• It is used in chloroquine-resistant p. falciparum.
• Not used for prophylaxis as it causes agranulocytosis & Stevens-
Johnson syndrome.
• No cross resistance
A.E:
• Sulfonamide: rashes, kidney damage, hemolysis & GIT upset.
• Pyrimethamine: folic acid deficiency, agranulocytosis & Stevens-
Johnson syndrome.
Disadvantages: slow blood schizonticide activity, drug resistance &
numerous & serious adverse effects.
C/I: pregnancy & nursing women, G-6-PD, renal impairment.
Dose: S 500 + P 25 mg 3 tab single dose.
Use: uncomplicsated ChQ resistant Falciparum malaria.
TETRACYCLINES
 slowly acting and weak erythrocytic
schizontocidal action against all plasmodial
species.
 In addition, preerythrocytic stage of P. falciparum
is inhibited.
 They are never used alone to treat malaria, but
only in combination with quinine or S /P for the
treatment of chloroquine-resistant falciparum
malaria.
 Tetracycline 250 mg QID or doxycycline 100 mg
OD are equally efficacious.

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ARTEMISININ DERIVATIVES
 Chinese traditional medicine as 'Quinghaosu'.
 It is a sesquiterpine lactone active against
[Link] resistant to all other antimalarial
drugs as well as sensitive strains.
 Potent and rapid blood schizontocide action is
exerted eliciting quicker defervescence and
parasitaemia clearance ( <48 hr) than
chloroquine or any other drug.
 Artemisinins do not kill hypnozoites but have
some action on falciparum

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 What are Artemisinins ?

Artemisinin derivatives

Dihydroartemisin

Ethyl Ether Methyl Ether

Arteether Artemether

Qinghaosu
Hemisuccinate
("ching-how-soo") Artesunate
 The duration of action is short and recrudescence
rate is high when they are used alone in short
courses
 Because artemisinins are short acting drugs,
monotherapy needs to be extended beyond the
disappearance of the parasites to prevent
recrudescence.
 After 5 days treatment recrudescence rate is -10%,
while with a 3 day course it is -50%.
 Recrudescence can be totally prevented by
combining 3 day artesunate/artemether with a
long-acting drug
 So far no resistance among P. falciparum patients
to artemisinin has been noted

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Mechanism of action
 The endoperoxide bridge in its molecule appears
to interact with haeme in the parasite.
 Iron-mediated cleavage of the bridge releases a
highly reactive free radicals species
 Activated by heme/ molecular iron to produce carbon centered free
radicals- the endoperozxide bridge is necessary for this action
 free radicals species binds to membrane
proteins, causes lipid peroxidation, damages
endoplasmic reticulum, inhibits protein synthesis
and ultimately results in lysis of the parasite.

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S/E
 artesunate/ artemether produce few adverse effects; most
are mild:
 nausea, vomiting, abdominal pain, itching and

 S-T segment changes, Q-T prolongation, first degree A-

Vblock,

 transient reticulopenia and leucopenia

 Intravenous artesunate is much safer than i.v. quinine.

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ACT
 A + S/P 100 + 3tab
 A + Mefloquine 100 + 750
 A + Lumefantrine 80 + 480

 Other uses
 Schistosomiasis
 Leishmaniasis

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 Treatment of malaria

P. vivax, P. ovale & P. malariae:

Chloroquine
NB: It is also allowed in pregnancy.
P. Falciparum (most cases are chloroquine-resistant):
• Quinine 600 mg salt/8h till patient become better and blood
is free of parasites (usually in 3-5 days).
• Followed by a single dose of Sulfadoxine/pyrimethamine (3
tablets).
• In pregnancy 7-day course of quinine alone should be
given.
 Chemoprophylaxis of malaria

Chloroquine-sensitive area:
• Chloroquine 150 mg base ( 2 tab/week)
Chloroquine-resistant area:
• Chloroquine ( 2 tab/week) plus proguanil
100 mg (one or two tab/ day)
or
• Mefloquine 250 mg (one tab./ week)
 Anti-malarial drugs
Drugs for the Exo-erythrocytic phase (liver) and
gametocytes :
• Primaquine
Drugs to suppress erythrocytic phase / Schizontocides /
Clinical cure :
• Chloroquine, Quinine, Pyrimethamine, Mefloquine,
Artemisinin
Radical cure : Exoerythrocytic phase
(hypnozoites) with the clinical cure thus achieve total
eradication of parasite
• Primaquine + Chloroquine
NMEP(1958),
NAMP,
 NVBDCP (2005)
MOA

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