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Antimalarial drugs

Dr. Vijendra R.

DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES


Protozoal infections
Protozoa
Eukaryotes & unicellular organisms
Most protozoal infections due to unhygienic
conditions
Less easily treated than bacterial infections &
antiprotozoal drugs are more toxic

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Protozoal infections
Common protozoal infections include
Malaria
Amoebiasis
Trypanosomiasis
Giardiasis
Leishmaniasis
Trichomoniasis
Toxoplasmosis

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Malaria
Plasmodium species which infect humans
1. Plasmodium vivax (tertian)
2. Plasmodium ovale (tertian)
3. Plasmodium falciparum (M. tertian)
4. Plasmodium malariae (quartan)

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Life cycle of malarial parasite

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Life cycle of malarial parasite

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Life cycle of malarial parasite

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Chemical classification
4 Aminoquinolines
CHLOROQUINE, HYDROXYCHLOROQUINE, AMODIAQUINE, PIPERAQUINE
8 Aminoquinolines
PRIMAQUINE, TAFENOQUINE, BULAQUINE
Cinchona alkaloids
QUININE, QUINIDINE
Quinoline methanol
MEFLOQUINE
Biguanides
PROGUANIL, CHLORPROGUANIL
Diaminopyrimidines
PYRIMETHAMINE
Sulfonamides
SULFADOXINE, DAPSONE
Antibiotics
TETRACYCLINE, DOXYCYCLINE, CLINDAMYCIN
Naphthoquinone
ATOVAQUONE
Sesquiterpene lactones:
ARTESUNATE, ARTEMETHER, ARTEETHER, ARTEROLANE
Amino-alcohols
HALOFANTRINE, LUMIFANTRINE
Naphthyridine
PYRONARIDINE

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Effect of drug on parasite viability

Liver stages Blood stages


Hypno- Gameto-
Group Drugs Sporozoite Primary Asexual
zoite cyte
1 Artemisinins - - - + +
Chloroquine - - - + +/-
Mefloquine - - - + -
Quinine /
- - - + +/-
Quinidine
Pyrimethamine - - - + -
Sulfadoxine - - - + -
Tetracycline - - - + -
Atovaquone /
2 - + - + +/
Proguanil
3 Primaquine - + + - +
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Chloroquine
Synthesized by Germans in 1934 ( resochin)
d & l isomers, d isomer is less toxic
Cl at position 7 confers maximal antimalarial
efficacy
Antimalarial activity: High against erythrocytic
forms of vivax, ovale, malariae & sensitive strains
of falciparum
Gametocytes of vivax

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Chloroquine
Mechanism of action

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Chloroquine
Other parasitic infections:
Giardiasis, taeniasis, extrainstestinal amoebiasis
Other actions:
Depressant action on myocardium, direct relaxant
effect
on vascular smooth muscles, anti-inflammatory,
antihistaminic , local anaesthetic
Resistance develops due to efflux mechanism
Well absorbed, tmax 2-3 hrs , 60 % protein bound
Concentrated in liver , spleen, kidney, lungs ,
leucocytes
Selective accumulation in retina: ocular toxicity
T1/2 = 3-10 days increases from few days to weeks
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Chloroquine
Pharmacokinetics
Chloroquine is administered in loading
dose in malaria
Chloroquine is well absorbed after oral administration.
It is extensively tissue bound & 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.
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
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Chloroquine
Adverse drug reactions
Intolerance:
Nausea, vomiting, anorexia
skin rashes, angioneurotic edema,
photosensitivity,
pigmentation, exfoliative dermatitis's
Long term therapy may cause bleaching of hair
Rarely thrombocytopenia, agranulocytosis,
pancytopenia

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Chloroquine
Adverse drug reactions
Ocular toxicity: High dose prolonged therapy
Temporary loss of accommodation
Lenticular opacities, sub capsular 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
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Chloroquine
Therapeutic uses
Hepatic Amoebiasis:
Giardiasis
Clonorchis sinensis
Rheumatoid arthritis
Discoid Lupus Erythematosus
Control manifestation of lepra reaction
Infectious mononucleosis

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4-aminoquinolones
HYDROXY CHLOROQUINE:
Less toxic, properties &uses similar
AMODIAQUINE:
As effective as chloroquine
Pharmacological actions similar
May be effective in Chloroquine resistant strains
Adverse events: GIT, headache , photosensitivity,
rarely agranulocytosis
Not recommended for prophylaxis
Pyronaridine: effective in resistant cases
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Quinine
1820 Pelletier & caventou isolated quinine from
cinchona bark.
Mechanism of action:
Similar to chloroquine
General protoplasmic poison
Pharmacokinetics-Administered orally is completely
absorbed
Tmax = 1-3 hrs , crosses placental barrier
Metabolized in liver degradation products excreted in
urine t = 10 hrs

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Pharmacological actions
Antimalarial action:
Erythrocytic forms of all malarial parasites including
resistant falciparum strains .
Gametocidal for vivax & malariae
Local irritant effect: Local pain sterile abscess.
3. Cardiovascular: depresses myocardium,
excitability,
conduc vity, refractory period, profound
hypotension IV.
4. Miscellaneous actions: Mild analgesic, antipyretic
activity , stimulation of uterine smooth muscle, curare
mimetic effect
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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
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Adverse drug reactions
Cinchonism: (resembles salicylism)
Tinnitus, nausea & vomiting
Headache mental confusion, vertigo, difficulty in
hearing & visual disturbances
Diarrhoea , flushing & marked perspiration
Still higher doses , exaggerated symptoms with
delirium, fever, tachypnoea, respiratory
depression ,
cyanosis.

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Adverse drug reactions
Idiosyncrasy : similar to Cinchonism but occurs in
therapeutic doses-pruritis, urticaria, hemolytic
anemia
and agranulocytosis
Cardiovascular toxicity: cardiac arrest,
hypotension
fatal arrhythmias
Hypoglycemia
Black water fever-intravascular hemolysis,
hemoglobinuria, fever & acute renal failure
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Primaquine
Primaquine-Converted to electrophiles Generates
reactive oxygen species
Liver Hypnozoites
Weak action against erythrocytic stage of vivax, so
used with suppressive in radical cure
No action against erythrocytic stage of falciparum
Has gametocidal action & is most effective
antimalarial to prevent transmission disease
against all
4 species
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Pharmacokinetics
Readily absorbed,
t1/2 = 3-6 hrs
Oxidized in liver
excreted in urine
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.
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Adverse effects
Gastrointestinal:
epigastric distress, abdominal
cramps ,
Hemopoetic:
mild anemia,
methaemoglobinemia,
cyanosis, hemolytic anemia in
G6PD deficiency
Avoided during pregnancy, G6PD
deficient
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Tafenoquine & Bulaquine
Tafenoquine:
More active slowly metabolized analog of
primaquine, has advantage that it can be given on
weekly basis.
Tried for radical cure in 3 days
Bulaquine:
Congener of primaquine developed in India
Comparable antirelapse activity when used for 5
days
Partly metabolized to primaquine
Better tolerated in G6PD deficiency

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Mefloquine
Quinoline methanol derivative developed to deal
with
chloroquine resistant malaria & MDR-Muti Drug
resistant species
Rapidly acting erythrocytic schizonticide, slower
than
chloroquine & quinine
Mechanism of action similar to chloroquine
Neither gametocidal, nor kills Hypnozoites

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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
Caution- minimum of 12hr interval after quinine
administration as both are cardiotoxic

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Uses
Effective drug for MDR falciparum
T/t of uncomplicated falciparum in MDR malaria
should be used along with Artesunate (ACT)
Prophylaxis in MDR areas 250 mg per week started
2-3 weeks before to assess side effects
Due to fear of drug resistance mefloquine should
not be used as drug for prophylaxis in residents of
endemic area

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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 arrhythmia, & QT
prolongation
Teratogenicity: Avoided in first trimester
Miscellaneous: allergic skin reactions, hepatitis &
blood dyscrasias
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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 can act against chloroquine, quinine &
pyrimethamine resistant strains
Adverse events; Nausea, vomiting, QT
prolongation, diarrhoea, itching , rashes
C/I: along with quinine, chloroquine,
antidepressants, antipsychotics
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Atovaquone
Synthetic naphthoquinone
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. Jiroveci & Toxoplasma gondi
infections
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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 cause
depression of myocardium, megaloblastic anemia
Not a drug for acute attack
Causal prophylaxis: 100 200 mg daily
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Sulfonamide + pyrimethamine
Pyrimethamine is diaminopyrimidine more potent
than
proguanil & effective against erythrocytic forms of all
species, toxoplasmosis, polycythemia vera
Inhibits dihydrofolate reductase enzyme
Tasteless so suitable for children
Used in uncomplicated chloroquine resistant malaria
Sulfadoxine(1500mg)+ Pyrimethamine(75mg)-single
dose
Adverse events: sulfa related
megaloblastic anemia, thrombocytopenia,
agranulocytosis.
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Artemisinin
Artemisinin is the active principle of the plant
Artemisia annua
Sesquiterpene lactone derivative
Most potent & rapid acting blood schizonticides
Short duration of action
Poorly soluble in water & oil
Artesunate
Artemether
Arteether
Arterolane
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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

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MOA-
2) Artemisinin free radicals specifically inhibit a
plasmodial
sarcoplasmic-endoplasmic calcium ATPase
Water soluble ester of dihydroartemisinin
Dose: can be given oral, IM,IV, rectal t1/2- 1-2hrs
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

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Artemisinin

Conventional treatment

Artemisinin

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Artemether
Methyl ether of dihydroartemisinin
Converted to DHA-dihydroartemisinin, not given IV, t1/2-3-10hrs
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 favoring
accumulation in brain
Given IM only T1/2-23hrs
Dose:3.2 mg/kg on day1 followed by 1.6 mg/kg daily for next 4
days
ARTEROLANE-available for oral use only in combination

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Adverse reactions
Leucopenia
Hypersensitivity: Drug fever, itching
GIT: nausea, vomiting, abdominal pain (common)
ECG changes: ST-T changes, QT prolongation
Abnormal bleeding, dark urine
Reticulocytopenia
D/I-concurrent administration with astemizole,
antiarrhythmics, tricyclic antidepressants and
phenothiazines increase the risk of cardiac
conduction
defects
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Artemisinin based combination therapy (ACT)
Artemisinin compounds 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
Artemisinin compounds with one long acting drug like
mefloquine 15 mg/kg single dose
Indicated by WHO in acute uncomplicated resistant
falciparum malaria
Rapid clinical & parasitological cure
High cure rates & low relapse rates
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Choice of ACT
Combinations which have been evaluated:
Artemisinin + piperaquine
mefloquine
Artesunate +
dihydroartemisinin + piperaquine
mefloquine
artemether + lumefantrine
mefloquine
naphthoquine
chloroquine
amodiaquine
sulfadoxinepyrimaethaminine
mefloquine
proguanil-dapsone
chlorproguanil-dapsone
atovaquone-proguanil
clindamycin
tetracycline
Doxycycline
There are now more trials involving Artemisinin & its derivatives than other antimalarial drugs, so although
there are still gaps in our knowledge, there is a reasonable evidence base on safety & efficacy from which to
base recommendations

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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

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Drugs not allowed for prophylaxis
Quinine ,
Artemisinin compounds
Pyrimethamine sulfadoxine
Amodiaquine
Drugs used in chloroquine resistant malaria
Mefloquine
Quinine
Sulfadoxine pyrimethamine
Artemisinin compounds

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Lumefantrine+artemether
Lumefantrine is highly effective, long acting oral
erythrocytic schizonticide related to mefloquine
MOA- similar to chloroquine
-also affects nucleic acid & protein synthesis of
parasite
Fatty food increases absorption
Highly lipophilic onset delayed ,
peak 6 hrs
Available as fixed dose combination
80 mg artemether bd with 480 mg lumefantrine bd for
3
days
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Tetracyclines
Tetracyclines & doxycycline
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
CLINDAMYCIN
Bacteriostatic antibiotic, erythrocytic
schizontocide
Potentiates the action of quinine & artemisinin
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Chloroquine sensitive malaria
Tab. Chloroquine phosphate 250 mg
Contains 150 mg of base
Give 4 tablets stat , 2 tablets after 8 hours & , 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
Primaquine 45 mg single dose for falciparum after
chloroquine (gametocidal)
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Chloroquine resistant malaria
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

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Chloroquine resistant malaria
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
Chloroquine resistant malaria
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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

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Complicated Falciparum malaria
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 & complete 7 days
course

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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
Chloroquine in usual doses
Mefloquine C/I in first trimester
Primaquine/ tetracycline avoided
Anemia: folic acid & iron
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