Chemotherapy of Tuberculosis  Medically important mycobacteria  Mycobacterium Tuberculosis  A typical Mycobacterium  Mycobacterium Leprae

Treatment Of Tuberculosis  Tuberculosis remains the primary cause of death due to infectious disease.  Organs involved primarily lungs  Drugs are divided into two groups :  First line  Second line

Antimycobacterial drugs  First line of drugs:  Isoniazid (INH)  Rifampicin  Ethambutol  Streptomycin  Pyrazinamide

Never use a single drug therapy  Isoniazid –rifampicin combination administered for 9 months will cure 95-98% of cases.  Addition of pyrazinamide for this combination for the first 2 months allows total duration to be reduced to 6 months.

Isoniazid  Bacteriostatic for resting bacilli.  Bactericidal for rapidly dividing bacilli.  Is effective against intracellular as well as extracellular bacilli

Mechanism Of Action  Is a prodrug  Cell wall synthesis inhibitor  Inhibits synthesis of Mycolic acids----  Which are essential components of  Mycobacterial cell walls.

Pharmacokinetics  Readily absorbed when given either orally or parenterally.  Aluminum containing antacids interfere with absorption.

Distribution  Diffuse rapidly into all body fluids and cells.  Detected in significant concentrations in pleural & ascitic fluids.  Its concentration in CSF is significant in inflammed meninges.  Penetrates well into caseous material.

Metabolism & Excretion  75% to 95% of a dose of INH is excreted in urine within 24 hours.  Mostly as metabolities.  The main excretory products in human result from enzymatic acetylation.

Clinical uses  Mycobacterial infections (it is recommended to be given with pyridoxine to avoid neuropathy).  Latent tuberculosis in patients with positive tuberculin skin test  Prophylaxis against active TB in individuals who are in great risk as very young or immunocompromised individuals.

Adverse effects  Peripheral neuritis  Optic neuritis &atrophy.  Allergic reactions ( fever,skin rash,systemic lupus erythematosus )  Hepatitis

Adverse effects (cont.)  Hematological reactions  Vasculitis  Arthritic symptoms

Adverse effects (cont.)  CNS toxicity include ;  Lack of mental concentration, memory loss.  Excitability & seizures  Psychosis  ( Respond to pyridoxine)

Drug Interactions of INH  Inhibits the hepatic microsomal enzymes, cytochrome P450 & decrease metabolism of other drugs ( especially, Phenytoin )and increase their toxicity.

Rifampicin  Bactericidal  Inhibits RNA synthesis----- by binding to the beta –subunit of bacterial DNA dependent RNA polymerase.

Site of Action  Intracellular bacilli  Extracellular bacilli  Bacilli in caseous lesions

Pharmacokinetics  Well absorbed orally.  Aminosalicylic acid delay the absorption of rifampicin, (They should be given separately at an interval of 8-12 hour ).

Metabolism & Excretion  Metabolized in liver by acetylation & enters enterohepatic circulation.  Half-life hours & increased in hepatic dysfunction.  Eliminated in bile & feces( 60-65% ) & 30% in urine.

Distribution  Distributed throughout the body organs & fluids including CSF in effective concentration.

Clinical uses  Mycobacterial infections  Prophylaxis of active tuberculosis.  Treatment of serious staphylococcal infections as osteomyelitis and endocarditis.  Meningitis by highly resistant penicillin pneumococci

Adverse effects  Harmless red-orange discoloration of body secretions( urine, sweat, tears) & contact lenses ( soft lenses may be permanently stained ).  Skin rash  Fever

Adverse Effects ( cont.)  Nausea & vomiting  Hepatotoxicity  ( Hepatitis, cholestatic jaundice)  If administered less than twice weekly causes a flu-like syndrome( fever, chills, myalgias, hemolytic anemia, thrombocytopenia & acute tubular necrosis.

Drug Interactions  Potent inducer of hepatic microsomal enzymes ( cytochrome P450)  Increase elimination of other drugs including :  Anticoagulants  Anticonvulsants  Contraceptives

Ethambutol  Bacteriostatic  Inhibits mycobacterial arabinosyl transferase ( inhibits polymerization reaction of arabinoglycan an essential component of mycobacterial cell wall )

Site Of Action  Intracellular & Extracellular bacilli

Phrmacokinetics  Well absorbed orally  Half-life 3-4 hours  75% of the drug is excreted unchanged in the urine, 15% as metabolities.

Clinical uses  Treatment of tuberculosis in combination with other drugs.

Adverse effects  Retrobulbar (optic) neuritis causing loss of visual acuity and red-green color blindness.  Relatively contraindicated in children( under 5 years).  GIT.upset.  Hyperuricemia

Pyrazinamide  Prodrug( converted to pyrazinoic acid,the active form.  Bactericidal  Acting on mycobacterial fatty acid synthase I gene involved in mycolic acid biosynthesis.

Site Of Action  Intracellular Bacilli

Phrmacokinetics  Well absorbed from GIT  Widely distributed including CSF  Half-life 9-10 hours  Excreted primarily by renal route.

Clinical uses  Mycobacterial infections (TB) mainly in multidrug resistance cases.  It is important in short –course (6 months ) regimens with isoniazid and rifampicin.  Prophylaxis of TB in combination with ciprofloxacin.

Adverse effects  Hepatotoxic  Hyperuricemia( provoke acute gouty arthritis )  Nausea & vomiting  Drug fever & skin rash

Streptomycin & Amikacin  Bactericidal  Inhibitors of protein synthesis by biding to 30 S ribosomal subunits.  Acting on extracellular bacilli

Clinical uses  Severe, life-threating form of T.B. as meningitis, disseminated disease, infections resistant to other drugs( Multidrug resistance tuberculosis).  In aerobic gram –ve bacterial infections.

Adverse Effects  Ototoxicity  Nephrotoxicity  Neuromuscular block

Contraindications  Myasthenia gravis  Pregnancy

Indication of 2 nd line treatment  Resistance to the drugs of 1 st line.  Failure of clinical response  There is contraindication for first line drugs.  Patient is not tolerating the drugs first line drugs.

Ethionamide  Blocks synthesis of mycolic acid.  Prodrug  Is converted to active form (sulfoxide ).

Pharmacokinetics  Absorbed from GIT, Given only orally  Rapidly & widely distributed  Half-life 2 hours  Metabolized in liver, less than 1% is excreted in active form in urine  Inhibits the acetylation of INH

Clinical uses  Is a secondary agent, to be used concurrently with other drugs when therapy with primary agents is ineffective or contraindicated.

Adverse Effects  Anorexia, nausea, vomiting, gastric irritation.  About 50% of patients are unable to tolerate a single dose more than 500mg.

Adverse Effects (cont.)  CNS symptoms include :  Mental depression  Drowsiness  Convulsions & peripheral neuropathy  Headache  ( Pyridoxine relieves the neurologic symptoms)

Adverse Effects(cont.)  Severe hypotension  Allergic skin reactions  Hepatitis  Alopecia  Metallic taste

Capreomycin  Aminoglycosides  It is an important injectable agent for treatment of drug-resistant tuberculosis.  It is nephrotoxic and ototoxic.  Local pain & sterile abscesses may occur.

Cycloserine  Inhibitor of cell wall synthesis  Cleared renally  The most serious side effects are peripheral neuropathy and CNS dysfunction, including depression & psychotic reaction.  Pyridoxine should be given.  Contraindicated in epileptic patients.

Amikacin  Used as alternative to streptomycin.  Used in multidrug- resistance tuberculosis.  No cross resistance between streptomycin and amikacin.

Ciprofloxacin & levofloxacin  Effective against typical and atypical mycobacteria.  Used against multidrug- resistant tuberculosis.  Used in combination with other drugs.

Rifabutin  As rifampicin, it is RNA polymerase inhibitor.  Cross resistance with rifampicin but not to all microorganisms.  Enzyme inducer of cytochrome p450.  Effective against typical and atypical mycobacteria.

Phrmacokinetics  Absorbed from GIT  Lipophilic drug  Excreted in urine & bile  Adjustment of dosage is not necessary in patients with impaired renal function.

Clinical uses  Treatment of T.B. in HIV- infected patients ( replaced rifampicin, because it is less potent enzyme inducer)  Prevention of tuberculosis  Prevention & treatment of disseminated atypical mycobacterial infections in AIDS patients

Adverse Effects  Skin rash(4%)  GIT intolerance (3%)  Neutropenia (2%)  Arthralgia  Orange-red discoloration ( skin,urine, as rifampicin ).

Drug Interactions  Enzyme inducer of cytochrome P450 enzymes.

Aminosalicylic Acid (PAS).  Similar in structure to sulfonamide and p- aminobenzoic acid.  Bacteriostatic  Folate synthesis inhibitor.

Pharmacokinetics  Well absorbed from GIT  Best given after meals  Distributed throughout the total body water & reaches high concentration in pleural fluid & caseous tissues.  CSF levels are low  Half-life one hour  80% of the drug is excreted in urine as metabolities.

Clinical uses  AS a second line agent is used in the treatment of pulmonary & other forms of tuberculosis.

Adverse effects  GIT upset ( anorexia, nausea, epigastric pain, diarrhea ).  Hypersensitivity reactions  Hematological troubles ( leukopenia, agranulocytosis, eosinophilia)  Crystalluria

Clofazimine

Drug Regimens  6 months duration  A) First 2 months:  INH+ Rifampin + Pyrazinamide + Ethambutol or Streptomycin  B) Last 4 months  INH + Rifampin

2- Drug Regimens  2- 9 months duration:  A) First 2 months:  INH + Rifampicin + Ethambutol  B) Last 7 months:  INH + Rifampicin

Drug Regimens(cont.)  If there is possibility of drug resistance, Ethambutol or Streptomycin or even second line drugs is added  Depending on :  Type of resistance  Sensitivity of microorganisms

Drug Regimens (cont.)  We give drug combination to :  1- Avoid the emergence of resistance  2- Increase therapeutic efficacy  3- Decrease : Dose, Frequency of dose administration, adverse effects

Treatment Of Tuberculosis In Pregnant Women  AS previously mentioned, but streptomycin is contraindicated because it can cause congenital ototoxicity

Drugs used in leprosy Dapsone  Inhibits folate synthesis.  Well absorbed orally,widely distributed.  Half-life 1-2 days,tends to be retained in skin,muscle,liver and kidney.  Excreted into bile and reabsorbed in the intestine.  Excreted in urine as acetylated.  It is well tolerated.

Clinical uses  Tuberculoid leprosy.  Lepromatous leprosy in combination with rifampin & clofazimine.  To prevent & treat Pneumocystis pneumonia in AIDS caused by Pneumocystis jiroveci ( Pneumocystis carinii).

Adverse effects  Haemolytic anaemia  Methemoglobinemia  Gastrointestinal intolerance  Fever,pruritus,rashes.  Erythema nodosum leprosum

Clofazimine  It is a phenazine dye.  Unknown mechanism of action,may be DNA binding.  Antiinflammatory effect.  Absorption from the gut is variable.  Given orally, once daily.  Excreted mainly in feces.  Stored mainly in reticuloendothelial tissues and skin.  Half-life 2 months.  Delayed onset of action (6 weeks).

Clinical uses  Multidrug resistance TB.  Lepromatous leprosy  Tuberculoid leprosy in :  patients intolerant to sulfones  dapsone-resistant bacilli.  Chronic skin ulcers caused by M.ulcerans.

Adverse effects  Skin discoloration ranging from red-brown to black.  Gastrointestinal intolerance.  Red colour urine.  Eosinophilic enteritis

Treatment of TB in pregnant women  INH ( pyridoxine should be given ),  Rifampicin, ethambutol  Pyrazinamide is given only if :  Resistant to other drugs is documented  Streptomycin is contraindicated.  Breast feeding is not contraindication to receive drugs, but caution should be observed.