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After reading this article we will learn about the first line and second line of antituberculosis drugs.
First Line Anti-T.B. Drugs:
These have high antitubercular efficiency as well as low toxicity and are used routinely.
These are:
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(i) Isoniazid
(ii) Rifampin
(iii) Pyrazinamide
(iv) Ethambutol
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(v) Streptomycin
Second Line Anti-T.B. Drugs:
These drugs have either low autitubercular efficiency or high toxicity or both and are used in special circumstances only.
These are:
Thiacetazone
(i) Paramino Salicylic acid (PAS)
(ii) Ethionamide
(iii) Cycloserine
(iv) Kanamyc in
(v) Amikacin
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(vi) Capromycin.
Isoniazid (Isonicotinic acid hydroxide):
It is a hydrazide of Isonicotinic acid which formed during synthesis of Thiosemicarbazone of Isonicotine aldehyde. It posses bacteriostatic and bacteriocidal activity.
Mechanism of Action:
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Actual Mechanism is not known but most possible action could be inhibition of synthesis of mycolic acids which are unique Fatty acid component of mycobacterial cell wall.
Pharmacokinetics:
Isoniazid is completely absorbed orally and penetrates all body tissues, tubercular cavities, placenta and meanings. It is extensively metabolised in liver and excreted in urine as acetyl isoniazid.
Resistance:
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If INH is given alone, after 2-3 months an apparent resistance emerges. Mechanism of resistance is attributed to failure of the drug being taken by organism.
Dose:
4-6 mg/kg may be increased up to 10-12 mg/kg.
Adverse Effects:
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Peripheral neuritis and a variety of neurological manifestations such as paresthesis, numbness, mental disturbances, rarely convulsions are the most important dose dependent effects. These are due to interference with utilization of pyridoxine and its increased excretion in urine. Pyridoxine given prophylactically (10 mg/day) prevents neurotoxicity even with higher doses.
Rifampin:
It is a semisynthetic derivative of rifamycin obtained from streptomyces mediterrranei. It has bacteriocidal action on M. tuberculosis, M. paratuberculosis and other subpopulations of TB bacilli. It acts best on slowly or intermittently dividing bacilli as well as on many atypical mycobacteria. Both extra and intracellular organisms are affected.
Mechanism of Action:
Inhibits bacterial DNA dependant RNA synthesis.
Pharmacokinetics:
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It is well absorbed orally, widely distributed in the body, penetrates cavities, caseous masses, placenta and meninges. It is metabolized in liver to an active de-acetylated metabolite, which is excreted mainly in bite, some in urine also. The t 1/2 of rifampin is 2-5 hours.
Resistance:
Mycobacteria and other organisms develop resistance to rifampin rather rapidly. Resistance is due to mutation. No cross resistance with any other antitubercular drug has been noted.
Dose:
10 Mg/kg body weight, available in capsule, suspension and syrup form.
Adverse Effects:
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Hepatitis, a major adverse effect generally occurs in patients with preexisting liver disease and is dose related. Respiratory syndrome, haemolysis, shock and renal failure are serous reactions but occur rarely.
Pyrazinamide:
It is chemically similar to isoniazid. It is parazine of carboxamine- N- Nicotinamide. It is white crystalline powder soluble in water, stable at room temperature. It is highly active against intracellularly located bacilli and in acidic medium, at pH 5-5.5. It is highly effective during the first 2 months of therapy when inflammatory changes are present.
Mechanism of Action:
Resembles to Isoniazid, it inhibits mycolic acid synthesis of TB bacilli by interacting with fatty acid synthatase encoding gene-leading to tuberculocidal action against TB bacilli.
Pharmacokinetics:
It is absorbed orally, widely distributed in body, has good penetration in CSF, extensively metabolized in liver and excreted in urine. It has plasma half life of 6-10 hours.
Resistance:
Resistance develops rapidly if it is used alone. It is due to mutation in the gene which encodes for the enzyme generating the active metabolite of pyrazinamide.
Dose:
25-30 mg/kg body weight, available in tablet and syrup form.
Adverse Reactions:
In higher doses it causes heptotoxicity. It is contraindicted in patients with liver disease.
Ethambutol:
It is a commonly used antitubercular drug, possess selective tuberculostatic activity. It is chemically N, N-di isopropyl ethylene diamine. It is odourless, white crystalline, soluble in water. When it is used in combination with Isoniazid and Pyrazinamide it has been found to hasten the rate of sputum conversion and prevent development of resistance in humans.
Mechanism of Action:
Action of Ethambutol is not fully understood but it has been found to inhibit arabinogalactan synthesis and to interfere with mycolic acid incorporation in mycobacterial cell wall.
Pharmacokinetics:
About 3/4th of oral dose is absorbed from G.I. tract. It is distributed widely but penetrates meninges incompletely and is temporarily stored in RBCs. Plasma half life is about 4 hours. It is excreted in urine by glomerular filtration and tubular secretion.
Resistance:
It is due to alteration in the drug target gene which develops slowly. No cross resistance with any other antitubercular drug has been noted.
Dose:
15-20 mg/kg body weights.
Adverse Reactions:
Loss of visual acquity or colour vision due to optic neuritis is the most important dose and duration dependant toxicity. In human loss of vision in 10% of individual after a dose of 25-50 mg/kg and this trouble begins after 7 months of initiation of therapy.
Streptomycin:
It was the first clinically useful anti- tubercular drug. It is an aminoglycoside antibiotic obtained from streptomyces griseus. It is tuberculocidal but less effective than isoniazid or Rifampin. It acts only on extracellular bacilli because of poor penetration into cells.
Mechanism of Action:
Inhibition of bacterial protein synthesis by binding with 30s subunit of bacterial ribosomes. After exposure to it sensitive bacteria becomes more permeable to ions, amino acids, and even proteins leak out followed by cell death.
Pharmacokinetics:
It is highly ionized. It is neither absorbed nor destroyed in G.I.T., however absorption from sites in muscles is rapid. It is distributed only extracellularly. It attains low concentrations in serous fluids like synovial, pleural, etc. It is not metabolised and exerted unchanged in urine through glomenular filtration. It’s plasma half-life 2.4 hours but it persists longer in tissues.
Resistance:
Develops rapidly when it is used alone. In case of streptomycin resistant infection it must be stopped at the earliest because of chances of streptomycin dependence.
Dose:
15 mg/kg body weight available in injectable form.
Adverse Reactions:
Vestibular and Auditory disturbances and in some cases nephrotoxicity.
Second Line TB drugs:
Thiacetazone:
Thiacetazone is used orally along with Isoniazid as a substitute for Paraaminosalicylic acid.
Mechanism of Action:
It is a tuberculostatic drug possess low efficacy.
Pharmacokinetics:
It is orally active, primarily excreted unchanged in urine with a half life of 12 hours.
Dose:
2.5 mg/kg body weight, frequently used as combined tablet with isoniazid.
Adverse Effects:
Major adverse effects are hepatitis, exfoliative dermatitis and rarely bone marrow depression.
Paraminosalicylic Acid (PAS):
It was introduced in 1946 on the basis of observed effects of salicylic acid on the metabolism of mycobacterium tuberculosis. Chemically it is related to sulfon amides. It is tuberculostatic drug active only on TB bacilli and not on other bacteria.
Mechanism of Action:
Competitively inhibits an enzyme dihydropteroate synthetase as they are structural analogues or antagonists of Paraaminobenzoic acid (PABA), leading to inhibition of synthesis of folic acid and subsequent metabolites resulting in tuberculostatic effect. PAS is not effective against sulfonamide sensitive organism and vice versa. Selectivity for T.B. may be due to difference in the affinity of Folate synthatase of T.B.
Pharmacokinetics:
It is absorbed completely by the oral route and distributed all over except in CSF. About 50% of Paraaminosalicylic acid is acetylated, competes with acetylation of isoniazid thus prolongs its t1/2. It is excreted rapidly by glomerular filtration and tubular secretion, t1/2 is about 1 hour.
Resistance:
Resistance to PAS develops slowly. Resistance not detected unless therapy is constituted at least 4 months and with increase in duration emergence of resistance also increases. It may go up to 75% at the end of one year.
Dose:
200 mg/kg b.w. available in tablet form.
Adverse Effects:
G.I. Irritation, hyper sensitization, haematological defects which consist of Leukopenia, agranulocytosis, eosinophilia, thrombocytopenia, liver dysfunction characterised by decrease information of prothrombin. Prolonged treatment cause goitre and electrolyte disturbances.
Ethionamide:
It is congener of Thio-iso-nicotinamide and a-ethyl derivative of hi-iso-nicotinamide that possess increased effectiveness. It is tuberculostatic drug acts on both extra and intracellular organisms. Chemically it is 2 ethyl-iso-thionicotin-amide. It is yellow, crystalline insoluble sulfide stable at all temperature. Inhibitory concentration against human strain is 0.25 µg/ml and for bovine strain is 5 µg/ml.
Pharmacokinetics:
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After oral administration of (1 gm.) peak concentration (20 µg/ml) is obtained in 3 hours. After 9 hrs. the concentration is reduced to 3 µg/ml and to 0.6 µg/ml after 20 hrs. It is rapidly and widely distributed. It also diffuses in CSF at effective concentrations. It is excreted rapidly through urine, less than 1% is excreted unchanged.
Adverse Effects:
G.I. disturbances, posterior hypotension, convulsion and hepatotoxicity.
Cycloserine:
It is a broad spectrum antibiotic obtained from streptomyces orchidaceus. It is tuberculostatic and inhibit some other gram positive bacteria. It is analogue of D-alanine, soluble in water and is stable in alkaline solution but destroyed when exposed to neutral or acidic pH.
Mechanism of Action:
Inhibits bacterial cell wall synthesis by inactivating the enzymes which racemize L-alanine and Link two D-alanine residues.
Pharmacokinetics:
Rapidly absorbed from oral administration. Peak concentration occurs after 4 hours and small quantity is obtained after 12 hrs. of administration. Highly diffusible in body fluids and tissues, concentrations in CSF correspond to plasma. Multiple doses lead to accumulation of drugs. Excretion is mainly through urine after injection 50% is excreted unchanged in 12 hrs. 65% in 72 hrs. and 35% is metabolised.
Resistance:
Develops slowly, no cross resistance.
Dose:
200 mg twice daily in Man. It should achieve plasma concentration 25-30 µ/ml.
Adverse Effects:
The CNS toxicity of cycloserine is high sleepiness, headache, tremor and Psychosis are major signs of toxicity.
