Antimalarial drugs

Antimalarial drugs
 Plasmodium species which
infect humans

Plasmodium vivax (tertian):

Plasmodium ovale (tertian)
Plasmodium falciparum (tertian)
Plasmodium malariae (quartan)

Plasmodium knowlesi:
Sir Ronald Ross
 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
– Primaquine, proguanil
• Supressives Prophylaxis:
– Supress the erythrocytic phase and thus attack of
malarial fever can be used as prophylactics
– 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 P.vivax & P.ovale from the body
– Supressive drugs + hypnozoitocidal drugs
– For vivax: primaquine 15 mg daily for 14 days
• Gametocidal:
– Destroy gametocytes and prevent transmission
– Primaquine, artemisinin – against all plasmodia
– Chloroquine, quinine – Pl Vivax
– Proguanil ,pyrimethamine – prevent development
of sporozoites
 Chemical classification
• 4 aminoquinolines:
– Chloroquine, Hydroxychloroquine, Amodiaquine,
Pyronaridine
• 8 aminoquinolines:
– Primaquine, Tafenoquine, Bulaquine
• 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:
– Synthesized by Germans in 1934 ( resochin)

– d & l isomers, d isomer is less toxic

– Cl at position 7 confers maximal antimalarial
efficacy
 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:
– High against erythrocytic forms of vivax, ovale,
malariae & sensitive strains of falciparum
– Gametocytes of vivax
– No activity against tissue schizonts
– Resistance develops due to efflux mechanism
2. Other parasitic infections:
– Giardiasis, taeniasis, extrainstestinal amoebiasis
3. Other actions:
– Depressant action on myocardium, direct relaxant
effect on vascular smooth muscles,
antiinflammatory, antihistaminic , local anaesthetic
 Pharmacokinetics
• Well absorbed, tmax 2-3 hrs , 60 % protein
bound
• 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
• Intolerance:
– Nausea, vomiting, anorexia
– skin rashes, angioneurotic edema,
photosensitivity, pigmentation, exfoliative
dermatititis
– Long term therapy may cause bleaching of hair
– Rarely thrombocytopenia, agranulocytosis,
pancytopenia
 Adverse drug reactions
• Occular toxicity: High dose prolonged therapy
– Temporary loss of accommodation
– Lenticular opacities, subcapsular cataract
– Retinopathy: constriction of arteries, edema, blue
black pigmentation , constricted field of vision.
• CNS:
– Insomnia, transient depression seizures,
rarely neuromyopathy & ototoxicity
• CVS:
– ST & T wave abnormalities, abrupt fall in BP &
cardiac arrest in children reported
Adverse effects are infrequent at doses normally
used for malaria prophylaxis and treatment, but are
more common with the higher or prolonged
doses given for resistant malaria or for
rheumatoid arthritis or lupus erythematosus.
Corneal deposits of chloroquine may cause
halos around lights or photophobia. These reverse when
the drug is stopped. Retinal toxicity may be irreversible.
In the early stage it takes the form of visual field
defects; late retinopathy classically gives the picture
of macular pigmentation surrounded by a ring of
pigment. The functional defect can take the form
of scotomas, photophobia, defective colour
vision resulting, in the extreme case, in blindness.
 Dosage
• 600 mg of base stat
• 300 mg base after 8 hours
• 150 mg of base BD for 2 days

• 200 mg oral tablet of chloroquine phosphate

consists of 150 mg base
Chloroquine is administered in loading dose
in malaria
• Chloroquine is well absorbed after oral
administration. It is extensively tissue bound
and sequestrated by tissues particularly liver,
spleen, kidney it has got large apparent
volume of distribution
• So it is given in loading dose to rapidly achieve
the effective plasma conc.
 Therapeutic uses
1. Hepatic amoebiasis:
2. Giardiasis
3. Clonorchis sinensis
4. Rheumatoid arthritis
5. Discoid Lupus Erythematosus
6. Control manifestation of lepra reaction
7. Infectious mononucleosis
• Hydroxy chloroquine:
– Less toxic, properties &uses similar
• Amodiaquine:
– As effective as chloroquine
– Pharmacological actions similar
– Chloroquine resistant strains may be effective
– Adverse events: GIT, headache , photosensitivity,
rarely agranulocytosis
– Not recommended for prophylaxis
• Pyronaridine: effective in resistant cases
Quinine as cinchona bark was introduced into
Europe from South America in 1633. It was
used for all fevers, amongst them malaria.

Further advance in the chemotherapy

of malaria was delayed until 1880, when
Charles Louis Alphonse Laveran, Prof. of Military
Medicine in Paris (Nobel prize winner 1907) finally
identified the parasites in the blood.
 Quinine
• 1820 Pelletier & caventou isolated quinine
from cinchona bark.
• Mechanism of action:
– Similar to chloroquine
Quinine (Chinine) is an alkaloid, obtained
from the bark of the South American Cinchona tree.
It binds to plasmodial DNA to prevent protein
synthesis. It is used to treat Plasmodium falciparum
malaria in areas of multiple-drug resistance. Apart
from its antiplasmodial effect, quinine is used for
myotonia and muscle cramps because it prolongs
the muscle refractory period. Quinine is included in
dilute concentration in tonics and aperitifs for its
desired bitter taste. Adverse effects include tinnitus,
diminished auditory acuity, headache, blurred vision,
nausea, and diarrhoea. Idiosyncratic reactions include
pruritus, urticaria, and rashes. Hypoglycemia may be
significant when quinine is given by i.v. infusion.
Amodiaquine is closely related to chloroquine, and
it probably shares its mechanisms of action and resi-
stance. Amodiaquine has been widely used to treat
malaria because of its low cost, limited toxicity, and,
in some areas, effectiveness against chloroquine-
resistant strains of P. falciparum. Important toxicities
of amodiaquine, including agranulocytosis, aplastic
anemia, and hepatotoxicity, have limited use, but
serious toxicity is rare.
 Pharmacological actions
1. Antimalarial action:
– Erythrocytic forms of all malarial parasites including
resistant falciparum strains .
– Gametocidal for vivax & malariae
2. Local irritant effect:
– Local pain sterile abcess.
3. Cardiovascular:
– depresses myocardium, ↓ excitability, ↓ conductivity,
↑ refractory period, profound hypotension IV.
4. Miscellaneous actions:
– Mild analgesic, antipyretic activity , stimulation of
uterine smooth muscle, curaremimitic effect
 Adverse drug reactions
Cinchonism:
• Tinnitus, nausea & vomiting
• Headache mental confusion, vertigo,
difficulty in hearing & visual disturbances
• Diarrhoea , flushing & marked perspiration
• Still higher doses , exagerated symptoms
with delirium , fever, tachypnoea,
respiratory depression , cyanosis.
 Adverse drug reactions
• Idiosyncrasy : similar to cinchonism but
occurs in therapeutic doses
• Cardiovascular toxicity: cardiac arrest,
hypotension ,fatal arrhytmias
• Black water fever:
• Hypoglycemia:
 Uses
• Malaria:
– uncomplicated resistant falciparum malaria
– Cerebral malarial
• Myotonia congenita: 300 to 600 mg BD/ TDS
• Nocturnal muscle cramps: 200 – 300 mg
before sleeping
• Spermicidal in vaginal creams
• Varicose veins: along with urethane causes
thrombosis & fibrosis of varicose vein mass
• Primaquine:
– Mechanism of action:

Primaquine

Converted to
electrophiles

Generates reactive
oxygen species

– Interferes with oxygen transport system

 Antimalarial action
• Liver hypnozoites
• Weak action against erythrocytic stage of
vivax, so used with supressives in radical cure
• No action against erythrocytic stage of
falciparum
• Has gametocidal action and is most effective
antimalarial to prevent transmission disease
against all 4 species
 Adverse effects

• Gastrointestinal:
– epigastric distress,
abdominal cramps ,
• Hemopoetic:
– mild anemia,
methaemoglobinemia,
cyanosis, hemolytic anemia
in G6PD deficiency
• Avoided during pregnancy,
G6PD deficient
 Uses
• Primary use is radical cure of relapsing malaria
15 mg daily for 14 days with dose of
chloroquine
• Falciparum malaria 45 mg of single dose with
chloroquine curative dose to kill gametes &
cut down transmission of malaria.
• Tafenoquine:
– More active slowly metabolized analog of
primaquine, has advantage that it can be given on
weekly basis.
• Bulaquine:
– Congener of primaquine developed in india
– Comparable antirelapse activity when used for 5
days
– Partly metabolized to primaquine
– Better tolerated in G6PD deficiency
 Mefloquine
• Quinoline methanol derivative developed to
deal with chloroquine resistant malaria
• Rapidly acting erythrocytic schizonticide ,
slower than chloroquine & quinine
• Effective against chloroquine sensitive &
resistant plasmodia
• Mechanism of action similar to chloroquine
 Pharmacokinetics
• Good but slow oral absorption
• High protein binding
• 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
• GIT:
– bitter in taste, nausea, vomiting , abdominal pain , diarrhoea
• Neuropsychiatric disturbances:
– anxiety, hallucinations, sleep disturbances, psychosis, errors
in operating machinery, convulsions
• CVS:
– Bradycardia, sinus arhythmia, & QT prolongation
• Teratogenicity:
– Avoided in first trimester
• Miscellaneous:
– allergic skin reactions, hepatitis & blood dyscrasias
 Uses
• Effective drug for MDR falciparum
1. T/t of uncomplicated falciparum in MDR malaria
should be used along with artesunate (ACT)
2. Prophylaxis in MDR areas 250 mg per week
started 2- 3 weeks before to asses side effects
• Due to fear of development of drug
resistance mefloquine should not be used as
drug for prophylaxis in residents of endemic
area
 Halofantrine
• Quinoline methanol
• Used in chloroquine resistant malaria since
1980
• Erratic bioavailabilty, lethal cardiotoxicity &
cross resistance to mefloquine limited its use
• Now a days used only when no other
alternative available
• Adverse events; Nausea, vomiting, QT
prolongation , diarrhoea, itching , rashes
• C/I: along with quinine, chloroquine,
antidepressants, antipsychotics.
 Atovaquone
• Synthetic napthoquinone
• Rapidly acting erythrocytic schizonticide for
plasmodium falciparum & other plasmodia
• MOA: Collapses mitochondrial membrane &
interferes ATP production
• Proguanil potentiates action of atovaquone
and prevents development of resistance
• Also used in P. Jivoreci & Toxoplasma gondii
infections
 Antifolates
Dihydrofolate reductase inhibitors
• Proguanil :
– Biguanide converted to cycloguanil active compound
– Act slowly on erythrocytic stage of vivax &
falciparum
– Prevents development of gametes
 Adverse effects:
 Stomatitis, mouth ulcers, larger doses depression of
myocardium , megaloblastic anemia
 Not a drug for acute attack
 Causal prophylaxis: 100 – 200 mg daily
Proguanil (t1/2 17 h) inhibits dihydrofolate reductase
which converts folic to folinic acid, deficiency of
which inhibits plasmodial cell division. Plasmodia,
like most bacteria and unlike humans, cannot make
use of preformed folic acid. Pyrimethamine and
trimethoprim, which share this mode of action, are
collectively known as the “antifols”. Their plasmod-
icidal action is markedly enhanced by combination
with sulphonamides or sulphones because there is
inhibition of sequential steps in folate synthesis.
Poguanil must be used daily when given for
prophylaxis, its main use, particularly in pregnant
women (with folic acid 5 mg/d).
Antifols
Pyrimethamine (t1/2 4 d) inhibits plasmodial dihydro-
folate reductase, for which it has a high affinity. It is
well absorbed from the GIT and is extensively
metabolized. Pregnant women should receive
supplementary folic acid when taking pyrimethamine.
Adverse effects reported include anorexia,
abdominal cramps, vomiting, ataxia, tremor, seizures,
and megaloblastic anaemia.

Pyrimethamine acts synergistically with Sulfadoxine

(as Fansidar®) 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 Pl. falciparum.
 Pyrimethamine
• Diaminopyrimidine more potent than proguanil
& effective against erythrocytic forms of all
species.
• Tasteless so suitable for children
 Adverse events: megaloblastic anemia,
thrombocytopenia, agranulocytosis.
 Sulfadoxine-pyrimethamine
• Sequential blockade
• 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
 Artemisinin
• Artemisinin is the active principle of the plant
artimisia annua
• Sesquiterpine lactone derivative
• Most potent and rapid acting blood
schizonticides
• Short duration of action
• high recrudescence rate
• Poorly soluble in water & oil
PLANT- ARTEMISIA ANNUA
 Artemisinin 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

Artemisinin

Conventional
Treatment

Artemisinin
 Artesunate
• Water soluble ester of dihydroartemisinin
• Dose: can be given oral, IM,IV, rectal
– Oral
• 100 mg BD on day 1
• 50 mg BD day 2 to day 5
– Parenteral
• 120 mg on day 1 (2.4 mg/kg BD )
• 60 mg OD ( 2.4 mg/kg) for 7 days
 Artemether
• Methyl ether of dihydroartemisinin
• Dose:
• Oral & IM
• 80 mg BD on day 1 (3.2 mg/kg)
• 80 mg OD (1.6 mg/kg) for 7 days
 Arteether
•Ethyl ether of dihydroartemisinin
• Therapeutically equivalent to quinine in
cerebral malaria
• A longer t1/2 & more lipophilic than
artemether favouring accumulation in brain
• Dose:3.2 mg/kg on day1 followed by 1.6
mg/kg daily for next 4 days
 Adverse events
• Leucopenia
• Hypersensitivity: Drug fever, itching
• GIT: nausea, vomiting, abdominal pain
(common)
• ECG changes: ST-T changes, QT prolongation
• Abnormal bleeding, dark urine
• Reticulocytopenia
Artemisinin based combination therapy (ACT)

• Artemisinin compunds are shorter acting drugs

• Monotherapy needs to be extended beyond
disappearance of parasite to prevent
recrudescence
• This can be prevented by combining 3-5 day
regimen of artemisin compounds with one long
acting drug like mefloquine 15 mg/kg single dose
• Indicated by WHO in acute uncomplicated
resistant falciparum malaria
 Why combination therapy
• Rapid clinical & parasitological cure
• High cure rates and low relapse rates
• Absence of resistance
• Good tolerability profile
 ACT Regimens in use
• Artesunate – Sulfadoxine, pyrimethamine:
– Adopted as first line in india under NMP
– ARTESUNATE 100 mg BD for 3 days with S-P, 3
tablets
• Artesunate Mefloquine:
– By combining artesunate further spread of
mefloquine resistance can be prevented
– Artesunate 100 mg BD for 3 days, + mefloquine
750 mg on second day & 500 mg on third day
 Artemether & lumefantrine
• Lumefantrine is highly effective , long acting
oral erythrocytic schizonticide related to
mefloquine
• Highly lipophilic onset delayed , peak 6 hrs
• Available as fixed dose combination
• 80 mg artemether BD WITH 480 mg
lumefantrine BD for 3 days
Other ACTs:
– DHA – Piperaquine, Artesunate- pyronaridine
 Tetracyclines
• Slow but potent action on erythrocytic stage
of all MP & Pre-erythrocytic stage of
falciparum
• Always used in combination with quinine or S-
P for treatment of chloroquine resistant
malaria
Management of Malaria
 Prophylaxis of malaria
• Indication:
• Duration :1-2 weeks before to 4 weeks
after returning from endemic area
• Drug regimens:
– Chloroquine sensitive malaria: 300 mg / week
– Chloroquine resistant malaria:
• Mefloquine 250 mg once a week ,
• Doxycycline 100 mg daily ,
• Atovaquone + proguanil daily
Drugs not allowed for prophylaxis
• Quinine , artemisinin compounds
– Shorter acting, higher toxicity
• Pyrimethamine sulfadoxine
• Amodiaquine
 Acute attack of chloroquine sensitive
malaria:
• Tab. Chloroquine phosphate 250 mg
– Contains 150 mg of base
– Give 4 tablets stat , 2 tablets after 8 hours and , 1
tablet BD for 2 days
• Patients who cannot take orally
– 3.5 mg/kg IM every 6 hrs for 3 days
• Tab primaquine 15 mg OD for 14 days in
Plasmodium vivax, ovale
• Primaqine 45 mg single dose for falciparum
after chloroquine (gametocidal)
 Acute attack of chloroquine resistant
malaria
A. Pts who can take orally:
– 3 tablets of (Pyrimethamine + sulfadoxine) single
dose followed by quinine 600 mg TDS for 2 days
or
– Tab Quinine 600 mg TDS X 3 days with Cap
doxycycline 100 mg BD for 7 days or
– Quinine 3 days with mefloquine or
– (Atovaquone 250 mg + proguanil 100 mg) 4
tab(Single dose ) for 3 days or
– artesunate 100 mg BD x 3 days with Sulfadoxine-
pyrimethamine or mefloquine
• Pts who cannot take orally
– Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline
over 4 hrs then
– 10 mg/kg in dextrose saline over 2 hrs every 8 hrly
till patient is able to swallow
– Then quinine 600 mg TDS for 7 days &
tetracycline/ doxycycline
Or
– artemether / arteether injection
 When should resistance be suspected
• All pts with complication
• Any pt who has already received chloroquine
last 1 month
• Hb continues to fall in absence of bleeding &
asexual forms persist along with symptoms
after 48 hrs of treatment
Severe and complicated falciparum malaria
• Hyperparasitaemia
• Hyperpyrexia
• Fluid electrolyte disturbances, acidosis
• Hypoglycemia
• Cardiovascular collapse
• Jaundice, severe anaemia
• Spontaneous bleeding
• Pulmonary edema
• Renal failure
• Hemoglobinuria, black water fever
• Cerebral malaria
 Treatment of severe and complicated
falciparum malaria
• Artesunate 2.4 mg/kg IV/IM, BD on day1
then 2.4 mg/kg daily for 7 days OR
• Artemether 3.2 mg/kg IM on day 1 then
1.6 mg/kg daily for 7 days OR
• Arteether 3.2 mg/kg IM 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: 20 mg quinine salt/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 body weight 8
hourly.
– When ever patient can swallow orally switch over
to oral quinine 10 mg/kg 8 hrly and complete 7
days course
• Malaria in children:
– Quinine parenteral high toxicity / oral well
tolerated
– Primaquine avoided in neonates
– Mefloquine not used in children below 15 kg
weight
• Acute malaria in pregnant women
– Chloroqune in usual doses
– Mefloquine C/I in first trimester
– Primaquine/ tetracycline avoided
– Anemia: folic acid & iron
 Practice points
• Most antimalarials are bitter in taste give
along with milk or fruit juice
• If vomiting occurs within hour of drug repeat
full dose, in case of mefloquine repeat half
dose
• If vomiting after 1 hour no need to repeat
• Postural hypotension : quinine, chloroquine
Drugs used in chloroquine resistant malaria

• Mefloquine
• Quinine
• Sulfadoxine pyrimethamine
• Artemisinin compounds