Antimalarial agents

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Antimalarial Agents

Saifuddin Lala MBA PHARMA 9426786383

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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

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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.

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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

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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.

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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