1. Presented by:Professor Dr. Imad A-J Thanoon Department of Pharmacology College of Medicine-University of Mosul

3. Mycobacterium Infections Common Infection Sites lung (primary site) brain bone liver kidney

4. Difficult to treat: 1.Most antibiotics are effective against rapidly growing organism in contrast to M.tb  slow growing 2.Mycobacterium Cell can be dormant, thus completely resistant to many antibiotics or killed very slowly by few drugs 3.The lipid rich mycobacterium Cell wall is impermeable to many drugs. 4.A substantial proportion are intracellular &chemotherapeutic agents penetrate poorly 5.Mycobacterium develop resistance to any single drug 6.Caseation &fibrosis block the blood vessels supplying necrotic area thus penetration of antitubercular drug difficult

5. Isoniazid (INH), Rifampicin, Pyrazinamide, Ethambutol, and Streptomycin are five first line agents for treatment of tuberculosis. Isoniazid and Rifampicin are the two most active drugs. An Isoniazid – Rifampicin combination administrated for 9 months will cure 95-98% of cases of TB. The addition of Pyrazinamide to an Isoniazid –Rifampicin combination for the first 2 months allow the total duration of therapy to be reduced to 6 months without loss of efficacy.

6. In practice, therapy is initiated with a four drug regimen of Isoniazid–Rifampin, Pyrazinamide, and either Ethambutol or Streptomycin

8. Antitubercular Therapy Effectiveness depends upon: Type of infection Adequate dosing Sufficient duration of treatment Drug compliance Selection of an effective drug combination

9. Isoniazid (INH) INH introduced in 1952, is the most active drug for the treatment of tuberculosis caused by susceptible strains. INH is the hydrazine of Isonicotinic acid.It is bactericidal for effectively growing tubercle bacilli. INH able to penetrate into phagocytic cells. Metabolised in the liver by acetylation ( watch for slow acetylator). Diabetic patients taking INH should monitor their blood glucose levels because hyperglycemia may occur.

10. Mechanism of action of INH: INH is a pro-drug that is activated in the body, the activated form of INH exerts its lethal effect by blocks mycolic acid synthesis, an essential components of mycobacterial cell walls. It is an enzyme inhibitors for drug metabolism, it inhibit meta. Of warfarin,diazepam,CBZ and phenobarbitone.

11. Adverse reactions : 1.allergic reactions : fever and skin rashes. 2.direct toxicity : INH induced hepatitis is the most frequent major toxic effect, caused by the acetyl hydrazine metabolite. 3.clinical hepatitis with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in 1% of INH recipients and can be fatal. 4.Peripheral neuropathy by ↑vitamin B6 excretion. More frequent in slow acetylators 5.CNS toxicity: memory loss, psychosis, and seizures. 6.Miscellaneous : hematological abnormality provocation of B6 deficiency, anemia, tinnitus, & GI discomfort. No dose modification in R-F C/I acute liver disease.

12. Rifampicin : Mechanism of action of Rifampicin : Rifampicin binds strongly to the B-subunit of bacterial DNA-dependant RNA polymerase and there by inhibit RNA synthesis, it is bactericidal.It act both intra & extracellular,and its bactericidal efficacy is about that of INH. Food interfere with the absorption, wide penetration to tissues(placenta, meninges,cavities, caseous mass) Eliminated in bile & undergo enterohepatic circulation.

14. Adverse reactions of Rifampicin : Rifampicin in part a harmless orange color to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained ). Occasional adverse effects include rashes, nephritis, and thrombocytopenia. It may cause cholestatic jaundice and occasionally hepatitis. Rifampin causes a flu-like syndrome characterized by fever, chills, myalgias, anemia, thrombocytopenia and some times is associated with acute tubular necrosis. Note: rifampicin cause oral contraceptives to become ineffective

15. Ethambutol : Is a synthetic drug Mechanism of action :Ethambutol is an inhibitor an essential component of the mycobacterial cell mall( by inhibiting the enzyme mycolic arabin transfersae required for polymerization reaction of arabinoglycan). Note: Dose to be reduced in RF,C/I < 6 years

16. Adverse reactions : The most common serious adverse events is retrobulbarneuritis causing loss of visual acuity and red-green color blindness. This dose–related side effect is more likely to occur at dosage of 25mg/kg/d visual acuity testing is desirable if the 25mg/kg/d dosage is used. Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination.

17. Pyrazinamide : Pyrazinamide is a weak tuberculocidal, more active in the first 2 months of therapy, active against intra & extracellular bacilli Mechanism of action :Act by inhibiting mycolic acid synthesis It is distributed throughout the body after oral use and excreted mainly by GF. It reduce the relapse rate from 10.3% to 3.4%

18. Adverse reactions of Pyrazinamide: Major adverse effects of Pyrazinamide include hepatatotoxixity ( in 1-5% of patients ), it is the most hepatotoxic drug, nausea, vomiting, drug fever and hyperuricemia, the latter occurs uniformly and is not a reason to half therapy. hyperuricemia may provoke acute gouty arthritis. ( it inhibit the excretion of urates).

20. Streptomycin : Is aminoglycosides group, which are group of bactericidal antibiotics and sharing chemical, antimicrobial, pharmacologic and toxic characteristics. More active against extracellular bacilli, absorption from IM site 30-60 minutes excreted unchanged in the urine.

21. Adverse effects of Streptomycin Streptomycin is ototoxic and nephrotoxic. vertigo and hearing loss are the most common side effects, and may be permanent. ototoxicity is dose related, and the risk is increased in elderly, as with all aminoglycosides, the dose must be adjusted according to renal function toxicity can be reduced by limiting therapy to no more than 6 months whenever possible.It can cause sterile abscess at the injection site.

22. Alternative second-line drugs in treatment of tuberculosis : The alternative drugs listed below are usually considered only :- in the case of resistance to the drugs of first choice ( which occur with increasing frequency ) in case of failure of clinical is available to deal with toxic effects.

23. Ethionamide : Ethionamide is chemically related to INH and also block the synthesis of mycolic acids. available only in oral form it is metabolized by the liver. Although effective in the treatment of tuberculosis, is poorly tolerated because of the intense gastric irritation and neurologic symptoms that commonly occur. Ethionamide is also hepatotoxic. neurologic symptoms may be alleviated by pyridoxine.

24. Capreomycin : Capreomycin (a peptide) is an important injectable agent for treatment of drug resistant tuberculosis. strains of m. tuberculosis that are resistant to streptomycin or amikacin. Capreomycin is nephrotoxic and ototoxic tinnitus, deafness, and vestibular disturbances occurs the injection causes significant local pain, and sterile abscessed may occur.

25. Cycloserine : Cycloserine is an inhibitor of cell wall synthesis, inhibit many gram negative and gram positive organisms, but it is used almost exclusively to treat tuberculosis resistant to first line agents. The most serious adverse effects are peripheral neuropathy,depression and psychotic reactions. pyridoxine 150mg /d should be given with Cycloserine.

26. Kanamycin and Amikacin : The pharmacology, mode of action, toxicity and antibacterial properties of kanamycin and Amikacin are similar to streptomycin, but prevalence of drug –resistant, strains is low

27. Ciprofloxacin and Levofloxacin : Quinolones are bactericidal. Floroquinolones are an important recent addition to the therapeutic regimens against tuberculosis, specially strains that are resistant to first –line agents. The drug most be used in combination with two or more other active agents. A floroquinolone plus Pyrazinamide may also be used to prevent disease following contact to active case of multi drug – resistant tuberculosis.