Antiparasitic Drugs.pptx

management of parasitic infections

1. ANTIPARASITIC AGENTS Dr. Vikram Sharma, MD MAMC 1

2. Classification of Parasites 2

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4. Non-malarial Protozoans & Infections 4

5. Protozoal Infection Causative organism Amebiasis E. histolytica, E. dispar, and E. moshkovskii Giardiasis Giardia intestinalis, a flagellated protozoan Trichomoniasis Trichomonas vaginalis Toxoplasmosis Toxoplasma gondii Cryptosporidiosis Cryptosporidium parvum, Cryptosporidium hominis Trypanosomiasis Trypanosoma brucei (African), Trypanosoma cruzi (American) Leishmaniasis Leishmania spp. Babesiosis Babesia microti or B. divergens Balantidiasis Balantidium coli Other coccidial infections Cyclospora cayetanensis, Cystoisospora belli, Microsporidia 5

6. Anti-Protozoal Drugs 6

7. Protozoal Infection Drug(s) Amebiasis Nitroimidazole group: Metronidazole, Tinidazole etc. Luminal amebicides: Paromomycin, I odoquinol , N itazoxanide Giardiasis Nitroimidazole group: Metronidazole, Tinidazole etc. Nitazoxanide Trichomoniasis Nitroimidazole group: Metronidazole, Tinidazole etc. Toxoplasmosis Pyrimethamine + S ulfadiazine + F olinic acid (leucovorin) Pyrimethamine- clindamycin Azithromycin/ Clarithromycin/ Atovaquone/ Dapsone + T rimethoprim - sulfamethoxazole/ pyrimethamine Spiramycin Cryptosporidiosis Nitazoxanide 7

8. Protozoal Infection Drug(s) African trypanosomiasis, or “sleeping sickness” Early Stage: Pentamidine or Suramin Late Stage: Nifurtimox-Eflornithine; or Melarsoprol American tryp. or Chaga’s disease Nifurtimox & Benznidazole Leishmaniasis Pentavalent antimony compounds: Sodium stibogluconate Miltefosin Liposomal amphotericin B Babesiosis Mild or moderate infections: Azithromycin + Atovaquone Severe infection: Clindamycin + quinine Balantidiasis Tetracycline Other coccidial infections T rimethoprim- sulfamethoxazole 8

9. Amphotericin B MOA: complexes with ergosterol precursors in cell membrane ↓ forming pores that allow ions to leave cell ↓ Cell Death 9

10. Amphotericin B Use : Visceral leishmaniasis 3 mg/kg intravenously on days 1–5, 14, and 21 for a total dose of 21 mg/kg Cutaneous leishmaniasis 3 mg/kg/d intravenously for 7-10 days . 10

11. E flornithine MOA: Enters cell via amino acid transporter ↓ Irreversible catalytic (suicide) inhibitor of ornithine decarboxylase ↓ Inhibition of first & rate limiting step in the biosynthesis of polyamines (putrescine, spermidine, and spermine) ↓ impaired cell division & normal cell differentiation 11

12. E flornithine Pharmacokinetics: given i.v. well distributed & penetrates into CSF E= 80 % unchanged in urine Therapeutic Uses: Late- stage West African trypanosomiasis along with Nifurtimox (NECT) (200 mg/kg IV every 12 h by 2- h infusion for 7 days + nifurtimox (orally at 15 mg/kg/d in three divided doses [every 8 h]) for 10 days) 12

13. 8- Hydroxyquinolines I odoquinol & clioquinol Therapeutic Uses : As luminal agent to eliminate intestinal colonization with E. histolytica & combined with metronidazole to treat amebic colitis or amebic liver abscess. Adults: 650 mg orally three times daily for 20 days Children: 30–40 mg/kg body weight orally, divided three times a day (not to exceed 1.95 g/d) for 20 days Adverse Reactions: Neuropathy Subacute myelo- optic neuropathy Peripheral neuropathy . 13

14. Melarsoprol MOA: Melarsoprol ↓ Melarsen oxide ↓ React avidly & reversibly with vicinal sulfhydryl groups & thereby inactivate many enzymes ( melarsen oxide–trypanothione adduct that inhibits trypanothione reductase) ↓ Free radical damage 14

15. Melarsoprol Therapeutic Uses: Late meningoencephalitic stage of East African (Rhodesian) trypanosomiasis. Late stage West African ( Gambianse ) trypanosomiasis not responding to NECT ( 2.2 mg/kg/d IV for 10 days) 15

16. Melarsoprol ADRs: Febrile reaction. Reactive encephalopathy (serious) Peripheral neuropathy Hypertension & myocardial damage Albuminuria Vomiting Abdominal colic 16

17. Melarsoprol Precautions & Contraindications: Should be given only to patients under hospital supervision Administration of melarsoprol to leprous patients may precipitate erythema nodosum Severe hemolytic reactions have been reported in patients with deficiency of glucose- 6- phosphate dehydrogenase Contraindicated during epidemics of influenza 17

18. NITROIMIDAZOLE Metronidazole & its analogs - T inidazole , S ecnidazole , & O rnidazol e Antimicrobial spectrum: Antibacterial: All anaerobic cocci Anaerobic gram-negative bacilli, including Bacteroides spp. Anaerobic spore- forming, gram-positive bacilli such as Clostridium Microaerophilic bacteria such as Helicobacter and Campylobacter spp. Antiprotozoal: T. vaginalis E. histolytica G. lamblia 18

19. NITROIMIDAZOLE Metronidazole & its analogs - T inidazole , S ecnidazole , & O rnidazol e MOA : 19

20. NITROIMIDAZOLE Metronidazole & its analogs - T inidazole , S ecnidazole , & O rnidazol e PK : Available for oral, i.v. & topical use Complete oral absorption t 1/2 - 8hrs 20

21. NITROIMIDAZOLE Therapeutic Uses : Trichomoniasis 2 g Metronidazole/ Tinidazole as a single oral dose for both males & females may be repeated after 4- 6 weeks In addition to oral therapy, use of a 500 to 1000 mg vaginal suppository may be beneficial in refractory cases. Amebiasis (along with luminal amebicides): Metronidazole is the agent of choice for treatment of all symptomatic forms of amebiasis, including amebic colitis & amebic liver abscess Adults: 500–750 mg metronidazole taken orally three times daily for 7–10 days. Children: 35–50 mg/kg/d given in three divided doses for 7–10 days Giardiasis Tinidazole (single 2g dose as first- line therapy ) 21

22. NITROIMIDAZOLE ADRs : Headache, nausea, dry mouth, metallic taste are common Vomiting, diarrhea , & abdominal distress are experienced occasionally. Dysuria, cystitis, and a sense of pelvic pressure have been reported. Dizziness, vertigo, very rarely, encephalopathy, convulsions, incoordination, & ataxia are neurotoxic effects that warrant drug discontinuation. Hypersensitivity reactions 22

23. NITROIMIDAZOLE D/I : Metronidazole has a disulfiram- like effect & some patients experience abdominal distress, vomiting, flushing, or headache if they drink alcoholic beverages during or within 3 days of therapy. CNS signs of lithium toxicity in patients receiving high doses of lithium. Prolong the prothrombin time of patients receiving therapy with warfarin anticoagulants. 23

24. Miltefosine Structure : alkylphosphocholine analogue; primarily anticancer MOA: Possibly alter ether- lipid metabolism, cell signaling , or glycosylphosphatidylinositol anchor biosynthesis. PK: well absorbed orally & distributed throughout body Long t 1/2 (1–4 weeks ) 24

25. Miltefosine Therapeutic Uses & Dosage: Visceral & cutaneous leishmaniasis ( 100-150mg/kg/d in two divided doses for 28 days) ADRs: Vomiting & diarrhea ( frequent ; 60%) Elevations in hepatic transaminases & serum creatinine Contraindication: Pregnancy 25

26. Nifurtimox & Benznidazole MOA: 26

27. Nifurtimox & Benznidazole PK: Nifurtimox Benznidazole Well absorbed orally Well absorbed orally D= Widely distributed incl. CNS D= Widely distributed incl. CNS M= Hepatic M= Hepatic E= Biliary E= Biliary t 1/2 = 3h t 1/2 = 12h 27

28. Nifurtimox & Benznidazole Therapeutic Uses & Dosage: American T rypanosomiasis ( T.cruzi ): Nifurtimox : 8–15 mg/kg/d (depending upon weight of pt.) in three to four divided doses for 90 days Benznidazole : 5–7 mg/kg/d in two divided doses (Adult), 10–15 mg/kg/d in two divided doses for 60 days African S leeping S ickness ADRs : Hypersensitivity reactions Nausea & vomiting resulting in weight loss on chronic therapy Peripheral neuropathy 28

29. Nitazoxanide MOA: Interferes with PFOR enzyme- dependent electron transfer reaction ↓ Interference with anaerobic metabolism PK: Well absorbed orally Metabolized to active form tizoxanide Tizoxanide >99.9% bound to plasma proteins 29

30. Nitazoxanide Therapeutic uses & Dosage: Cryptosporidiosis Luminal Amebicide Giardiasis Children: Tab.100 mg PO q12h for 3 days (1-4 years); Tab. 200 mg PO q12h for 3 days (4- 11 years) Adults: Tab. 500 mg PO q12h for 3 days ADRs : greenish tint to urine (rare) 30

31. Paramomycin Structure : Aminoglycoside of neomycin/kanamycin family Mechanism of Action: Same mechanism of action as neomycin / kanamycin (binding to the 30S ribosomal subunit); has same spectrum of antibacterial activity. Pharmacokinetics: Not absorbed from GI tract; thus, actions of oral dose are confined to GI tract , with 100% of oral dose recovered in the feces 31

32. Paramomycin Uses : Amoebiasis (colitis/hepatic) along with Nitroimidazole as luminal amebicide. Giardiasis where Metronidazole is C/I (pregnancy) Dosing for adults & children is 25–35 mg/kg/d in three divided oral doses. Cutaneous Leishmaniasis ( 15% ointment twice daily for 20 days) Visceral leishmaniasis : Paromomycin sulphate { 15mg/kg (11 mg/kg base) i.m daily for 21 days ± Trichomoniasis : Metronidazole resistant trichomoniasis ( 6.25% vaginal cream for 2 weeks ) Adverse Effects : (Rare) Abdominal pain & cramping, epigastric pain, nausea & vomiting, steatorrhea, diarrhea liposomal amphotericin B/Miltefosine . 32

33. Pentamidine Pharmacokinetics: Given parenteral ( i.v / i.m / inhalation) Poor oral absorption but well absorbed from i.m. site 70 % plasma protein bound, do not cross BBB Not metabolized → Unchanged in urine Therapeutic uses & dosage: Early stage of African trypanosomiasis (T. brucei gambiense ): [ i.m. or i.v. injection in doses of 4 mg/kg daily for 7 days] Cutaneous Leishmaniasis [2–3 mg/kg IV or IM daily or every second day for 4–7 doses] 33

34. Pentamidine ADRs: Common (50% ) Hypotension, tachycardia, headache on i.v. administration Hypoglycemia ( Paradoxically, pancreatitis, hyperglycemia , development of insulin- dependent diabetes have been seen in some patients) Nephrotoxicity Rashes Thrombophlebitis Anemia, neutropenia Elevation of hepatic enzymes Sterile abscesses at i.m. injection site 34

35. Sodium Stibogluconate Sructure : Pentavalent (Sb +5 ) antimony compound MOA: 35

36. Sodium Stibogluconate PK : Given i.v. / i.m. ( Rapidly absorbed from i.m. site) aVd : 0.22l/kg ; t 1/2 : Biphasic (2 hrs & 33- 76 hrs) Therapeutic Uses : ( Now obsolete in India) Visceral leishmaniasis ( i.m / i.v. 20 mg/kg/d for 28 days) Cutaneous leishaniasis ( i.m / i.v. 20 mg/kg/d for 20 days) 36

37. Sodium Stibogluconate ADRs : Chemical pancreatitis Elevation of serum hepatic transaminase levels Bone marrow suppression Muscle & joint pain Weakness & malaise Reversible polyneuropathy 37

38. Suramin MOA : Unknown PK: Given i.v. 99.7% plasma protein bound, do not cross BBB Renal Excretion t 1/2 = 41- 78 days Uses: Early- stage T. brucei rhodesiense infection (First line therapy) After test dose of 100 mg (adults) or 2mg/kg (pediatric) for detecting sensitivity Adult: 1g slow i.v infusion on days 1, 3, 5, 14, & 21. Pediatric: 20 mg/kg, given according to same schedule as adults. 38

39. Suramin ADRs : Common immediate reactions - m alaise, nausea, & fatigue Most serious immediate reaction - nausea, vomiting, shock, & loss of consciousness { rare (~1 in 2000 patients)} Most common problem encountered after several doses - renal toxicity. Delayed neurological complications - headache, metallic taste, paresthesias , & peripheral neuropathy. . 39

40. Helminths 40

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42. Nematodes ( round worms ) - ascarids ( Ascaris ), filarias, hookworms, pinworms ( Enterobius ), & whipworms ( Trichuris trichiura ) Cestodes ( tape worms ) - multiple species of flat worms, Taenia saginatum, Taenia solium ( cysticercosis ), H ydatid ( echinococcus ) Trematodes ( flukes ) – L iver flukes, L ung flukes, S chistosoma 42

43. Antihelminthic 43

44. INTRODUCTION Helminth means worms Anthelmintics are drugs used to treat parasitic infe ction due to worms. Anthelmintics act through two mechanism Vermicide (kill) used to kill parasitic intestinal worms . Vermifuge (expel) used to destroy or expel worms in the intestine . 44

45. Based On Chemical Structures Benzimidazoles : Albendazole , Mebendazole , Flubendazole, Cyclobendazole Thiabendazole, Fenbendazole, Oxibendazole, Parbendazole Quinolines & isoquinolines [Heterocyclics]: Oxamniquine, Praziquantel Piperazine derivatives : Piperazine citrate, Diethyl carbamazine Vinyl pyrimidines : Pyrantel pamoate, Oxantel Amides : Niclosamide Natural products : Ivermectin Organo phosphorus : Metrifonate Imidazothiazoles : Levamisole Nitro derivatives : Niridazol 45

46. BENZIMIDAZOLES H eterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene & imidazole. 46

47. MOA S electively bind s to nematode ß- tubulin inhibiting polymerization , thus preventing formation of microtubules , stopping cell division. Impaired uptake of glucose, leading to depletion of glycogen, & reduced stores of ATP . 47

48. Albendazole USES : DOC: R oundworm , P inworm , H ookworm A lternative : T hreadworm , F ilariasis , H ydatid disease & C ysticercosis ADR : Well tolerated; gastrointestinal side effects are known P rolonged use as in hydatid or in neurocysticercosis causes headache, alopecia, jaundice, neutropenia. DOSE : 400mg/kg adult dose 48

49. Mebendazole USES: whipworm eggs, pinworm, hookworms, & roundworm AD R S: Well tolerated, mild nausea, vomiting, diarrhea, & abdominal pain , hypersensitivity reactions (rash, urticarial) DOSE: 100 mg chewable tablet, 100 mg/5ml suspension 49

50. Thiabendazole USES: Primary drug in roundworm & pinworm ADR: GIT upset, alopecia & agranulocytosis ( high dose ) 50

51. QUINOLINE & ISOQUINOLINE Oxamniquine MOA: possibly acts by DNA binding , resulting in contraction & paralysis of worms & eventual detachment from terminal venules in mesentry , & death. A cts mainly on male worms USE : Schistosoma mansoni DOSES : O ral route after meals depends upon geographical areas In western hemisphere - 15 mg/kg as a single dose I n Africa - 15–60 mg/kg over 1–3 days 51

52. Praziquantel MOA : Praziquantel works by causing severe spasms & paralysis of the worms' muscles. This paralysis is caused by rapid Ca 2+ influx inside schistosome W orms are then either completely destroyed in intestine or passed in stool . USES : T apeworm ( neurocysticercosis , schistosomes ) A ll F lukes except liver fluke X nematodes 52

53. Praziquantel DOSE : oral dose is 600mg tablet two to three times in a day ADR : Bitter taste, nausea, abdominal , pain , h eadache , dizziness & sedation 53

54. PIPERAZINE DERIVATIVES Piperazine Citrate MOA : GABA receptor agonist binds selectively to receptors → hyperpolarization of ascaris muscles → flaccid paralysis of the worm → dislodged from intestinal lumen DOSE : 3.5g as single dose daily for two consecutive days For oxyuriasis (thread worms) - 2.5 g given for 7 days USES : common roundworms (ascariasis) , pinworms (enterobiasis; oxyuriasis ) ADR : nausea, vomiting, abdominal pain, headache neurotoxicity , allergic reactions ( rare ) 54

55. Diethyl Carbamazine MOA : Microfilaricidal → death of microfilaria by blocking cycloxygenase pathway in parasites → alters microfilarial membranes → readily phagocytosed by the tissue bound monocytes USES : Filariasis, topical eosinophilia DOSE : 2 - 3 mg/kg for filariasis 6 mg / kg x 4-7 days for eosinophilia ADR : nausea, vomiting, lethargy, febrile reactio n 55

56. VINYL PYRIMIDINES Pyrantel Palmoate MOA : D epolarizing neuromuscular blocking agent → induces marked persistent activation of nicotinic receptors → spastic paralysis of worm DOSES : O ral suspension or liquid - 50 mg/ml S ingle dose of 11 mg/kg for A scarasis & E nterobiasis 56

57. VINYL PYRIMIDINES Pyrantel Palmoate USES: A lternative to mebendazole for ascariasis & enterobiasis ADR: Nausea, vomiting, diarrhea, stomach/abdominal cramps , h eadache , dizziness, loss of appetite 57

58. AMIDES Niclosamide MOA : A cts by inhibiting oxidative phosphorylation in mitochondria → interfering with anerobic generation of ATP in tapeworm → energy depletion USE: active against most tapeworms 58

59. AMIDES Niclosamide DOSE: 2 gm as single dose after a light breakfast A dvantage : Tastless & non - irritant, minimal absorption from GIT so minimal systemic toxicity 59

60. NATURAL PRODUCTS Ivermectin avermectin analogue ; Japan; 1970s MOA: USE: Broad spectrum Filarial Nematodes → ↓ Microfilarial load Currently investigated for COVID 19 60

61. NATURAL PRODUCTS Ivermectin ADR: Mild side effects; n ausea , abdominal pain, constipation, pruritus, lethargy & transient ECG changes DOSE: single 10- 15 mg oral dose + 400 mg albendazole given annually for 5-6 years has been used for filariasis 61

62. IMIDAZOTHIAZOLES Levamisole USE : active against large number of nematodes but their use is restricted to only A scariasis & A ncyclostomiasis because of poor action against other worms. MOA : S timulate ganglia in worms → cause tonic paralysis → explusion of live worms Also interfere with carbohydrate metabolism → (-) Fumarate reductase . 62

63. IMIDAZOTHIAZOLES Levamisole ADRS : Nausea, abdominal pain, fatigue, drowsiness or insomnia D0SE : 5mg as a single dose repeated after 1 month to prevent recurrence 63

64. ORGANOPHOSPHOROUS COMPOUNDS Metrifonate Irreversible organophosphate acetylcholinesterase inhibitor. Prodrug which is activated non- enzymatically into the active agent dichlorvos Used as insecticide D ose - 7.5mg/kg given orally three times at intervals of 2 weeks. 64

65. Niridazole Recommended daily dose by oral route is 25mg/kg daily in two divided doses NITRO DERIVATIVES 65

66. Anthelmintics Parasite covered Albendazole, Mebendazole Nematodes, Cestodes, Cutaneous & Visceral Larva migrans (2 nd line) Triclabendazole Fasciola hepatica, Paragonimus skyrjabni (2 nd line) Ivermectin Onchocerciasis, River Blindness, Lymphatic filariasis, Loiasis , Strongyloides stercoralis , Disseminated Strongyloidiasis, Cutaneous larva migrans (creeping eruption), Pediculosis, Scabies Metronidazole Dracunculus medinensis Praziquantel Fluke (except Liver fluke) & tapeworm Diethylcarbamazine Filaria l worms (W. bancrofti , B. malayi ) Bithional Fasciola hepatica, Paragonimus skyrjabni 66 Anti-Parasitic Spectrum

67. THANK YOU 67