ANTI- TUBERCULOSIS DRUGS

Tuberculosis

Tuberculosis is one of the world’s most widespread and deadly illnesses.

Mycobacterium tuberculosis, the organism that causes tuberculosis infection and disease, infects an estimated 20 – 43% of the world’s population.

3 milion people worldwide die each year from the disease

Tuberculosis

Infection with M tuberculosis begins when a susceptible person inhales airborne droplet nuclei containing viable organisms. Tubercle bacilli that reach the alveoli are ingested by alveolar macrophages. Infection follows if the inoculum escapes alveolar macrophage mirobicidal activity.

Tuberculosis

Symptoms and Signs:1. Malaise2. Anorexia3. Weight loss4. Fever5. Night sweats6. Chronic cough, blood with sputum7. Rarely, dyspnea

Anti Mycobacterial Drugs

Mycobacteria are intrinsically resistant to most antibiotics.

They grow slowly compared with other bacteria, antibiotics that are most active against growing cells are relatively ineffective. so, that’s why we use combination of drugs.

Mycobacterial cells can also be dormant and thus completely resistant to many drugs or killed only very slowly.

Anti Mycobacterial Drugs

Drugs Used in Tuberculosis First-line drugs :1. Rifampin, 2. Isoniazid (INH), 3. Pyrazinamide, 4. Ethambutol, and5. Streptomycin These drugs are the first-line agents for the treatment of

tuberculosis. Isoniazid and Rifampin are the two most active drugs.

Mnemonics RIPES

It is a chemo not antibiotic. Isoniazid is the most active drug for the

treatment of tuberculosis caused by susceptible strains.

It is small (MW137) and freely soluble in water.

It has the structural similarity to pyridoxine = (Vit.B6)

It is bactericidal for actively growing tubercle bacilli.

1-ISONIAZID (INH)

ISONIAZID (INH)

It is less effective against atypical mycobacterial species.

Isoniazid penetrates into macrophages and is active against both extra- and intracellular organisms.

Mechanism of Action and Basis of Resistance

DNA

Mycolic acid, essential component of cell wall

KatG enzyme, a mycobacterial catalase

peroxidase enzyme, activates INH

INH, a prodrug

The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a ß-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and kills the cell.

CLINICAL USES

1. Infections caused by mycobacterium

tuberculosis along with other

antitubercular drugs Dosage: 300mg/day per oral adults, or

900mg twice/week. 5mg/kg/day in children.

2. INH is the primary drug used to treat latent tuberculosis, 300mg/day alone

or 900mg twice/week for 9 months.

Adverse Reactions of INH:

The incidence and severity of untoward reactions related to dosage and duration of administration.

1. Immunologic reactions:

Fever

Drug induced systemic lupus erythematosusSkin rashes

Adverse Reactions of INH:

2. Direct toxicityIsoniazid induced hepatitis (most common major

toxic effect). Clinical hepatitis with◦ loss of appetite, ◦ nausea, ◦ vomiting, ◦ jaundice and ◦ right upper quadrant pain, there is histologic evidence of

hepatocellular damage and necrosis. The risk of hepatitis depends on age, rarely occurs under age of 20,

2.3% for aged 50 and above.

Adverse Reactions of INH:

The risk of hepatitis is higher in ◦ alcoholics, ◦ pregnancy and ◦ postpartum period.

3. Peripheral neuropathy in 10-20% of patients given dosages greater than 5mg/kg/day but infrequently seen with the standard 300mg adult dose.◦ It is more likely to occur in slow acetylators and patients

with malnutrition, alcoholism, diabetes and AIDS. Neuropathy is due to relative deficiency of pyridoxine.

Adverse Reactions of INH:

4. CNS toxicity, which is less common includes memory loss, psychosis and seizures. These may also respond to pyridoxine.

5. Miscellaneous adverse effects:– Provocation of pyridoxine deficiency anemia,

tinnitus and gastrointestinal discomfort. Drug interactions: isoniazid can reduce

the metabolism of phenytoin.

Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei.

It is active in vitro against gram positive and gram negative cocci, some enteric bacteria, mycobacteria and chlamydia.

2-RIFAMPIN

ANTIMICROBIAL ACTIVITY AND RESISTANCE

Rifampin binds to the β subunit of bacterial DNA–dependent RNA polymerase and thereby inhibits RNA synthesis. Resistance results from any one of several possible point mutations in rpoB, the gene for the β subunit of RNA polymerase.

Rifampin

These mutations result in reduced binding of rifampin to RNA polymerase.

Human RNA polymerase does not bind rifampin and is not inhibited by it.

Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and phagocytic cells.

CLINICAL USES:

1. Mycobacterial infections:

Rifampin usually600mg/day, 10mg/kg/day,

orally must be administered with isoniazid

or other antituberculous drugs to patients

with active tuberculosis to prevent emergence of drug resistant mycobacteria.

CLINICAL USES:

2. Atypical mycobacterial infections.

3. Leprosy.

4. As alternative of isoniazid in prophylaxis of latent tuberculosis.

5. To eliminate meningococcal

carriage, staphylococcal carriage

6. Osteomyelitis and prosthetic valve endocarditis caused by staphylococci

Adverse effects:

1. Rifampin imparts a harmless orange color to urine, sweat, tears and contact lenses.

2. Occasional adverse effects:

rashes

cholestatic jaundice

Flu-like syndrome characterized by fever,

chills, myalgias, anemia,

thrombocytopenia, acute tubular necrosis.

hepatitis

nephritis

Ethambutol is a synthetic water soluble, heat stable compound, the dextro-isomer of the structure dispensed as the dihydrochloride salt.

Ethambutol inhibits mycobacterial arabinosyl

transferases. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall.

3-Ethambutol

Mechanism of action:

Clinical Uses of Ethambutol

Tuberculosis: 1. Ethambutol hydrochloride 15-25mg/kg/d is usually

given as a single daily dose in combination with isoniazid or rifampin.

Adverse effects:1. Retrobulbar (optic) neuritis resulting in loss of visual

acuity and red green color blindness. Usually occur at doses of 25mg/kg/day continued for several months.

Precaution & contraindication

Periodic visual acuity testing is desirable if the 25mg/kg/day dosage is used.

It is relatively contraindicated in children too young to permit assessment of visual acuity and red green color discrimination.

Pyrazinamide (PZA) is a relative of nicotinamide, stable and slightly soluble in water.

It is inactive at neutral PH, But at PH 5.5 it inhibits tubercle bacilli, and some other mycobacteria at concentrations of approximately 20mcg/ml.

4-PYRAZINAMIDE

The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes.

Pyrazinamide is converted to pyrazinoic acid, the active form of the drug, by microbial pyrazinamidase, which is encoded by pncA.

The drug target and mechanism of action are unknown.

Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA that impair conversion of pyrazinamide to its active form.

Clinical Uses of Pyrazinamide

Pyrazinamide is an important front line drug used in conjuction with isoniazid & rifampin in short course (i.e 6 months) regimens as a sterilizing agent active against residual intracellular organisms that may cause relapse.

Advese effects of Pyrazinamide

1. Hepatotoxicity (in 1-5% of patients-major adverse effect).

2. Hyperuricaemia (it may provoke acute gouty arthritis).

3. Nausea, vomiting, & drug fever.

Streptomycin was isolated from a strain of Streptomyces griseus.

Mechanism of action: Like all aminoglycosides, streptomycin

irreversibly inhibits bacterial protein synthesis. Protein synthesis is inhibited in at least three ways:

5-STREPTOMYCIN

Mechanism of Action of Strept.

1. interference with the initiation complex of peptide formation.

2. Misreading of mRNA, which causes incorporation of incorrect aminoacids into the peptide, resulting in a nonfunctional or toxic protein.

3. Breakup of polysomes into nonfunctional monosomes.

CLINICAL USES

Tuberculosis:

Streptomycin is used when an injectable drug is needed, principally in individuals with severe, possibly life threatening forms of tuberculosis eg, meningitis and disseminated disease.

Adverse Effects

Ototoxicity

Nephrotoxicity

Toxicity is dose related and the risk is increased in elderly

ALTERNATIVE SECOND-LINE DRUGS FOR TUBERCULOSIS

The alternative drugs are usually consider only;

1. In case of resistance to first line agents. 2. In case of failure of clinical response to convential therapy 3. In case of serious treatment limiting adverse drug reactions 4. when expert guidance is available to deal with the toxic effects.

ETHIONAMIDE

Ethionamide is chemically related to isoniazid.

It is poorly water soluble and available only in oral form.

Mechanism of action: Ethionamide blocks synthesis of mycolic

acids in susceptible organisms.

CAPREOMYCIN Capreomycin is an antibiotic from streptomyces

capreolus

Mechanism of action : It is a peptide protein synthesis inhibitor. Capreomycin is an important agent for the

treatment of drug resistant tuberculosis. Strains of M tuberculosis that are resistant to

streptomycin or amikacin usually susceptible to capreomycin

CYCLOSERINE :

Cycloserine is an antibiotic produced by streptomyces orchidaceus.

Cycloserine is a structural analog of D- alanine.

Mechanism of action : It inhibits the incorporation of D- alanine into

peptidoglycan pentapeptide by inhibiting alanine racemase, which converts L-alanine to D- alanine, and D- alanyl-D –alanine ligase (finally inhibits mycobacterial cell wall synthesis).

Aminosalicylic acid (PAS):

Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against mycobacterium tuberculosis.

it is structurally similar to p-aminobenzoic acid(PABA) and the sulfonamides.

Fluoroquinolones :

Ciprofloxacin, Levofloxacin, gatifloxacin, moxifloxacin can inhibit strains M tuberculosis.

They are also active against atypical mycobacteria.

Moxifloxacin is the most active against M tuberculosis.

Fluoroquinolones are an important addition to the drugs available for tuberculosis, especially for strains that are resistant to first line agents.

Dosage : Ciprofloxacin 750mg BD,POLevofloxacin 500mg OD.POMoxifloxacin 400mg OD. PO

Mechanism of action:

They inhibit bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA Gyrase) and topoisomerase IV.

Inhibition of DNA Gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication.

RIFABUTIN Rifabutin is derived from rifamycin and is

related to rifampin. It has significant activity against

mycobacterium tuberculosis , M avium- intracellulare and mycobacterium fortuitum

Dosage 300mg/day.

RIFAPENTINE :

Rifapentine is an analog of rifampin. It is active against both M tuberculosis and M

avium

Mechanism of action: It is a bacterial RNA polymerase inhibitor. Pharmacokinetics: Rifapentine and its active metabolite, 25

desacetyl rifapentine have an elimination half life of 13 hours.