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  • Oxidative damage to the membranes , digestive proteases & other critical biomolecules of malarial parasite Heme polymerase present inside lysosomes of the malarial parasite which convert toxic heme to non toxic hemozoinNow chloroquine concentrates in the acidic lysosomes binds to liberated heme to form hemequinoline complex which interupts the hemepolymerisation by inhibiting enzyme heme polymerase Chloroquine also inhibits RNA & DNA synthesis at higher conc but these effects are unlikely to be involved in MOA MECHANISM OF QUININE & MEFLOQUINE ARE SIMILAR
  • Retinopathy: constriction of arteries, edema, blue black pigmentation , constricted field of vision. These changes are reversible on stopping therapy
  • Toxicity, cost, long t1/2 restricts use
  • 11.malaria

    1. 1. Antimalarials
    2. 2. • Introduction:– Most devastating parasitic infection– 1-3 million deaths world wide each year– India 8 lac deaths• Etiology: Plasmodium• Transmission : Female anopheles
    3. 3. • Clinical features:a) Cold stage: onset with fatigue, headache, chills,nausea, followed by rigors. Skin feels cold lastsfor 1 hrb) Hot stage: feels, burning hot , casts off hisclothes , skin is hot & dry to touch, lasts for 2 to6 hrsc) Sweating stage: fever comes down with profusesweating & temperature drops rapidly to normal.Skin is cool & moist. Pt feels relieved lasts for 2to 4 hrs
    4. 4. Life cycle of malarial parasiteSporogeny(sexual)Schizogony(asexual)Man : Intermediate hostMosquito : Definitive hostTrue causal prophylacticsCausalprophylacticsSupressivesGametocidalSporonticide
    5. 5. • Classification of antimalarial drugs– Based on stage of life cycle they affect– Based on chemical structure
    6. 6. • Based on stage of parasite they affect:– True causal prophylactics:– Causal prophylactics: Primaquine,Pyrimethamine,proguanil– Supressives: quinine, 4-aminoquinolines,mefloquine,artemisinin– Radical curatives: primaquine,pyrimethamine– Gametocidal:• Supressives (Chloroquine, quinine, artesunate )– Pl Vivax ,• Primaquine – against all,• Proguanil ,pyrimethamine – prevent development ofsporozoites
    7. 7. • Based on chemical structure:– Cinchona alkaloids: quinine,quinidine– 4 aminoquinolines: chloroquine,hydroxychloroquine, amodiaquine, pyronaridine– 8 aminoquinolines: primaquine, tafenoquine,bulaquine– quinoline methanol: mefloquine, halofantrine,lumefantrine– Antifolates:• Diaminopyrimidine: pyrimethamine• Biguanides: proguanil• Sulfonamides: sulfadoxine
    8. 8. – Antibiotics: tetracycline, doxycycline, clindamycin– Hydronaphthoquinone: Atovaquone– Qinghaosu compounds: Artesunate, artemether,arteether
    9. 9. • Chloroquine:– Germans 1934 resochin– closely resembles 8 amino quinolines– d & l isomers, d isomer is less toxic– Cl at position 7 confers maximal antimalarialefficacy
    10. 10. • Mechanism of actionHemoglobin Globin utilized bymalarial parasiteHeme (highly toxic for malaria parasite)ChloroquineQuinine,mefloquine (-) (+)Heme polymeraseHemozoin (Not toxic to plasmodium)
    11. 11. • Pharmacological actions:1. Antimalarial activity:• Highly against erythrocytic forms of vivax, ovale,malariae & sensitive strains of falciparum• Gametocytes of vivax , ovale, malariae• No activity against tissue schizonts• Resistance develops due to efflux mechanism2. Other parasitic infections:• Giardiasis, taeniasis, extrainstestinal amoebiasis3. Other actions:• Depressant action on myocardium, direct relaxanteffect on vascular smooth muscles, antiinflammatory,antihistaminic , local anaesthetic
    12. 12. • Pharmacokinetics:– Well absorbed, tmax 2-3 hrs , 55 % protein bound– Conc in liver , spleen, kidney, lungs , leucocytes– T1/2 = 3- 5 hrs increases from few days to weeks• Adverse drug reaction:– Intolerance:• skin rashes, angioneurotic edema, photosensitivity,pigmentation, exfoliative dermatititis• Long term therapy may cause bleaching of hair• Rarely thrombocytopenia, agranulocytosis,pancytopenia
    13. 13. • Occular toxicity: High dose prolonged therapy– Temporary loss of accommodation– Lenticular opacities, subcapsular cataract– Retinopathy: constriction of arteries, edema, blueblack pigmentation , constricted field of vision.These changes are reversible on stopping therapy• CNS:– Insomnia, transient depression seizures,rarely neuromyopathy & ototoxicity• CVS:– ST & T wave abnormalities, abrupt fall in BP &cardiac arrest in children reported
    14. 14. • Dosage:• Therapeutic uses:1. Hepatic amoebiasis:2. Giardiasis3. Clonorchis sinensis4. Rheumatoid arthritis5. DLE6. Control manifestation of lepra reaction
    15. 15. • Hydroxy chloroquine:– Less toxic, properties &uses similar• Amodiaquine:– As effective as chloroquine in single dose– Pharmacological actions similar– Chloroquine resistant strains may be effective– Adverse events: GIT, headache , photosensitivity,rarely agranulocytosis– Not recommended for prophylaxis• Pyronaridine: China , effective in resistant cases
    16. 16. • Quinine:– 1820 Pelletier & caventou isolated quinine fromcinchona bark.– Pharmacological actions:1. Antimalarial action: primarily on erythrocyticforms of all malarial parasites especiallyresistant falciparum strains . gametocidal forvivax & malariae2. Local irritant effect: depresses variety ofenzymatic processes, reduces ciliary activity ,inhibits phagacytosis & growth of protoplasmso called general protoplasmic poison. Localpain sterile abcess.
    17. 17. 3. Cardiovascular: depresses myocardium,↓ excitability, ↓ conductivity, ↑ refractoryperiod, profound hypotension IV.4. Miscellaneous actions: mild analgesic, antipyreticactivity , stimulation of uterine smooth muscle,curaremimitic effect on skeletal muscles• Pharmacokinetics:• administered orally is completely absorbed• Tmax = 1-3 hrs , crosses placental barrier• Metabolized in liver degradation productsexcreted in urine t ½ = 10 hrs
    18. 18. • Adverse drug reactions:• Cinchonism:– Mild: Nausea, headache visual impairment– Tinnitus, nausea & vomiting– Headache mental confusion, vertigo, difficulty inhearing & visual disturbances– Diarrhoea , flushing & marked perspiration– Still higher doses , exagerated symptoms withdelirium , fever, tachypnoea, respiratorydepression , cyanosis.
    19. 19. • Idiosyncrasy : similar to cinchonism but occursin therapeutic doses• Cardiovascular toxicity: cardiac arrest,hypotension ,fatal arrhytmias• Black water fever:– Triad of hemolysis, hemoglobinemia, hemoglobinuriawith fever– Rare type of hypersensitivity to quinine therapyhaving immunological basis. Presence ofincompletely supressed falciparum malaria.• Hypoglycemia:
    20. 20. • Uses:– Malaria:• uncomplicated resistant falciparum malaria• Cerebral malarial– Myotonia congenita: heriditory myopathycharacterized by tonic spasm of skeletal muscle,benefitted by 300 to 600 mg BD/ TDS– Nocturnal muscle cramps: 200 – 300 mg beforesleeping– Spermicidal in vaginal creams– Varicose veins: along with urethane causesthrombosis & fibrosis of varicose vein mass
    21. 21. • Primaquine:– Mechanism of action:– Interferes with oxygen transport systemPrimaquineConverted toelectrophilesGenerates reactiveoxygen species
    22. 22. • Antimalarial action:– Liver hypnozoites– Weak action against erythrocytic stage ofvivax, so used with supressives in radical cure– No action against erythrocytic stage offalciparum– Has gametocidal action and is most effectiveantimalarial to prevent transmission diseaseagainst all 4 species• Pharmacokinetics:– Readily absorbed, t1/2 = 3-6 hrs– Oxidised in liver, excreted in urine
    23. 23. • Adverse effects:– Gastrointestinal: epigastric distress, abdominalcramps , can be minimised by taking drug with orafter food , or with antacids– Hemopoetic: mild anemia, methemoglobinemia,cyanosis, hemolytic anemia in G6PD deficiency– Avoided during pregnancy, G6PD deficient• Uses:– Primary use is radical cure of relapsing malaria 15mg daily for 14 days with dose of chloroquine– India 5 day therapy– Falciparum malaria 45 mg of single dose withchloroquine curative dose to kill gametes & cutdown transmission of malaria.
    24. 24. • Tafenoquine:– More active slowly metabolized analog of primaquine,has advantage that it can be given on weekly basis.• Bulaquine:– Congener of primaquine developed in india– Comparable antirelapse activity when used for 5 days– Partly metabolized to primaquine– Better tolerated in G6PD deficiency
    25. 25. • Mefloquine;– Quinoline methanol derivative developed to dealwith chloroquine resistant malaria– Rapidly acting erythrocytic schizonticide , slowerthan chloroquine & quinine– Effective against chloroquine sensitive & resistantplasmodia• Pharmacokinetics:– Good but slow oral absorption– High protein binding– Concentrated in liver, lung, intestine– extensive metabolism in liver, primarily secretedin bile , under goes enterohepatic circulation– Long t1/2 = 2 – 3 weeks
    26. 26. • Adverse events:1. GIT: bitter in taste, nausea, vomiting , abdominalpain , diarrhoea2. neuropsychiatric disturbances: disturbed sense ofbalance, anxiety, hallucinations, sleepdisturbances, psychosis, errors in operatingmachinery, convulsions3. CVS: Bradycardia, sinus arhythmia, & QTprolongation4. Teratogenicity: avoided in first trimester5. Miscellaneous: allergic skin reactions, hepatitis &blood dyscrasias
    27. 27. • Uses:– Effective drug for MDR falciparum1. T/t of uncomplicated falciparum in MDR malaria25 mg/kg (1.5 gm) in 2 divided doses taken onsame day2. Prophylaxis in MDR areas 5 mg/kg (250 mg) perweek started 2- 3 weeks before to asses sideeffects• Due to fear of development of drugresistance mefloquine should not be used assingle drug for prophylaxis.
    28. 28. • Halofantrine:– Quinoline methanol– Used in chloroquine resistant malaria since1980– Erratic bioavailabilty, lethal cardiotoxicity &cross resistance to mefloquine limited its use– Now a days used only when no otheralternative available– Adverse events; Nausea, vomiting, QTprolongation , diarrhoea, itching , rashes– C/I: along with quinine, chloroquine,antidepressants, antipsychotics.
    29. 29. Drugs affecting synthesis &utilisation of folate:
    30. 30. PABA +Dihydropterine+ Glutamic acidDi hydrofolicacidTetra hydrofolicacidDihydrofolatereductaseѲsulfonamidesѲDHFRinhibitors
    31. 31. Sulfonamides:Sulfanilamide moeity structural analogof PABA,PABA essential for folate synthesisSulfonamides compete with PABA forfolate synthetaseWeak effect , potentiate action of DHFRinhibitors ,hence used in combinationAdvantages of combinationSupradditive , sequential blockCombination faster acting
    32. 32. Dihydrofolate reductase inhibitors:• Proguanil :– Biguanide converted to cycloguanil active compound– Act slowly on erythtocytic stage of vivax & falciparum– Sporonticidal & also prevents development ofgametes Adverse effects: Stomatitis, mouth ulcers, larger doses depression ofmyocardium , megaloblastic anemia Not a drug for acute attack Causal prophylaxis: 100 – 200 mg daily
    33. 33. • Pyrimethamine:– Diaminopyrimidine more potent than proguanil &effective against erythrocytic forms of all species.– Tasteless so suitable for children Adverse events: megaloblastic anemia,thrombocytopenia, agranulocytosis.– Generally combined with sulfadoxine 500 mg +pyrimethamine 25 mg, 3 tablets once for acuteattack– Not recommended for prophylaxis due to severecutaneous reactions like exfoliative dermatitis &stevenson johnson syndrome.
    34. 34. ARTEMISININ DERIVATIVATIVES:• Mechanism of action:• Antimalarial action:Shorter acting drugs, so recrudescencePrevented by combining with long acting drugs• Dose: Artesunate, arteether, artemether• Adverse events:– No serious adverse events– Most common GIT , Itching & fever– Abnormal bleeding, dark urine , ST-T changes,QT prolongation– Transient reticulocytopenia & leucopenia• Use:
    35. 35. Artemisinin based combination therapy:• WHO: acute uncomplicated Pl Falciparum betreated only by combining one Artemisinin withother effective erythrocytic schizonticide?• ACT Regimens in use:– Artesunate – Sulfadoxine, pyrimethamine:• Adopted as first line in india under NMP• ARTESUNATE 100 mg BD for 3 days with S-P, 3 tablets– Artesunate Mefloquine:• By combining artesunate further spread of mefloquineresistance can be prevented• Artesunate 100 mg BD for 3 days, + mefloquine 750 mg onsecond day & 500 mg on third day
    36. 36. • Artemether & lumefantrine:– Lumefantrine is highly effective , long acting oralerythrocytic schizonticide related to mefloquine– Same mechanism of action– Highly lipophilic onset delayed , peak 6 hrs– Slower acting than chloroquine, 99 % bound ,metabolized by CYP3A4, T1/2= 2-3 days– Available as fixed dose combination– Adverse events: headache, dizziness, sleepdisturbances, abdominal pain, arthralgia, pruritis &rash– 80 mg artemether BD WITH 480 mg lumefantrineBD for 3 days• DHA – Piperaquine, Artesunate- pyronaridine
    37. 37. • Tetracyclines:– Slow but potent action on erythrocytic stage ofall MP & Pre-erythrocytic stage of falciparum– Always used in combination with quinine or S-P for treatment of chloroquine resistantmalaria• Atovaquone:– Synthetic napthoquinone derivative, rapidlyacting erythrocytic schizonticide forplasmodium falciparum & other plasmodia– Pnemocystis carinnii & toxoplasma gondii– Mechanism of action:– Combined with proguanil– 250 mg of atovaquone + 100 mg proguanil
    38. 38. Management of malaria:• Prophylaxis;– Indication– Duration :– Drug regimens:• Chloroquine sensitive malaria: 300 mg / week• Chloroquine resistant malaria: mefloquine, doxy,malarone• Drugs not allowed for prophylaxis: quinine,artemisinin, pyrimethamine, sulfadoxine,amodiaquine– Other measures– Causal prophylaxis– Supressive prophylaxis
    39. 39. Treatment of acute attack• Diagnosis , thick & thin smear• Acute clinical attack of chloroquinesensitive malaria:– Chloroquine /– Amodiaquine: 600 mg base followed by 200mg base on day1 then 400 mg OD on day 2 &day3/– Quinine– Patients who cannot take orally• 2.5 mg/kg IM every 4 hrs or 3.5 mg/kg IM every 6hrs• 10 mg/kg IV over 4 hrs then 5 mg/kg over 2 hrs BD– Role of primaquine– Precautions:
    40. 40. • Treatment of chloroquine resistant malaria acuteattackA. Pts who can take orally:– Pyrimethamine sulfadoxine 3 tabs , quinine for 2 daysor– Quinine 3 days with doxy 7 days or– Quinine 3 days with mefloquine– (Atovaquone 250 mg + proguanil 100 mg) 4 tab 3 days– Sodium artesunate 100 mg BD day1 , 50 mg BD for 4days
    41. 41. • Pts who cannot take orally– Inj Quinine Hcl 20 mg/kg in 500 ml dextrose salineover 4 hrs then– 10 mg/kg in dextrose saline over 2 hrs every 8 hrlytill pt able to swallow– Then quinine 600 mg TDS for 7 days &tetracycline/ doxycycline– Or artemether / arteether injection• When should resistance be suspected:– All pts with complication– Any pt who has already received chloroquine last 1month– Hb continues to fall in absence of bleeding &asexual forms persist along with symptoms after48 hrs of treatment
    42. 42. • Severe / Complicated / cerebral malaria– CNS symptoms, convulsions, coma– Hypoglycemia, metabolic acidosis, renal failureor other complications– Quinine is drug of choice IV dose– S-P , doxycycline added with oral therapy– BP, blood sugar, ECG Monitored during quininetherapy.– Supportive measures:• ICU administration• Good nursing care,Tepid sponging, Na bicarbonate• Hypoglycemia, anemia, BP , Increase ICT– GC, urea, mannitol not used now a days
    43. 43. • Malaria in children:– Quinine parenteral high toxicity / oral well tolerated– Chloroquine convulsions in infants & small children– Primaquine avoided in neonates– Mefloquine not used in children below 15 kg weight• Acute malaria in pregnant women– Chloroqune, quinine, S-P in usual doses– Mefloquine C/I in first trimester– Primaquine/ tetracycline avoided– Anemia: folic acid & iron
    44. 44. • Vaccines for malaria:– Pre-erythrocytic stage vaccines• RTS VACCINE designed to prevent invasion ofhepatocytes by sporozoites– Erythrocytic stage vaccine:• Aim is to reduce or eliminate number of blood stageparasites• Malarial surface protein 1 (MSP1) vaccine• Apical merozoite antigen 1 (AMA1) vaccine– Transmission blocking vaccines:• Designed to prevent mosquitoes that feed onvaccinated individuals from becoming infected &reduce transmission (indirect prevention)– Multicomponent vaccines: combinationvaccines• Combination vaccine of 3 blood stage antigens