7. ANTIPROTOZOAL DRUGS presentation.pptx

pharmacology

1. ANTI-PROTOZOAL DRUGS 8/3/2021 1

2. Introduction Some common protozoa diseases: Malaria, Trypanosomiasis , Leishmaniasis , Toxoplasmosis Giardiasis, Amoebiasis , Cryptosporidiosis Vaginitis. 8/3/2021 2

3. MALARIA 8/3/2021 3

4. Four (4) species of plasmodia Disease is caused by parasites belonging to the genus Plasmodium . Four (4) species of plasmodia infect humans : Plasmodium vivax , Plasmodium falciparum , Plasmodium ovale and Plasmodium malariae . The insect vector is the female Anopheles mosquito, which breeds in stagnant water. 8/3/2021 4

5. Life cycle of Plasmodium 8/3/2021 5

6. Life cycle of Plasmodium 8/3/2021 6

7. SITES OF ACTION BY ANTIMALARIAL DRUGS Drugs used in the treatment of malaria may have several sites of action: D rugs used to treat the acute attack of malaria act on the parasites in the blood; Drugs used for chemoprophylaxis (causal prophylactics) act on merozoites emerging from liver cells D rugs used for radical cure are active against parasites in the liver S ome drugs act on gametocytes and prevent transmission by the mosquito. 8/3/2021 7

8. Classification of Anti malarial drugs Anti malarial drugs can be classified according to; Anti malarial activity and Structure. 8/3/2021 8

9. 1. Classification according to anti malarial activity a. Tissue schizonticides for causal prophylaxis: - Pyrimethamine and Primaquine have this activity. - They act on the primary tissue forms of the plasmodia which after growth within the liver, initiate the erythrocytic stage. By blocking this stage, further development of the infection can be theoretically prevented. However since it is impossible to predict the infection before clinical symptoms begin, this mode of therapy is more theoretical than practical. 8/3/2021 9

10. b. Tissue schizonticides for preventing relapse: - Primaquine is the prototype drug; pyrimethamine also has such activity. - These drugs act on the hypnozoites of P. vivax and P. ovale in the liver that cause relapse of symptoms on reactivation. c. Blood schizonticides : chloroquine , quinine, mefloquine , halofantrine , pyrimethamine , sulfadoxine , sulfones , tetracyclines . They act on the blood forms of the parasite and thereby terminate clinical attacks of malaria. These are the most important drugs in anti malarial chemotherapy. 8/3/2021 10

11. d. Gametocytocides : - These drugs destroy the sexual forms of the parasite in the blood and thereby prevent transmission of the infection to the mosquito. Chloroquine and quinine have gametocytocidal activity against P. vivax and P. malariae , but not against P. falciparum. Primaquine has gametocytocidal activity against all plasmodia, including P. falciparum . e. Sporontocides : These drugs prevent the development of oocysts in the mosquito and thus ablate the transmission. Primaquine and chloroguanide have this action. 8/3/2021 11

12. 2. Classification according to structure Aryl amino alcohols: Quinine, quinidine (cinchona alkaloids), mefloquine , halofantrine . 4-aminoquinolines: Chloroquine , amodiaquine . Folate synthesis inhibitors: Type 1 – competitive inhibitors of dihydropteroate synthase – sulphones , sulphonamides ; Type 2 – inhibit dihydrofolate reductase – biguanides like proguanil and chloroproguanil ; diaminopyrimidine like pyrimethamine 8-aminoquinolines: Primaquine 8/3/2021 12

13. Antimicrobials: Tetracycline, doxycycline, clindamycin, azithromycin, fluoroquinolones . Peroxides: Artemisinin ( Qinghaosu ) derivatives and analogues – artemether , arteether , artesunate , artelinic acid. Naphthoquinones : Atovaquone Iron chelating agents: Desferrioxamine . 8/3/2021 13

14. 4-AMINOQUINOLINES They are antimalarial agents  useful in treating erythrocytic plasmodial infection. They include: Chloroquine Hydroxychloroquine Amodiaquine 8/3/2021 14

15. Chloroquine Chloroquine ( 1940s) i s a very potent blood schizonticidal agent effective against the erythrocytic forms of all four plasmodial species. Does not have any effect on sporozoites , hypnozoites or gametocytes . Except TROPHOZOITES 8/3/2021 15

16. Mechanism of Action Diffuse freely into the parasite lysosome. At the acid pH of the lysosome, it is converted to a protonated, membrane-impermeable form and is 'trapped' inside the parasite . Acts mainly on haem disposal. Preventing digestion of haemoglobin by the parasite. Reducing the supply of amino acids necessary for parasite viability. It also inhibits haem polymerase-the enzyme that polymerises toxic free haem to haemozoin-rendering it harmless to the parasite. 8/3/2021 16

17. RESISTANCE Plasmodium falciparum is now resistant to chloroquine in most parts of the world. Resistance appears to result from enhanced efflux of the drug from parasitic vesicles. Resistance of P. vivax to chloroquine is also a growing problem in many parts of the world. 8/3/2021 17

18. Pharmacokinetics Generally administered orally, IM, SC or slow IV injection (in severe cases). It is completely absorbed from GIT, extensively distributed throughout the tissues and concentrated in parasitized red cells. Release from tissues and infected erythrocytes is slow. Metabolized in the liver and excreted in the urine Elimination is slow, The major phase having a half-life of 50 hours , and a residue persists for weeks or months . 8/3/2021 18

19. Side effects Nausea and vomiting Dizziness and blurring of vision, headache, convulsion Urticaria Retinopathies due to Large doses. Fatal Dysrhythmias , if high doses are used. Hypotension due to Bolus IV injections NB: Chloroquine is considered to be safe for use by pregnant women. 8/3/2021 19

20. Hydroxychloroquine Essentially equivalent to chloroquine against P. falciparum malaria. Preferred over chloroquine for treatment of mild rheumatoid arthritis and lupus erythematosus . In the high doses it may cause less ocular toxicity than chloroquine 8/3/2021 20

21. Amodiaquine MOA: Similar to that of chloroquine USES antimalarial and anti-inflammatory agent More effective than chloroquine in treating (chloroquine-resistant  Plasmodium falciparum ) malaria infections May afford more protection than chloroquine when used as weekly prophylaxis 8/3/2021 21

22. Drug interaction It should not be given with mefloquine because of increased risk of seizures. Opposes the action of anticonvulsants Increases plasma levels of digoxin and cyclosporin Toxicity: Agranulocytosis and hepatotoxicity due to direct dose-dependent toxicity. 8/3/2021 22

23. Pharmacokinetics Rapidly absorbed from the GIT a fter oral administration In the liver it is metabolized to N- desethyl - amodiaquine (DEAQ) which concentrates in blood cells. Concentration of amodiaquine in blood is quite low. DEAQ is responsible for most of the observed antimalarial activity. Amodiaquine and DEAQ are over 90% bound to plasma proteins 8/3/2021 23

24. QUINOLINE-METHANOLS The two most widely used quinoline-methanols are: Quinine Mefloquine - It is a blood schizonticidal drug effective against the erythrocytic forms of all four species of plasmodium - It has no effect on exoerythrocytic forms or on the gametocytes of P. falciparum. 8/3/2021 24

25. Quinine Quinine and Q uinidine are the most important among many alkaloids derived from cinchona bark. It is a blood schizonticidal drug effective against the erythrocytic forms of all four species of plasmodium It has no effect on exoerythrocytic forms or on the gametocytes of P. falciparum . 8/3/2021 25

26. Mechanism of Action It is said to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme . Quinine is not so extensively concentrated in the plasmodium as chloroquine 8/3/2021 26

27. Pharmacokinetics Quinine is usually administered orally and well absorbed Given by slow IV infusion for severe P. falciparum infections and in patients who are vomiting Bolus intravenous administration is contraindicated because of the risk of cardiac dysrhythmias 8/3/2021 27

28. Pharmacokinetics The half-life of the drug is 10 hours Metabolized in the liver and the metabolites are excreted in the urine Renal excretion of quinine itself is more rapid when the urine is acidic There is no accumulation of the drugs in the body on continued administration. 8/3/2021 28

29. Side effects Bitter taste (oral compliance is often poor) Nausea and vomiting ‘ Cinchonism '- characterized by nausea, dizziness, tinnitus, headache and blurring of vision Stimulate insulin release (induce hypoglyceamia ) Hypotension 8/3/2021 29

30. Side effects- cont Neurotoxicity - visual and auditory disturbances Blood dyscrasias (especially thrombocytopenia) Hypersensitivity reactions Confusion Hot and flushed skin Cautions: May cause milder haemolysis especially in people with G6PD deficiency In patients with cardiac dysrhythmias Severe hypersensitivity 8/3/2021 30

31. Contraindication & Drug interaction Contraindication Tinnitus Optic neuritis Myasthenia gravis Haemoglobinuria Drug interaction Absorption of quinine can be delayed by antacids containing aluminum. The renal clearance of quinine can be decreased by cimetidine and increased by rifampicin. 8/3/2021 31

32. Mefloquine A blood schizonticidal quinoline -methanol compound Active against P. falciparum and P. vivax . I t has no effect on hepatic forms of the parasites. Mefloquine is frequently combined with pyrimethamine . The anti-parasite action is similar to that of quinine. 8/3/2021 32

33. Pharmacokinetics Given orally and is rapidly absorbed It is not given parenterally due to severe local reaction . It has a slow onset of action and a very long plasma half-life (up to 30 days ). Excretion is mainly by the faecal route.   Side effects GIT disturbances CNS toxicity- giddiness, confusion, dysphoria and insomnia 8/3/2021 33

34. Contraindication and Drug Interactions In persons with History of seizures, Severe neuropsychiatric disturbances, Adverse reactions to quinoline antimalarials increases the risk of seizure when taken with Anti-epileptics Calcium channel blockers Β -blockers Antimalarials 8/3/2021 34

35. QINGHAOSU (ARTEMISININ) AND RELATED COMPOUNDS The qinghaosu -based compounds are derived from the herb qing hao ( Artemisia annua ) Artemisinin , is a fast-acting blood schizonticide Artesunate (water-soluble derivative) and the synthetic analogues artemether and artether have higher activity and are better absorbed . The mechanism of action is not known It may involve damage to the parasite membrane by carbon- centred free radicals or covalent alkylation of proteins. 8/3/2021 35

36. Pharmacokinetics Artemisinin can be given orally, IM or by suppository Artemether : orally or IM, and Artesunate : orally, IM or IV. Rapidly absorbed and widely distributed. Converted in the liver to the active metabolite dihydroartemisinin . The half-life of artemisinin is about 4 hours, artesunate 45 minutes and artemether 4-11 hours . 8/3/2021 36

37. Side effects Transient heart block Decrease in blood neutrophil count Brief episodes of fever Neurotoxicity 8/3/2021 37

38. HYDROXY-NAPHTHOQUINONE DRUGS Atovaquone mimick the natural substrate ubiquinone . Used in combination with the anti- folate drug proguanil for synergistic effect Side effects of such combination treatment include abdominal pain, nausea and vomiting. CAUTION: Pregnant or breast-feeding women should not take atovaquone . 8/3/2021 38

39. DRUGS AFFECTING THE SYNTHESIS OR UTILISATION OF FOLATE Anti- folate drugs are classified into: T ype 1 : inhibit the synthesis of folate by competing with p - aminobenzoic acid. E.g. sulfonamides and the sulfones Type 2 : prevent the utilization of folate by inhibiting dihydrofolate reductase . E.g. Pyrimethamine and proguanil Combination of Type 1 and 2 compounds have synergistic properties 8/3/2021 39

40. They have a slow action against the erythrocytic forms of the parasite, Proguanil is believed to have an additional effect on the initial hepatic stage but not on the hypnozoites of P. vivax . Pyrimethamine is used only in combination with either dapsone or a sulfonamide. 8/3/2021 40

41. The main sulfonamide used in malaria treatment is sulfadoxine . The only sulfone used is dapsone Sulfonamides and sulfones are active against the erythrocytic forms of P. falciparum. Less active against those of P. vivax Have no activity against the sporozoite or hypnozoite forms of the plasmodia. 8/3/2021 41

42. Pharmacokinetics P yrimethamine and P roguanil are given orally and are well, although slowly, absorbed. Pyrimethamine has a plasma half-life of 4 days, and effective 'suppressive' plasma concentrations may last for 14 days; it is taken once a week. Half-life of proguanil , a prodrug is 16 hours Metabolized in the liver to its active form cycloguanil , which is excreted mainly in the urine . 8/3/2021 42

43. Side effects P yrimethamine-dapsone combination: - Eosinophilic alveolitis . Haemolytic anaemia , Agranulocytosis . Pyrimethamine-sulfadoxine combination: Skin reactions, Allergic alveolitis Blood dyscrasias . Pyrimethamine : megaloblastic anaemia NB :Folic acid supplements should be given if this drug is used during pregnancy . 8/3/2021 43

44. Doxycycline Used for the prophylaxis of malaria in areas of widespread mefloquine or chloroquine resistance . Doxycycline is also used as an alternative to mefloquine Doxycycline is also used as an adjunct to quinine in the treatment of falciparum malaria ADULT and CHILD over 12 years, 100 mg once daily started 1–2 days before entering endemic area and continued for 4 weeks after leaving. Affects bone formation during early life and should not be given during pregnancy, breast-feeding and the first eight years of life. 8/3/2021 44

45. AMOEBIASIS AND AMOEBICIDAL DRUGS Entamoeba histolytica is the causative agent of amoebiasis . May manifest as a severe colitis ( dysentery ) and sometimes liver abscesses Organism has a simple life cycle, and humans are the chief hosts. 8/3/2021 45

46. Anti- amoebiasis Drugs M etronidazole (or tinidazole ) followed by diloxanide for acute invasive intestinal amoebiasis resulting in acute severe amoebic dysentery Diloxanide for chronic intestinal amoebiasis Metronidazole followed by diloxanide for hepatic amoebiasis Diloxanide for the carrier state 8/3/2021 46

47. Metronidazole Kills the trophozoites of E. histolytica but has no effect on the cysts. Drug of choice for invasive amoebiasis of the intestine or the liver Less effective against organisms in the lumen of the gut MOA: It inhibits nucleic acid synthesis by disrupting the DNA of microbial cells. Leads to parasite apoptosis. 8/3/2021 47

48. Pharmacokinetics U sually given orally and is rapidly and completely absorbed, Metronidazole has a half-life of about 7 hours while tinidazole has half-life of 12-14 hours Metabolized in liver and mostly excreted in urine Distributed rapidly throughout the tissues and body fluids including CSF. 8/3/2021 48

49. Side effects Metallic , bitter taste in the mouth Minor GI disturbances and CNS symptoms (dizziness, headache, sensory neuropathies ) Disulfiram -like reaction with alcohol CAUTION Pregnancy: avoid high dose regimens Breast-feeding: avoid large single doses   8/3/2021 49

50. Clinical effects of disulfiram -like reaction Concurrent use of oral metronidazole with alcohol has been associated with a disulfiram -like reaction resulting in the ff symptoms; hypotension, tachycardia, Metallic , bitter taste in the mouth Minor GI disturbances and CNS symptoms (dizziness, headache, sensory neuropathies ) reaction with alcohol   8/3/2021 50

51. Side effects- Disulfiram -like rxtn   8/3/2021 51

52. AMOEBICIDES Diloxanide and Diloxanide furoate D iloxanide and diloxanide furoate are the drugs of choice for the asymptomatic infected patient. Both drugs have a direct amoebicidal action, affecting the parasites before encystment . Diloxanide furoate is given orally , Unabsorbed moiety being the amoebicidal agent. Other drugs include iodoquinol , dehydroemetine and paromomycin . 8/3/2021 52

53.   TRYPANOSOMIASIS T hree main species of trypanosome that cause disease in humans are: Trypanosoma gambiense and Trypanosoma rhodesiense , which cause sleeping sickness in Africa Trypanosoma cruzi , which causes Chagas ' disease in South America. NB: T . rhodesiense causes the more aggressive form of sleeping sickness. 8/3/2021 53

54. TRYPANOCIDAL DRUGS African sleeping sickness : Suramin or Pentamidine used in the haemolymphatic stage. Arsenical melarsoprol for the late stage with CNS involvement. Other agents include N ifurtimox and E flornithine For Chaga’s disease: Nifurtimox or Benznidazole 8/3/2021 54

55. Side effects Suramin : optic atrophy, adrenal insufficiency , skin rashes, haemolytic anaemia and agranulocytosis . Pentamidine isothionate : decrease in blood pressure with tachycardia, breathlessness and vomiting. Later serious toxicity, such as kidney damage, hepatic impairment, blood dyscrasias and hypoglycaemia . 8/3/2021 55

56. LEISHMANIASIS Insect vector is sandfly The parasite exists in two forms: Flagellated form ( promastigote ) Non-flagellated intracellular form ( amastigote ). 8/3/2021 56

57. Typical Symptoms A simple skin infection giving rise to an unpleasant chancre that may heal spontaneously mucocutaneous form (' espundia ‘) in which there may be large ulcers of the mucous membranes A serious visceral form ( ' kala-azar ‘) where the parasite spreads through the bloodstream and causes hepatomegaly, splenomegaly, anaemia and intermittent fever. 8/3/2021 57

58. ANTI-LEISHMANIAL DRUGS For visceral leishmaniasis Pentavalent antimony compounds ( sodium stibogluconate and meglumine antimoniate ) Others include Amphotericin, P entamidine Isethionate and Miltefosine . 8/3/2021 58

59. TRICHOMONIASIS AND TRICHOMANICIDAL DRUGS Caused by Trichomonas vaginalis Virulent strains cause inflammation of the vagina in females and sometimes of the urethra in males . Treated with Metronidazole or Tinidazole 8/3/2021 59

60. GIARDIASIS Caused by Giardia lamblia Trophozoite colonises the upper gastrointestinal tract, and the cysts pass out in the faeces Metronidazole is the drug of choice 8/3/2021 60

61. TOXOPLASMOSIS Caused by Toxoplasma gondii The cat is the definitive host and humans can be intermediate hosts. Asymptomatic or self-limiting, but can severely damage the developing fetus and may be fatal in immunosuppressed patients. 8/3/2021 61

62. Anti-toxoplasmosis Drugs Pyrimethamine -sulfadiazine Alternatively: Trimethoprim- sulfamethoxazole Pentamidine (parenteral) Azithromycin 8/3/2021 62

63. 8/3/2021 63 THANK YOU