ANTIMALARIAL DRUGS

Dr Pratibha Omkar
• A 67 year old female from Western Africa initially presented to
the Emergency Department (ED) complaining of fatigue and
subjective fevers for the past 2 days. Patient complained that
her fevers were associated with headaches, chills, rigors.
Patient had recently traveled from an endemic region.

• Lab tests including complete blood count, chemistry, liver

function tests, peripheral smears, and reticulocyte level were
done.

• Blood smears were positive for P. falciparum malaria and

rest all tests were found to be within normal limits.
 Introduction
• Tropical disease caused by a bite of an infected
Anopheles mosquito

• Annual incidence is approx. 200 million cases

• Symptoms appear after 8 to 10 days after bite
• Incubation period 10-30 days
• It is a Single cell protozoan called plasmodium

• 4 clinically important species:

• P. Falciparum
• P. Vivax
• P. Ovale
• P. malariae
• P. Knowleski

• Falciparum and Vivax - common

 Life cycle of the malarial parasite
True causal prophylactics
Sporonticide
Schizogony
Sporogeny (asexual)
(sexual)
Causal
prophylactics

Supressives

Man : Intermediate host

Mosquito : Definitive host Gametocidal
Classification of antimalarial drugs

– Therapeutic classification

– Chemical classification
 Therapeutic classification
• Causal prophylaxis: (Primary tissue schizonticides)
– Destroy parasite in liver cells and prevent invasion of
erythrocytes (prevent maturation of sporozoites to schizonts)
– Pyrimethamine, proguanil (falciparum only)
– Primaquine ( all species)

• Supressive Prophylaxis: (chemoprophylaxis)

– Suppress the erythrocytic phase and thus attack of malarial
fever (destroys merozoites released from liver so erythrocytic
phase is prevented)
– Chloroquine, proguanil, mefloquine, doxycycline
 Therapeutic classification

• Clinical cure: erythrocytic schizonticides

– used to terminate an episode of malarial fever
• Fast acting high efficacy
– Chloroquine, quinine, mefloquine, atovaquone,
artemisinin
• Slow acting low efficacy drugs
– Proguanil, pyrimethamine, sulfonamides,
tetracyclines
 Therapeutic classification
• Radical curatives:
– Eradicate all forms of exo and erythrocytic phase
(P.vivax & P.ovale) from the body
– For vivax: primaquine 15 mg daily for 14 days
– Falciparum : choloroquine
• Gametocidal:
– Destroy gametocytes and prevent transmission
– Primaquine, artemisinin – against all plasmodia
– Chloroquine, quinine – P. Vivax ,ovale amd malariae
– Proguanil ,pyrimethamine – prevent development of
sporozoites (makes gametocytes ineffective in
mosquito).
 Chemical classification
• 4 aminoquinolines:
– Chloroquine, Hydroxychloroquine, Amodiaquine,
Pyronaridine,piperaquine
• 8 aminoquinolines:
– Primaquine, Tafenoquine, Bulaquine, Etaquine
• Cinchona alkaloids:
– Quinine, Quinidine
• Quinoline methanol:
– Mefloquine
• Biguanides
– Proguanil, Chlorproguanil
 Chemical classification
• Diaminopyrimidines
– Pyrimethamine
• Sulfonamides
– Sulfadoxine, dapsone
• Tetracyclines:
– tetracycline, doxycycline
• Naphthoquinone:
– Atovaquone
• Sesquiterpene lactones:
– Artesunate, artemether, arteether
 Chloroquine

• Rapidly action erythrocytic schizontocide against all

species

Mechanism :
• Accumulation in parasitised erythrocytes – being a
basic drug diffuses into lysosome- inhibits peptide
formation and synthesis of amino acid.
 Mechanism of action
Hemoglobin Globin utilized by
malarial parasite

Heme (highly toxic for malaria parasite)

Chloroquine
Quinine, (+) Heme Polymerase
mefloquine (-)

Hemozoin (Not toxic to plasmodium)

 Pharmacological actions
1. Antimalarial activity:
– Clinical cure of vivax,ovale,malariae and few
falciparum.
– Chemoprophylaxis and radical cure
– Also used in malaria in pregnancy
– Resistance develops due to efflux mechanism
2. Other actions:
– Depressant action on myocardium, direct
relaxant effect on vascular smooth muscles,
– Antiinflammatory, antihistaminic , local
anaesthetic
Pharmacokinetics:
• Well absorbed orally, tmax 2-3 hrs , 50 % protein bound
(I.M or slow I.V)
• High affinity for melanin and chromatin, so concentrated
in liver , spleen, kidney, lungs , leucocytes
• Selective accumulation in retina: occular toxicity
• t1/2 = 3-10 days increases from few days to weeks
Adverse drug reactions
– Nausea, vomiting, anorexia
– Skin rashes,photosensitivity, urticaria and blurred
vision
– Larger doses leads to retinopathy
– Insomnia, transient depression seizures,
rarely neuromyopathy & ototoxicity
– Bolus I.V leads to hypotension and T wave
abnormalities
Dose :
• 600 mg of base stat
• 300 mg base after 8 hours
(250 mg oral tablet of chloroquine phosphate - 150 mg
base )
Therapeutic uses:
1. Hepatic amoebiasis: 600mg base for 2 days
followed by 300 mg daily for 2-3 weeks
2. Giardiasis
3. Rheumatoid arthritis: 400mg / day for 4- 6
weeks then 200mg/day maintainence
4. Discoid Lupus Erythematosus
5. Lepra reaction
6. Infectious mononucleosis: symptomatic relief
 Amodiaquine:

– Identical to CQ in properties but less bitter

– Chloroquine resistant strains may be effective
–
– Used in combination with artesunate or
pyrimathamine/sulfadoxine in Cq resistant

– Withdrawn – hepatotoxicity and agranulocutosis

 Quinine
• Alkaloid obtained from cinchona bark.

• Mechanism of action: Similar to chloroquine . Also

believed to act as a protoplasmic posion to the parasite o
and hamper the supply of aminoacids and peptides.

Pharmacokinetics :
• Well absorbed orally and widely distributed in body
tissues( oral and slow I.V)
• Metabolized in liver, excreted in urine (t1/2 10-11hrs)
 Pharmacological actions
1. Antimalarial action:
– Erythrocytic forms of all malarial parasites
including resistant falciparum strains .
– Gametocidal for vivax & malariae
3. Cardiovascular:
– depresses myocardium, profound hypotension IV.
4. Miscellaneous actions:
– Mild analgesic, antipyretic activity , stimulation of
uterine smooth muscle
Adverse drug reactions

• Bitter in taste. Bolus I.V leads to hypotension and

arrhythmias
• Cinchonism:
• Tinnitus, blurred vision, headache, diarrhoea
• Mental confusion, vertigo, difficulty in hearing &
visual disturbances
• Still higher doses -exagerated symptoms with delirium ,
fever, tachypnoea, respiratory depression cyanosis.
• Black water fever: (Marked haemolysis with renal
failure)
• Hypoglycemia: stimulates insulin release
Uses
• Malaria:

– Uncomplicated resistant falciparum malaria

10MG/KG 8th hrly to complete 7 day course

– Complicated and severe Cerebral malaria

20mg/kg diluted in 10ml/kg 5 % dextrose-saline and
infused i.v over 4 hours followed by 10mg/kg

• Nocturnal muscle cramps: 200 – 300 mg before

sleeping
 Primaquine
Mechanism :not clear
• Quinone metabolite inhibits coenzyme –Q
governed respiratory process in exoerythrocytic
phase
Pharmacokinetics :
• Readily absorbed,
• t1/2 = 6-8 hrs
• Oxidised in liver and excreted in urine within 24
hours
Antimalarial action:
• Pre-erythrocytic phase

• Liver hypnozoites (exo-erythrocytic stage)

• Weak action against erythrocytic stage of vivax, so

used with supressives in radical cure

• Has gametocidal action -effective against all 4 species

 Adverse effects
• Nausea ,epigastric distress, abdominal cramps ,
leucopenia (oxidative property)
• Hemolytic anemia in G6PD deficient
• Contraindicated in pregnancy
Uses :
• Vivax malaria :Radical cure of relapsing malaria, 15 mg
daily for 14 days with dose of chloroquine

• Falciparum malaria 45 mg of single dose with

chloroquine to kill gametes & cut down transmission
 Mefloquine

• Quinoline methanol derivative developed to deal with

chloroquine resistant malaria
• Mechanism of action similar to chloroquine
Pharmacokinetics :
• Good but slow oral absorption (no parenteral )
• Concentrated in liver, lung, intestine
• Extensive metabolism in liver, primarily secreted in bile
, under goes enterohepatic circulation
• Long t1/2 = 2 – 3 weeks
 Adverse events
• bitter in taste, nausea, vomiting , abdominal pain ,
diarrhoea
– anxiety, hallucinations, sleep disturbances, psychosis
– Bradycardia, sinus arhythmia, & QT prolongation
– Avoided in first trimester
Uses:
• Effective drug for MDR falciparum
1. Uncomplicated falciparum in MDR malaria -used
along with artesunate (ACT)
2. Prophylaxis in MDR areas 250 mg per week started
2- 3 weeks before to asses side effects
 Dihydrofolate reductase inhibitors

Proguanil :
• Act slowly on erythrocytic stage of all species
• Preerythrocytic of vivax
• Absorbed orally but slow, metabolized and excreted
in urine, t1/2 is 16-20hrs
• Causal prophylaxis: 100 – 200 mg daily with
Atovaquone in visiting CQ resistant areas

Dihydrofolic acid tetrahydrofolic acid

dihydrofolate reductase
 Pyrimethamine
• Effective against erythrocytic forms of all species.
• Abrsorbed orally but slow, gets concentrated in liver,
spleen, kidney and lungs
• t1/2 - 4 days and prophylactic concentration remain in blood
for 2 weeks
 Adverse events: megaloblastic anemia, thrombocytopenia,
agranulocytosis.
• Used in combination with sulphanomide/ dapsone for
falciparum malaria
 Sulfadoxine-pyrimethamine

• sulfadoxine 500 mg + pyrimethamine 25 mg, 3 tablets

once for acute attack
• Not recommended for prophylaxis
• Use:
– single dose treatment of uncomplicated chloroquine
resistant falciparum malaria
– patients intolerant to chloroquine
– First choice treatment for toxoplasmosis
 Case scenario
• A boy, 14 years old was admitted to hospital with abdominal
pain fever with chills and rigors. This patient was from another
hospital with a diagnosis of suspected peritonitis. He has been
hospitalized for five days before.
• Abdominal CT-scan showed hepatomegaly with moderate
ascites, bilateral pleural effusion, and small multiple peri-
aortic nodules.
• Diagnosis of lymphoma was evocated by a radiologist. History
of travel in malaria-endemic areas was one month ago

• At admission, the patient presented with Glasgow Coma Scale

13, fever, pallor, icteric, abdominal pain, hepatomegaly and
splenomegaly.
• The first day after admission, blood test results showed anemia
(6.2g/dL), leukocytosis (43,380/mm3), thrombocytopenia
(40,000/mm3), hypoglycemia (26mg/dL), hyperuricemia
(124mg/dL), hypoalbuminemia and prolonged hemostasis.

• Urinalysis showed hemoglobinuria, and urine culture result

came out with E.coli.

• A blood smear revealed Plasmodium falciparum in ring stage,

schizonts, and gametocytes

• Urinalysis result was dark with positive urobilinogen and blood.

 Drug of choice in a patient with severe
complicated falciparum malaria is:

(a) Chloroquine
(b) Quinine
(c) Artesunate
(d) Artemether
 Artemisinin derivatives
• Artemisinin is the active principle - plant artimisia annua
• Sesquiterpine lactone derivative

• Most potent and rapid acting blood schizonticides with

parasitaemia clearance <48hrs

•
Artemisin derivatives :
• Artesunate

• Artemether

• Arteether
Mechanism of action
• These compounds have presence of endoperoxide bridge
• Endoperoxide bridge interacts with heme in parasite
• Heme iron cleaves this endoperoxide bridge
• There is generation of highly reactive free radicals which
damage parasite membrane by covalently binding to
membrane proteins
Antimalarial action :
• Mainly schizonticides and are effective against
plasmodium vivax as well as chloroquine resistant and
sensitive strains of plasmodium falciparum
• Useful in cerebral malaria and MDR MALARIA

Artesunate
• Water soluble ester ,given oral, IM,IV (rectal)
• Absorption is incomplete but fast, reach peak <60mins
• Rapidly converted to DHA with t1/2 30-60mins
• 1st choice- severe malaria- oral with 3 other dugs as ACT combination
• 50 mg tablet available, 60mg/vial injection
Artemether
• Lipid soluble Methyl ether
• absorption after Oral & IM - slow 2-6 hrs, undergoes
first pass with t1/2 of 3-10hrs

Arteether
• Ethyl ether of dihydroartemisinin
• Available only as I.M for complicated malaria
because of its longer t1/2- 23 hrs.
• equivalent to quinine in cerebral malaria
• Dose:3.2 mg/kg on day1 followed by 1.6 mg/kg daily
for next 4 days
 Artemisinin based combination therapy (ACT)
• Rapid clinical & parasitological cure
• Low relapse rates and high cure rate
• Absence of resistance
• Good tolerability profile
ACT COMBINATIONS
1. Artesunate/ Lumefantrine
2. Artesunate/ Mefloquine

3. Artesunate/ sulfadoxine and pyrimethamine

4. Artesunate/ Amodiaquine
5. Dihydroartemisinin/ piperaquine
Uses :
• Uncomplicated falciparum malaria

• For Vivax malaria: CQ-resistant infections and when

quinine+ doxycycline/clindamycin cannot be used

• Severe and complicated malaria

 Adverse events

• Leucopenia
• Hypersensitivity: Drug fever, itching
• GIT: nausea, vomiting, abdominal pain
• ECG changes: ST-T changes, QT prolongation
• Abnormal bleeding, dark urine
• Reticulocytopenia
Drug interactions :
• Drugs prolonging Q-T like astemizole,
antiarrhythmics, TCA and phenothiazines increase
risk
 Antibiotics
• Tetracycline (500mg BD) and Doxycycline
(100mg/day orally)
• Blood schizonticidal for all malarial parasites
• Used as a second line therapy for chemoprophylaxis
in CQ resistant malaria
• Used with artesunate/Quinine in MDR falciparum
malaria
• Clindamycin (20mg/kg/d orally TDS ) 7 days with
quinine 650mg TDS for 3-7 days

• Suggested for choloroquine resistant falciparum

• Antibiotics are not given in pregnant women

Management of Malaria
 Prophylaxis of malaria
• 1-2 weeks before to 4 weeks after returning from endemic
area
• Drug regimens:
– Chloroquine sensitive malaria: 300 mg / week
– In travellers , 10mg/kg one week before and till one
month after return
– Chloroquine resistant malaria:
• Mefloquine 250 mg 1- 2 weeks before and weekly till
one month after return
• Doxycycline 100 mg day before travel and taken for 4
weeks after return
 Acute attack of chloroquine sensitive
malaria:
• 1. Vivax (also Ovale, malariae) malaria:
Chloroquine 600 mg,300mg after 8 hours
and for next 2 days+ Primaquine 15mg daily for 14 days

• 2. Falciparum malaria
Chloroquine 600mg stat, 300mg after8 hours and next 2
days + primaquine 45mg single dose
 Acute attack of chloroquine resistant
malaria
• Artesunate 100 mg BD x 3 days with
Sulfadoxine(1500mg)-pyrimethamine (75mg) single
dose
• Artesunate 100 mg BD x 3 days with mefloquine
750mg on 2nd day and 500mg on 3rd day
• Quinine 600 mg TDS X 7 days with Cap doxycycline
100 mg for 7 days or + clindamycin 600mg BD 7 days
• Artemether 80mg + Lumefantrine 480mg BD for 3
days
• Arterolane 150mg+ Piperaquine 750mg once daily- 3
days
 Severe and complicated falciparum
malaria
• Artesunate 2.4 mg/kg I.V/I.M, BD on day1 then 2.4
mg/kg daily for 7 days
OR
• Artemether 3.2 mg/kg I.M on day 1 then 1.6 mg/kg
daily for 7 days
• OR
• Arteether 3.2 mg/kg I.M on day1, followed by 1.6
mg/kg daily for next 4 days
– Switchover to 3 Day oral ACT in between
whenever patient can take oral medication
 OR
• Quinine: quinine 20mg/kg on admission (i.v.
infusion in 5% dextrose/dextrose saline over a period
of 4 hours) followed by maintenance dose of 10
mg/kg for 4 hours every 8th hourly
– When ever patient can swallow orally switch over
to oral quinine 10 mg/kg 8 hrly and complete 7
days course
In Pregnancy :

• Uncomplicated malaria: artemether + lumefantrine

• Quinine 600mg TDS- 7 days + clindamycin 300mg

TDS/QID for 7 days (first trimester)

• Artemesinin based therapy : 3 days regimen as an

alternative
Malaria in children :
• Dihydro-artemisinin + piperaquine in children
weighing less than 25 kg

• Parenteral artesunate in children weighing less than

20 kg.

• For infants <5 kg with uncomplicated P. falciparum-

ACT at the same mg/kg body weight dose as for
children weighing 5 kg. (artemether 20mg +
lumefantrine 120 mg ) 3 days
Thank you