Antituberculosis Drugs
المرحلة الثالثةادوية\د.شهباء
العدد5
14\3\2018
تسلسل14
Principles of antituberculous therapy
Kill a large number of actively mulutiplying bacilli: isoniazid achieves thisTreat persisters i.e semidormant bacilli that metabolise slowly or intermittently: rifampicin and pyrazinamide
Prevent the emergene of drug resistance by multiple therapy to suppress single-drug –resistant :isoniazid and rifampicin are best
Combined formulations are used to ensure that poor compliance does not result on monotherapy with consequent drug resistance.
First line treatment of TB
IsoniazidRifampicin
Pyrazinamide
Ethambutol
Isoniazid
Mechanism of action
is selectively effective against mycobacterium tuberculosis because it prevents the synthesis of components that are unique to mycobacterial cell wall,mycolic acid. So, it bactericidal against actively multiplying bacilli and bacteriostatic against non-dividing bacilli is, a synthetic analog of pyridoxine,it is prodrug.
Isoniazid
Pharmacokinetics:orally administerd,readily absorbed impaired with food ,diffuses into all body fluid,cells,necrotuc tissue.Readily crossing tissue barriers, entering cells and CSF.
Is inactivated by conjugation with N-acetyl group and the rate of the reaction is bimodel (slow and fast) acetylator,liver disease decrease metabolism,exc.through kidney.
Isoniazid
Adverse effectsLiver damage
Peripheral neuropathy (give pyridoxine B6).
Drug interaction (enzyme inhibitor).
Others like mental abnormalities, convultion,optic neuritis,rash,fever.
Rifampicin:(Rifampin,Rifabutin,Rifapentine).
has bactericidal activity against the tubercle bacillus.Mechanism of action
Acts by inhibiting m RNA synthesis, by suppressing the initiation step.
Rifapentine has longer duration give twice weekly for 2 months,then once weekly for 4 months.
Rifabutin is derivative of Refampin.used in T.B Patient with HIV treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors,
Because it is less potent inducer of cytochrome p450
Enzyme.,it also cause uveitis ,hyperpigmentation,
Neutropenia.
Rifampicin
In addition to tubercle bacillus it has a wide range of antimicrobial activity. So can used against leprosy, severe legionnaires’ disease (with erythromycin or ciprofloxacin) And severe staphylococcus infection (with flucloxacillin or vancomycin).it act against G+ and G-.the resistance by mutation in the affinity of bacteria for drug or decreased permeability.
Note: you should save rifampicin for TB in the third world
Rifampicin
PharmacokineticWell absorbed from the gastrointestinal tract. It penetrates into most tissues. Enter into the CSF when meninges are inflamed is sufficient to maintain therapeutic concentration at normal doses but transfer is reduced as inflammation subsides.
Is metabolized in the liver
Is a very effective enzyme inducer.
Exc. Via bile into feces or via urine.
Rifampicin
Adverse reactionsFlushing, and itching with or without a rash.
Thrombocytopenia.
Hepatitis
Flu-like syndrome
Acute hemolytic anemia and thrombocytopenia.
Red discoloration of the urine tears and sputum contact lens.
Pyrazinamide
Is a synthetic,orally,bacteriocidal, and is included on first –choice combination regimens because of its particular ability to kill intracellular persisters, i.e. mycobactyeria that are dividing or semi-dormant, often within cells.Pyrazinamide
Mechanism of action
Its action is dependent on the activity of intrabacterial pyrazinamidase, which converts pyrazinamide to the active pyrazinoic acid; this enzyme is most effective in an acidic environment such as the interior of cells.
Distributes throughout the body penetrate CSF.
Pyrazinamide
Adverse effectsHyperuricemia and arthralgia (gouty attack).
Hepatitis
Sideroblastic anemia and urticaria
Ethambutol
Being bacteriostatic, is used in conjunction with other antituberculous drugs to delay or prevent the emergence of resistant bacilli.absorbed orally,distrib-Uted well throughout the body,CSF in T.B meningitis
Adverse effects
Is relatively non-toxic main problem is rare optic neuritis loss ability to discriminate between red and green.
Urate excretion is decreased,gout exacerebrated.
Peripheral neuritis
Alternative second line drugs
They are used either because of1- they are no more effective than the first line and their toxicity are often more serious
2- they are particularly active against atypical strains of mycobatria
Alternative second line of drugs in treatment of TB, its used in a case of resistance to drugs of first choice
1-Ethionamide: its chemically related to INH and its adverse effect gastric irritation, hepatotoxic, neurologic symptom may be alleviated by pyridoxine(B6).
2- capreomycin: its inhibit protein synthesis resistant tuberculous strain, its nephrotoxic and ototoxic, vestibular disturbance and sterile abcess may occur at site of injection.
3-cycloserine: it inhibit cell wall synthesis the adverse effect: peripheral neuropathy and psychotic reaction like depression so give with it pyridoxine 150mg per day.
4- kanamycin and amikacin: they like streptomycin.
5-ciprofloxacin and levofloxacin: used with combination with pyrazinamide.6- Amino salicylic acid
It is baceriostatic that acts as a competitive inhibitor for p-aminobenzoic acid in folate synthesis. It is poorly tolerated
Chemotherapy for leprosy
Bacilli from the skin lesion or nasal discharge of infected patients enter susceptible individuals via abraded skin or the respiratory system,it is chronic disease treatment for 2 months.Triple drug regimen of
Dapsone + clofazimine + rifampicin
Dapsone
Structurally related to sulfonamides,inhibit folate synthesis,it is bacteriostatic for myco bacterium leprae,is well absorbed from the GIT,is distributed throughout the body,with high levels concentrated in the skin,undergoes hepatic acetylation,eliminated through urine.Adverse effect,hemolysis in G6PD deficiency,methe-moglobinemia,peripheral neuropathy,erythema nodosum leprosum(serious skin complication),treated with corticosteroid.