Antimycobacterials

1. Antimycobacterials J. Mojžiš

2. Introduction • The most widely encountered mycobacterial infections is tuberculosis • Members of the genus Mycobacterium also cause leprosy as well as several tuberculosis-like human infections • Mycobacterial infections are intracellular and, generally, result in the formation of slow-growing granulomatous lesions that are responsible for major tissue destruction

3. Lippincot´s Pharmacology; 2009

4. Isoniazid (INH) • Mechanism of action: INH is a prodrug that is activated by a mycobacterial catalase-peroxidase (KatG) • Two different target enzymes for isoniazid: enoyl acyl carrier protein reductase and a β-ketoacyl-ACP synthase  production of mycolic acids. The activated drug covalently binds to and inhibits these enzymes, which are essential for the synthesis of mycolic acid • Mycolic acid is a very-long-chain, β-hydroxylated fatty acids found in mycobacterial cell walls.

5. Antibacterial spectrum • For bacilli in the stationary phase - bacteriostatic • For rapidly dividing organisms – bactericidal • Effective against intracellular bacteria • INH specific for treatment of M. tuberculosis, although M. kansasii may be susceptible at higher drug levels

6. Pharmacokinetics • Orally administered isoniazid is readily absorbed (absorption is impaired if INH is taken with food, particularly carbohydrates, or with aluminum-containing antacids) • The drug diffuses into all body fluids, cells, and caseous material (necrotic tissue resembling cheese that is produced in tubercles) including CSF • It undergoes N-acetylation (fast and slow acetylators) • Excretion is through glomerular filtration

7. Adverse effects • Peripheral neuritis: (paresthesias of the hands and feet) - appears to be due to a relative pyridoxine deficiency. (supplementation of 25-50 mg per day of pyridoxine (vitamin B6). • Hepatitis and idiosyncratic hepatotoxicity: Potentially fatal hepatitis is the most severe side effect (toxic metabolite of monoacetylhydrazine. Higher risk - elderly, among patients who also take rifampicin, or alcoholics • Other adverse effects: Mental abnormalities, convulsions in patients prone to seizures, and optic neuritis have been observed. Hypersensitivity reactions include rashes and fever. • Drug interactions: Because isoniazid inhibits metabolism of phenytoin - potentiates the adverse effects of that drug (nystagmus and ataxia). Slow acetylators are particularly at risk.

8. Rifampicin • Derived from Streptomyces, has a broader antimicrobial activity than isoniazid • Mechanism of action:it blocks transcription by interacting with the β subunit of bacterial but not human DNA-dependent RNA polymerase. • The drug is thus specific for prokaryotes

9. Antimicrobial spectrum • it is bactericidal for both intracellular and extracellular mycobacteria, including M. tuberculosis, M. kansasii. • It is effective against many G+ and G- organisms and is frequently used prophylactically for individuals exposed to meningitis caused by meningococci or H. influenzae • Rifampicin is the most active antileprosy drug at present

10. Pharmacokinetics • Good absorption p.o. • Distribution – all fluids and organs including CFS • Elimination of metabolites and the parent drug is via the bile into the feces or via the urine • Urine and feces as well as other secretions have an orange-red color; patients should be forewarned. Tears may permanently stain soft contact lenses orange-red

11. Adverse effects • Generally well tolerated • The most common adverse reactions include nausea, vomiting, and rash • Hepatitis and death due to liver failure is rare (attention in patients who are alcoholic, elderly, or have chronic liver disease) • Often, when rifampicin is dosed intermittently, or in daily doses of 1.2 grams or greater, a flu-like syndrome is associated with fever, chills, and myalgias

12. Pyrazinamide • synthetic, orally effective, bactericidal agent • mechanism of its action is unknown • It must be hydrolyzed to pyrazinoic acid (active form) • It is active against tubercle bacilli in the acidic environment of lysosomes as well as in macrophages • It distributes throughout the body, penetrating the CSF • 1-5% patients taking isoniazid, rifampicin, and pyrazinamide may experience liver dysfunction. • Urate retention can also occur and may precipitate a gouty attack

13. Ethambutol • Bacteriostatic, specific for most strains of M. tuberculosis and M. kansasii. • It inhibits arabinosyl transferase—important for the synthesis of the mycobacterial arabinogalactan cell wall • It can be used in combination with other anti-TBC • Absorbed after p.o. administration, well distributed throughout the body. Penetration into CNS -therapeutically adequate in tuberculous meningitis.

14. Both parent drug and metabolites are excreted by glomerular filtration and tubular secretion. • The most important adverse effect is optic neuritis, which results in diminished visual acuity and loss of ability to discriminate between red and green. • Discontinuation of the drug results in reversal of the optic symptoms. In addition, urate excretion is decreased by the drug; thus, gout may be exacerbated

15. Lippincot´s pharmaology, 2009

16. Alternate second-line drugs • Streptomycin: it is the first antibiotic effective in the treatment of TBC; its action is directed against extracellular organisms. • Capreomycin: This is a peptide that inhibits protein synthesis. It is administered parenterally. Reserved for the treatment of MDR TBC. Careful monitoring of the patient is necessary to prevent its nephrotoxicity and ototoxicity.

17. Cycloserine - orally effective; it antagonizes the steps in bacterial cell wall synthesis; distributed well throughout body fluids, including the CSF. Accumulation occurs with renal insufficiency. Adverse effects involve CNS disturbances, and epileptic seizure activity may be exacerbated. Peripheral neuropathies are also a problem, but they respond to pyridoxine. • Ethionamide: This is a structural analog of isoniazid, but it is not believed to act by the same mechanism. It is effective after p.o. and is widely distributed throughout the body, including the CSF. Adverse effects that limit its use include gastric irritation, hepatotoxicity, peripheral neuropathies, and optic neuritis. Supplementation with vitamin B6 (pyridoxine) may lessen the severity of the neurologic side effects.

18. Fluoroquinolones: The fluoroquinolones, such as moxifloxacin and levofloxacin, have an important place in the treatment of multidrug-resistant tuberculosis. Some atypical strains of mycobacteria are also susceptible. • Macrolides: The macrolides, such as azithromycin and clarithromycin, are part of the regimen that includes ethambutol and rifabutin used for the treatment of infections by M. avium-intracellulare complex. Azithromycin is preferred for HIV-infected patients because it is least likely to interfere with the metabolism of antiretroviral drugs.

19. Chemotherapy for Leprosy MDT – multidrug therapy 1. line • Dapson • Clofazimine • Rifampicin

20. 2. line • Ofloxacin • Minocycline • Claritromycine

21. Dapsone - structurally related to the sulfonamides and similarly inhibits folate synthesis via dihydropteroate synthetase inhibiton • It is bacteriostatic for Mycobacterium leprae • Dapsone is also employed in the treatment of pneumonia caused by Pneumocystis jiroveci in patients infected with the HIV. • The drug is well absorbed from the gastrointestinal tract and is distributed throughout the body, with high levels concentrated in the skin. • enterohepatic circulation; eliminated through the urine.

22. Adverse reactions include hemolysis, especially in patients with G-6-PD deficiency, as well as methemoglobinemia, peripheral neuropathy, and the possibility of developing erythema nodosum leprosum (a serious and severe skin complication of leprosy).

23. Clofazimine - phenazine dye that binds to DNA and prevents it from serving as a template for future DNA replication • Its redox properties may lead to the generation of cytotoxic oxygen radicals that are also toxic to the bacteria. • Clofazimine is bactericidal to M. leprae and has some activity against M. avium-intracellulare complex. • Following oral absorption, the drug accumulates in tissues, allowing intermittent therapy, but it does not enter the CNS. • Patients may develop a red-brown discoloration of the skin. Eosinophilic enteritis has been reported as an adverse effect. • The drug also has some anti-inflammatory activity

24. Antifungal, antiparasitic, antiviral chemotherapeuticsand antihelmintics

25. Mycoses – caused by fungi - often chronic. Many are superficial (only involve the skin - cutaneous mycoses). Fungi may also penetrate the skin - subcutaneous. Systemic mycoses - often life- threatening. Unlike bacteria, fungi are eukaryotic - they have rigid cell walls composed of N-acetylglucosamine- rather than peptidoglycan (typical for most bacterial cell walls).

26. The fungal cell membrane contains ergosterol (cholesterol in mammalian membranes) - useful in targeting agents against fungal infections. • Fungal infections - generally resistant to antibiotics used in bacterial infections, and conversely, bacteria are resistant to antifungal agents. • Rise in fungal infections (candidemia = the fourth most common cause of septicemia) - associated with  numbers of chronic immune suppression (organ transplant, chemotherapy, HIV.

27. Antifungal drugs • POLYENES:AMPHOTERICIN NYSTATIN GRISEOFULVIN • AZOLES :CLOTRIMAZOLE MICONAZOLE, KETOCONAZOLE FLUCONAZOLE,ITRACONAZOLE • OTHER:FLUCYTOSINE

28. Mechanism ofaction AMPHOTERICIN, NYSTATIN cell membrane sterol binding ergosterol  cholesterol cell wall synthesis inhibition GRISEOFULVIN nucleic acid synthesis inhibition Pharmacokinetics poor GI absorption nystatin– p.o., vag., topical amphotericin – p.o, i.v. absorption  with milk, fat ingestion; concentration in skin, hair, nails(griseofulvin) Polyenes

29. AMPHOTERICIN generalisedfungal infections (cryptococcuc, candidosis) NYSTATIN p.o. in GI mycosis vaginal mycosis locally (skin, mucosa) GRISEOFULVIN dermatophytes Indications

30. AMPHOTERICIN frequent: fever, headache, flebitis, nephrotoxicity, anemia rare: anaphylaxis, hepatotoxicity, vertigo, thrombocytopenia NYSTATIN p.o.  localy: no side effects GRISEOFULVIN GI troubles, cutaneous Side effects

31. Mechanism of action  ergosterol synthesis by fungal cyt P450 binding KETOKONAZOL MIKONAZOL FLUKONAZOL ITRAKONAZOL Pharmacokinetics variable GI absorption good diffusion (except CNS) biliary elimination good GI absorption good tissue diffusion excretion: unchanged -urinary (fluconazole)metabolites: urine  bile(itraconazole) Azoles

32. Indications  side effects KETOCONAZOLE MICONAZOLE rare GI problems skin intolerance FLUCONAZOLE ITRACONAZOLE well tolerated, nausea, headache KETOCONAZOLE superfitial  visceral mycoses MICONAZOLE superfitial skin mycoses FLUCONAZOLE ITRACONAZOLE large scale of s.c.  systemic mycoses

33. Newer azoles Voriconazole Broad- spectrum agent. Treatment of invasive aspergillosis and serious infections caused by Scedosporium apiospermum and fusarium species. Orally active; penetrates well, incl. CNS. Metabolised (CYP450 2C19, 2C9 a 3A4)– possibility of drug interactions. Adverse effects: - similar to other azoles - transient visual disturbance shortly after a dose of the drug

34. Posaconazole • Oral, broad-spectrum, structure similar to itraconazole. • Approved to prevent Candida and Aspergillus infections in severely immunocompromised and for the treatment of oropharyngeal candidiasis. • Relatively well tolerated. • To be effective, posaconazole must be administered with a full meal or nutritional supplement (increased bioavailability). • Adverse effects: • GI (nausea, vomiting, diarrhea, abdominal pain) - headache, elevation of liver function tests, • in patients with concomitant cyclosporine or tacrolimus for management of transplant rejection - rare cases of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and pulmonary embolus

35. Mechanism of action FLUCYTOSINE interacts with RNA - disturbs the building of certain proteins b) inhibits fungal DNA synthesis drug has to be intrafungally converted into the cytostatic fluorouracil Pharmacokinetics good absorption good CNS penetration (75%) renal elimination in unchanged form Other antifungal drugs

36. Indications  side effects • FLUCYTOSINE • systemic candidosis • septicemies • Side effects • GIT • hematologic • hepatal

37. Antiparasitic drugs • Antimalarial agents • Antiamebiasis agents • Antitrichomoniasis agents • Antitrypanosomiasis agents

38. Antimalarial agents Anopheles Plasmodium

39. Malaria treatment • Aim:prevention of mortality  decrease in morbidity by safe  effective drugs • Malaria remains the world’s most devastating human parasitic infection, afflicting more than 500 million people and causing from 1.7 million to 2.5 million deaths each year. • monotherapy was usually used in malaria treatment, e.g. quinine, quinidine, cloroquine, primaquine,mefloquine,sulfadoxine-pyrimethamine(SP)

40. Pharmacokinetics  side effects Pharmacokinetics • total GI resorption • good tissue diffusion • hepatal metabolism • renal excretion Side effects • hemolytic anemia (G-6-P-dehydrogenase deficit) • cloroquinefree of teratogenic effect • SPsecond line drug in pregnancy (more effective because of less resistance)

41. Resistanceto antimalarials 2003: South America  South-East Asia cloroquine, SP cloroquine, SP, mefloquine, quinine

42. Intensification of resistance to cloroquine in Africa (1980-2003) In Africa CQ resistance has spread rapidly since first identified in Kenyaand Tanzania in 1979.

43. Prevention of resistance spreading • WHO –alternative combination therapy instead of monotherapy in countries with increasing appearance of resistance

44. Artemisinin Artemisinin and its derivatives - potent antimalarial activity. Immediate onset and rapid reduction of parasitaemia with complete clearance in most cases within 48 hours Efficacy is high even in areas with multidrug resistant strains. Artemisinin is the extraction product from the herb Artemisia annua L. It was used in traditional Chinese Medicine for the treatment of febrile diseases.

45. Artemisinin Mechanism of action • it contain peroxide group • iron-mediated cleavage of the peroxide bridge and generation of an free radical • the artemisinin radical binds subsequently to membrane proteins, and alkylation reactions eventually cause destruction of the parasite NÚ • artemisinin is extremely well tolerated and virtually without adverse effects • There has been no reports of clinical resistance to the artemisinin so far

46. Antiamebiasis agents Entamoeba histolytica

47. Effective drugs Entamoeba histolytica • in intestinal lumen • in intestinal mucosa (ulcerations) • absces (liver) • Drugs acting in intestine paromomycine • Drugs acting in tissues emetin metronidazole cloroquine

48. Antitrichomoniasis agents Trichomonas vaginalis

49. Metronidazole Mechanism of action • trichomonadocidal without known resistance Pharmacokinetics • good absorption after p.o. • systemic  local (intravaginal) combination therapy Side effects • rare, nausea, glossitis, constipation • headache • urticaria

50. Antitrypanosomiasis agents Tse-tse Trypanosoma gambiense