ANTITUBERC

ULAR AGENTS

Rushikesh Diware
Asst. Professor
RSCP Buldhana
Introduction
• Tuberculosis is a chronic granulomatous disease Cause by Mycobacterium tuberculosis

• Major health problem in developing countries.

• About 1/3rd of the world’s population is infected with Mycobact. tuberculosis,

• out of which 10–15% develop the disease over their life time.

• currently infects over 2 billion people worldwide, with 30 million new cases reported every year

• As per WHO statistics for 2014, there were 9.6 million new TB cases globally,

• to which India was the highest contributor with 2.2 million cases.

• India has the dubious distinction of being the highest TB burden country

• about 600 people die from TB every day. accounts for at least 3 million deaths annually worldwide
 Introduction
• TB kills more adults in india than any other infectious disease.

• In 2012 the government of india has declared tb to be a notifiable disease,

• Any doctor who treats a tb patient, has to notify it to the govt. Control and treatment of TB in india

• It is covered under a national programme which provides free treatment to all TB cases.

• The revised national tuberculosis control programme (RNTCP) was launched in 1997

• Treatment guidelines have been successively revised, the last time in 2016

• Common infection sites of the tuberculosis are lungs (primary site), brain, bone, liver, and kidney
• symptoms are cough, tachycardia, cyanosis,and respiratory failure
Types of TB

• Pulmonary tuberculosis (respiratory tract).

• Genitourinary tuberculosis (genitourinary tract).

• Tuberculous meningitis (nervous system).

• Miliary tuberculosis (a widespread infection).

Atypical” mycobacteria
• Mycobacteria other than M. tuberculosis and M. leprae, commonly known as “atypical”
mycobacteria

• were first established as etiological agents of diseases in the 1950s

• primarily saprophytic species that are widely distributed in soil and water

• not normally considered particularly virulent or infectious.

• Diseases attributed to atypical mycobacteria are on the increase

• Because of immunocompromised individuals, AIDS epidemic, use of immunosuppressive

agents
• Mycobacterium avium and Mycobacterium intracellulare MAC Mycobacterium kansasii,
Historical Development
• 1938 sulfanilamide found had weak bacteriostatic properties.

• Sulfone derivative dapsone (4,4-diaminodiphenylsulfone) was investigated clinically

• Used for treatment of leprosy and also has useful antimalarial

• 1944 aminoglycoside antibiotic streptomycin by Waksman et al. in accompanied in the modern

era of tuberculosis treatment

• Discovery of p-aminosalicylic acid (PAS) first and then, in 1952, of isoniazid

• usefulness of the synthetic drug ethambutol and, eventually, of the semisynthetic antibiotic
rifampin was discovered.
Combination therapy
• Use of two or more antitubercular drugs,

• To reduce the emergence of strains of M. tuberculosis resistant

• The choice of a combination depends on various factors, including the location of the
disease (pulmonary, urogenital, gastrointestinal, or neural), the results of susceptibility
tests and the pattern of resistance in the locality, the physical condition and age of the
patient, and the toxicities of the individual agents.

• For some time, a combination of isoniazid and ethambutol, with or without streptomycin,
was the preferred choice of treatment among clinicians in this country.
• Rifampin shortened period required for successful therapy with ethambutol and isoniazide
Drug of Choice

• As per latest survey, in India ~ 3% of new cases and 12–17% of previously

treated patients have MDR-TB.

• 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 when first line drugs cannot be used, or to
supplement them.
Drugs used in the treatment of tuberculosis

• 1. First-line drugs: Isoniazid, streptomycin, rifampicin, ethambutol,

and pyrazinamide.

• 2. Second-line drugs: Ethionamide, p-amino salicylic acid, ofloxacin,

ciprofloxacin, cycloserine, amikacin, kanamycin, viomycin, and
capreomycin.
Classification

• A) Synthetic Antitubercular Agents: Isoniazide, Ethionamide,

Ethambutol, Pyrazinamide, Para amino Salicylic acid

• B) Anti Tubercular antibiotics: Rifampin, Rifabutin, Cycloserine,

Streptomycin, Capreomycin Suphate
• Directly observed treatment short course’ (DOTS)
 Isoniazide

• Isoniazid is an excellent antitubercular drug, and an essential component of all antitubercular regimens,

• primarily tuberculocidal.

• Fast multiplying organisms are rapidly killed, but quiescent ones are only inhibited.

• Acts on extracellular as well as on intracellular

• Equally active in acidic or alkaline medium.

• It is one of the cheapest antitubercular drugs.

• However, most nontubercular mycobacteria are not inhibited by INH

Cont…
• Isonicotinic acid hydrazide, isonicotinyl hydrazide, or INH (Nydrazid)

• occurs as a nearly colorless crystalline solid is very soluble in water.

• prepared by reacting the methyl ester of isonicotinic acid with hydrazine.

• remarkably effective agent and continues to be one of the primary drugs (along with rifampin,
pyrazinamide, and ethambutol) for the treatment of tuberculosis.

• Not uniformly effective against all forms of the disease.

• tubercle bacillusDevelope resistant to isoniazid during therapy

• overcome with the use of combinations.

Cont….
• The activity of isoniazid is manifested on the growing tubercle bacilli and not on resting forms

• cause the bacilli to lose lipid content by a mechanism that has not been fully elucidated.

• isoniazid inhibit the synthesis of mycolic acids,

• high–molecular-weight, branched β-hydroxyl fatty acids that constitute important components of the cell

walls of mycobacteria

• A mycobacterial catalase–peroxidase enzyme complex is required for the bioactivation of isoniazid

• Activeted substrate attack on critical enzyme required for mycolic acid synthesis

• loss of catalase and peroxidase activities manin cause of INH Resistant

• gene, katG
MOA_Isoniazide
• Inhibition of synthesis of mycolic acids

• Unique fatty acid components of mycobacterial cell wall.

• The lipid content of mycobacteria exposed to INH is reduced.

• Two gene products labelled ‘InhA’ and ‘KasA’, which function in mycolic acid synthesis targets
of INH action.

• Drug is activeted 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

Kinetics
• completely absorbed orally and penetrates all body tissues, tubercular cavities,
placenta and meninges

• Extensively metabolized in liver; most important pathway being N-acetylation by NAT2

• t½ of INH is 1 hr Fast acetylators (30–40% of Indians)

• t½ of INH is 3 hr. Slow acetylators (60–70% of Indians)

• Aluminium hydroxide inhibits INH absorption.

• inhibiting CYP2C19 and CYP3A4 INH retards phenytoin, carbamazepine, diazepam,

theophylline and warfarin metabolism
ADR
• incidence of toxic effects is remarkably low
• Peripheral neuritis and a variety of neurological manifestations
(paresthesias, numbness, mental disturbances, rarely convulsions)

• Due to interference with production of the active coenzyme pyridoxal

phosphate from pyridoxine

• Hepatitis rare in children, but more common in older

• half-life, 45–80 minutes

• If INH is given alone after 2–3 months an apparently resistant infection emerges.

• global weighted mean of any INH resistance 7.4%.

• In India resistance to INH alone or in combination with other anti-TB drugs is estimated to be 18%

• It is extensively metabolized in liver; most important pathway being N-acetylation by NAT2

• The acetylated metabolite is excreted in urine.

• Aluminium hydroxide inhibits INH absorption.

• retards phenytoin, carbamazepine, diazepam, theophylline and warfarin metabolism by inhibiting

CYP2C19 and CYP3A4,
 Ethionamide (Eto)
• moderate efficacy
• introduced in 1956
• Acts on both extra- and intracellular bacilli
• Chemically it resembles INH, but contains sulfur.
• The mechanism of action is also similar to INH
• it is converted by mycobacteria into an active intermediate
• which interferes with mycolic acid synthesis.
• Resistance to Eto mostly results from mutation of the gene
• 2-Ethylthioisonicotinamide (Trecator SC)
• weak bacteriostatic activity
• 2-substitution enhances activity
 Ethionamide (Eto)
• Few atypical mycobacteria including MAC are also susceptible.

• Ethionamide is rapidly and completely absorbed following oral administration.

• It is widely distributed throughout the body and extensively metabolized

• Eto is nearly completely absorbed orally, distributed all over and crosses into CSF.

• It is completely metabolized in liver and has a short t½ of 2–3 hours forms that are excreted in the
urine.

• Less than 1% of the parent drug appears in the urine

• considered a secondary drug for TB

• used in the treatment of isoniazid resistant tuberculosis or when the patient is intolerant to

isoniazid and other drugs

• ADR: Gastrointestinal intolerance, Visual disturbances and hepatotoxicity have also been

reported

• frequent adverse effects are—anorexia, nausea, vomiting, salivation, metallic taste, epigastric

discomfort, sulfurous belching and hepatitis

• also causes aches and pains, peripheral neuritis, behavioural

• To improve tolerance, dosing may initiated at 250 mg/day, and increased every 5–6

• days to reach 750 mg/day

• (10–15 mg/kg/day). Pyridoxine (100 mg/day) can mitigate the neurological adverse effects.

• Ethionamide is used only for drug-resistant TB.

• It is acomponent of the RNTCP standardized regimen for MDR-TB

• and an optional drug for inclusion into the treatment regimen

• of MAC infection in AIDS patients. It is also a reserve drug for leprosy

Ethambutol (E)
• (+)-2,2-(ethylenediimino)-di-1-butanol dihydrochloride,

• white crystalline powder freely soluble in water and slightly soluble in alcohol

• active only against dividing mycobacteria

• no effect on encapsulated or other nonproliferating forms.

• inhibition of the incorporation of mycolic acids into the cell walls of these organisms

• Stereospecific

• The dextro isomer is 16 times as active as the meso isomer

• rapidly absorbed after oral administration, t half 2 hours

• Tuberculostatic and is active against MAC as well
• Inhibit arabinosyl transferases (encoded by embABgenes)

• side effects are few.

• ADR: Loss of visual acuity/ colour vision, field defects due to retrobulbar neuritis is the most important dose and duration

• of therapy dependent toxicity.

• Patients should be instructed to stop the drug at the first indication of visual impairment

• toxicity is largely reversible.

• few other symptoms: nausea, rashes, fever, rarely peripheral neuritis,

• Safe during pregnancy. Ethambutol is used in MAC infection as well

 Pyrazinamide (Z)

• Short-term tuberculosis treatment regimens

• 1952
• Potential hepatotoxicity also obviates long-term use of the drug
• Maximally effective in the low pH environment
• bacterial resistance to pyrazinamide develops rapidly should always be used in
combination
• drug penetrates inflamed meninges and, therefore, is recommended for the
treatment of tuberculous meningitis.
• half-life ranges from 12 to 24 hours
• Pyrazinamide and its metabolites are reported to interfere with uric acid excretion
• should be used with great caution in patients with hyperuricemia or gout
• apparently does not inhibit mycolic acid biosynthesis
• comparatively low short-term toxicity.
• Since pyrazinamide is not active against metabolically inactive tubercle
bacilli,
• it is not considered suitable for long-term therapy.
• Potential hepatotoxicity also obviates long-term use of the drug.
• Pyrazinamide is maximally effective in the low pH environment that
exists in macrophages (monocytes).
• of pyrazinamide to pyrazinoic acid by an amidase present in
mycobacteria
• The drug penetrates inflamed meninges and, therefore, is recommended for the treatment of
tuberculous meningitis.

• Unchanged pyrazinamide, the corresponding carboxylic acid (pyrazinoic acid), and the 5-
hydroxy metabolite are excreted in the urine.

• The elimination half-life ranges from 12 to 24 hours

• once-daily or even twice weekly dosing schedules.

• Pyrazinamide and its metabolites are reported to interfere with uric acid excretion.

• the drug should be used with great caution in patients with hyperuricemia or gout.

• Frequent adverse effects are abdominal distress

• and arthralgia. flushing, rashes, fever and loss of

• diabetes control are occasional

p-Aminosalicylic Acid (PAS)
• 4-Aminosalicylic acid occurs as a white to yellowish white
• crystalline solid that darkens on exposure to light or air.
• slightly soluble in water but more soluble in alcohol.
• Alkali metal salts and the nitric acid salt are soluble in water, but
• the salts of hydrochloric acid and sulfuric acid are not.
• PAS is administered orally in the form of the sodium salt
• Gastrointestinal irritation
• oral absorption of PAS is rapid and nearly complete
• Introduced in 1946
• PAS is related to sulfonamides and acts probably by the same
mechanism, i.e. inhibition of folate synthase.
• It is not active against other bacteria,
• this selectivity may be due to difference in the affinity for folate
synthase of M.tuberculosis compared to that of other bacteria.
• tuberculostatic and one of the least active drugs
• ADR:Frequent anorexia, nausea and epigastric pain. rashes, fever,
malaise, hypokalaemia, goiter, liver dysfunction and rarely blood
dyscrasias.
• Prevent the incorporation of p-aminobenzoic acid (PABA) into the
dihydrofolic acid molecule catalyzed by the enzyme dihydrofolate synthetase.
• PAS is administered orally in the form of the sodium salt,
• Symptoms of gastrointestinal irritation are common with both the acid and
the sodium salt.
• Various enteric-coated dosage forms have been used
• Other forms that are claimed to improve gastrointestinal tolerance include
the calcium salt, the phenyl ester, and a combination with an anion exchange
resin (Rezi-PAS).
• An antacid such as aluminum hydroxide is frequently prescribed
Antitubercular Antibiotics

• RIFAMYCINS

• a group of chemically related antibiotics obtained by fermentation from cultures of

Streptomyces mediterranei.

• They belong to a class of antibiotics called the ansamycins that contain a macrocyclic
ring bridged across two nonadjacent positions of an aromatic nucleus.

• The term ansa means “handle,” describing well the topography of the structure.

• The rifamycins and many of their semisynthetic derivatives have a broad spectrum of
antimicrobial activity.
RIFAMYCINS

• They are most notably active against Gram-positive bacteria and M. tuberculosis.

• However, they are also active against some Gram-negative bacteria and many
viruses.

• Rifampin, a semisynthetic derivative of rifamycin B, was released as an

antitubercular agent in the in 1971.

• A second semisynthetic derivative, rifabutin, was approved in 1992 for the

treatment of atypical mycobacterial infections.
• All of the rifamycins (A, B, C, D, and E) are biologically active.
• Some of the semisynthetic derivatives of rifamycin B are the most potent
known inhibitors of DNA directed RNA polymerase in bacteria and act as
bactericidal.
• no activity against the mammalian enzyme.
• Rifamycins bind to the β subunit of bacterial DNA-dependent RNA
polymerases to prevent chain initiation.
• Bacterial resistance to rifampin has been associated with mutations leading
to amino acid substitution in the subunit.
• A high level of cross-resistance between various rifamycins has been
observed
Rifampin (Rifampicin, R)
(Rifadin, Rimactane, Rifampicin)
• is the most active agent in clinical use for the treatment of tuberculosis.

• A dosage of as little as 5 μg/mL is effective against sensitive strains of M. tuberculosis.

• Rifampin is also highly active against staphylococci and Neisseria, Haemophilus, Legionella, and
Chlamydia spp.

• Gram-negative bacilli are much less sensitive to rifampin

• resistance to rifampin develops rapidly in most species of bacteria, including the tubercle bacillus.

• Consequently, rifampin is used only in combination with other antitubercular drugs,

• ordinarily not recommended for the treatment of other bacterial infections

5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-
(4-methyl-1-piperazinyl)-formamidoyl]-2,7-(epoxypentadeca-1,11-13-
trienimino)-naphtho-[2,1-b] furane-1,11(2H)dion-21 acetate
• Both extra- and intracellular bacilli are affected
• interrupts RNA synthesis by binding to β subunit of mycobacterial
DNA-dependent RNA polymerase (encoded by rpoB gene)
• Mycobacteria and other organisms develop resistance to rifampin
rather rapidly
• Rifampin is a microsomal enzyme inducer—increases several CYP450
isoenzymes, including CYP3A4, CYP2D6, CYP1A2 and CYP2C subfamily
• enhances its own metabolism
Cont..
• Interfae with warfarin, oral contraceptives, corticosteroids, sulfonylureas, HIV protease
inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), theophylline,
metoprolol, fluconazole, ketoconazole, clarithromycin, phenytoin, etc.
• ADR: Hepatitis, a major adverse effect
• Cutaneous: flushing, pruritus + rash (especially on face and scalp), redness and watering
of eyes.
• • Flu like symptoms: chills, fever, headache,
• malaise and bone pain.
• • Abdominal cramps, nausea, vomiting, diarrhoea.
• Urine and secretions may become orange-red—
• but this is harmless.
• Other serious but rare reactions are:
• • Purpura, haemolysis, shock and renal failure
Other uses of rifampin
• 1. Leprosy 2. Prophylaxis of Meningococcal and H. influenzae
• meningitis and carrier state.
• 3. Second/third choice drug for MRSA, diphtheroids
• and Legionella infections.
• 4. Combination of doxycycline and rifampin is the first line therapy of
brucellosis
Rifabutin
• It is related to rifampin in structure and mechanism
• spiroimidazopiperidyl derivative of rifamycin
• less active against M.tuberculosis, and more active against MAC.
• Majority of M.tuberculosis isolates resistant to R are cross resistant to
rifabutin.
• not an option for treatment of MDR-TB.
• The only place of rifabutin in the treatment of TB is as a substitute for R
• minimise drug interactions due to strong enzyme inducing property of R.
Rifabutin is a much weaker inducer of CYP enzymes than R. This is especially
needed in HIV coinfected patients of TB who receive a protease
1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl)-1-oxorifamycin XIV.
It is also known as (9S, 12E, 14S, 15R, 16S, 17R, 18R, 19R, 20S, 21S, 22E, 24Z)-
6,16,18,20-tetrahydroxy-1'-isobutyl-14-methoxy-7,9,15,17,19,21,25-heptamethyl-spiro
ADR and Kinetics
• The primary indication of rifabutin is for prophylaxis and treatment of MAC
infection in HIV-AIDS patients.
• For prophylaxis of MAC, rifabutin alone 300 mg/day is an alternative to
azithromycin/clarithromycin
• treatment of MAC infection, it is combined with 2–3 other anti-MAC drugs.
• ADR:Gastrointestinal intolerance, rashes, granulocytopenia, myalgia and uveitis
have been reported
• Reactions similar to those caused by R can also occur.
• Oral bioavailability of rifabutin is low (~20%),
• but t½ is much longer (>30 hours).
• very lipophilic compound with a high affinity for tissues.
 Cycloserine

• D-()-4-Amino-3-isoxazolidinone (Seromycin)
• Antibiotic that has been isolated from the fermentation beer of three
• different Streptomyces species: S. orchidaceus, S. garyphalus,
• and S. lavendulus.
• It occurs as a white to pale yellow crystalline material very soluble in
water.
• It is stable in alkaline, but unstable in acidic, solutions.
• The compound slowly dimerizes to 2,5-bis(aminoxymethyl)-3,6-
diketopiperazine in solution or standing
• preventing the synthesis of cross-linking peptide in the formation of
bacterial cell walls
• its relatively weak potency and frequent toxic reactions
• recommended for patients who fail to respond to other
tuberculostatic drugs
• It is usually administered orally in combination with other drugs,
commonly isoniazid.