LS 3.1 ANTI MALARIAL DRUGS BMPT 121.pptx

Pharmacology 3rd year mbchb notes

1. ANTI MALARIAL DRUGS Lecturer: John Chitoti Pharmacologist University of Lusaka BMPT 121 Class

2. 3.1 ANTI-MALARIAL DRUGS

3. ANTI-MALARIAL DRUGS LEARNING OBJECTIVES: To classify anti-malarial drugs according to plasmodium life-cycle stage affected, chemoprophylactic use and mechanism of action To describe the mechanisms of action of anti-malarial drugs Describe the relevant pharmacology (mechanisms of actions, clinical indications, adverse effects, drug interactions, precautions and contraindications) of selected anti-malarial drugs

4. ANTI-MALARIAL DRUGS INTRODUCTION : Anti-malarial drugs are designed to prevent or cure malaria Anti-malarial drugs may be used for some or all of the following: Treatment of malaria in individuals with suspected or confirmed infection Prevention of infection in individuals visiting a malaria-endemic region who have no immunity (malaria chemoprophylaxis) Routine intermittent treatment of certain groups in endemic regions (intermittent preventive therapy) e.g. in pregnancy

5. ANTI-MALARIAL DRUGS INTRODUCTION …. CONT’D : Most anti-malarial drugs target the erythrocytic stage of malaria infection, which is the phase of infection that causes symptomatic illness Treatment of the acute blood stage infection is necessary for malaria caused by all malaria species For infection due to P. ovale or P. vivax , terminal prophylaxis is required with a drug active against hypnozoites (which can remain dormant in the liver for months, and occasionally years, after the initial infection)

6. Life cycle of Plasmodiu m * 6

7. Drug treatment of malaria Current practice in treating cases of malaria is based on the concept of combination therapy Advantages of combination therapy: (1) reduced risk of treatment failure (2) reduced risk of developing resistance (3) reduced adverse effects Prompt parasitological confirmation by microscopy or rapid diagnostic tests, is recommended in all patients suspected of malaria before treatment is started Treatment solely on the basis of clinical suspicion should only be considered when a parasitological diagnosis is not accessible 7

8. Classification BASED ON LIFE-CYCLE STAGE AFFECTED BY THE DRUG Drugs acting on intrahepatic stages Causal prophylactic drugs: Inhibit liver stage from initiating erythrocytic stage ( tetracyclines , primaquine , proguanil , atovaquone-proguanil , pyrimethamine ) Hypnozoitocidal : Destroy exo-erythrocytic hypnozoites of P. vivax and P. ovale after treatment of acute erythrocytic phase to produce radical cure ( primaquine ) 8

9. Classification BASED ON LIFE-CYCLE STAGE AFFECTED BY THE DRUG …. Cont’d Drugs acting on erythrocytic stages Clinical cure: Fast action on erythrocytic stages ( artemisinin derivatives and quinolines ) Suppressive therapy: Slower suppressive action on erythrocytic stages (anti-folates, tetracyclines , clindamycin) 9

10. Classification BASED ON LIFE-CYCLE STAGE AFFECTED BY THE DRUG …. Cont’d Gametocytocidal drugs Destroy sexual forms of the parasite in erythrocytes preventing transmission to mosquito ( artemisinin derivatives, primaquine ) Sporonticidal drugs Destroy sporozoites ( primaquine , pyrimethamine , proguanil ) 10

11. CLASSIFICATION BASED ON CHEMOPROPHYLACTIC USE Causal prophylaxis Inhibit liver stage from initiating erythrocytic stage ( atovaquone-proguanil , primaquine , chloroquine , pyrimethamine , proguanil , doxycycline) Clinical or suppressive prophylaxis Inhibit development of merozoites in erythrocytes ( atovaquone-proguanil , mefloquine , proguanil , pyrimethamine , primaquine , dapsone ) 11

12. CLASSIFICATION BASED ON MECHANISM OF ACTION Quinolines : Inhibit polymerisation of haem (toxic to plasmodia) to haemozoin which is non-toxic, thus cause death of plasmodia Artemisinins : 1. Binds haem iron and generate oxygen radicals which damage proteins in the parasite 2. Damages Ca 2+ ATPase (calcium transporter) Anti-folates: Inhibit DNA synthesis ( pyrimethamine , proguanil , sulfonamides and dapsone ) Atovaquone: Inhibits electron transport chain in the mitochondria Tetracyclines and clindamycin: Inhibit protein synthesis (ribosome inhibition) 12

13. SPECIFIC ANTI-MALARIAL DRUGS 13

14. Quinoline derivatives Include: 4-Methanolquinolines: quinine and quinidine 4-Aminoquinolines: chloroquine and amodiaquine 8-Aminoquinolines: primaquine and tafenoquine Others: mefloquine , piperaquine , naphthoquine , lumefantrine and halofantrine 14

15. Quinoline derivatives: mechanism of action Quinolines have activity against the erythrocytic stage of infection ( primaquine also kills intrahepatic forms and gametocytes) They act by accumulating in the parasite food vacuole and forming a complex with haem They inhibit haem polymerase activity resulting in accumulation of cytotoxic free haem ( haem polymerase polymerises haem to the non-toxic haemozoin ) 15

16. Quinine & quinidine Quinine is a derivative from the bark of the South American Cinchona tree and exists in oral and parenteral forms Quinidine is a stereoisomer of quinine available in parenteral formulation and is very effective for treatment of severe malaria Quinidine is a more active anti-malarial than quinine but more cardiotoxic 16

17. Quinine & quinidine …. Cont’d Antimalarial effects Blood schizonticide for all human plasmodia species Weak gametocide against P. vivax and P. malariae Adverse effects Cinchonism : Tinnitus, high tone hearing impairment, vertigo, nausea, vomiting, abdominal pain, dysphoria , headaches, dizziness and disturbed vision. These effects typically resolve with cessation of the medication. 17

18. Quinine & quinidine …. CONT’D Other adverse effects: Hypersensitivity reactions, neurotoxicity, skeletal muscle paralysis and hypoglycaemia Quinine is associated with black-water fever in patients sensitized to quinine ( characterised by intravascular haemolysis , haemoglobinuria , disseminated intravascular coagulation and renal failure) Quinine and quinidine have a narrow therapeutic window; overdosage may lead to cardiotoxicity , including arrhythmias and hypotension, respiratory depression, blindness or deafness 18

19. Quinine & quinidine: CLINICAL USES Used in the treatment of severe, acute P.falciparum malaria Quinine can be given oral, IM or by slow IV infusion. For severe disease, quinine is given IM or IV. Quinidine is given by slow IV infusion Quinine, in therapeutic doses, is safe in infants, children, pregnancy (all trimesters) and lactation 19

20. Quinine & quinidine: contraindications Hypersensitivity to quinine, quinidine or mefloquine Prolonged QT interval Myasthenia gravis Optic neuritis Glucose-6-phosphate dehydrogenase deficiency (intravascular haemolysis may occur) History of black water fever Haemolytic uremic syndrome Thrombotic thrombocytopenia purpura and thrombocytopenia 20

21. Mefloquine Structurally similar to quinine It is active against all the four human malaria pathogens: P. falciparum, P. vivax , P. malariae and P. ovale It is a blood schizonticide with a long half-life Used in the treatment of acute malarial infections and prophylaxis of chloroquine -resistant P. falciparum malaria 21

22. Mefloquine …. CONT’D Adverse effects Nausea, vomiting, diarrhoea , abdominal pain, dizziness, n europsychiatric manifestations (affective and anxiety disorders, hallucinations, sleep disturbances, nightmares, psychosis, toxic encephalopathy and convulsions) and bradycardia Contra-indications Seizure disorders, psychiatric disorders, children under 2 years, patients with cardiac conduction abnormalities, concurrent administration with drugs that alter cardiac conduction, pregnancy 22

23. chloroquine Has activity against the blood stages of P. ovale , P. malariae , and susceptible strains of P. vivax and P. falciparum Uses: Treatment of acute malaria for chloroquine -sensitive malaria strains (P. ovale , P. malariae , and some strains of P. vivax ) and chemoprophylaxis for susceptible strains of plasmodium. Given orally. Parental chloroquine is very toxic and cause severe hypotension. Widespread resistance in most malaria-endemic countries has led to decline in its use for the treatment of P. falciparum, although it remains effective for treatment of P. ovale , P. malariae , and, in most regions, P. vivax 23

24. Chloroquine : adverse effects Include: Headaches, dizziness, abdominal discomfort, vomiting, diarrhea and rashes , pruritus in some patients, neuromyopathy with long-term prophylaxis, retinopathy with prolonged high doses (as in treatment of rheumatoid arthritis) and i diosyncratic reactions, such as erythema multiforme and bone marrow toxicity, and haemolysis in patients with G-6-PD deficiency. Can provoke psoriasis. Cardiotoxic in high doses and when given parenterally . 24

25. Amodiaquine It is similar in structure to chloroquine There is cross resistance between chloroquine and amodiaquine , although amodiaquine retains some activity against chloroquine resistant parasites in vivo and in vitro Amodiaquine is commonly used in malaria endemic countries to treat chloroquine -resistant infections and is available in co-formulation with artesunate . Given orally. Adverse effects: GI effects, bradycardia , agranulocytosis and hepatotoxicity Amodiaquine is not used for chemoprophylaxis (increased risk of agranulocytosis and hepatotoxicity with repeated doses) 25

26. Primaquine Mechanism of action: Disrupts mitochondria (blocking oxidative metabolism) and binds to DNA interfering with DNA function Active against blood schizonts (slow acting blood schizonticide ), tissue schizonts , hypnozoites of P.ovale and P. vivax , sporozoites and gametocytes of P. falciparum It is largely used to effect radical cure of P.ovale and P. vivax (prevents relapse of P. ovale and P. vivax malaria by eliminating dormant hypnozoites ). It is given in conjunction with chloroquine or artemisinin derivatives in the treatment of P. ovale and P. vivax . 26

27. Primaquine …. CONT’D Also used as a gametocytocidal drug in P. falciparum infections to prevent transmission (in conjunction with another effective blood schizonticidal drug) It is given orally Adverse effects: Anorexia, nausea, vomiting, abdominal cramps, chest pain, weakness, anaemia , bone marrow suppression, intravascular haemolysis in people with G-6-PD deficiency 27

28. Tafenoquine Analogue of primaquine with similar mechanism of action and same clinical indications The main advantage of tafenoquine is that it has a long half-life (2–3 weeks) and therefore a single treatment may be sufficient to clear hypnozoites Like primaquine , tafenoquine causes hemolysis in people with G6PD deficiency 28

29. Anti-folates Inhibit enzymes involved in folate synthesis, a pathway in the biosynthesis of purines and pyrimidines , thereby halting the processes of DNA replication, cell division and reproduction Type 1 anti-folate drugs: sulfonamides and dapsone ; inhibit dihydropteroate synthetase [thus inhibit synthesis of folic acid] Type 2 anti-folate drugs: pyrimethamine and proguanil ; inhibit dihydrofolate reductase thereby blocking the conversion of dihydrofolate to tetrahydrofolate [thus inhibit utilization of folic acid] The sulfonamides used in malaria treatment include sulfadoxine 29

30. MechanismS of action of anti-folates 30

31. ANTI-FOLATES: ANTI-MALARIAL ACTIVITY Have activity on sporozoites ( proguanil and pyrimethamine ), hepatic schizonts ( proguanil , pyrimethamine ) and blood schizonts (all the anti-folates) Are slow acting compared to quinolines and artemisinins Combination of pyrimethamine with sulfonamide or dapsone is synergistic 31

32. ANTI-FOLATES: INDICATIONS IN MALARIA Treatment of malaria ( pyrimethamine -sulfonamide combination) [used in combination with artemisinins ] Chemoprophylaxis ( dapsone , proguanil , pyrimethamine-dapsone ) Intermittent preventive therapy in pregnancy ( sulfadoxine-pyrimethamine ) Sulfonamides are not recommended for chemoprophylaxis because of severe skin reactions experienced 32

33. ANTI-FOLATES: Adverse effects All: Gastrointestinal upset, headache and skin rashes Pyrimethamine : Bone marrow suppression, megaloblastic anaemia with high doses Sulfonamides: Severe cutaneous toxicity, including erythema multiforme , Stevens-Johnson syndrome and toxic epidermal necrosis. Sulfadoxine can precipitate hemolysis in patients with G-6-P-D deficiency. Proguanil : Hair loss and mouth ulcers 33

34. Anti-folates: contra-indications Hypersensitivity to any sulfonamide, pyrimethamine , or any component of the formulation Porphyria Megaloblastic anemia First trimester of pregnancy Sulfonamides: G-6-P-D deficiency, children <2 months of age due to competition with bilirubin for protein binding sites (can result in kernicterus); pregnancy (at term) Repeated prophylactic use of anti- folates is contraindicated in patients with renal failure, hepatic failure, or blood dyscrasias 34

35. Atovaquone-proguanil   Atovaquone inhibits electron transport in mitochondria resulting in the inhibition of key metabolic enzymes responsible for the synthesis of nucleic acids and ATP Acts on hepatic schizonts and merozoites It is used for treatment and chemoprophylaxis of P. falciparum malaria (always in combination with proguanil for synergy and to prevent emergence of resistance). The combination retains excellent clinical efficacy for P. falciparum treatment and prevention throughout the world even in the presence of anti-folate resistance. 35

36. Atovaquone-proguanil …. CONT’D  It is administered orally with meals (absorption is significantly increased with a high-fat meal) Adverse effects include abdominal pain, vomiting, diarrhea, headache and pruritus and transient increases in transaminases Contraindications: Life-threatening allergic reaction to atovaquone or any component of the formulation 36

37. Halofantrine Halofantrine is chemically related to quinine and acts acting as a blood schizonticide effective against all plasmodium parasites Use: Treatment of multi-drug resistant P. falciparum malaria Oral absorption is increased by a fatty meal and it has very variable bioavailability 37

38. Halofantrine …. CONT’D Adverse effects Ventricular arrhythmias (prolongation of PR and QT interval) that have been associated with death. Cardiotoxicity has limited its use Other adverse effects include nausea, abdominal pain, diarrhea, and pruritus Contraindications Heart disease, infants and young children (weight under 10 kg), pregnancy, lactation, and patients that have taken mefloquine previously 38

39. Lumefantrine Is similar in structure to halofantrine , quinine and mefloquine , and has same mechanism of action Is active against most chloroquine -resistant parasites although there is cross-resistance with halofantrine and mefloquine Lumefantrine is a long-acting drug always given in combination with artemether in a widely used fixed-dose combination (Zambia has adopted this combination as first line antimalarial) 39

40. Lumefantrine …. Cont’d The bioavailability is highly variable and increases up to three-to-four fold when taken with a high fat meal Lumefantrine is well tolerated, with rare mild adverse reactions such as diarrhea, nausea, abdominal pain and vomiting There is no evidence of significant cardiotoxicity associated with lumefantrine use 40

41. Artemisinin derivatives   The artemisinins are derived from the leaves of the Chinese sweet wormwood plant, Artemisia annua They have been used in China for the treatment of malaria for over 2000 years and came to attention outside of China in the 1970s and 1980s Artemisinins act by binding iron in haem , leading to the generation of free oxygen radicals that damage parasite proteins. Binds and inhibits Ca 2+ ATPase (calcium transporter). 41

42. Artemisinins …. Cont’d Artemisinins act rapidly, killing blood stages of all plasmodium species Artemisinins have the fastest parasite clearance times of all anti- malarials currently used Artemisinins act primarily on the trophozoite phase and are also active against gametocytes, the parasite form that is infectious to mosquitoes, and their use has been associated with reduced malaria transmission 42

43. EXAMPLES OF ARTEMISININ DERIVATIVES Artemisinin Dihydroartemisinin : Active metabolite to which artemisinin is reduced. It is the most effective artemisinin compound and the least stable. Artemether : A methyl ether derivative of dihydroartemisinin . Used in a fixed-dose combination with lumefantrine . 43

44. EXAMPLES OF ARTEMISININ DERIVATIVES Artesunate : A hemisuccinate derivative of the active artemisinin metabolite dihydroartemisin . Currently it is the most frequently used of all the artemesinin -type drugs. It is mostly used in combination therapy (with SP, mefloquine and amodiaquine ). Given IV or IM for severe malaria. Arte-ether: An ethyl ether derivative of dihydroartemisinin 44

45. artemisininS : CLINICAL USE WHO recommends the use of artemisinins (in combination with other anti- malarials ) as first line drugs for the treatment of P. falciparum malaria Treatment of severe malaria: IV/IM artesunate (it is superior to quinine for treatment of severe malaria with respect to clearing parasitemia and reducing mortality) 45

46. ArtemisininS : Adverse effects Artemisinins are generally well tolerated Adverse effects that have been associated with artemisinins include headaches, nausea, vomiting, abnormal bleeding, dark urine, itching, drug fever, transient neurological abnormalities ( nystagmus and disturbances in balance) and Type 1 hypersensitivity reactions 46

47. Pyronaridine Mechanism of action: Unknown Well absorbed orally Used in combination with artesunate . Artesunate-pyronaridine has generally demonstrated excellent efficacy against falciparum and vivax malaria. It is generally well tolerated Adverse effects include eosinophilia and elevated aminotransferases 47

48. Tetracyclines & clindamycin Inhibit protein synthesis They all act on the trophozoite stage ( erythrocytic ). Tetracyclines also act on hepatic schizonts . Tetracycline and doxycycline are used in combination with quinine or artemisinin derivatives for the treatment of acute cases of P. falciparum infections. Doxycycline has a longer half life than tetracycline so is used more commonly. 48

49. Tetracyclines & clindamycin …. Cont’d Clindamycin is used in conjunction with quinine for the treatment of acute cases of P. falciparum malaria Tetracyclines and clindamycin have a very slow anti-malaria action and should not be used as monotherapy for treatment of malaria Doxycycline is also used for P. falciparum malaria chemoprophylaxis in areas where chloroquine resistance exists 49

50. Causes of Malaria treatment failure Wrong diagnosis Incorrect choice of drugs Sub-optimal regimen (dose, schedule, duration) Non-adherence Sub-optimal absorption (nausea, diarrhea, vomiting, malabsorption) Idiosyncratic pharmacokinetics (e.g. increased drug elimination) Poor quality drugs Interactions with other pharmaceuticals Resistance of the pathogen to the drug 50

51. Anti-malarial drug resistance Anti-malarial drug resistance has been defined as: "the ability of a parasite to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within tolerance of the subject” The drug in question must gain access to the parasite or the infected red blood cell for the duration of the time necessary for its normal action. Cases where anti-malarial prophylaxis has failed are excluded Drug resistance is caused by spontaneous mutations that result in reduced sensitivity of the parasite to the anti-malarial drug 51

52. Anti-malarial drug Combination therapy Combination therapy is 'the simultaneous use of two or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasite'. Combination therapy reduces the emergence of resistant strains and optimizes parasite clearance thus improving cure rates, with greater reduction in morbidity and mortality compared to monotherapy 52

53. Anti-malarial drug Combination therapy …. Cont’d To realize the two advantages, the partner medicines in a combination must independently be sufficiently efficacious in treating malaria The combinations of drugs currently prescribed can be divided into two categories: Non- artemisinin based combinations Artemisinin based combinations (ACTs) 53

54. Non- artemisinin based combinations Sulfadoxine-pyrimethamine (SP) This fixed-dose combination has been used for many years, causes few adverse effects, is cheap and effective in a single dose, thus decreasing problems associated with adherence and compliance In technical terms SP is not generally considered a true combination therapy since the components do not possess independent curative activity (they have the same biochemical target). SP should no longer be used alone for treatment of falciparum malaria. 54

55. Non- artemisinin based combinations …. Cont’d Quinine plus tetracycline/doxycycline This combination retains a high cure rate in many areas Quinine plus clindamycin Similar cure rate to quinine + tetracycline, therefore is an appropriate alternative regimen 55

56. Artemisinin -based combination therapies (ACTs) In general, artemisinins should not be used as a single agent, to prevent emergence of drug resistance and to avoid the need for prolonged therapy ACTs combine the highly effective short-acting artemisinins with a longer-acting partner to protect against artemisinin resistance and to facilitate dosing convenience Examples of ACTs: (1) Artemether-lumefantrine (2) Artesunate-amodiaquine (3) Artesunate-mefloquine (4) Artesunate-sulfadoxine-pyrimethamine (5) Dihydroartemisinin-piperaquine (6) Artemisinin-naphthoquine (7) Artesunate-pyronaridine 56

57. Artemisinin -based combination therapies …. Cont’d Artemisinins have a very different mode of action from other anti- malarials and this makes them particularly useful in the treatment of resistant infections However in order to prevent the development of resistance to artemisinins , it is recommended that they are only used in combination with another non- artemisinin based therapy Artemisinins produce a very rapid reduction in the parasite biomass and cause a reduction in the transmission of gametocytes, thus decreasing the potential for the spread of resistant strains At present there is no known resistance to artemisinins 57

58. Students must be able to comprehend: Classification of anti-malarial drugs according to plasmodium life-cycle stage affected, chemo-prophylactic use and mechanism of action Mechanisms of action of anti-malarial drugs Relevant pharmacology (mechanisms of actions, clinical indications, adverse effects, drug interactions, precautions and contraindications) of selected anti-malarial drugs LEARNING OUTCOMES

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