This document discusses various antimalarial drugs, classifying them and describing their mechanisms of action, pharmacokinetics, uses, and side effects. It covers quinoline derivatives like chloroquine and amodiaquine, mefloquine, quinine, proguanil, pyrimethamine, sulfadoxine-pyrimethamine, primaquine, artemisinin and its derivatives, atovaquone, and others. The drugs act against different life stages of the malaria parasite in the liver or blood and are used for prophylaxis, treatment, or radical cure of malaria caused by various Plasmodium species.

1. 1
ANTIMALARIAL DRUG
BY
KUBER BAJGAIN

2.  Plasmodium vivax (tertian)
 Plasmodium ovale (tertian)
 Plasmodium falciparum (tertian)
 Plasmodium malariae (quartian)
Plasmodium species which infect humans
Malaria is a mosquito-borne infectious disease. It is
naturally transmitted by the bite of a female Anopheles
mosquito that is infected by Plasmodium

3. LIFE CYCLE OF
PLASMODIUM
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4. 4

5. CLASSIFICATION OF ANTIMALARIAL
DRUG
i. 4-Aminoquinolines: Chloroquine,
Amodiaquine,
Piperaquine
ii. Quinoline-methanol: Mefloquine
iii. Cinchona alkaloid: Quinine, Quinidine
iv. Biguanides: Proguanil,
Cholrproguanil
v. Diaminopyrimidine Pyrimethamine
vi. 8-aminoquinoline Primaquine,
Tafenoquine
vii. Sulfonamide and sulfone Sulfadoxine, Dapsone
Sulfamethopyrazine 5

6. CLASSIFICATION OF ANTIMALARIAL
DRUG
viii. Antibiotics Tetracycline,
Doxycycline
Clindamycin
ix. Sesquiterpine lactones Artesunnate,
Artemether
Arteerther, Arterolane
x. Amino alcohols Halofantrine,
Lumefantrine
xi. Naphthyridine Pyronarindine
xii. Naphthoquinone Atovaquone
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7. ANTIMALARIAL THERAPY
Antimalarial therapy is given in following ways
1. Causal prophylaxis:
 Destroy parasite in liver cells and prevent invasion of
erythrocytes
 Drug : Primaquine, proguanil
2. Suppressive Prophylaxis:
 Suppress the erythrocytic phase and thus attack of
malarial fever can be used as prophylactics
 Drug : Chloroquine, proguanil, mefloquine,
doxycycline
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8. ANTIMALARIAL THERAPY
3.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
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9. ANTIMALARIAL THERAPY
4. 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
5. Gametocidal:
 Destroy gametocytes and prevent transmission
 Drugs :Primaquine, artemisinin – against all plasmodia
Chloroquine, quinine – P Vivax
Proguanil ,pyrimethamine – prevent development of
sporozoites
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10. CHLOROQUINE
 Synthesized by Germans in 1934 ( resochin)
 d & l isomers, d isomer is less toxic
 Cl at position 7 confers maximal antimalarial
efficacy
 Rapidly acting erythrocytic schizontocide
against all species of plasmodia
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11. CHLOROQUINE
MOA: Hemoglobin Globin utilized by
malarial parasite
Heme (highly toxic for malaria
parasite)
Chloroquine
Quinine, (+) Heme Polymerase
mefloquine (-)
Hemozoin (Not toxic to plasmodium) 11

12. CHLOROQUINE
Pharmacological actions:
1. Antimalarial activity:
 High against erythrocytic forms of P. vivax, P. ovale, P.
malariae & sensitive strains of P. falciparum
 Gametocytes of P. vivax, P. malariae, P. ovale
 No activity against tissue schizonts
2. Other parasitic infections:
 Giardiasis, taeniasis, hepatic amoebiasis
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13. CHLOROQUINE
3. Other actions:
 Anti-inflammatory, local irritant, , local anaesthetic ,
weak smooth muscle relaxant , antihistaminic,
antiarrhythmatic
Pharmacokinetics:
 Well absorbed, peak plasma concentration in 2-5 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
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14. CHLOROQUINE
Adverse effect
 Well tolerated , extraordinarily safe if taken in proper
doses
 Acute chloroquine toxicity is encountered most
frequently when therapeutic or high doses are
administered too rapidly by parenteral routes
 Frequent side effect are nausea, vomiting ,anorexia, GI
upset, headache, visual disturbances, urticaria, Pruritus
(primarily in Africans )
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15. CHLOROQUINE
Prolonged medication with suppressive doses
occasionally causes side effects such as headache,
blurring of vision, diplobia, confusion, convulsions,
bleaching of hair, widening of the QRS interval, and T-
wave abnormalities.
Contraindication
 Psoriasis ,porphyria
 Retinal and visual field abnormalities or myopathy
 Calcium , magnesium containing antacids
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16. CHLOROQUINE
USES
 Malaria
 Extra intestinal amoebiasis
 Rheumatoid arthritis
 Discoid lupus erythematousus
 Lepra reaction
 Photogenic reaction
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17. AMODIAQUINE(AQ)
 Almost identical to CQ
 Low cost , limited toxicity
 May effectiveness against CQ resistant of P. falciparum .
 Imp. Toxicities : agranulocytes, aplastic anemia,
hepatotoxicity
 Not recommended for Chemoprophylaxis
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18. MEFLOQUINE(MQ) `
 Effective against CQ resistant P. falciparum
 Exact Mechanism of action is unknown but may similar
to that of chloroquine
Pharmacokinetics
 Oral absorption is good and peak plasma concentration
are reached in about 18 hours.
 Highly protein bound, extensively distributed in tissues
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19. MEFLOQUINE(MQ) `
 Extensive metabolism occurs in liver, primarily secreted
in bile, under goes enterohepatic circulation
 Elimination half life : about 20 days
Antimalarial action:
 Has strong blood schizonticidal activity against P.
falciparum, P. vivax
 has no activity against early hepatic stages and mature
gametocytes of P. falciparum or latent tissue forms of P.
vivax
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20. MEFLOQUINE(MQ)
Adverse effects
 Mainly dose related (more common with higher dose )
 Common reaction are nausea, vomiting , abdominal pain
, diarrhoea, headache, sinus bradycardia, Q-T
prolongation
 Neuropsychiatric disturbances( anxiety, hallucinations,
sleep disturbances, psychosis, ataxia )
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21. MEFLOQUINE(MQ)
Uses
 Effective against DR P. falciparum and P. vivax
 As prophylactic
Contraindication and cautions
 Contraindicated if there is history of epilepsy ,
psychiatric disorder, arrhythmias .
 Should not co administered with quinine/quinidine,
halofantrine
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22. QUININE
 Derived from bark of Cinchona tree.
 Moa is similar to chloroquine
 Erythrocytic schizontocide for all species
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23. QUININE
PHARMACOLOGICAL ACTIONS
1. Antimalarial action :
 acts primarily against asexual erythrocytic forms
 The alkaloid also is gametocidal for P. vivax and P.
malariae but not for P. falciparum.
 Quinine is more toxic and less effective than
chloroquine against malarial parasites susceptible to
both drugs.
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24. QUININE
2. Local irritant
 Intensely bitter and irritant . Orally it causes nausea,
vomiting, epigastric discomfort
 Injections can cause pain and local necrosis in the
muscle and thrombosis in vein.
3. Cardiovascular:
 depresses myocardium, ↓ excitability, ↓
conductivity, ↑ refractory period, profound
hypotension IV.
4. Miscellaneous actions:
 Mild analgesic, antipyretic activity , stimulation of
uterine smooth muscle, curare mimitic effect
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25. QUININE
Pharmacokinetics
 Administered orally , completely absorbed
 PPB: 70% ( mainly binds to alpha acid glycoprotein)
 Peak plasma level reaches in 1-3 hours
 Metabolized in liver degradation products excreted in
urine
 t ½ = 10-12 hrs
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26. QUININE
Adverse drug effect
1.Cinchonism:
 Ringing in ears , 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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27. QUININE
2. Idiosyncrasy/hypersensitivity
3. Cardiovascular toxicity: cardiac arrest, hypotension
,fatal arrhythmias
 “Blackwater fever”~the triad of massive hemolysis,
hemoglobinemia, and hemoglobinuria leading to anuria,
renal failure, and even death¾is a rare type of
hypersensitivity reaction to quinine therapy .
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28. QUININE
USES
1. Malaria:
 uncomplicated resistant falciparum malaria
 Complicated and severe malaria including cerebral
malarial
2. Treatment of Nocturnal Leg Cramps
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29. PROGUANIL
 proguanil in body is cyclized to cycloguanil, a cyclic
triazine metabolite
 In sensitive P. falciparum malaria, it exerts activity
against both the primary liver stages and erythrocytic
stage.
 Also active against erythrocytic stage of P. vivax.
 Half life : 16 hrs
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30. PROGUANIL
MOA
proguanil selectively inhibits the bifunctional
dihydrofolate reductase-thymidylate synthetase of
sensitive plasmodia, causing inhibition of DNA synthesis
and depletion of folate cofactors
Toxicity and side effect
 In prophylactic doses occasional nausea and diarrhea
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31. PROGUANIL
 High dose may cause vomiting, abdominal pain,
diarrhea, hematouria, and the transient
appearance of epithelial cells and casts in the
urine
USES
 For causal prophylaxis
MALARONE- proguanil +atovaquone, used for
multi drug resistance malaria.
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32. PYRIMETHAMINE
 Diaminopyrimidine more potent than proguanil &
effective against erythrocytic forms of all species.
 Tasteless so suitable for children
 Longer half life than cycloguanil (t1/2: 4 days)
 Used only in combination with sulfonamide or dapsone
 Adverse events: relatively safe
 megaloblastic anemia, thrombocytopenia,
agranulocytosis( may occur with higher doses)
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33. SULFADOXINE-
PYRIMETHAMINE(S/P)
 Form supra-additive synergistic combination with
pyrimethamine sequential block
 Not recommended for prophylaxis
Use:
 single dose treatment of uncomplicated chloroquine
resistant falciparum malaria
 patients intolerant to chloroquine
 First line therapy for treatment of toxoplasmosis
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34. PRIMAQUINE
 Inactive against asexual blood stages parasites
 Drug of choice for the eradication of dormant liver forms
of P. vivax and P. ovale
 exert a marked gametocidal effect against all four species
of plasmodia that infect humans
 Plasma half life : 6-8 hrs
 Excreted in urine
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35. PRIMAQUINE
MOA:
 Has not been elucidated
 May converted into electrophilic intermediates that act as
oxidation-reduction mediators . This could contribute to
antimalarial effect by generative reactive oxygen species
or by interfering with mitochondrial electron transport in
the parasite
Toxicity and Side Effects
 Nausea, vomiting, epigastric distress(can be minimized
by taking with food)
 Methaemoglobinemia 35

36. PRIMAQUINE
Therapeutic or higher doses of primaquine may cause acute
hemolysis and hemolytic anemia in humans with G6PD
deficiency
USES
 Radical cure of acute vivax and ovale infection
 Terminal prophylaxis of vivax and ovale infection
 Chemoprophylaxis of malaria
 Gametocidal action
 Pneumocystis jiroveci infection
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37. ARTEMISININ AND DERIVATIVE
 It is a Sesquiterpine lactone extracted from Artemisia sp.
 More rapid parasite clearance and fever resolution than
any other currently licensed Antimalarial drug.
 Suited for severe treatment of severe malarial infection
caused by P. falciparum
 Important Derivatives are Artesunate
Artemether
Dihydroartemisinin
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38. ARTEMISININ AND DERIVATIVE
 MOA:
 Contentious
 heme iron within the parasite catalyzes cleavage
of the endoperoxide bridge. This releases highly
active carbon centered free radical species that
bind to membrane protein , causes lipid
peroxidation, damages endoplasmic reticulum
 Results lysis of the parasite
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39. ARTEMISININ AND DERIVATIVE
Artesunate
 Sodium salt is water soluble and administered by oral,
i.m. or i.v. routes
 peak plasma > 60 min
Artemether
 Lipid soluble and administered by oral , im
 Peak plasma : 2-6 hrs
Both artesunate and artemether are converted extensively
to dihydroartemisinin,
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40. ARTEMISININ AND DERIVATIVE
Adverse effect
 Very few adverse effect: most are mild
 Nausea, vomiting, abdominal pain, itching, drug
fever, dizziness,
 Safe in pregnancy
Uses
 Uncomplicated falciparum malaria
 Severe and complicated falciparum malaria
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41. ATOVAQUONE(MEPRON)
 hydroxynapthoquinone
 Rapidly acting erythrocytic schizonticide for plasmodium
falciparum & other plasmodia
MOA: Collapses mitochondrial membrane ; interferes ATP
production and pyrimidine biosynthesis
 Proguanil potentiates action of atovaquone and prevents
development of resistance
 Also used in Pneumocystis Jivoreci & Toxoplasma gondii
infections
 Contraindicated in pregnancy
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