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Antimalarials

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drugs used in malaria

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Antimalarials

  1. 1.  Malaria - caused by sporozoites of Plasmodium  Transmitted by infected female Anopheles  Symptoms: chills, rigor, fever, headache, sweating  Chronic- progressive spleenomegaly  Sym appear after 7-10 days of mosquito bite  Incubation period 10-30 days.
  2. 2.  Clinically important species of plasmodium P.falciparum, P.vivax, P.ovale, P.malariae  Definitive host- female anapheles mosquito  Intermediate host- human being P.vivax:  causes benign tertian malaria  Relapse can occur due to hypnozoites in liver P.ovale:  Has periodicity & relapses, milder
  3. 3. P.falciparum:  Malignant tertian malaria  Forms RBC rosettes  Blocks vital organs-renal failure & encephalopathy  Exo-erythrocytic stage absent  Relapse do not occur, recrudescence can occur P.malariae:  Quartan malaria,Exo-erythrocytic stage absent  relapse can occur, rare.
  4. 4. 1) 4-Aminoquinolines – Chloroquine Amodiaquine Piperaquine. pyronaridine 2) Quinoline-methanol – Mefloquine. 3) Cinchona alkaloid - Quinine Quinidine 4) Biguanides –------- Proguanil Chlorproguanil 5) Diaminopyrimidines – Pyrimethamine 6) 8-Aminoqunilones–---- Primaquine Bulaquine
  5. 5. 7) Sulfonamides and sulfones – Sulfadoxine Sulfamethopyrizone Dapsone 8) Tetracyclines –---------- Tetracycline Doxycycline 9) Sesquiterpinelactones –----- Artesunate Artemether Arteether 10) Amino alcohols –------------ Halofantrine Lumefantrine 11) Acridine –--------------- Mepacrine Quinacrine 12) Naphthoquinone –-----------Atovaquone
  6. 6. Schizonticides 1)Tissue (Hepatic) schizonticides:  Primary- proguanil & pyrimethamine  Active against pre-erythrocytic state of P.Falc  Secondary- primaquine  Acts on both pre & exo erythrocytic cycle of all Ps
  7. 7.  Destroy blood schizonts  Prevent erythrocytic schizogony 1) Fast acting high efficacy-  Chloroquine, quinine, mefloquine, lumefantrine, atremisinin & atovaquone  Used to terminate attack of malaria promptly 2) Slow acting low efficacy-  Pyrimethamine+sulfadoxine, proguanil & doxycycline.  Used in combination to terminate clinical attack
  8. 8. Gametocides  Destroy gametocytes so mosquito can’t transmit  Primaquine for all species  Chloroquine & quinine- except P.falciparum Sporontocides  Makes gametocytes ineffective in mosquito  proguanil & pyrimethamine  No clinical advantage
  9. 9. Causal prophylactics  Prevent pre-erythrocytic phase  proguanil & pyrimethamine – P.Falciparum only  Primaquine- all Ps, toxic  If G6PD levels are normal 0.5mg/Kg daily till stay in endemic region.
  10. 10.  Blood schizonticides are used - kills merozoites  Prevents erythrocytic phase  No effect on hepatic phase  Following drug regimens are used. 1) Areas with CQ-sensitive P. falc or P. viv only  Tab.Chloroquine 300mg(free base) [500mg chl. phosphate contains 300mg free base]  Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas.  Primaquine 15mg/d X 14 days after leaving
  11. 11. 2) Areas with chloroquine-resistant P. falciparum  T.Mefloquine 250 mg once weekly, 1 week before and 4 weeks after travel. 3) Areas with chloroquine or mefloquine-resistant Plasmodium falciparum  Atovaquone/proguanil 1 adult tablet daily 1-2 days before & 7 days after travel  An adult tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride. (or)  Doxycycline: 100mg daily, a day before travel and taken till 4 weeks after return from endemic area.
  12. 12. a)Vivax (ovale, malariae) malaria 1.Chloroquine 600mg stat followed by 300mg after 8 hrs and for next 2 days(total 25mg/kg over 3 days) + Primaquine 15mg (0.25mg/kg daily) for 14 days In chloroquine resistance 2) Quinine- 600mg 8 hourly x7 days+ Doxycycline- 100mg daily x 7days+ Primaquine- 15mg daily X 14 days
  13. 13. B) Chloroquine sensitive falciparum malaria  Chloroqiuine as above + Primaquine- 45 mg single dose as gametocide C) Chloroquine resistant falciparum malaria 1.Artesunate- 100mgBD(4mg/kg daily) x 3 days+ Sulfadoxine-1500mg(25mg/kg)+ Pyrimethamine- 75mg(1.25mg/kg) single dose  First line ACT 2.Artesunate- 100mgBD(4mg/kg daily) x 3 days+ Mefloquine- 750mg(15mg/kg)on 2nd day and 500mg(10mg/kg) on 3rd day
  14. 14. 3. Artemether- 80mg + Lumefantrine- 480 mg B.D X 3days 4. Arterolane 150 mg + Piperaquine 750mg od X3 days 5.Quinine 600mg 8hly X 7 days+ Doxycycline100mg daily X 7days or Clindamycin 600mg 12hly X 7 days  In India irrespective of CQ – resistance status are treated with ACT.
  15. 15. 1. Artesunate- 2.4mg/kg i.v or i.m, f/b 2.4mg/kg after 12 and 24 hrs Then OD for 7 days. 2. Artemether- 3.2mg/kg i.m on 1st day f/b 1.6mg/kg for next 7 days 3. Arteether- 3.2mg/kg on 1st day f/b 1.6mg/kg for next 4 days Switch over to 3 day oral ACT in between whenever the patient is able to take oral med
  16. 16. 4. Quinine diHCL-20mg/kg(loading dose) diluted in 10ml/kg 5%dextrose/dextrose-saline and infused i.v over 4 hours, f/b 10mg/kg(maintenance dose) i.v infusion over 4 hours(adults) or 2 hours (children) every 8 hours, until patient can swallow. Switch over to oral quinine 10mg/kg 8hourly to complete 7 day course. Falciparum malaria during pregnancy  Q 600mgTDS 7d+ clindamycin 300md 7d all tri  3 day ACT regimen in 2nd & 3rd tri alt to above
  17. 17. Radical cure: Drugs which attack the exo-erythrocytic stage given together with a clinical curative achieve total eradication of parasite.  Drug of choice for vivax and ovale malaria is Primaquine: 15mg daily for 14 days. It should given with or immediately after chloroquine or other schizonticide only to persons who test negative to G6PD deficiency.  Anti relapse treatment is restricted to: a) Areas with low levels of transmission. b) Patients treated during an epidemic along with effective vector measures to cut down transmission.
  18. 18. Chloroquine  Available as Cl.Phosphate for oral use PK  A-almost completely absorbed from GIT.  D-large aVd, extensively tissue bound.  M- liver, initial t1/2- 3-4 days, terminal t1/2- 1-2mts  E-urine  ROA- oral/ I.M/ slow I.V infusion
  19. 19. MOA  Preferentially accumulates in Parasitized RBC  Being basic diffuses freely in to parasite lysosome  Gets ionized in acidic pH of lysosome  Inhibits peptide formation & AA synthesis  Inhibits parasite haem polymerase→  Host haem is not converted to haemozoin  Free haem is toxic to malarial parasite
  20. 20. Antimalarial action & clinical use  It is rapidly acting erythrocytic schizonticide against all species of plasmodia. Uses 1) Drug of choice for clinical cure and prophylaxis of all types of malaria. 2) Extra-intestinal amoebiasis 3) Rheumatoid arthritis 4) DLE- very effective. Less effective in SLE. 5) Lepra reactions. 6) Photogenic reactions 7) Infectious mononucleosis – symptomatic relief.
  21. 21. Resistance  Most common in P.falciparum  Due to mutation in putative chloroquine transporter (PfCRT). Adverse effects  Nausea, anorexia, uncontrollable vomiting, epigastric pain, difficulty in accommodation, and headache.  Parenterally – hypotension, cardiac depression, arrhythmias, convulsions  Prolonged use: loss of vision due to retinal damage.
  22. 22. CI  Retinal & visual field abnormalities.  Aggravates psoriasis & porphyria.  G6PD deficiency- haemolytic anemia. DI  Antacids ↓ absorption  C+ metoclopramide precipitates extra pyramidal side effects.  Safe in pregnancy and children >2yrs
  23. 23. Amodiaquine  Similar to chloroquine  Withdrawn-risk of agranulocytosis, hepatotoxic.  Reintroduced in chloroquine resistant areas  Resistant P.falciparum responds to amodiaquine combination regimens  Artesunate + amodiaquine or  Pyrimethamine-sulfadoxine + amodiaquine.  Toxicity is rare with combination.
  24. 24. Piperaquine  Piperaquine is chloroquine analogue.  Used for Rx of P.falciparum malaria in fixed dose combination with dihydroartemisinin  Longer t1/2- 35 days, reduces rate of relapse Pyronaridine  Amodiaquine analogue used in china.  Combined with artesunate for chloroquine resistant falciparum & vivax malaria  Effective orally & has low toxicity.
  25. 25. Quinine  Alkaloid derived from cinchona bark  Rx and prevention of malaria since 1820 PK  A- well absorbed from GIT.  D-large aVd, extensively tissue bound.  M- liver, t1/2- 10-11 hrs  E- urine  ROA- oral/ slow I.V infusion
  26. 26. MOA  Not clear  Like chloroq inhibits parasite haem polymerase.  Acts as a protoplasmic poison to parasite & hampers supply of AA & peptides. Antimalarial action & clinical use  Similar to chloroquine.  No effect on pre-erythtocytic stages and on hypnozoites of relapsing malaria, but kills vivax gametes.  Main drug for chloroquine resistant P.fal malaria
  27. 27. Other uses  Nocturnal leg cramps- varicose veins Diabetes mellitus Arthritis  Quinine + clindamycin- 1st line Rx of Babesiosis Resistance  To P.falciparum reported in Thailand.  Due to ↑ expression of P-glycoprotein
  28. 28. Adverse effects  Bitter taste- poor compliance  Gastric irritant – nausea, vomiting  Bolus I.V admin- hypotension & arrhythmias  Stimulates insulin release- Hypoglycemia.  Hence quinine usually infused with 5%dextrose.  May lead to hypoglycemic coma in P.f malaria.  Black water fever- erratic use in other fever.  Leads to marked haemolysis & renal failure.
  29. 29. Cinchonism  A syndrome due to intake of a large single dose or higher therapeutic doses taken for a few days.  Characterized by  Sweating  Tinnitus  Blurred vision  Headache  Diarrhoea  Cardiac arrhythmias  Neurotoxicity (higher doses)  Hematological toxicity (hemolysis in G6PD def)
  30. 30. Contraindications (CI)  Visual & auditory problems  Cardiac abnormalities Drug interactions (DI)  Antacids ↓ absorption  Quinine raises plasma levels of digoxin  Shouldn’t be given concurrently with mefloquine both effect cardiac conduction- arrhythmias
  31. 31. Mefloquine PK  A- orally well absorbed  D- highly protein bound, extensively distributed  M- liver, undergoes enterohepatic circulation.  E- feces, t1/2- 20 days, weekly dosing in chemoprophylaxis, single dose regimen for clinical cure.  ROA- oral, can’t give parenterally-pain, irritation MOA & Resistance  Similar to quinine
  32. 32. Antimalarial action & uses  Blood schizonticide  used for chemoprophylaxis and clinical cure  Not useful in severe & complicated malaria Adverse effects  Nausea  Vomiting  Neuropsychiatric side effects in 0.5% patients  Vertigo, Confusion, vivid dreams, seizures  Abnormal AV conduction  CI with quinine or halofantrine
  33. 33. Primaquine PK  A- orally well absorbed.  D- wide, not extensively tissue bound.  M- liver, active metabolites- toxic.  E- urine, t1/2-3-6 hrs.  ROA- oral MOA  Not clear  Quinone metabolite inhibits coenzyme-Q in parasite, also hemolysis in host.
  34. 34. Antimalarial action & uses  Tissue schizonticide, gametocidal.  Effective on both pre & exo erythrocytic state  Not effective on erythrocytic state.  Mainly used for radical cure and to prevent relapse in P.vivax & P.ovale  Other use- primaquine + clindamycin in Pneumocystis jiroveci pneumonia  Improved tolerance over cotrimoxazole
  35. 35. Adverse effects  Git distress, nausea  Head ache  Pruritis  Leukopenia  G6PD def pt- fatal haemolytic anemia  CI in pregnancy  Other congeners-  Bulaquine, etaquine, tafenoquine
  36. 36.  Bulaquine : developed in India,  Prodrug for primaquine  Dose- 25mg/d starting on 2nd day of chloroquine therapy  primaquine or bulaquine not given parenterally  Produces marked hypotension  Etaquine & tafenoquine more potent and longer acting  Tafenoquine –orally once weekly.
  37. 37. Pyrimethamine-sulfonamide/dapsone  Pyrimethamine selectively inhibits plasmodial folate reductase enzyme.  Slow acting erythrocytic schizonticide  Sulfonamides are added to prevent resistance.  Sulfadoxine/sulphamethopyrazine/dapsone  Inhibit dihydropteroate synthase enzyme  Used for clinical cure of P.falciparum malaria.  Q+Sd+P- chloroquine resistant P.falc .  Other uses:  Toxoplasmosis : in immunodeficient P(50- 75mg/d)+sulfadiazine(2-4g/d) 1-3 wk 1st line therapy.
  38. 38. Adverse effects  Pyrimethamine -megaloblastic anemia  Folinic acid is added to therapy to prevent this  Anorexia, vomiting, atrophic glossitis, seizures  P+Sd- exfoliative dermatitis stevens johnson syndrome. Allergic alveolitis, blood dyscrasias  P+D- Haemolytic anemia, Agranulocytosis Eosinophilic alveolotis
  39. 39. Tetracycline & Doxycycline  Slow acting & weak erythrocytic schizonticides  Effective against all species.  Use – combination with quinine for CQ resistant falciparum & vivax malaria.  Dose: Tetracycline- 250mg QID Doxycycline- 100mg OD  Doxycycline 100mg/day is 2nd line prophylactic treatment for travellers to chloroquine resistant P.falciparum areas.
  40. 40. Proguanil (Chloroguanide)  Inhibitor of plasmodial dihydrofolate reductase PK  A- rapid, t1/2 16hrs, administered OD. Antimalarial action  Slow acting erythrocytic schizonticide for all Ps.  Acts on pre-erythrocytic stage of P.vivax  No effect on exoerythrocytic cycle & gametes  Resistance develops rapidly when used alone  Hence used in combination
  41. 41.  250 mg Atovaquone + Prouguanil 100mg OD X 2days prior to & 7 days after exposure for chemoprophylaxis of P.falciparum malaria.  AQ 1000mg + PG 400 mg OD X3 days preferred for Rx of CQ R P.viv & MDR P.fal  Combined formulations should be taken with food  AE: less severe
  42. 42. Atovaquone  Used in combination with proguanil  FDC prevent resistance & better tolerated MOA  Not clear, disrupts plasmodial mitochondrial electron transport  Inhibits pyrimidine & ATP synthesis PK  A-BA poor & erratic, ↑ with fatty meal  D- PB-99%  M- long t1/2 (2-3 d) partly due to EH recycling  E- feces
  43. 43. Uses  Chemoprophylaxis & Rx of P.fal with PG  Other- mild to mod Pneumocystis.carinii pneumonia in pt intolerant to cotrimoazole  Rx or suppression of Toxoplasma gondii encephalitis AE  Abd pain, N, V, Headache, rash  Reversible elevation in liver enzymes DI  Metoclopramide, tetracycline, rifampicin ↓AQ plasma levels
  44. 44.  Artemether, Artesunate, Arteether are Sesquiterpinelactone endoperoxidases  Artemisinin is active principle of the plant Artemisia annua used in Chinese traditional medicine as” Quinghaosu.”  Active against P.falciparum resistant to all drugs as well as sensitive strains.  Artemether, Artesunate, Arteether semisynthetic derivatives of Artemisinin with improved potency better BA
  45. 45. Pk  Artemisinin is poorly soluble in water & oil,  Artemether is soluble in oil , given orally, i.m, t1/2 4-11 hrs.  Artesunate is water soluble , given orally, i.m, i.v t1/2<1 hr . Both are prodrugs.  Active metabolite Dihydroartemisinin also used orally  Arteether (i.m in oil) was produced in India in 1990. longer t1/2 23 hrs  Arterolane –synthetic compound given orally.
  46. 46. Antimalarial action  Potent and rapid blood schizonticide and parasitemia clearance is<48 hrs.  Action on a wide range of forms – from ring forms to early schizonts, thus have the broadest time window of anti-malarial action.  Do not kill hypnozoites but some action on gametes.  Recrudescence depends on dose, duration, as well as severity of disease.
  47. 47. MOA  Involves two steps  Initially intraparasitic protoporphyrin –IV catalyses break down of endoperoxide bridge (-O-O-) of artemisinin molecule  Generation of highly reactive free radicals ->  Damage parasite membrane by covalently binding to proteins  Free radicals specifically inhibit plasmodial sarcoplasmic-endoplasmic Ca ATPase labelled PfATP6
  48. 48. AE:  N, V, Abd pain, itching  Temp QT prolongation may occur  Transient reticulopenia and leucopenia are rare Halofantrine  Potent blood schizonticide  A- erratic, ↑with food  MOA possible inhibition of proton pump  Manifests lethal cardiotoxicity & cross resistance with mefloquine  USE: restricted for MDR P.fal 500mg QID X 1 d repeated after 1wk
  49. 49. AE:  Abd pain, Vomiting cough, rash, prutitis  Transient elevation in liver enzymes  Cardiotoxicity: prolong QT & PR interval, dose related defects in cardiac conduction  Worsens with mefloquine  Embryotoxic in animals avoided in pregnancy Lumefantrine Used in combination with Artemether for MDR P.fa BD X 3days Combination not cardiotoxic  Given with fatty meal ↑ BA
  50. 50. Artemisinin based combination therapy (ACT)  WHO recommended that acute uncomplicated resistant falciparum malaria should be treated by combining artemisinin compounds with another erythrocytic schizonticide.  Most important consideration for companion drug is elimination half life as effective concentrations in blood must be maintained for at least 3asexual cycles.  Short half life drugs Ad. for 7 days.  Long half life drugs Ad. for 1-3days.
  51. 51.  Advantages of ACT over other drugs:  Rapid clinical and parasitological cure.  High cure rates(>95%) and low recrudescence rate.  Absence of parasitic resistance.  Good tolerability profile. ACT regimens in use are: 1.Artesunate- 100mgBD(4mg/kg daily) x 3 days+ Sulfadoxine-1500mg(25mg/kg)+ Pyrimethamine- 75mg(1.25mg/kg) single dose  First line ACT  But not effective against multidrug resistant strains.
  52. 52. 2.Artesunate- 100mgBD(4mg/kg daily) x 3 days+ Mefloquine- 750mg(15mg/kg)on 2nd day and 500mg(10mg/kg) on 3rd day  First line treatment for uncomplicated falciparum malaria in S-E Asia.  Further spread of mefloquine resistance is prevented. 3. Artemether- 80mg + Lumefantrine- 480 mg B.D X 3days components protect each other from plasmodial resistance. Active in multidrug resistance areas. Artemether reduces symptoms and lumefantrine prevents recrudescence.
  53. 53. 4. Arterolane 150 mg + Piperaquine 750mg od X3 days 5. Dihydroartemisinin 120mg +piperaquine 750mg daily X 3days  Well tolerated even in children 6. Artesunate 200mg + Amodiaquine 600mg/day X 3days. 7. Artesunate 100-200mg + pyronaridine 300 - 600mg/day X 3days.
  54. 54. Thank you

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