Anti malarial drugs department of pharmacy IOM, MMC. Nepal

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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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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