ANTI MALARIAL DRUGS 2014

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Anti malarial drugs:

Anti malarial drugs 1 G.Vishnupriya pharma MD

Introduction:

I ntroduction The oldest diseases known to mankind that has profound impact on our history. Malaria is a vector-borne infectious disease caused by single-celled protozoan parasites of the genus Plasmodium. Malaria is transmitted from person to person by the bite of female mosquitoes. 2

Incidence & prevalence of malaria:

INDIA: NMEP started in 1958 caused malaria complete disappearance but came back in 1970 and still now prevails a major disease changed to NAMP then finally named it to NVBDCP WHO : 2012 estimated 627 000 deaths (with an range of 473 000 to 789 000), mostly among African children. Mortality rates ↓ 45% globally since 2000, by 49% in the African Region. Incidence & prevalence of malaria 3

Causes of malaria:

Causes of malaria Plasmodium falciparum : Falciparum malaria or Malignant Tertian malaria Plasmodium vivax : Benign Tertian, Tertian Malaria Plasmodium malariae : Quartan malaria Plasmodium ovale : Ovale tertian Malaria  Plasmodium knowlesi  a species that causes malaria among monkeys . 4

Transmission of malaria :

Transfusion of infected blood, congenitally, and by sharing needles, but mainly by the bites of  female Anopheles   mosquitoes Man develops disease after 10 to 14 days of being bitten by an infective mosquito Life cycle of malarian parasite : Hepatic cycle/pre or exo Erythrocytic cycle Erythrocytic cycle 3)Sexual forms Transmission of malaria 5

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Symptoms & diagnosis of malaria:

Symptoms & diagnosis of malaria P. falciparum: Most dangerous invading erythrocytes of any age, producing endotoxin-like products, cause heavy parasitemia, hypoglycemia, and shock with multiorgan failure. Delay in treatment may lead to death. If treated early, the infection usually responds within 48 hours. 7

Symptoms cont…:

P. vivax has low mortality rate - untreated adults relapses caused by the reactivation of latent tissue forms. (3) P. ovale affects periodicity and relapses similar to those of P. vivax, but it is milder. (4) P. malariae causes a generally indolent infection that is common in localized areas of the tropics. Clinical attacks may occur years or decades after infection. Symptoms cont … 8

Diagnosis Of malaria:

Clinical Diagnosis Malaria Blood Smear Fluorescent microscopy Antigen Detection Serology Polymerase Chain Reaction Diagnosis Of malaria 9

Severe falciparum malaria:

Severe falciparum malaria Coma / cerebral malaria, convulsions Renal Impairment Noncardiogenic pulmonary edema Liver Dysfunction Hypoglycemia 10

Severe malari cont…:

Metabolic acidosis/ acidemia Hematological abnormality like hemoglobinuria , Normocytic anemia, bleeding, DIC Other complications : jaundice, extreme weakness, hyperparasitemia , impaired consciousness Hypotension/shock Severe malari cont … 11

Aim of treatment:

1.prevent & treat clinical attack of malaria (prophylactic) 2.completely eradicate the parasite from pt’s body (clinical cure) 3.reduce the human reservoir of infection – cut down transmission to mosquito (gametocidal) Aim of treatment 12

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Classification of anti malarial drugs:

4- Aminoquinolines – Chloroquine , Amodiaquine , Piperaquine Quinoline - methanol – Mefloquine Chinchona alkaloid - Quinine, Quinidine Biguanide - Proguanil Diaminopyrimidine - Pyrimethamine 8-Aminoquinoline – Primaquine,Tafenoquine Classification of anti malarial drugs 14

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Sulfonamides & sulfone - Sulfadoxine , Sulfamethopyrazine , Dapsone Antibiotics - Tetracycline,Doxycycline , Clindamycine Sesquiterpine - Artesunate Lactones - Artemether , Arteether,Arterolane Amino alcohols - Halofantrine,Lumefantrine Napthyridine - Pyronaridine Napthoquinone - Atovaquone 15 Classification cont..

Chloroquine:

D iscovered in 1934 by Hans Andersag  and coworker Produced in U.S , introduced into clinical practice in 1947 for the prophylactic treatment of malaria Spectrum of activity Rapid acting Erythrocytic schizonticide against all species of malaria MOA : A ccumulates in acidic vacuole of parasite it increases ph & inhibits heme polymerisation. By formation CQ -heme complex it damages plasmodial membrane complex inhibits formation of hemozoin Chloroquine 16

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Resistance to chloroquine PFCRT gene seen in chloroquine resistant p.falciparum it pumps out the drug protecting heme ↓ ability of parasite to accumulate drug is the cause NVBDCP : first line treatment against P.vivax & it slowly developing resistance too within 1-2wks of treatment P.vivax resistance to Chloroquine : Q uinine with Doxycycline/Clindamycin or ACT followed by Primaquine for radical cure is treatment of choice 17

Pharmacokinetics of chloroquine:

Absorbed orally, rapid absorption from IM, SC. Concentrated in various tissues like liver, spleen, kidney, lungs & melanin. Distribution in brain & spinal cord with large apparent volume of distribution -13000 liters in adult, loading dose – to attain therapeutic concentration in plasma & steady state concentration t1/2 : 214 h, 60% plasma protein bound Metabolism- two active forms Pharmacokinetics of chloroquine 18

PK Cont….:

Desethylchloroquine & Bisdesethyl chloroquine by CYP-450 in liver 50% eliminated by systemic and remaining eliminated renally On parentral administration entry is rapid & removal is slow causes toxicity T o prevent it slow IV & S.C/I.M is given in small divided doses PK Cont…. 19

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1.Malaria prophylaxis : 300mg once a week for prevention person visiting endemic area should receive one week before and four week after Dose of Chloroquine Uncomplicated vivax / ovale / malaria: 600mg(10mg/kg)- 300mg(5mg/kg) after 8hrs,continue for next 2 days total 25mg/kg over 3 days + primaquine 15mg(0.25mg/kg)daily for 14 days Chloroquine sensitive falciparum Dose as above + primaquine 45mg(0.75mg/kg) single dose( gametocidal ) Therapeutic uses OF Chloroquine 20

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Other uses of Chloroquine : Extra intestinal amoebiasis/hepatic amaoebiasis : 500mg TDS for 2 Days/ 200mg BD for 2-3 wks Giardiasis : Metronidazole is preferred Clonorchis sinensis : 250mg daily for 6wks Rheumatoid arthritis :250mg 6-12 mths once a week Lepra reaction –TYPE 2 SLE :250-500mg daily 1-4wks followed by maintenance 21

Adverse effects of Chloroquine:

Common: Nausea, vomiting, anorexia, itching, epigastric pain, difficult in accommodation, headache are frequent & unpleasant Toxic effects after prolonged use : Skin eruptions, headache, blurring of vision, diplopia, confusion & convulsions. EKG changes : abnormal T waves, Wide QRS interval reversible Discoloration of nail beds, hairs & mucous membrane Haemolysis & blood dyscrasis Adverse effects of Chloroquine 22

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Retinopathy with reduced visual acuity - accumulation of drug in melanin rich tissues (Bulls eye maculopathy ) –reversible Ototoxicity irreversible Myopathy, cardiomyopathy, peripheral neuropathy, suicidal tendency occurs Periodic neurological and retinal check up should be done Adverse effects of chloroquine cont … 23

ADR cont…:

>5g Cardiovascular – hypotension due to vasodilatation, suppressed myocardiac function, cardiac arrhythmias & cardiac arrest CNS – mental confusion, convulsion & coma ADR cont … 24

Interactions & precautions of chloroquine:

with M efloquine convulsion will occur Digoxin level increases used along With gold & phenylbutazone dermatitis will occur Drug should be avoided in patients with ocular ,hepatic disease ,hemorrhage, hematological disease, peptic ulcer & neurological disease Interactions & precautions of chloroquine 25

Interactions cont…:

Epilepsy attacks will be precipitated in epileptic patients Myasthenia gravis will worsen Haemolysis occurs in G6PD deficient patients Aggrevates exfoliative dermatitis & psoriasis Interactions cont… 26

Amodiaquine:

↓ cost & safety in chloroquine resistance P.falciparum in certain areas Faster action & better tolerance than chloroquine Prophylactically not used because of hepatotoxicity & agranulocytosis in certain areas can be used in clinical attacks Dosage : 25-35mg/kg for 3 days (10mg/kg is given immediately following 5mg/kg after 6hrs then 5mg/kg for next 2 days ) Mechanism, resistance, uses & ADR are similar to chloroquine Amodiaquine 27

piperaquine:

Chloroquine Congener with similar mechanism High efficacy, erythrocytic schizonticide with prolonged action & onset is slow Activity: Chloroquine sensitive & C hloroquine resistant P. falciparum malaria piperaquine 28

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Mefloquine : Tested during world war II, introduced in 1963 Its 4-quinoline methanol related chemically to quinine used in chloroquine resistant P.falciparum malaria Faster acting erythrocytic schizonticide slower than Chloroquine or quinine. Effective against Chloroquine sensitive organism also Its suppressive prophylactic for multi resistant falciparum & other types of malariae 29

Mefloquine spectrum activity cont..:

Relapses - vivax , due to long t1/2 chances of resistant strains are high Cross resistance is seen with Quinine & Halofantrine MOA of Mefloquine : Similar to morphological changes in the intraerythrocytic parasite of C hloroquine & Quinine Act in cytosol of the parasite Mechanism is unclear it can also inhibit heme polymerization forming toxic complex with heme & damages membrane Mefloquine spectrum activity cont.. 30

Resistance of Mefloquine: :

Enhanced translation of Pfmdr1 gene Pharmacokinetics of M efloquine : Well absorbed orally, enhanced in presence of food High plasma protein bound 98% & concentrated in many organs Metabolism in liver, 1 0 secreted in bile, undergoes enterohepatic circulation, t1/2: 2-3wks Resistance of M efloquine : 31

Uses of Mefloquine:

1.Prophylaxis : R eserved for prevalent Chloroquine resistant P.falciparum areas Dose: 5mg/kg or 250mg/wk for adults 1-2wks before travel. 2.Treatment of malaria : R eserve drug for multi drug resistance mainly Chloroquine resistant vivax or falciparum 3.Current recommendation : With A rtesunate as ACT For uncomplicated falciparum malaria Uses of M efloquine 32

Dose of Mefloquine:

25mg/kg - 1.25gm single or 2 doses of 750 & 500mg 12hr apart Children weight < 45kg : First dose 15mg/kg → 10mg/kg after 12h after meals with plenty of water since its irritant Adverse drug reactions : Common : Dizziness, nausea, vomiting, diarrhoea ,abdominal pain, sinus bradycardia & QT prolongation Dose of M efloquine 33

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Dose related effects : Neuropsychiatric reactions present Rare-hematological , hepatic & cutaneous toxicity Safe during pregnancy but should be avoided in first trimester Drug Interactions : Halofantrine or Quinidine/Quinine or Chloroquine with this drug causes QT lengthening & cardiac arrest reported. Avoided : Epileptic patients, Neuropsychiatric disorders 34

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Quinine Isolated from bark of chinchona tree in 1820,due to military importance many drugs were developed Its levorotatory alkaloid Spectrum Activity of Quinine : Erythrocytic schizonticide for all species Concentrated in food vacuole , less effective more toxic than C hloroquine Kills vivax & malariae gametes & also effective against Chloroquine resistant & falciparum resistant strains 35

:

Terminates acute attack but does not completely eliminate the parasite totally D oxycycline or Clindamycin are used Its local irritant , anesthetic ,weak analgesic & antipyretic MOA of Quinine It forms heme – quinine complex , Inhibits polymerization of heme to hemozoin Damages parasite membrane & kills it Resistance: Similar to M efloquine Have emerged in some parts of India 36

pharmacokinetics of Quinine:

Rapidly absorbed orally, peaks -5hr 70% bound to alpha1 acid glycoprotein ↑ during malarial infection Metabolized in liver by CYP3A4 Excreted in urine, crosses placental barrier t1/2 9-18 hr, vol of distribution 100 L in adults pharmacokinetics of Quinine 37

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Uses of Quinine 1. Uncomplicated C hloroquine resistant malaria : Its used orally alternative to S/P-ACT NVBDCP : 7 day quinine 600mg 8hrly+ Doxycycline 100mg daily/clindamycin 600mg 12hrly is second line treatment in chloroquine resistance to falciparum & vivax malaria 38

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Uses of quinine cont … Complicated & severe malaria-cerebral malaria: Dose : (7 days course) Loading dose : 20mg/kg i.v over 4hrs diluted in 5% dextrose to prevent hypoglycemia Maintenance Dose : 10mg/kg over 4hr in adults or 2hr in children every 8hr Then switch over to oral 10mg/kg 8hrly 39

Uses quinine cont…:

Parental Artemisinin are fast ,more effective, better tolerated and now preferred over Quinine for severe malaria 2. Nocturnal muscle cramps & myotonia congenita – Single tablet 300mg bed time Adverse effects of Quinine H igher doses : Affects hearing & vision Cardio depressant , anti arrhythmic & hypotensive actions similar to Quinidine On rapid i.v it causes hypoglycemia Uses quinine cont… 40

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Toxicity : 8-10g taken in single dose may be fatal Cinchonism :reversible Ringing in ears, nausea, vomiting, headache, mental confusion, vertigo, difficulty in hearing & visual disturbance, diarrhoea ,flushing & marked perspiration Poisoning higher doses: QT prolongation during i.v some develop idiosyncratic/hypersensitive reactions 41

ADR quinine cont…:

Occasionally : H aemolysis in pregnant women – falciparum malaria causing hemoglobin urea & kidney damage Caution : pregnant women only life threatening infection it can be used ADR quinine cont … 42

Proguanil:

Slow acting erythrocytic schizontocide Inhibits preerythrocytic stage of P.fal. gametocytes prevents its development It gets converted to active form cycloguanil, which inhibits plasmodial DHFRase MOA : Inhibits DHFRase-thymidylate synthetase Depletes folinic acid & DNA synthesis inhibition Proguanil 43

Resistance - proguanil:

partial cross resistance with pyrimethamine, resistance develops due to mutation of DHFRase –thymidylate Pharmacokinetics Slow absorption Except erythrocytes n o accumulation in tissue Peak plasma concentration : 5hr, t1/2:16-20h, Noncumulative, well tolerated Racial variations seen Excreted : urine Resistance - proguanil 44

Uses of proguanil:

Prophylaxis : ( P.falciparum & vivax ) Dose: > 200mg daily in adults & children 4weeks after leaving endemic area Currently its either prophylaxis nor for clinical attack Causal prophylaxis : 400mg proguanil + Atovaquine 1g for 3 days in multidrug resistance suppressive prophylactic : With chloroquine in moderately CQ resistant P.falciparum areas . Uses of proguanil 45

Adverse effects of proguanil:

Mild abdominal symptoms , Occasional stomatitis, haematuria , rashes & transient loss of hair Pyrimethamine It direct inhibitor of DHFRase Its slow acting blood schizonticide & More potent than P roguanil Used with Sulfonamide or D apsone to prevent resistance ,it may be due to mutation in DHFRase . resistance with falciparum is common than vivax Adverse effects of proguanil 46

Pyrimethamine cont….:

Pharmacokinetics: Slow & good absorption Attains good concentration in organs Metabolized & excreted in urine t1/2: 4 days,prophylactically stays in blood – 2wks Uses: S uppressive treatment chloroquine resistant falciparum Toxoplasmosis -high doses given Pyrimethamine cont…. 47

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Adverse drug reactions of pyrimethamine : Nausea , rashes , megaloblastic anemia & granulocytopenia with higher doses. Sulfonamide – pyrimethamine Supra additive synergism - sequential block Faster acting against chloroquine resistant p.falciparum Has long half life In India - with artesunate for all falciparum cases 48

Sulfonamide - pyrimethamine:

Fixed dose Combinations : Pyrimethamine 25mg + sulfadoxine 500mg Pyrimethamine 25mg + sulphamethopyrazine 500mg Pyrimethamine 25mg +dapsone 100mg : given in 2 nd & 3 rd trimester of pregnancy with folic acid In resistance quinine given with these combination Sulfonamide - pyrimethamine 49

Sulfonamide – pyrimethamine cont…:

ADR : Exfoliative dermatitis, stevens johnson syndrome Precautions Avoided in pregnancy due to antifolate & teratogenic effects, avoid in children Sulfonamide – pyrimethamine cont… 50

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Primaquine 8 – Aminoquinoline Radical cure : given with chloroquine only agent active against dormant hepatic forms of vivax & ovale Gametocidal action against all four species of plasmodium Mechanism of action Primaquine : Not clear, its converted & produces active oxygen interfere with plasmodial mitochondrial function Resistance induced among p.vivax 51

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Pharmacokinetics of primaquine : Well absorbed oral, wide distribution Half life 3-8h,peak :1-2hrs Generates 3 active metabolite ,excreted in urine Uses of primaquine 1.Radical cure a) P.vivax & ovale : Given in acute attack or throughout incubation period prevents relapse 52

Uses of primaquine cont..:

P rophylactically : before & after leaving the endemic area to eradicate hepatic forms Effective vector control is possible or used in areas of low transmission b) F alciparum malaria: 45mg with chloroquine or ACT used like gametocidal & cut down transmission or where effective control is needed Uses of primaquine cont.. 53

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Primaquine cont.. 2. AIDS: 15mg/day with clindamycin 600mg TDS alternatively used Adverse drug reaction of Primaquine Therapeutic doses: Haemolysis & methaemoglobinaemia commonly seen in G6PD deficiency Causes nausea, headache, epigastric pain &abdominal cramps on empty stomach Rarely : leucopenia, leucocytosis & agranulocytosis 54

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Precaution - Primaquine G6-PD deficiency checked & blood counts repeated if >30mg of P rimaquine given AVOID In patient with haemolysis ,Rheumatoid arthritis & SLE 55

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Tafenoquine Newer 8-aminoquinolone single dose for vivax hypnozoites Some activity was seen against asexual erythrocytic stage of P.vivax,P.falciparum & chloroquine resistant state Tafenoquine pharmacokinetics: With long half life 16-19 days, acts lasting upto a week Causes haemolysis in G6PD deficient patient, anaemia , haemolysis & methaemoglobinaemia reported Its undergoing phase-3 trial in India with 3 day chloroquine to prevent relapse in vivax ,likely to be single dose radical cure 56

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Tetracyclines & Doxycyclins Erythrocytic schizonts are inhibited by all malarial parasite Tetracycline used in combination with quinine in treatment of chloroquine resistant as well vivax malaria Avoid in children & pregnant women Dose: 250mg QID or Doxycycline 100mg OD equally effective 57

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Doxycycline cont.. Doxycycline used in places where high resistance present 200mg D oxycycline combined with artesunate to treat mefloquine/chloroquine/s-p resistant malaria 100mg/day of Doxycycline used 2 nd line prophylactic for short travels to chloroquine resistant P.falciparum Adverse effects: Photosensitivity & suprainfection 58

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C lindamycin: Slow erythrocytic schizontocide , bacteriostatic With Quinine used in treatment of resistant P.Falciparum Its used where tetracyclines can not be used in pregnancy & children less than 8 years old 59

Artemisinin compounds:

Derived from plant Artemisia annua – (Chinese traditional medicines) Its sesquiterpine lactone endoperoxide , poorly soluble in oil & water-used orally/rectally Other compounds : D ihydroartemisinin (oral) Artemether(oral or i.m) & artesunate (oral/rectal/ i.v / i.m ) Arteether –(i.m) produced in India in 1990 Artemisinin compounds 60

Artemisinin comp cont…:

Arterolone - (oral) synthetic compound are developed Spectrum Actions : Rapidly acting erythrocytic schizonticides clears parasite in < 48hrs Safe & 10-100 times potent compared to other antimalarials Active against P.falciparum resistant to all other anti malarial drugs as well sensitive strains Artemisinin comp cont … 61

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They are lethal to early gamete stage by reducing number of gametes MOA: Endoperoxide moiety produces carbon centered radicals by intramolecular rearrangement which modify & damages malarial proteins High reacted free radicals inhibit plasmodial sarcoplasmic endoplasmic calcium ATPase –(pf ATP6) Resistance ↓ s response & combination of drug with different mechanism & longer acting drugs given with these drugs in 3 days course will solve the problem Artemisinin comp cont … 62

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Artemisinin comp cont … Pharmacokinetics ORAL absorption of A rtesunate - rapid peak of <60min, causes auto induction by CYP2B6 & CYP3A4 Artemether absorption is delayed 2-4h, to increase absorption taken with food,CYP3A4 metabolism extends ½ life to 3-10h Both these drugs get converted to dihydroartemisinin presystemically 63

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Artemisinin comp cont … Half life is 1-2h Artemisinin and dihydroartemisinin extensively metabolised little amount excreted in urine Arteether long half life 24h can be used alone in 3days with very low recrudescence Dose: 12mg of total oral dose for both children & adults in which 4mg/kg given on first day followed by 2mg/kg for 4 days(5 daystreatment ) 64

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Artemisinin comp cont … Parenteral: Artesunate-120mg i.v/i.m on first day followed by 60gm for next 4 days by same route Artemether: 2mg/kg for 5 days Arteether: for complicated malaria in adults i.m 150mg daily is preferred since it has long t1/2 24h its used in 3 day course but WHO recommends 5 day Course Uses For uncomplicated falciparum malaria,Chloroquine resistant & sensitive strains:FDC of ACT used 65

Artemisinin comp cont…:

in vivax where Chloroquine is resistant & Q uinine + Clindamycin cannot be used Artemisinin (ACT) is used Single dose Primaquine used to kill circulating gametes after ACT therapy Severe complicated malaria: Parentral artemisinin high effective &lower mortality Quinine is used alternative when artemisinin cannot be used During pregnancy quinine i.v given during 1 st trimester of pregnancy since safety of artemisinin compounds not yet proved Artemisinin comp cont … 66

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Adverse effects : Mild :nausea, vomiting, abdominal pain, itching &drug fever Headache, tinnitus, dizziness, bleeding, dark urine, S-T segment changes, Q-T prolongation, first degree A-V block, transient reticulopenia & leucopenia are rare Halofantrine ( phenanthrene methanol) Not preferred due to erratic bioavailability & cardiotoxicity & extensive cross resistance with MEFLOQUINE It was used in multidrug resistant strain of both falciparum & vivax,it’s a blood schizonticide 67

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Lumefantrine B elongs to the arylaminoalcohol has a similar mechanism of action it alters protein & nucleic acid synthesis. racemic fluorine derivative developed in China. It is only available in an oral preparation coformulated with artemether . This ACT is highly effective against multidrug resistant P. falciparum . 68

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Lumefantrine cont … orally active, long acting, highly effective blood schizonticide Pharmacokinetics Its lipophilic ,absorption starts after 2hrs peaks 6-8h 99%plasma protein bound Metabolized by CYP3A4 ½ Life 4-6 days Taken with fatty diet to achieves adequate blood levels Dose: 480mg BD - 3days,adult & chidren >35kg 4tab given with artemether 80mg BD Children 26-35 kg-3tab,16-25kg-2tab,5-15kg-1tab 69

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Lumefantrine cont … Uses : In combination with artemether 20mg+lumefantrine 120mg in one tab used as FDC Both drugs prevent resistance Decreases gametocyte number & prevents recrudescence It achieves 99% cure rates Adverse effects Minor effects: Gastrointestinal disturbances, headache, dizziness rashes & pruritis Little Q-T prolongation seen Avoided in pregnant & lactating women 70

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Pyronaridine Newer drug from M epacrine developed in china Mechanism similar to chloroquine High effective erythrocytic schizonticide,effective against chloroquine sensitive & resistant vivax & falciparum malaria Slow onset & long duration of action, concentrated in RBC Water soluble, t1/2 : 7days Orally & parenterally used , well tolerated At high dose used analgesic/anti pyretic 71

Pyronaridine:

Its used FDC with Artesunate in multi drug resistant falciparum & vivax Clinical trial proves >95% success rate in India This ACT not approved for use in India Adverse effects: Abdominal pain, vomiting, headache, dizziness , loss of appetite, palpitation Dose: Artesunate 100-200mg(2-4mg/kg)+ pyronaridine 300-600mg(6-12mg/kg)/day-3days Pyronaridine 72

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Atovaquone : H ydroxy naphthoquinone antiparasitic drug active against all Plasmodium species. Rapid acting erythrocytic schizontocide & inhibits pre- erythrocytic stage of falciparum. Also active against pneumocystis jiroveci & Toxoplasma gondii combined with proguanil Where its resistant, reduces relapse & which is synergistic. Collapses mitochondrial membrane interferes with cytochrome electron transport . 73

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Dosage 250 mg of atovaquone and 100 mg of proguanil hydrochloride for adults. QID with food Tablets containing 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride for paediatric use. Given 3 days for uncomplicated chloroquine resistant falciparum & vivax used in some countries but not in India Uses: Mild –mod malaria chloroquine & multi drug resistant Can be used prophylactically by non immune travellers visiting endemic areas, 74

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In oppurtunistic infections, pneumonia, Toxoplasmosis & B abesiosis Pharmacokinetics poorly absorbed following oral administration can be improved by taking the drug with fatty foods. 99 % bound to plasma proteins and has plasma half-life of around 66–70 h due to enterohepatic recycling . It is excreted in the faeces as unchanged drug 75

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Adverse effects Skin rashes, headache, fever, insomnia, nausea, diarrhoea , vomiting, raised liver enzymes, hyponatraemia Rarely: haematological disturbances. Drug interactions ↓ plasma concentrations with Tetracycline and Acyclovir, antidiarrhoeal drugs, Benzodiazepines, cephalosporins , laxatives, Opioids and P aracetamol . Atovaquone ↓ the metabolism of zidovudine and cotrimoxazole . it displace other highly protein-bound drugs from plasma-protein binding sites. 76

Act regimens:

Antimalarial drugs alone – Resistance & fail to prevent malaria WHO :Acute uncomplicated resistant P.F malaria should be treated only by combining one of the artemisinin compounds with another effective erythrocyte schizontocide . Advantages of ACT over other antimalarials : Rapid clinical & parasitological cure. High cure rates, low relapse rate. No resistance. Good tolerability. Act regimens 77

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ACT regimens for uncomplicated falciparum malaria . 1.Artesunate – mefloquine (AS/MQ) Artesunate 100 mg BD (4 mg / kg / day) 3 days + Mefloquine 750 mg (15 mg / kg) on 2 nd day and 500 mg (10 mg / kg) on 3 rd day (total 25 mg / kg). 2.Artimether – lumefantrine (1:6) Artemether (80 mg BD) + lumefantrine (480 mg BD) 3 DAYS 78

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Adult and child >35 kg :4 tab BD; child 25 – 35 kg : 3 Tabs bid; 15 – 25 kg :2 tab BD; 5 – 15 kg 1 tab BD, All for 3 days 3.Artesunate – sulfadoxine + pyrimethamine Artesunate 100 mg BD (4 mg / kg / day ) 3 days + sulfadoxine 1500 mg (25 mg / kg) and pyrimethamine 75 mg (1.25 mg / kg) single dose Act reg cont ……. 79

ACT regimen cont…:

4.Arterolane – Piperaquine . Arterolane (as maleate )150mg+ Piperaquine750mg daily -3days One capsule OD for 3 days 5. Dihydroartemisinin - Piperaquine (DHA/PPQ 1:8) DHA120mg(2mg/kg)+piperaquine960mg(16mg/kg)daily for 3 days 6. Artesunate – Amodiaquine (AS/AQ) Artesunate 200mg(4mg/kg)+ Amodiaquine (10mg/kg)per day-3 days ACT regimen cont … 80

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ACT regimen cont … Artesunate 25mg/50mg/100mg+Amodiaquine 67.5mg/135mg/270mg FDC approved in India 7.Artesunate - Pyronaridine (1:3) Artesunate 100-200mg (2-4mg/kg) + pyronaridine 300-600mg(6-12mg/kg)per day- 3 days. TREATMENT OF UNCOMPLICATED MALARIA a) Vivax ( ovale,malariae ) : Chloroquine 600mg (10mg/kg base) followed by 300mg(5mg/kg)after 8hrs for next 2 days(total 25mg/kg over 3 days) + Primaquine 15mg(0.25mg/kg)daily -14days 81

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ACT regimen cont … In occasional case of chloroquine resistance: Quinine 600mg(10mg/kg)8hrly – 7days + Doxycycline 100mg daily -7 days or + Clindamycin 600mg 12hrly -7days +Primaquine (as above) (or) ACT based combination + primaquine (as above) B) Chloroquine - sensitive falciparum malaria Chloroquine (as above) + primaquine 45mg(0.75mg/kg)single dose ( gametocidal ) 82

Chloroquine resistant falciparum malaria:

Artesunate 100mg BD (4mg/kg/day) – 3 days + Sulfadoxine 1500mg(25mg/kg)+ Pyrimethamine 75mg (1.25mg/kg) single dose Or Artesunate 100mg BD(4mg/kg/day)- 3 days + Mefloquine 750mg(15mg/kg) on 2 nd day & 500mg(10mg/kg) on 3 rd day or 3. Artemether 80mg+ lumefantrine 480mg BD – 3 days(Child 25-35kg BW ¾ Dose;15-25 kg BW ½ dose;5-15 kg BW ¼ dose Chloroquine resistant falciparum malaria 83

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(or) 4.Arterolane (as maleate ) 150mg + Piperaquine 750mg OD – 3 days Or 5. Quinine 600mg(10mg/kg)8hrly – 7 days + Doxycycline 100mg daily -7 days Or Clindamycin 600mg 12hrly -7 days 84

Treatment of complicated severe falciparum malaria:

Artesunate 2.4 mg/kg IV or i.m as a first dose followed by 2.4mg/kg after 12 & 24h then OD -7days switch over to 3 day Oral ACT in between whenever patient can take & tolerate oral medication (or) 2) Artemether 3.2 mg/kg IM on first day followed by 1.6 mg/kg daily for seven days switchover to 3 days oral ACT inbetween whenever patient can take & tolerate oral medication (Or) Treatment of complicated severe falciparum malaria 85

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Arteether 3.2mg/kg i.M on the first day followed by 1.6mg/kg daily for next 4 days switchover to 3 days oral act in between whenever patient can take & tolerate oral medication Or Quinine di hcl 20mg/kg loading dose diluted in 10ml/kg 5%dextrose/dextrose –saline infused i.V -4hrs,followed 10mg/kg(maintenance dose) i.V. Infusion over 4hrs(in adults)or 2h(in children)every 8hrs until patient can swallow switchover to oral quinine 10mg/kg 8hrly to complete 7 day course 86

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Drugs Used in pregnancy: Proguanil with folic acid 5mg/day Chloroquine in usual doses Quinine in low dose – chloroquine resistant malaria high dose- induce labour Pyrimethamine + Dapsone -2 nd & 3 rd trimester with folinic acid Chloroquine , quinine & proguanil safe but pyrimethamine with folinic acid can be used 87

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NEWER DRUGS 4(1H )-quinolone-3-diarylethers : selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax . They target both the liver and blood stages of the parasite as well as gametocytes , the zygote, the ookinete , and the oocyst . 88

ELQ300:

preclinical candidate, ELQ-300 has good oral bioavailability at efficacious doses in mice Metabolically stable highly active in blocking transmission in rodent models of malaria. Given its predicted low dose in patients and its predicted long half-life, ELQ-300 has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria. ELQ300 89

Malaria Vaccine:(RTS,S/AS) :

A Phase III trial began in May 2009 and has completed enrolment in 2011 are expected to become available to WHO in 2014-2015 . evaluated as an addition to, not a replacement for, existing preventive, diagnostic and treatment measures. The need for long-lasting insecticidal nets, rapid diagnostic tests and artemisinin -based combination therapies will continue   Malaria Vaccine:( RTS,S/AS) 90

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References : Pharmacological basis of Therapeutics – Goodman & Gilman 12t h Edition Principles of pharmacology – HL Sharma & KK sharma 2 nd edition Text book of pharmacology – K. D. Tripathi.7 th Edition Pharmacology & Therapeutics - R.S.Satoskar - Twentieth second Edition. 91

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www.ncbi.nlm.nih.gov/pubmed www. ranbaxy.Com www.who.int/malaria/areas/vaccine/en. 92

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93 Thank u

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