Ethionamide

It is chemically related to INH and therefore it blocks the production of mycolic acids.


Pharmacokinetics:
It is given orally. It is metabolized by liver. Its dosage of 1 gm/day gives 20μg/ml of serum concentrations in plasma and tissues.

Adverse effects:
It is hepatotoxic.

Para-aminosalicylic acid

It is structurally similar to para-aminobenzoic acid (PABA).


Mechanism of action:
It competes for the enzyme involved in the conversion of PABA to dihydrpteroic acid that results in the inhibition of Purine and as a result DNA synthesis is stopped.

Pharmacokinetics:
It is widely distributed in tissues and rapidly excreted in urine.

Dosage:
Its usual adult dose is 8-12 g/day orally in divided doses.

Adverse effects:
It may cause anorexia, nausea, fever and skin rashes. Furthermore, nephrotoxicity, hepatotoxicity and granulocytopenia.

Pyrazinamide

It is closely related to nicotinamide.


Mechanism of action:
Its exact mechanism of action is unknown but it is thought to be converted into pyrazinoic acid (active form of the drug) with the help of mycobacterial pyrazinamidase, which causes the inhibition of tubercle bacilli at concentration of 20 μg/ml at 5.5 pH.

Therapeutic uses:
In combination with isoniazid and rifampin. It is also used for tuberculosis for short course that is 6 months.

Pharmacokinetics:
It is well absorbed from GIT. It is widely distributed in body tissues. Its half life is 8-11 hours.

Ethambutol

The word ethambutol is made by the combination of “ethyl” + “amine” + “butanol”. It is bacteriostatic in nature.


Mechanism of action:
It causes inhibition of mycobacterial arabinosyl transferases which is involved in polymerization reaction of arabinoglycan, which is an essential component of mycobacterial cell wall.

It is also thought to inhibit RNA synthesis.

Pharmacokinetics:
It is well absorbed from the gut. It is well distributed throughout the body. Peak level of 2-5 μg/ml is achieved in 2-4 hours. It can cross the blood brain barrier when the meninges is inflamed. 20% percent of the metabolites are excreted in feces and 50% is excreted in urine.

Therapeutic uses:
Ethambutol is found to be more effective against M. tuberculosis and M. kansasii.

It can be used for tuberculous meningitis.

Dosage:
Its usual dose is 15mg/kg/day.

Adverse effects:
It may cause fever and skin rashes. It may cause optic neuritis and reduction in visual acuity. It may also cause a loss of red and green color discrimination.

Rifampin

It is also called as rifampicin. It is a semisynthetic derivative of rifamycin which is an antibiotic produced by a bacterium Streptomyces mediterranei.


Rifampin is a blend of rifamycin and piperazine.
Mechanism of action:

Rifampin is bactericidal for mycobacteria. Human RNA polymerase is not affected by rifampin.

Pharmacokinetics:
It is well absorbed orally.

It readily penetrates most of the tissues and phagocytic cells and that is why it is widely distributed in body fluids and tissues.

It is excreted through liver into the bile where it undergoes enterohepatic recirculation.

Deacylated metabolite is excreted in feces and small amount is excreted through urine.

Therapeutic uses:
It is used in mycobacterial infections such as tuberculosis and leprosy. It is also used in prophylaxis in contact of children with Haemophilus influenzae type b disease.

In combination therapy, it is also used for serious Staphylococcal infections.

Dosage:
Its usual dose is 600mg/day with isoniazid, ethambutol or other anti-tuberculous drugs.

Adverse effects:
It produces harmless orange colour to urine, sweat and tears. It may cause rashes, light chain proteinuria, thrombocytopenia and nephritis.

Resistance:
Resistance is found to be due to alteration in the genetic material of bacteria DNA dependent RNA polymerase.

Isoniazid

It is also referred to as INH as its full name is “Isonicotinic acid hydrazide”.
Mechanism of action:
It causes a decreased synthesis of mycolic acid. Mycolic acid is a constituent of mycobacterial cell wall that is thought to be responsible for the acid fastness of the bacteria.

Where,

KatG is mycobacterial catalase (peroxidase),

AcpM is Acyl carrier protein,

KaSA is Beta ketoacyl carrier protein synthetase.

Here in the above diagram, mycolic acid synthesis is blocked as mycolic acid is produced by the incorporation of cyclopropane ring near the centre of acyl chain.

Pharmacokinetics:
It is readily absorbed by GIT. 300 mg of oral dose achieves peak plasma concentration of 3-5μg/ml in 1-2 hours. The drug diffuses easily into bodily fluids and cells.

It is metabolized by liver N-acetyltransferase (in which its acetylation occurs).

Average half life in peoples with rapid acetylation is 1 hour and in peoples with slow acetylation it is 3 hours.

Elimination is done via urine.

Therapeutic uses:
It is used in the prophylaxis as well as treatment of tuberculosis.

Dosage:
The usual adult dose is 5mg/kg/day to a maximum of 300 mg/day.

Adverse effects:
It may cause fever, skin rashes, Insomnia and restlessness. It may also induce hepatitis characterized by loss of appetite, nausea and vomiting. Hepatitis is thought to be associated to the metabolite monoacetylhydrazine.

Sometimes peripheral neuropathy (neuropathy is caused by pyridoxine deficiency and isoniazid causes an increased pyridoxine excretion) is also observed.

Resistance:

Resistance is found to be due to chromosomal alterations resulting in change in genetic material of KatG or due to over expression of enoyl acyl carrier protein reductase.

Classification of anti-tuberculosis

First line drugs:

Isoniazid, Rifampin, Ethambutol, Streptomycin, Pyrazinamide

Second line drugs:
Ethionamide, Cycloserine, Tetracycline, para-aminosalicylic acid, Amikacin, Fluoroquinolones