Antimalarial drugs

Antimalarial drugs

1. Antimalarial Drugs

2. M alaria Malaria is an acute infectious disease Causative agent : Plasmodium species Protozoan parasite 4 species infecting humans P. falciparum P. vivax P. malariae P. ovale Transmitted by female Anopheles mosquito Is characterized by high fever with rigor, anaemia, profuse sweating

3. Types of malaria Plasmodium falciparum Plasmodium vivax Plasmodium malariae Plasmodium ovale most dangerous species causes an acute, rapidly fulminating disease i.e. characterized by persistent high fever, orthostatic hypotension, and massive erythrocytosis capillary obstruction and death if treatment is delayed Causes a milder form of the disease Common to many tropical regions rarely encountered

4. Life cycle of Malaria Hepatic (Pre erythrocytic) stages -parasites localize in liver -patient is asymptomatic Erythrocytic stages -parasite invade RBCs -patient develops fever cycle Development of sexual forms -occurs in Anopheles mosquitos

5. Life cycle of Malaria

6. Antimalarial Drugs CLASSES DRUGS 4-Aminoquinolines Chloroquine (CQ) Amodiaquine (AQ) Piperaquine 2. Quinoline - methanol Mefloquine 3. Cinchona alkaloid Quinine, Quinidine Biguanide Proguanil ( Chloroguanide ) Diaminopyrimidine Pyrimethamine 6. 8-Aminoquinoline Primaquine Tafenoquine

7. Antimalarial Drugs CLASSES DRUGS 7. Sulfonamides and sulfone Sulfadoxine Sulfamethopyrazine Dapsone 8. Antibiotics Tetracycline Doxycycline Clindamycin 9. Sesquiterpine lactones Artesunate Artemether Arteether Arterolane 10. Amino alcholos Halofantrine Lumefantrine 11. Naphthyridine Pyronaridine 12. Naphthoquinone Atovaquone

8. Drugs used in malaria Tissue schizontocides - drugs eliminating developing or dormant liver forms Blood schizontocides - drugs acting on erythrocytic parasites Gametocides - drugs that kill sexual stages and prevent transmission to mosquitoes

9. Forms of Antimalarial Drugs Clinically malarial infections can be controlled by the drugs used in following ways: Causal prophylaxis Suppressive prophylaxis Clinical cure Radical cure Gametocidal

10. Causal prophylaxis Drugs prevent the maturation of or destroy the sporozoites within the infected hepatic cell- thus prevent erythrocytic invasion Primaquine – for all species of malaria but not used due to its toxic potential Proguanil - primarily for P. falciparum and not effective against P. vivax (weak activity), rapid development of resistance

11. 2. Suppressive prophylaxis Schizontocides inhibit erythrocyte phase and prevent the rupture of the infected erythrocytes, lead to freedom from rigors and pyrexia Includes quinine, chloroquine , proguanil , pyrimethamine , artemicinin and tetracycline

12. 3. Clinical cure Erythrocytic schizontocides are used to terminate episodes of malarial fever Fast acting high efficacy drugs: Chloroquine , quinine, mefloquine , halofantrine , artemicinin Used singly to treat malaria fever Faster acting, preferably used in falciparum malaria where delayed treatment may lead to death even if parasites are clear from blood Slow acting low efficacy drugs: Proguanil , pyrimethamine , sulfonamides , tetracyclines Used only in combination

13. 4. Radical cure Drug attack exoerythrocytic stage ( hypnozoites ) given with clinical curative for the total eradication of the parasite from the patient’s body Radical cure of the P. falciparum malaria can be achieved by suppressives only For radical cure of P . vivax infection, primaquine and proguanil are effective

14. 5. Gametocial Removal of male and female gametes of Plasmodia formed in the patient’s blood It has no benefit for treated patient Primaquine and artemisinins are highly effective against gametocytes of all species

15. Antimalarial drugs CHLOROQUINE (CQ) Rapidly acting erythrocytic schizontocide against all species of Plasmodia Drug of choice for treating acute attacks caused by sensitive strains of P. vivax or P. falciparum Controls most clinical attack in 1-2days with disappearance of parasite from peripheral blood in 1-3days No effect on exo - erythrocytic phase Neither prevent primary infection nor relapse in P. vivax and P.ovale Drug of choice for use in pregnancy, prophylaxis

16. Chloroquine Mechanism of action

17. Chloroquine Mechanism of action The parasite digests the host cell’s hemoglobin to obtain essential amino acids The process releases large amounts of heme , which is toxic to the parasite To protect itself the parasite ordinarily polymerizes the heme to nontoxic hemozoin , which is sequestered in the parasite’s food vacuole Cholroquine prevents the polymerization to hemozoin The accumulation of heme results in lysis of both the parasite and the red blood cell

18. Chloroquine Pharmacokinetics Rapidly and completely absorbed from GI tract Substantial amount is deposited in erythrocytes, liver, spleen, kidney, lung, melanin containing tissues and leukocytes Slow release from these sites helps in maintaining the therapeutic plasma levels – when used for prophylaxis, it is administered just once a week Also crosses the blood- brain barrier and traverses the placenta Excreted predominantly in the urine

19. Chloroquine A dverse effects CNS - mild headache, confusion, psychosis, convulsion, impaired hearing Eye (with high dose)- loss of vision due to retinal d amage, reversible corneal damage GIT - Nausea, vomiting, anorexia, epigastric pain, d iarrhea( can be minimized by taking with meal) Skin - uncontrolled itching, urticaria , exfoliative dermatitis Parenteral administration- Hypotension, cardiac a rrhythmias, cardiac depression

20. Chloroquine Uses Extraintestinal amoebiasis Rheumatoid arthritis Discoid lupus erythematosus Lepra reaction Photogenic reactions Infectious mononucleosis

21. Chloroquine Contraindications Patient with psoriasis, porphyria In dermatitis, liver damage, alcoholism, neurological, retinal and hematological diseases

22. MEFLOQUINE (MQ) Fast acting erythrocytic (blood) schizontocide but slower than CQ or quinine Effective against CQ-sensitive as well as resistant Plasmodia Efficacious suppressive prophylactic for multi-resistant P. falciparum

23. Mefloquine Mechanism of action Like CQ, it accumulates in infected RBCs, binds to heme and this complex damages the parasite’s membrane However recent evidence suggests that the site of action of MQ is in the parasitic cytosol rather than in the acidic vacuole

24. Mefloquine Pharmacokinetics Prolonged absorption after oral ingestion It is highly plasma protein bound and concentrated in the liver, lung and intestines Extensive metabolism occurs in liver and is primarily secreted in bile It has a long half life (17days) due to its concentration in various tissues and its continuous circulation through the enterohepatic and enterogastric systems Its major excretory route is feces

25. Mefloquine A dverse effects MQ is bitter in taste At high doses: Nausea, vomiting, diarrhea, abdominal pain, bradycardia Ataxia, hallucinations, depression MQ is safe in pregnancy Rare events of toxicity are seen Contraindications In patients with anxiety, depression, psychosis, and in cardiac conduction defects

26. Mefloquine Drug interactions Cardiac arrests are possible if MQ is taken concurrently with quinine or quinidine Uses Effective for multidrug resistant P. falciparum However its use is restricted due to its toxicity, cost and long half life

27. QUININE Quinine is a l-isomer of alkaloid obtained from cinchona bark and quinidine (antiarrhythmic) is its d-isomer An effective erythrocytic schizontocide as suppressive and used to prevent or terminate attacks of vivax , ovale , malariae , sensitive falciparum Moderately effective against hepatic form (pre- exoerythrocyte and gametocytes)

28. Quinine Mechanism of action Like CQ it is a weak base, and acts by inhibiting polymerization of heme to hemozoin Free heme or heme -quinine complex damages parasite’s membrane and kills it Pharmacokinetics Well absorbed from GI tract, even in patients with diarrhea Metabolized in liver and excreted in urine

29. Quinine Adverse effects Cinchonism : Higher dose symptoms include nausea, vomiting, tinnitus , vertigo , headache, mental confusion, difficulty in hearing and visual defects, diarrhea, flushing Rapid i.v. injection: Hypotension and cardiac arrhythmias Can cause profused hypoglycemia

30. Adverse effects Pregnancy: Causes abortion in early pregnancy by stimulating myometrium and premature labor by stimulating uterus Hypoglycaemia Clinical uses Malarial attacks Uncomplicated resistant falciparum Complicated and severe malaria including cerebral malaria Is not highly active, adjunctive therapy with doxycycline, tetracycline and clindamycin is needed

31. PROGUANIL (CHLOROGUANIDE) Slow acting erythrocytic schizontocide Cyclized in body to a triazine derivative( cycloguanil ) Cycloguanil inhibits plasmodial dihydrofolate reductase ( DHFRase ) Resistance developed due to mutational changes in the plasmodial DHFRase enzyme

32. Proguanil Slow but adequate absorption from the gut Partly metabolized and excreted in urine Half life 16-20 hour ; noncumulative Adverse effects Mild abdominal upset, vomiting Occasional stomatitis Haematuria , rashes and transient loss of hair Note : Safe during pregnancy

33. PYRIMETHAMINE Slow acting erythrocytic schizontocid e Direct inhibitor of plasmodial dihydrofolate reductase ( DHFRase ) Conversion of dihydrofolic acid to tetrafolic acid is inhibited High doses inhibits Toxoplasma gondii Resistance develops by mutation in DHFRase enzyme

34. Pyrimethamine Adverse effects Occasional nausea and rashes Folate deficiency rare Megaloblastic anaemia and granulocytopenia with higher dose Can be treated with folinic acid Combined with a sulfonamide (S/P) or dapsone for treatment of falciparum malaria

35. SULFONAMIDE-PYRIMETHAMINE(S/P) Sulphadoxine is a sulfonamide thus competes with para –amino benzoic acid – inhibits the formation of dihydropteric acid Pyrimethamine inhibits DHFRase enzyme as a result of which conversion of dihydrofolic acid to tetrahydrofolic acid is blocked – thus inhibits DNA synthesis Effective blood schizontocide against Plasmodium falciparum Treatment and prophylaxis of falciparum malaria resistant to chloroquine

36. Sulfonamide- Pyrimethamine (S/P ) Adverse effects Mild GIT upset Megaloblastic anemia, bone marrow depletion Rashes, urticaria , serum sickness, drug fever Exfoliative dermatitis, Stevens Johnson syndrome Nephrotoxicity

37. PRIMAQUINE Poor erythrocytic schizontocide Has marked effect on primary and secondary hepatic phases of malarial parasite Highly active against gametocytes and hypnozoites Mechanism of action Intermediate act as oxidant that are responsible for the schizontocial action

38. Primaquine Pharmacokinetics Readily absorbed after oral absorption Oxidized in liver with a plasma half life of 3-6 hours Excreted in urine within 24 hour Not a cumulative drug

39. Primaquine Adverse effects Abdominal pain, gastrointestinal upset, weakness or uneasiness chest Leucopenia (high dose) Hemolysis Methaemoglobinaemia Tachypnoea Cyanosis

40. Primaquine Contraindications Should not be given during pregnancy because fetus is glucose-6-phosphate dehydrogenase ( G-6-PD) deficient Clinical uses radical cure of relapsing malaria ( P.ovale and P.vivax ) single 45mg dose given with curative dose of chloroquine to kill gametes ( P. falciparum )

41. TETRACYCLINE AND DOXYCYCLINE ( Antibiotics) Used against chloroquine resistant malaria Kills erythrocytic stage of the malarial parasite Tetracycline is used for acute attack only Doxycycline is used for prophylaxis and acute attack For treating acute attack they are used in combination with quinine Should not be given to children and pregnant women

42. CLINDAMYCIN ( Antibiotics) Active against the erythrocytic stage of the malaria parasite Liver stage and gametocytes are not affected Drug used adjunct to quinine to treat malaria caused by chloroquine resistant Plasmodium falciparum Can be used in children and pregnant women

43. ARTEMISININ AND ITS DERIVATIVES: Active principle of plant A rtemisia annua Sesquiterpene lactone endoperoxide It includes: Artesunate Artemether Arteether Arterolane

44. Mechanism of action

45. 1. ARTESUNATE Its sodium salt is water soluble and is administered by oral, i.m . or i.v. route Rapidly converted to active metabolite dihydroartemisinin (DHA) After repeated dosing, artesunate causes autoinduction of its own metabolism by CYP2B6 and CYP3A4

46. 2. ARTEMETHER Lipid soluble and is administered orally or i.m . Absorption after oral or i.m . dosing is slower taking 2-6 hrs Undergoes substantial first pass metabolism and is converted to DHA Extensive metabolism by CYP3A4 yields a variable half life of 3-4 hrs

47. 3. α / β ARTEETHER Available for i.m . administration only to adults for complicated malaria Due to its longer elimination (t 1/2 =23hrs), it is recommended in a three day schedule

48. ARTEMISININ Adverse effects First degree A-V block Q-T prolongation Transient reticulopenia and leucopenia (rare) Bleeding, dark urine Headache, tinnitus, dizziness Abdominal pain, itching, nausea, vomiting

49. Artemisinin Drug interaction Concurrent administration of artemisinins with drugs prolonging Q-T like astemizole , antiarrhythmics , tricyclic antidepressants and phenothiazines may increase the risk of cardiac conduction

50. ARTEMISININ BASED COMBINATION THERAPY (ACT) One of artemisinin compound in combination with another effective erythrocytic schizontocide is used. C onsideration must be made about t 1/2 of companion drug to maintain its effective concentration in the blood for at least 3-4 asexual cycles of the parasite. Kills >95% of the p lasmodia

51. Advantages of ACT Rapid clinical and parasitological cure High cure rates(>95%) and low recrudescence rate Absence of parasite resistance Good tolerability profile Dosing schedule is simpler

52. 1. Artesunate-sulfadoxine + pyrimethamine (AS-S/P) First line drug for uncomplicated falciparum malaria Not effective against multidrug- resitant strains which are non responsive to S/P Fewer side effects than AS/MQ 2. Artesunate / mefloquine (AS/MQ) Highly effective and well tolerated in uncomplicated falciparum malaria

53. 3.Artemether-lumefantrine(AS/LF) Clinical efficacy: 95-99% Must be administered with fatty food or milk to allow absorption and ensure adequate blood level of AS/LF Quickly reduces parasite biomass, resolve symptoms, prevent recrudescence, check gametocyte population

54. AS/LF Adverse drug reaction Headache, dizziness, abdominal pain, arthralgia, myalgia , pruritus and rashes Drug interaction Not to be given with drugs metabolized by CYP2D6( e.g. metoprolol ) as lumefantrine inhibits isoenzyme CYP2D6 Contraindication during first trimester of pregnancy and lactation period

55. 4. Dihydroartemisinin (DHA)- piperaquine Used in dose ratio of 8:1 for multidrug resistant P lasmodium falciparum G ood safety profile and even tolerated by children (>98% response rate) Adverse drug reaction Dizziness, rashes Vomiting and GI symptoms

56. 5. Artesunate-amodiaquine (AS/AQ) First line therapy of uncomplicated falciparum malaria To be taken twice daily for three day treatment Other recently developed ACT are: 6. Arterolane-piperaquine Acts rapidly at all stages of asexual schizogony of malarial parasite including multidrug resistant P. falciparum 7. Artesunate-pyronaridine Under clinical trial

57. CEREBRAL MALARIA M ost severe neurological complication of infection with  Plasmodium falciparum Aggregation of infected and non infected red cells and plugging in capillary endothelium of brain due to secreted proteins on red cell surface by late stage schizonts Enhanced by the pro-inflammatory status of the host and virulence characteristics of the infecting parasite variant Manifested by confusion, coma and death due to anoxia, ischaemia and haemorrhage

58. Drugs used in Cerebral malaria Q uinine by slow intravenous infusion Artemisinin derivatives  that produce a very rapid therapeutic response and are effective against multi-drug resistant P . falciparum are preferred Some of the drugs used as a combination therapy for cerebral malaria are: A rteether with quinine  Artemether with quinine

59. REFERENCES Tripathi KD, Essentials of MEDICAL PHARMACOLOGY, Jaypee Brothers Medical Publishers (P) Ltd, 7 th edition, 2013. Finkel Richard et all, Pharmacology, Lippincott’s Illustrated Reviews, 4 th edition. The treatment of complicated and severe malaria , BRITISH MEDICAL BULLETIN .

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