Antimalarial drugs

Antimalarial drugs

• 1.
  Antimalarial Drugs Dr NaserAshraf Tadvi
• 2.
  Plasmodium species which infecthumans • Plasmodium vivax (tertian): • Plasmodium ovale (tertian) • Plasmodium falciparum (tertian) • Plasmodium malariae (quartan) Sir Ronald Ross
• 3.
  Symptoms of malaria •Cold stage: – Feeling intense cold and vigorous shivering (15-60 minutes) • Hot stage: – Intense heat, dry burning skin, throbbing headache (2-6 hours) • Sweating stage: – Profuse sweating, ↓ Temperature, feeling of exhaustion (2-4 hours)
• 4.
  Life cycle ofthe malarial parasite Sporogeny (sexual) Schizogony (asexual) Man : Intermediate host Mosquito : Definitive host True causal prophylactics Causal prophylactics Supressives Gametocidal Sporonticide
• 5.
  Objectives of antimalarialtreatment • Prevent clinical attack of malaria (Prophylaxis) • Treat clinical attack of malaria (Clinical curative) • To completely eradicate parasite from patient body (Radical Curative) • Cut down human –mosquito transmission (Gametocidal)
• 6.
  Classification of antimalarials •Therapeutic classification • Chemical classification
• 7.
  Therapeutic classification • Causalprophylaxis: (Tissue schizonticides) – Destroy parasite in liver cells and prevent invasion of erythrocytes – Primaquine, proguanil • Supressives Prophylaxis: – Destroy merozoites released from liver – Supress the erythrocytic phase and thus attack of malarial fever can be used as prophylactics – Chloroquine, proguanil, mefloquine, doxycycline
• 8.
  Therapeutic classification • Clinicalcure: 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
• 9.
  Therapeutic classification • Radicalcuratives: – Eradicate all forms of P.vivax & P.ovale from the body – Supressive drugs + hypnozoitocidal drugs – For vivax: primaquine 15 mg daily for 14 days • Gametocidal: – Destroy gametocytes and prevent transmission – Primaquine, artemisinin – against all plasmodia – Chloroquine, quinine – Pl Vivax – Proguanil , pyrimethamine – prevent development of sporozoites
• 10.
  Chemical classification • 4aminoquinolines: Chloroquine, Amodiaquine • 8 aminoquinolines: Primaquine, Tafenoquine, Bulaquine • Quinoline methanol: Mefloquine • Cinchona alkaloids: Quinine, Quinidine • Biguanides: Proguanil • Diaminopyrimidines: Pyrimethamine • Sulfonamides: Sulfadoxine, dapsone • Tetracyclines: tetracycline, doxycycline • Naphthoquinone: Atovaquone • Sesquiterpene lactones: Artesunate, artemether, arteether
• 11.
  • Chloroquine: – Synthesizedby Germans in 1934 ( resochin) – d & l isomers, d isomer is less toxic – High against erythrocytic forms of vivax, ovale, malariae & sensitive strains of falciparum – No activity against tissue schizonts
• 12.
  Hemoglobin Globin utilizedby malarial parasite Heme (highly toxic for malaria parasite) Chloroquine Quinine, (+) Heme Polymerase mefloquine (-) Hemozoin (Not toxic to plasmodium) Mechanism of action
• 13.
  Mechanism of resistance •pfcrt gene : – Plasmodium falciparum chloroquine resistant gene identified in membrane of acidic vacuoles of chloroquine resistant falciparum – Pumps out chloroquine • Pfmdr gene encoded p-glycoprotein: – Confers resistance to many antimalarials like quinine, mefloquine
• 14.
  Other actions 1. Otherparasitic infections: – Giardiasis, taeniasis, extrainstestinal amoebiasis 2. Other actions: – Cardiac depressant, – Direct relaxant effect on vascular smooth muscle – antiinflammatory, antihistaminic, local anaesthetic
• 15.
  Pharmacokinetics • Well absorbed,tmax 2-3 hrs , 50 % 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
• 16.
  Adverse drug reactions •Nausea, vomiting, anorexia • Skin rashes, photoallergy • Loss of vision due to retinal damage, corneal deposits • Loss of hearing, mental disturbances, Myopathy • Graying of hair • IV use: hypotension and T wave abnormalities in ECG
• 17.
  Dosage • 600 mgof base stat • 300 mg base after 8 hours • 150 mg of base BD for 2 days • 200 mg oral tablet of chloroquine phosphate consists of 150 mg base
• 18.
  Chloroquine is administeredin loading dose in malaria • Chloroquine is well absorbed after oral administration. It is extensively tissue bound and sequestrated by tissues particularly liver, spleen, kidney it has got large apparent volume of distribution • So it is given in loading dose to rapidly achieve the effective plasma conc.
• 19.
  Therapeutic uses 1. Malaria 2.Giardiasis 3. Rheumatoid arthritis 4. Extraintestinal Amoebiasis 5. Discoid Lupus Erythematosus 6. Control manifestation of lepra reaction 7. Infectious mononucleosis 8. Photogenic reactions 9. Clonorchis sinensis
• 20.
  Amodiaquine • As effectiveas chloroquine • Pharmacological actions similar • Chloroquine resistant strains may be effective • Adverse events: – Itching is most common – GIT, headache , photosensitivity, rarely agranulocytosis • Not recommended for prophylaxis • Dose: 25-35 mg/kg for 3 days
• 21.
  Piperaquine • High efficacy,slow onset and long acting (t½ = 3-4 weeks) • Slower onset due to larger volume of distribution • Coformulated with dihydroartemisin • More effective in chloroquine resistant falciparum malaria • Well tolerated in children
• 22.
  Mefloquine • Quinoline methanolderivative • Rapidly acting erythrocytic schizonticide , slower than chloroquine & quinine • Effective against chloroquine sensitive & resistant plasmodia • Mechanism of action similar to chloroquine
• 23.
  Pharmacokinetics • Good butslow oral absorption • High protein binding • Concentrated in liver, lung, intestine • Extensive metabolism in liver, primarily secreted in bile , undergoes enterohepatic circulation • Long t1/2 = 2 – 3 weeks
• 24.
  Adverse events • GIT:bitter taste, nausea, vomiting, abdominal pain , diarrhoea • Neuropsychiatric disturbances: – anxiety, hallucinations, sleep disturbances, psychosis, errors in operating machinery, convulsions • CVS: Bradycardia, sinus arhythmia, & QT prolongation • Teratogenicity: Avoided in first trimester • Miscellaneous: allergic skin reactions, hepatitis
• 25.
  Uses • Effective drugfor MDR falciparum 1. T/t of uncomplicated falciparum in MDR malaria should be used along with artesunate (ACT) 2. Prophylaxis in MDR areas 250 mg per week started 2- 3 weeks before to assess side effects • Due to fear of development of drug resistance mefloquine should not be used as drug for prophylaxis in residents of endemic area
• 26.
  Quinine • Alkaloid obtainedfrom cinchona bark • Mechanism of action similar to chloroquine • Actions: – Antimalarial action • All Erythrocytic forms including Pl. Falciparum • Gametocidal for vivax and malariae – Local irritant – Cardiac depressant – Analgesic, antipyretic, curaremimetic, uterine stimulant
• 27.
  Quinine • Uses – Malaria:resistant falciparum malaria, Cerebral malarial – Myotonia congenita: 300 to 600 mg BD/ TDS – Nocturnal muscle cramps: 200 – 300 mg before sleeping – Spermicidal in vaginal creams – Varicose veins: along with urethane • Adverse effects – Cinchonism – Cardiotoxicity – Black water fever – Hypoglycemia
• 28.
  Primaquine Intermediate metabolites Generates intraparasitictoxic oxidative species Disrupt electron transport in plasmodial mitochondria Primaquine (Mechanism of action)
• 29.
  Antimalarial action • Liverhypnozoites • Weak action against erythrocytic stage of vivax, so used with supressives in radical cure • No action against erythrocytic stage of falciparum • Has gametocidal action and is most effective antimalarial to prevent transmission disease against all 4 species
• 30.
  Adverse effects • Gastrointestinal: –epigastric distress, abdominal cramps , • Hemopoetic: – mild anemia, methaemoglobinemia, cyanosis, hemolytic anemia in G6PD deficiency • Avoided during pregnancy, G6PD deficient
• 31.
  Uses • Primary useis radical cure of relapsing malaria 15 mg daily for 14 days with dose of chloroquine • Falciparum malaria 45 mg of single dose with chloroquine curative dose to kill gametes & cut down transmission of malaria.
• 32.
  • Tafenoquine: – Moreactive 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
• 33.
  Atovaquone • Synthetic napthoquinone •Rapidly acting erythrocytic schizonticide for P.falciparum & other plasmodia • MOA: • Collapses mitochondrial membrane & interferes ATP production • Proguanil potentiates action of atovaquone and prevents development of resistance • Atovaquone 250 mg + proguanil 100 mg 4 tablets daily single dose for 3 days in resistant malaria • Also used in P. Jivoreci & Toxoplasma gondii infections
• 34.
  Drugs affecting synthesis& utilisation of folate Dihydrofolate reductase Sulfadoxine Ѳ Pyrimethamine Proguanil Ѳ
• 35.
  Pyrimethamine • Diaminopyrimidine morepotent 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 acute attack • Not recommended for prophylaxis due to severe cutaneous reactions like exfoliative dermatitis & stevenson johnson syndrome.
• 36.
  Proguanil • Biguanide convertedto active compound cycloguanil • Act slowly on erythrocytic stage of vivax & falciparum • Sporonticidal & also prevents development of gametes  Adverse effects:  Stomatitis, mouth ulcers, larger doses depression of myocardium , megaloblastic anemia  Not a drug for acute attack  Causal prophylaxis: 100 – 200 mg daily
• 37.
  Halofantrine • Quinoline methanol •Used in chloroquine resistant malaria since 1980 • Erratic bioavailabilty, lethal cardiotoxicity & cross resistance to mefloquine limited its use • Now a days used only when no other alternative available • Adverse events; Nausea, vomiting, QT prolongation , diarrhoea, itching , rashes
• 38.
  Artemisinin derivatives Arteether Artemether Artesunate Qinghaosu ("ching-how-soo") Artemisininderivatives Dihydroartemisinin
• 39.
  Mechanism of action •These compounds have presence of endoperoxide bridge which interacts with heme in parasite • Heme iron cleaves this endoperoxide bridge • There is generation of highly reactive free radicals which damage parasite membrane by covalently binding to membrane proteins
• 40.
  Antimalarial action Artemisinin Artemisinin Conventional Treatment
• 41.
  Artesunate • Water solubleester of dihydroartemisinin • Dose: can be given oral, IM,IV – Oral : 100 mg BD – Parenteral : 2.4 mg/kg BD • Advantages • Rapid substantial reduction of the parasite biomass & symptoms • Effective action against multi-drug resistant P. falciparum • Reduction of gametocyte carriage • No documented/ minimal parasite resistance yet • Few reported adverse effects.
• 42.
  Artemisinin derivatives • Artemether:Methyl ether of dihydroartemisinin – Dose Oral & IM : 80 mg BD • Arteether : –Ethyl ether of dihydroartemisinin –Therapeutically equivalent to quinine in cerebral malaria –A longer t1/2 & more lipophilic than artemether favour accumulation in brain Dose: 150 mg O.D. intramuscular x 3 days
• 43.
  Adverse events • GIT:nausea, vomiting, abdominal pain (common) • Leucopenia • Hypersensitivity: Drug fever, itching • ECG changes: ST-T changes, QT prolongation • Abnormal bleeding, dark urine • Reticulocytopenia
• 44.
  Artemisinin based combinationtherapy (ACT) • Artemisinin compounds are shorter acting drugs • Monotherapy needs to be extended beyond disappearance of parasite to prevent recrudescence • This can be prevented by combining 3-5 day regimen of artemisin compounds with one long acting drug like mefloquine 15 mg/kg single dose • Indicated by WHO in acute uncomplicated resistant falciparum malaria
• 45.
  Why combination therapy •Rapid clinical & parasitological cure • High cure rates and low relapse rates • Absence of resistance • Good tolerability profile
• 46.
  ACT Regimens inuse • 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: – Artesunate 100 mg BD for 3 days, + mefloquine 750 mg on second day & 500 mg on third day
• 47.
  Artemether & lumefantrine •Lumefantrine is highly effective , long acting oral erythrocytic schizonticide related to mefloquine • Highly lipophilic onset delayed , peak 6 hrs • Available as fixed dose combination • 80 mg artemether BD WITH 480 mg lumefantrine BD for 3 days Other ACTs: – DHA – Piperaquine, Artesunate- pyronaridine
• 48.
  Other ACT regimensfor uncomplicated Falciparum malaria • Artesunate 100 mg BD + Amodiaquine 300 mg BD X 3 DAYS • Dihydroartemisinin 120 mg + Piperaquine 960 mg X 3 days • Arterolone 150 mg + piperaquine 750 mg daily X 3 days
• 49.
  Management of Malaria
• 50.
  Prophylaxis of malaria •Indication: • Duration :1-2 weeks before to 4 weeks after returning from endemic area • Drug regimens: – Chloroquine sensitive malaria: 300 mg / week – Chloroquine resistant malaria: • Mefloquine 250 mg once a week , • Doxycycline 100 mg daily , • Atovaquone + proguanil daily Drugs not allowed for prophylaxis • Quinine , artemisinin compounds • Pyrimethamine sulfadoxine • Amodiaquine
• 51.
  • Tab. Chloroquinephosphate 250 mg – Contains 150 mg of base – Give 4 tablets stat , 2 tablets after 8 hours and , 1 tablet BD for 2 days • Patients who cannot take orally – 3.5 mg/kg IM every 6 hrs for 3 days • Tab primaquine 15 mg OD for 14 days in Plasmodium vivax, ovale • Primaqine 45 mg single dose for falciparum after chloroquine (gametocidal) Acute attack of chloroquine sensitive malaria:
• 52.
  Treatment of uncomplicatedfalciparum malaria A. Pts who can take orally: – Artesunate 100 mg BD x 3 days with Sulfadoxine 1500 mg + pyrimethamine 75 mg (Single dose) – Any other ACT When should resistance be suspected – All patients with complication – Any patient who has already received chloroquine last 1 month – Hb continues to fall in absence of bleeding & asexual forms persist along with symptoms after 48 hrs of treatment
• 53.
  Severe and complicatedfalciparum malaria • Hyperparasitaemia • Hyperpyrexia • Fluid electrolyte disturbances, acidosis • Hypoglycemia • Cardiovascular collapse • Jaundice, severe anaemia • Spontaneous bleeding • Pulmonary edema • Renal failure • Hemoglobinuria, black water fever • Cerebral malaria
• 54.
  Treatment of severeand complicated falciparum malaria • Inj Artesunate 2.4 mg/kg IV/Im followed by 2.4 mg/kg after 12 and 24 hours and then once daily for 7 days OR • Artemether 3.2 mg/kg IM on day 1 then 1.6 mg/kg daily for 7 days OR • Arteether 150 mg IM daily for 3 days – Switchover to 3 Day oral ACT in between whenever patient can take oral medication – Or – Inj quinine diHCL 20 mg/ kg diluted in 10 ml/kg 5 % dextrose or DNS intravenously over 4 hours followed by 10 mg/kg maintenance dose every 8 hours till patient can swallow
• 55.
  • Malaria inchildren: – Quinine parenteral high toxicity / oral well tolerated – Primaquine avoided in neonates – Mefloquine not used in children below 15 kg weight • Acute malaria in pregnant women – Chloroqune in usual doses – Mefloquine C/I in first trimester – Primaquine/ tetracycline avoided – Anemia: folic acid & iron
• 56.
  Practice points • Mostantimalarials are bitter in taste give along with milk or fruit juice • If vomiting occurs within hour of drug repeat full dose, in case of mefloquine repeat half dose • If vomiting after 1 hour no need to repeat • Postural hypotension : quinine, chloroquine