Antitubercular Drugs

PHRM 304

Mycobacterium tuberculosis
Main etiological agent of tuberculosis (TB) 2nd leading infectious cause of death after HIV Can remain dormant for years Most host never develop the disease In 2007, 353,000 TB patient were found In Bangladesh (6th in the world, WHO)

Mycobacterium tuberculosis

Antitubercular drugs
Combined treatment of two or more drugs is used. Advantages: Prevents emergence of resistance Additive effect: smaller dose is sufficient

First-line agents
Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin

Second-line agents
Ethionamide, p-aminosalicylic acid, cycloserine, capreomycin, and kanamycin Active antibacterial agents, but they usually are less well tolerated or have a higher incidence of adverse effects Utilized in cases of resistance, retreatment, or intolerance to the first-line drugs

First-line agent

HYDRAZIDE AND DERIVATIVES

Hydrazide
N-N covalent bond Four substituents One acyl group

Hydrazide

Isoniazid (INH)

Isoniazid (INH)
Isoniazid (INH) is a synthetic antibacterial agent Considered to be the primary drug for treatment

Mechanism of action
Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG. Inhibiting the synthesis of mycolic acids, important constituents of the mycobacterial cell wall Most active drug for tuberculosis

Mechanism of action
In the bacterium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellularly.
O C OH

Active compounds (R1 and/or R2 = alkyl ; R3 = H) Destroyed the activity (R1 and R2 = H/alkyl; R3 = alkyl)

Hydroxamic acid

Amide

Iproniazid
Tuberculostatic Psychostimulant Hepatotoxic: no longer used

Hydrazone

Isoniazid hydrazone Synthesis: INH react with aldehyde and ketone Prodrug: Similar activity Activate in GI tract

Second-line agent

P-AMINOSALICYLIC ACID

p-aminosalicylic acid

Commonly known as PAS Used in combination of other TB drugs

p-aminosalicylic acid
It was the second antibiotic found to be effective in the treatment of tuberculosis, after streptomycin. PAS is always used in combination with other anti-TB drugs.

p-aminosalicylic acid
Its potency is less than that of the current five first-line drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, and streptomycin) for treating tuberculosis, but it is still useful in the treatment of multidrug-resistant (MDR) tuberculosis.

Structure variation results inactive or less active compounds:

Replace with Alkoxy, amides, hydroxy, 3o amine Replace with Amino, thiol

-NH2 -OH

Replace with -COOH Alkyl ester, amides, nitrates

Mechanism of action
The mechanism of action is very similar to that of sulfonamides, which inhibit dihydropteroate synthase and thus the biosynthesis of folic acid. Structurally similar to PABA & sulfonamides.