Anti-Tubercular Agents, pharmacology of Isoniazid and Rifampicin, Study notes of Pharmacology

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Antitubercular Drugs

Tuberculosis

• TB is a bacterial airborne infection
• First disease to be declared as global health

emergency by WHO in 1993

• It is treatable, curable, and preventable
• It affects all organs except for hair and nail
• Duration of treatment is 6 months to 2 years

• Mycobacterium , from the Greek “mycos,” refers to

Mycobacteria’s waxy appearance, which is due to the

composition of their cell walls.

• More than 60% of the cell wall is lipid, mainly mycolic

acids

According to clinical utility anti-TB drugs can be divided into:

First line: These drugs have high antitubercular efficacy

as well as low toxicity; are used routinely.

Second line: These drugs have either low antitubercular

efficacy or higher toxicity or both; and are used as

reserve drugs.

First line drugs Second line drugs

Isoniazid (H) Fluoroquinolones

Cycloserine (Cs), Rifabutin, Para-aminosalicylic acid (PAS) Injectable drugs: Kanamycin (Km), Amikacin (Am), Capreomycin(Cm)

Treatment

• Tuberculosis disease is treated with antibiotics. The most common antibiotics used are:
• Isoniazid

• Rifampicin
• pyrazinamide
• Ethambutol,
• streptomycin
• To be effective, these medications need to be taken daily for 4–6 months. It is dangerous to stop the medications early or without medical advice. This can allow TB that is still alive to become resistant to the drugs.
• Tuberculosis that doesn’t respond to standard drugs is called drugresistant TB and requires more toxic treatment with different medicines.

Goals of antitubercular chemotherapy are:

(c) Prevent emergence of resistance

• So that the bacilli remain susceptible to the drugs.

Short Course Chemotherapy

❑WHO introduced 6 – 8 month multidrug ‘short

course’ regimens in 1995 under the DOTS

programme.

❑An expert group framed clearcut treatment guidelines

in 1997 for different categories of TB patients, who

were grouped according to site and severity of disease,

sputum smear positivity/negativity and history of

previous treatment (new case/ previously treated case)

into 4 categories:

• DOTS= ‘ D irectly O bserved T reatment S hort course’ 1. Category I: New case of sputum smear positive or severe pulmonary TB, or severe forms of extrapulmonary TB (meningitis, etc.). 2. Category II: Defaulted, irregularly treated and relapse cases. 3. Category III: New sputum smear negative pulmonary TB and less severe forms of extrapulmonary TB (glandular/skin TB, etc.).

(nonreplicating) are only inhibited. ▪ It acts on extracellular as well as on intracellular ▪ TB (bacilli present within macrophages), and is equally active in acidic or alkaline medium. ▪ It is one of the cheapest antitubercular drugs. Use of combination therapy (isoniazid + pyrazinamide + rifampin) provides the basis for “short-course” therapy and improved remission rates

• Primary drug for TB
• Synthetic analog of pyridoxine
• Isoniazid is PRODRUG (activated by mycobacterial Catalase peroxidase)

• Bacteriostatic for “resting bacilli”
• Bactericidal for dividing microorganism ❖ Mycolic acid is an essential components of mycobacterial cell walls. ❖ Isoniazid Inhibits synthesis of mycolic acid ❖ Destroying cell wall of mycobacteria

Mechanism of Action

• Isoniazid enters bacilli by passive diffusion.

Metabolism and activation of INH

• Pro-drug INH is metabolized in humans by NAT2 isoforms to its principal metabolite, N-acetyl isoniazid, which is excreted by the kidney.
• Isoniazid diffuses into mycoplasma where it is “activated” by KatG (oxidase/peroxidase) to the nicotinoyl radical, which reacts spontaneously with NAD+ or NADP+

to produce adducts that inhibit important enzymes in cellwall and nucleic acid synthesis.

• DHFR, dihydrofolate reductase. ✔ Two gene products labelled ‘InhA’ and ‘ KasA’, which function in mycolic acid synthesis are the targets of INH action. ✔ INH enters sensitive mycobacteria which convert it by a catalase-peroxidase enzyme into a reactive metabolite. ✔ This then forms adduct with NAD that inhibits InhA and KasA. ✔ The reactive INH metabolite forms adduct with NADP as well which inhibits mycobacterial DHFRase resulting in interruption of DNA synthesis

• Incidence of primary INH resistance varies widely

among different populations, depending on the extent of

use and misuse of INH in that area.

Pharmacokinetics

❑INH completely absorbed orally.

❑Penetrate all the body tissue, tubular cavities, placenta, and meninges. ❑Extensively metabolized in liver, most important pathway being N-acetylation. ❑The acetylated metabolic is excreted in urine.