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ANTIMALARIAL DRUG

BYKUBER BAJGAIN

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

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LIFE CYCLE OF PLASMODIUM

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CLASSIFICATION OF ANTIMALARIAL DRUG

i. 4-Aminoquinolines: Chloroquine, Amodiaquine, Piperaquine

ii. Quinoline-methanol: Mefloquineiii. Cinchona alkaloid: Quinine, Quinidineiv. Biguanides: Proguanil, Cholrproguanilv. Diaminopyrimidine Pyrimethamine vi. 8-aminoquinoline Primaquine, Tafenoquinevii. Sulfonamide and sulfone Sulfadoxine, Dapsone

Sulfamethopyrazine

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CLASSIFICATION OF ANTIMALARIAL DRUG

viii. Antibiotics Tetracycline, Doxycycline

Clindamycinix. Sesquiterpine lactones Artesunnate,

ArtemetherArteerther,

Arterolanex. Amino alcohols Halofantrine,

Lumefantrine xi. Naphthyridine Pyronarindine xii. Naphthoquinone Atovaquone

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ANTIMALARIAL THERAPYAntimalarial therapy is given in following ways1. 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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ANTIMALARIAL THERAPY3.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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ANTIMALARIAL THERAPY4. Radical curatives:

Eradicate all forms of P.vivax & P.ovale from the bodySupressive 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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CHLOROQUINESynthesized by Germans in 1934 ( resochin)d & l isomers, d isomer is less toxic Cl at position 7 confers maximal antimalarial

efficacyRapidly acting erythrocytic schizontocide

against all species of plasmodia

CHLOROQUINEMOA: Hemoglobin Globin utilized by

malarial parasite

Heme (highly toxic for malaria parasite)

Chloroquine Quinine, (+) Heme Polymerase mefloquine (-) Hemozoin (Not toxic to plasmodium)

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CHLOROQUINEPharmacological 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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CHLOROQUINE3. 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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CHLOROQUINEAdverse 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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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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CHLOROQUINEUSES Malaria Extra intestinal amoebiasis Rheumatoid arthritis Discoid lupus erythematousus Lepra reaction Photogenic reaction

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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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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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MEFLOQUINE(MQ) ` Extensive metabolism occurs in liver, primarily secreted

in bile, under goes enterohepatic circulation Elimination half life : about 20 daysAntimalarial 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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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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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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QUININE Derived from bark of Cinchona tree. Moa is similar to chloroquine Erythrocytic schizontocide for all species

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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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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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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QUININE Adverse drug effect1. 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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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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QUININE USES1. Malaria: uncomplicated resistant falciparum malaria Complicated and severe malaria including cerebral

malarial2. Treatment of Nocturnal Leg Cramps

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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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PROGUANILMOA

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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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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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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SULFADOXINE-PYRIMETHAMINE(S/P) Form supra-additive synergistic combination with

pyrimethamine sequential block Not recommended for prophylaxisUse:

single dose treatment of uncomplicated chloroquine resistant falciparum malaria

patients intolerant to chloroquine First line therapy for treatment of toxoplasmosis

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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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PRIMAQUINEMOA:

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

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PRIMAQUINETherapeutic 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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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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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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ARTEMISININ AND DERIVATIVEArtesunate Sodium salt is water soluble and administered by oral,

i.m. or i.v. routes peak plasma > 60 minArtemether 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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ARTEMISININ AND DERIVATIVEAdverse 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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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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