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1
Antimalarial Agents
Saifuddin Lala MBA PHARMA 9426786383
2
IntroductionMalaria is a protozoal disease,
caused by Plasmodium vivax Plasmodium malariae Plasmodium ovale Plasmodium falciparumMost of the serious complications
and death occur due to Plasmodium falciparum.
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Structure of plasmodium
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Types of malaria
• P vivax and P ovale• with a fever every 2nd day
Benign tertian
• P malariae• with a fever every 3rd day
Benign quartan
• P falciparum• This type of malaria is more
dangerous because of the complications
Malignant
tertian
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symptoms of malariaFever Shiveringpain in the jointsRepeated vomitingGeneralized convulsion
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Life cycle of the malarial parasite
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Classification 4-Aminoquinolines: Chloroquine, Amodiaquine,
Piperaquine Quinoline-methanol: Mefloquine Cinchona alkaloid: Quinine, Quinidine Biguanides: Proguanil, Cholrproguanil
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Diaminopyrimidines: Pyrimethamine 8-Aminoquinoline: Primaquine, Bulaquine Sulfonamides and sulfone: Sulfadoxine,
Sulfamethopyrazine, Dapsone Tetracyclines : Tetracycline, Doxycycline
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Sesquiterpine lactones: Artesunate, Artemether,
ArteetherAmino alcohols: Halofantrine, LumefantrineMannich base: PyronaridineNaphthoquinone : Atovaquone
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Antimalarial therapy and the parasite life cycle
• Blood schizonticidal agents• Quinine,mefloquine,atovaquone,Pyrimet
hamine,artemether,artesunate
Drugs used to treat
acute attack
• Tissue schinzonticidal • Primaquine and tafenoquine
Drugs that effect a
radical cure
• Kill the sporozoites• Chloroquine,mefloquine,proquanil,pyrime
thamine
Drugs used for chemoprophyla
xis
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Malarial Parasite Developmental Stages Targeted by Antimalarial Drugs
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Inhibition of haem polymerase
Parasite
Haemoglobin convert into haem
Haem is free and toxic
Haemozoin
Haem Polymerase
Inhibition of haem polymerase cause toxicity and death of the parasite
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Chloroquine 4-Aminoquinoline derivatives Uncharged at neutral pHDiffuse freely into lysosome of
parasiteAt acid pH of lysosome, it
converted to a protonated, membrane impermeable form and is ‘trapped’ inside the parasite.
At high conc. It inhibits protein RNA and DNA synthesis.
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ChoroquineDrug Mechanism of
ActionUses Adverse
Effect
Chloroquinephosphate(ARALEN)
Tablet- 250mg, 500mg
Half-life- 3-5 days
Metabolise via CYPs
concentrating in parasite food vacuoles
preventing the polymerization of the hemoglobin breakdown product heme, into hemozoin,
parasite toxicity due to the buildup of free heme
Acute malarial attack
Suppressive prophylaxis
Pruritus,Diarrhea, Loss of appetite, Nausea,Stomach cramps,Vomiting ,Retinopathy
Other formulation
hydroxychloroquine sulfate (Rx) - Plaquenil Use for treatment purpose
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ResistancePlsmodium falciparum is now resistant
to chloroquine in most of the part.
Resistance appears to result from enhanced efflux of the drug from parasitic vesicles as result from enhanced efflux of the drug from parasitic vesicles as a mutation in plsmodium transporter genes. (pfcrt gene)
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Contraindications & Cautions Chloroquine is contraindicated in patients with psoriasis
or porphyria, in whom it may precipitate acute attacks of these diseases.
It should generally not be used in those with retinal or visual field abnormalities or myopathy.
Chloroquine should be used with caution in patients with a history of liver disease or neurologic or hematologic disorders. The antidiarrheal agent kaolin and calcium- and magnesium-containing antacids interfere with the absorption of chloroquine and should not be coadministered with the drug.
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Quinoline-Methanols derivatives
Drug Mechanism of action
Uses Adverse Effects
Quinine sulfate Qaulaquine(oral)8-14 hrIV
Metabolise via CYP3A4
Same as Chloroquine
Inhibition of haempolymerase
Treatment of severe falciparum malaria
Combine with tetracycline,doxycycline, or clindamycin
Cinchonism, sinus arrhythmia,atrioventricular block, prolongedQT interval, ventriculartachycardia, hypoglycemia
Contra indication
Digoxin therapy, warfarin therapy, patients with tinnitus or optic neuritis.
Resistance- pfmdr1 point mutations can contribute to quinine resistance, in particular the N1042D mutation. The mechanism is same as chloroquine.
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Quinidine
Drug Mechanism of action
Uses Adverse Effects
Quinidine gluconate(IV)
Same as Chloroquine
Inhibition of haempolymerase
Severe malaria,Patient unable totake oral medicationCombine with tetracycline,doxycycline, or clindamycin
Cinchonism, tachycardia,prolongation of QT intervals,Ventricular arrhythmias,hypotension, hypoglycemia
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Mefloquine
Drug Mechanism of action
Uses Adverse Effects
Mefloquine(LARIAM)
Half life – 30 days
CYP3A4
Same as Chloroquine
Inhibition of haempolymerase
Chemoprophylaxis and treatment
nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrohea, abdominal pain, headache, rash, and dizziness, seizures and psychosis
Contraindication- patients with a history of seizures, depression, bipolar disorder and other severe neuropsychiatric conditions,
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Inhibit electron transfer chain
8-aminoquinolineMore active against liver
hynozoites (Tafenoquine , Etaquine and Primaquine)
Use to Prevent the transmission of disease.
Active against P.vivax and P.ovale
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Mechanism of actionPrimaquine may be converted to
electrophilic intermediates that act as oxidation-reduction mediators. Such activity could contribute to antimalarial effects by generating reactive oxygen species or by interfering with mitochondrial electron transport in the parasite
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Primaquine
Drug Mechanism of action
Uses Adverse Effects
Primaquine
Halflife- 7 hr
metabolized by CYP1A2
Inhibits electron transport chain in Plasmodiumactive against hepatic stages of all human malaria parasites. active against the hypnozoite stages of P vivax and P ovale.
For presumptive anti-relapse therapy
Prophylaxis for short-duration travel toareas with principally
Radical cure of P.vivax and P. ovale (toeliminatehypnozoites)
GI disturbances,methemoglobinemia, hemolysis in personswith G6PD deficiency
Bind with acute-phase reactant protein α1-glycoprotein in liver
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G6pd defficiencyX chromosome linked genetic
metabolic condition-glucose 6-phosphate dehydrogenase- in red cell
Red cell can’t regenerate the NADPH
Primaquine oxidative metabolites derivative of primaquine decrease the concentration of NADPH metabolic function of red cell impaired and heamolysis occur…
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Hydroxynaphthaoquinone Drugs Inhibit electron transfer chain Atavaquone is used for
treatment of malaria and can prevent its development
Resistance to atavaquone is rapid and result from a single point mutation in the gene of cytochrome b.
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Atovaquone
Drug Mechanism of action
Uses Adverse Effects
Atovaquone Mepron tablet250mgoral suspension750mg/5mL
Inhibits electron transport chain in Plasmodium
Treatment of acute attack of malaria
Abdominal painCoughDepression DiarrheaDyspneaFever HeadacheInfectionInsomnia
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Atovaquone-proguanil
Drug Mechanism of action
Uses Adverse Effects
Atovaquone-proguanilMALARONE (oral) tablet250mg/100mg
Half-life: Atovaquone, 2-3 days; proguanil, 12-21 hr
Atovaquone: Selective inhibitor of parasite mitochondrial electron transport Proguanil: Primary effect through metabolite cycloguanil, a dihydrofolate reductase inhibitor in malaria parasite, which leads to disruption of deoxythymidylate synthesis
Treatment of acute attack of malaria
Abdominal pain Transaminase increasesHeadacheVomitingNausea
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Inhibit DNA replication transcription
The quinghaousu based compound are derivative from the herb quin hao.
Artimisinin generate carbon centered free radical by breaking down ferrrous porphyrin IX
This radical cause alkylation of protein or damage the cell membrane
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Artesunate
Drug Mechanism of action
Uses Adverse Effects
Artesunate (IV)60mg/vial
Half-Life: 40-50 min
may inhibit DNA replication & transcription
Treatment of acute attack of malariaCerebral malaria
Cardiotoxicity (high doses)Neurotoxicity observed in animal studiesDrug induced feverSkin rash
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Artemether-lumefantrine
Drug Mechanism of action
Uses Adverse Effects
Artemether-lumefantrine(COARTEM)
tablet20mg/120mg
Half-Life:artemether 2 hr; lumefantrine 3-6 days
Both artemether and lumentantrine inhibit nucleic acid and protein synthesisMetabolism vialumefantrine: CYP2D6 artemether: CYP3A4
Treatment of acute attack of malaria
Cerebral malaria
Abdominal painAnorexiaArthralgia Chills Dizziness Fatigue HeadacheMyalgia
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Drugs affecting synthesis and utilization of folate
PABA
Folate
Tetrahydrofalate
Synthesis of thymidylate
DNA synthesi
s
Dihydropteroate synthetase
Dihydrofolate reductase
31
Proguanil
Drug Mechanism of action
Uses Adverse Effects
Proguanil Paludrine tablet26.3mg
Half-life, Elimination: 3.7-9.6 hr
inhibit plasmodial dihydrofolate reductase
Treatment of acute attack of malaria
Abdominal painHemolytic anemia in G6PD deficiencyNauseaVomiting
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Pyrimethamine
Drug Mechanism of action
Uses Adverse Effects
Pyrimethamine Daraprim tablet25mg
Half life: 96 hr
Folic acid antagonist
Treatment of acute attack of malaria
Abdominal crampsAbnormal skin pigmentationAnaphylaxisAnorexiaArrhythmias (large doses)Atrophic glossitisDepressionFeverInsomniaLightheadednessMalaiseSeizures
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Pyrimethamine/sulfadoxine
Drug Mechanism of action
Uses Adverse Effects
pyrimethamine/sulfadoxine (Rx) – Fansidar
tablet25mg/500mg
Pyrimethamine: 96 hrSulfadoxine: ~200 hr
Folic acid antagonists
Treatment of acute attack of malaria
AgranulocytosisAnemiasInsomniaLightheadednessMalaiseSeizuresAbnormal skin pigmentationDermatitis
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AntibioticsDoxycline and tetracycline used
in acute attack of malaria and chemopropylaxis purpose.
Sometimes given in combination with other drug.
Clindamycin is also used.
35
Tetracycline
Drug Mechanism of action
Uses Adverse Effects
Doxycycline Doryx (oral orIV)
Tetracycline (oral orIV)
Tetracycline Inhibit the protein synthesis by compettition with tRNA for A site
Oral quinine and Doxycycline for acute attacks
Oral chloroquine and Doxycycline for chemoprophylaxis
Nausea, vomiting, diarrhea,abdominal pain, dizziness,photosensitivity, headache,staining of teeth
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Clindamycin
Drug Mechanism of amalctosobion
Uses Adverse Effects
Clindamycin (oral orIV)
Inhibit the ribosomal translocation
Treatment of malaria
Always use in combinationwith quinine-quinidine
Diarrhea, nausea, rash
37
4-Aminoquinolone derivatives
Pyronaridine, a chloroquine relative, is being used in combination with artesunate as a promising new artemisinin- based combination therapy.
Pyronaridine-artesunate has been studied in Phase II and Phase III clinical trials, and has been shown to be effective against uncomplicated P. falciparum and blood stage P. vivax.
Pyronaridine-artesunate is available as Pyramax® tablets and pediatric granule formulations,and manufacture of this compound is being undertaken by Shin Poong Pharmaceuticals.
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8-Aminoquinolone derivativesTafenoquine is a lead candidate
drug aimed at a radical cure of P. vivax, and is being studied in a Phase II/III.
A fixed dose artemisinin combination therapy, artesunate-amodiaquine (Coarsucam) has been approved by WHO and developed by Sanofi- Aventis.
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Artemisinin derivatives
The endoperoxide feature of artemisinins, which confers antimalarial activity, is shared by ozonide OZ439, a synthetic endoperoxide.
OZ439 carries the hope of providing a single dose oral cure in humans when used in combination.
OZ439 is a rapidly acting agent against asexual stage parasites.This drug is currently undergoing Phase IIa trials.
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Newer targetTE3, a prodrug of a bis-ammonium
compound that acts on phospholipid metabolism through the inhibition of de novo phosphatidylcholine synthesis, combined with a putative activity on heme detoxification.
This new class of compounds has shown potent in vivo antimalarial activity in the primatemodel Aotus and is not cross resistance in vitro with known antimalarials.
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osmidomycinosmidomycin, which inhibits the 1-
desoxy-D-xylulose-5-phosphate reductoisomerase in the mevalonate-independent pathway of isoprenoid synthesis in the apicoplast.
The apicoplast, a specialized parasite organelle of algal origin, appears to be important for lipid and heme biosynthesis.
42
References
1) Rang H P. Dale M M. How drugs act: molecular aspects, Pharmacology, Fifth edition. Elsevier publishers. P.703-709
2) Katzung B., Masters S., Trevor A., Basic and clinical pharmacology, New york: Mc Graw Hill Medical Publisher;2009;p.699-705
3) Seth S., Seth V., Textbook of pharmacology ,New Delhi: Elsevier, publisher;2009;p.VIII.63
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4) Hobbs C., Duffy P., Drugs for malaria: something old, something new, something borrowed, F1000 Biology Reports 2011, 3(24),1-9
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Thank you