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Lecture Notes B Pharm VI Sem BP 601T MEDICINAL CHEMISTRY III Unit III
Anti tubercular Agents

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

Anti-tubercular Agents:
Synthetic anti tubercular agents: Isoniozid*, Ethionamide, Ethambutol, Pyrazinamide, Para amino salicylic acid*
Anti-tubercular antibiotics: Rifampicin, Rifabutin, Cycloserine, Streptomycin, Capreomycin sulphate

❖ Anti-tubercular Agents
• Tuberculosis (TB)
- Tuberculosis (TB) is an infectious disease usually caused by the bacterium Mycobacterium
tuberculosis (MTB).
- Tuberculosis generally affects the lungs, but can also affect other parts of the body.
- Most infections do not have symptoms, in which case it is known as latent tuberculosis.
- Latent tuberculosis infection (LTBI) means a patient is infected with Mycobacterium tuberculosis, but
the patient does not have active tuberculosis.
- About 10% of latent infections progress to active disease which, if left untreated, kills about half of
those infected.
- The classic symptoms of active TB are a chronic cough with blood-containing sputum, fever, night
sweats, and weight loss.
- Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit,
speak, or sneeze. People with latent TB do not spread the disease.
- Active infection occurs more often in people with HIV/AIDS and in those who smoke.
- Diagnosis of active TB is based on chest X-rays, as well as microscopic examination and culture of body
fluids. Diagnosis of latent TB relies on the tuberculin skin test (TST) or blood tests.
• Mycobacterium
- Mycobacteria are designated as the transition forms existing between bacteria and fungi.
- The Greek prefix “myco” - means "fungus" alluding to the way mycobacteria have been observed to
grow in a mold-like fashion on the surface of cultures. It has a positive gram stain and a spirochete
spine.
- Mycobacterium refers to a genus of acid-fast organisms.
- Mycobacteria are aerobic and non-motile bacteria.
- Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. This genus
includes pathogens known to cause serious diseases in mammals, including tuberculosis
(Mycobacterium tuberculosis) and leprosy (Mycobacterium leprae) in humans.
Note By:
✓ Robert Koch discovered the tuberculosis bacillus.
✓ Albert Calmette and Camille Guérin achieved the first genuine success in immunization against tuberculosis
in 1906, using attenuated bovine-strain tuberculosis. It was called Bacille Calmette–Guérin (BCG). The BCG
vaccine was first used on humans in 1921 in France

Albert Calmette Camille Guérin Robert Heinrich Hermann Koch

Born: 12 July 1863 Nice, France
Died: 29 October 1933 (aged 70)
Paris
Nationality: France
Known for Bacillus Calmette-Guérin
antivenin
Scientific career: Bacteriology
Institutions Pasteur Institute
Born: 22 December 1872 Poitiers
Died: 9 June 1961 (aged 88) Paris
Nationality: France
Known for Bacillus Calmette-Guérin
antivenin
Scientific career: Bacteriology
Institutions Pasteur Institute
Born: 11 December 1843 Clausthal
Died: 27 May 1910 (aged 66) Baden
Nationality: German
Known for Discovery bacteriology Koch's
postulates of germ theory Isolation of
anthrax, tuberculosis and cholera.
Nobel Prize in Medicine (1905)

Lecture Notes_Dr. S. Mondal_B. Pharm 6th Semester_GITAM (Deemed to be University) Page | 1

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

• Comparison between cell envelopes of mycobacteria and other bacteria

(a) The innermost layer of the mycobacterial cell envelope is composed of peptidoglycan and is lined by
a layer of arabinogalactan. The presence of mycolic acids covalently bound to arabinogalactan,
aswell as the interaction of glycolipids and lipoglycans with mycolic acids in the outer layer, confers
high hydrophobicity to the mycobacterial cell wall
(b) Gram-negative cell walls contain a thin peptidoglycan layer that lines the plasma membrane and
an outer membrane composed of lipopolysaccharides, responsible for their antigenic properties;
(c) The cell walls of Gram-positive bacteria are thick and mainly composed of a peptidoglycan layer
adjacent to the plasma membrane.
• Common infection sites of the tuberculosis
- Common infections of TB are lungs (primary site), brain, bone, liver, and kidney. The main symptoms
are cough, tachycardia, cyanosis and respiratory failure. Depending upon the site of infection, the
disease can be categorized as follows:
o Pulmonary tuberculosis (respiratory tract).
o Genitourinary tuberculosis (genitourinary tract).
o Tuberculous meningitis (nervous system).
o Miliary tuberculosis (a widespread infection).

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

• Drugs used in the treatment of tuberculosis.

- Drugs used in the treatment of tuberculosis can be divided into two major categories:
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.

• General mechanism of anti-tubercular agents

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

❖ Isoniazid (INH)

• Synthesis

• 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.
- Isoniazid is a prodrug that is activated on the surface of M. tuberculosis by katG enzyme to
isonicotinic acid. Isonicotinic acid inhibits the bacterial cell wall mycolic acid, thereby making M.
tuberculosis susceptible to reactive oxygen radicals. Isoniazid may be bacteriostatic or bactericidal in
action, depending on the concentration of the drug attained at the site of infection and the
susceptibility of the infecting organism. The drug is active against susceptible bacteria only during
bacterial cell division.

KatG is mycobacterial catalase (peroxidase),

AcpM is Acyl carrier protein,

KaSA is Beta ketoacyl carrier protein synthetase.

• The biotransformation of isoniazid

• Adverse Reactions:
- Peripheral neuropathy, elevated serum transaminases (SGOT; SGPT), bilirubinemia, bilirubinuria,
jaundice, hepatitis (may be fatal), nausea, vomiting, epigastric distress, pancreatitis, blood dyscrasias,
hypersensitivity reactions, hyperglycemia, pellagra, metabolic acidosis, rheumatic syndrome.
• Dose: Prophylaxis: 300 mg once daily. Active infection: 5 mg/kg daily; max 300 mg once daily.

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

❖ Ethambutol (EMB, E)

• Synthesis

• 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.

Note By:
o Mycobacterium kansasii is a bacterium in the Mycobacterium family.
o The genus includes species known to cause serious diseases in mammals, including tuberculosis and leprosy,
but this species is generally not dangerous to healthy people.
o Gram-positive, non-motile, moderately-long too long and acid-fast rods.

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

❖ Pyrazinamide (PZA)

• Synthesis

• Mechanism of action
- Pyrazinamide diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme
pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid.
- Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the
protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The
net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.
- Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase-I (FAS), which is required by
the bacterium to synthesize fatty acids.
- Pyrazinoic acid was proposed to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation
process.

• Pharmacokinetics
- Pyrazinamide is well absorbed orally. It crosses inflamed meninges and is an essential part of the
treatment of tuberculous meningitis. It is metabolised by the liver and the metabolic products are
excreted by the kidneys.
- The metabolic route constitutes of hydrolysis by hepatic microsomal pyrazinamidase into
pyrazinoic acid, which may be then, oxidized by xanthine oxidase to 5-hydroxy pyrazinoic acid.
The later compound may appear free either in the urine or as a conjugate with glycine.

• Dose: Daily administered dose is 20–35 mg/kg in 3–4 equally spaced doses and maximum is 3 g
daily.
• Adverse effects
- The most common (approximately 1%) side effect of pyrazinamide is joint pains (arthralgia)
- The most dangerous side effect of pyrazinamide is hepatotoxicity.
- Other side effects include nausea and vomiting, anorexia, sideroblastic anemia, skin rash, urticaria,
pruritus, dysuria, interstitial nephritis, malaise; rarely porphyria, and fever.

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

❖ Ethionamide (ETH)

- Ethionamide is an antibiotic used to treat tuberculosis. Specifically, it is used, along with other
antituberculosis medications, to treat active multidrug-resistant tuberculosis.
- It is no longer recommended for leprosy.
- Ethionamide is well absorbed orally with or without food, but is often administered with food to improve
tolerance.
- It crosses the blood brain barrier to achieve concentrations in the cerebral-spinal fluid equivalent to
plasma.
- The antimicrobial spectrum of ethionamide includes M. tuberculosis, M. bovis and M. segmatis.
• Synthesis

• Mechanism of action
- Ethionamide (ETH) is a prodrug which is activated by the enzyme ethA, a mono-oxygenase in
Mycobacterium tuberculosis, and then binds NAD+ to form an adduct (ETH-NAD) which inhibitory effect
on the mycolic acid synthesis.

• Dose
- Initiate dose at 250 mg/day for 1-2 days; Then increase to 250 mg twice daily for 1-2 days with gradual
increases to highest tolerated dose; 750 mg/day average dose.
• Adverse effects
o Most common side effects: nausea, vomiting, diarrhea, abdominal pain, excessive salivation,
metallic taste, stomatitis, anorexia and weight loss.
o Ethionamide can cause hepatocellular toxicity and is contraindicated in patients with
severe liver impairment.

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

❖ Para-amino-salicylic acid (PAS)

- Para-amino-salicylic acid, also known as 4-Aminosalicylic acid.

- Amino-salicylic acid is bacteriostatic against Mycobacterium tuberculosis (prevents the multiplying of
bacteria without destroying them).
- It also inhibits the onset of bacterial resistance to streptomycin and isoniazid.

• Synthesis

• Mechanism of action
- There are two mechanisms responsible for amino-salicylic acid's bacteriostatic action against
Mycobacterium tuberculosis.
o Amino-salicylic acid is an inhibitor of bacterial folate metabolism (inhibit Dihydrofolate reductase).
o Amino-salicylic acid also inhibit the synthesis of the cell wall component, mycobactin, thus reducing
iron uptake by M. tuberculosis.

• Dose: Dose administered orally 14–16 g daily after meals in three to four divided doses.
• Adverse effects
- The most common side effect is gastrointestinal intolerance manifested by nausea, vomiting, diarrhea,
and abdominal pain.
- Hypersensitivity reactions: Fever, skin eruptions, dermatitis, or lymphoma-like syndrome, leucopenia,
agranulocytosis, thrombocytopenia, hemolytic anemia, jaundice, hepatitis, hypoglycemia, optic neuritis,
encephalopathy, Loeffler's syndrome, and vasculitis and a reduction in prothrombin.

▪ Loeffler's syndrome”, which manifests as eosinophils accumulation in the lung.

▪ Lymphoma-Like Syndrome was a protracted fever, an alteration of the general status (asthenia, anorexia,
and weight loss), and a clinical lymphoproliferative syndrome defined by lymphadenopathies with malignancy
criteria.
▪ Optic neuritis occurs when swelling (inflammation) damages the optic nerve — a bundle of nerve fibers that
transmits visual information from your eye to your brain. Common symptoms of optic neuritis include pain
with eye movement and temporary vision loss in one eye.
▪ Encephalopathy is a general term describing a disease that affects the function or structure of your brain.

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

❖ Rifampicin (R, RMP, RA, RF, or RIF)

- Rifampicin (Rifampin) is a member of the class of rifamycins that is a semisynthetic antibiotic derived
from Amycolatopsis rifamycinica (previously known as Amycolatopsis mediterranei and
Streptomyces mediterranei).
- Rifampicin is the 3-(4-methyl-1-piperazinyl)-iminomethyl derivative of rifamycin.
- Rifampicin is a broad antibacterial spectrum antibiotic used to treat several types of mycobacterial
infections including Mycobacterium avium complex, leprosy, and in combination with other
antibacterial to treat latent or active tuberculosis.
- Rifampin is bactericidal, and acts on both intracellular and extracellular organisms.
- Rifampin is well absorbed when taken orally and is distributed widely in body tissues and fluids,
including the CSF. It is metabolized in the liver and eliminated in bile and, to a much lesser extent, in
urine.
• Mechanism of action
o Rifampin acts via the inhibition of DNA-dependent RNA polymerase, leading to a suppression of RNA
synthesis and cell death.
o Rifampin is bactericidal for mycobacteria. Human RNA polymerase is not affected by rifampin.

Rifampicin Rifamycin

• Dose: 10-20 mg/kg/day intravenously/orally or 10-20 mg/kg orally twice weekly (DOT); not to
exceed 600 mg/day.

• Adverse effects
o The most serious adverse effect is hepatotoxicity.
o The more common side effects include fever, gastrointestinal disturbances, rashes, and
immunological reactions.

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

❖ Rifabutin (Rfb)
- Rifabutin is a member of the class of rifamycins that is a semisynthetic antibiotic derived from
Amycolatopsis rifamycinica.
- A broad-spectrum antibiotic that is being used as prophylaxis against disseminated Mycobacterium
avium complex infection in HIV-positive patients.
- Rifabutin is now recommended as first-line treatment for tuberculosis.
- Rifabutin is used in the treatment of Mycobacterium avium complex disease, a bacterial infection
most commonly encountered in people with late-stage AIDS.
- It has also found to be useful in the treatment of Chlamydophila pneumoniae infection.
- Rifabutin is well absorbed when taken orally and is distributed widely in body tissues and fluids,
including the CSF. It is metabolized in the liver and eliminated in bile and, to a much lesser extent, in
urine.
• Mechanism of action
o Rifabutin acts via the inhibition of DNA-dependent RNA polymerase in gram-positive and some
gram-negative bacteria, leading to a suppression of RNA synthesis and cell death.

o During Hepatic metabolism of Rifabutin the five metabolites that have been identified, 25-O-
desacetyl and 31-hydroxy are the most predominant. The former metabolite has an activity equal to
the parent drug and contributes up to 10% to the total antimicrobial activity.

• Dose
o Child and adult: 5 to 10 mg/kg once daily
o Maximum dose: 300 mg daily
o Patient with severe renal impairment: reduce the dose by half.
• Adverse effects
o Common side effects:
▪ Diarrhea
▪ Stomach upset or pain
▪ Changes in taste
▪ Nausea
▪ Vomiting
▪ Belching
▪ Bloating
▪ Loss of appetite
▪ Headache
▪ Skin rash Rifabutin
▪ Itching or
▪ Red, orange, or brown discoloration of your skin, tears, sweat, saliva, urine, or stools
(this side effect is harmless and will disappear when the medication is stopped).

▪ Chlamydia pneumoniae is a species of Chlamydia, an obligate intracellular bacterium that infects humans
and is a major cause of pneumonia. It was known as the Taiwan acute respiratory agent.
▪ Mycobacterium avium complex (MAC) is a group of bacteria related to tuberculosis. These germs are very
common in food, water, and soil. Almost everyone has them in their bodies. When you have a strong immune
system, they don't cause problems. It is transmitted via inhalation into the respiratory tract and ingestion into
the GI tract.

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

❖ Cycloserine (Cs)
- Cycloserine is a broad-spectrum antibiotic (may be bactericidal or bacteriostatic) used in the treatment
of Tuberculosis and certain Urinary Tract Infections (UTI).
- D-cycloserine is a 4-amino-1,2-oxazolidin-3-one that has ‘R’-configuration. It is an antibiotic
produced by Streptomyces garyphalus or S. orchidaceus.
- Cycloserine, is a GABA transaminase inhibitor and inhibition of peptidoglycan synthesis.
- Cycloserine rapidly and almost completely absorbed (70 to 90%) from the gastrointestinal tract.
- Cycloserine can crosses the placental barrier, but it doesn’t bind to plasma proteins.
- Cycloserine excreted primarily in urine by glomerular filtration. Small amounts of drug are excreted in
feces and breast milk. Elimination plasma half-life in adults is 10 hours. Drug is hemodialyzable.
• Synthesis

• Mechanism of action
- Cycloserine disrupts D-alanine incorporation into peptidoglycan during bacterial cell wall synthesis.
- Cycloserine is an analog of the amino acid D-alanine. It interferes with an early step in bacterial cell
wall synthesis in the cytoplasm by competitive inhibition of two enzymes, L-alanine racemase, which
forms D-alanine from L-alanine, and D-alanylalanine synthetase, which incorporates D-alanine into the
pentapeptide necessary for peptidoglycan formation and bacterial cell wall synthesis.

• Dose: 250-500 mg once or twice daily, rarely exceeding 1000 mg.

• Adverse effects
o CNS: seizures, drowsiness, somnolence, headache, tremor, dysarthria, vertigo, confusion, memory
loss, suicidal tendencies, psychosis, hyper-irritability, character changes, aggression, paresthesia,
paresis, hyperreflexia, coma.
o CV: sudden-onset heart failure.
o Skin: rash.
o Other: hypersensitivity reactions (allergic dermatitis).

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

❖ Capreomycin sulphate
- Capreomycin is an aminoglycoside antibiotic used as an adjunct drug in tuberculosis.
- Capreomycin is effective against a number of Gram-positive and Gram-negative organisms but is
primarily active against mycobacteria. It has been used in the treatment of certain resistant strains of
Mycobacterium tuberculosis.
- It was isolated from Streptomyces capreolus in 1961 and was subsequently found to contain two
components (I and II) and later to be composed of four (IA, IB, IIA, IIB).
- It is used in the treatment of MDR-tuberculosis in conjunction with other anti-tuberculosis drugs.
- Capreomycin belongs to the third line drugs which are least effective and have the most toxic effects.
- The third line drugs have to be used for infections with tubercle bacilli, likely to be resistant to first-
and second-line drugs or when first- and second-line drugs have been abandoned because of unwanted
reactions. To decrease the possibility of resistant organisms from emerging, ‘Compound Drug Therapy’
is used where a concoction of several drugs is administered.
- Capreomycin not absorbed in significant quantities from the gastrointestinal tract and must be
administered parenterally.

Types R1 R2

Capreomycin IA OH β-Lysine

Capreomycin IB H β-Lysine

Capreomycin IIA OH NH2

Capreomycin IIB H NH2

• Mechanism of action
- Capreomycin inhibit protein synthesis by binding
to the 70S ribosomal unit.
- Capreomycin also binds to components in the
bacterial cell which result in the production of
abnormal proteins. These proteins are necessary
for the bacteria's survival.
- Therefore, the production of these abnormal
proteins is ultimately fatal to the bacteria.
• Dose:
- 1g IM or IV infusion 2 or 3 times weekly;
maintain therapy for tuberculosis for 12 to 24
months; 20 mg/kg/day maximum.

• Adverse effects
- High incidence: hematuria, urine output or urinary frequency significantly increased or decreased,
loss of appetite or extreme thirst (hypokalemia, renal toxicity).
- Less incidence: hearing loss, tinnitus, gait instability, dizziness, dyspnea, lethargy, extreme weakness
(neuromuscular blockade, renal toxicity, hypokalemia), nausea or vomiting.
- Significant renal toxicity: blood creatinine increase, blood urea nitrogen increase, poor creatinine
clearance, proteinuria (need routine blood monitoring of renal functions and urine analysis) during
usage of this medication.
- Damaging to the 8th cranial nerve.

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BP601T. MEDICINAL CHEMISTRY – III Unit: III: Anti-tubercular Agents

❖ Streptomycin
- Streptomycin is an aminoglycoside antibiotic indicated to treat multi-drug resistant mycobacterium
tuberculosis and various non-tuberculosis infections.
- Streptomycin, an antibiotic derived from Streptomyces griseus, was the first aminoglycoside
antibiotics.
- Sir Selman Waksman and eventually Sir Albert Schatz were recognized with the Nobel Prize in
Medicine for their discovery of Streptomycin and its antibacterial activity.
- Although streptomycin originally had broad gram-negative and gram-positive coverage, its spectrum of
activity has been significantly narrowed due to antibiotic resistance.
- Due to poor oral absorption, aminoglycosides including streptomycin are administered parenterally.
Streptomycin is available as an intramuscular injection, and in some cases may be administered
intravenously.
• Mechanism of action
- Streptomycin is a protein synthesis inhibitor. It binds to the small S12 and 16S rRNA of the 30S
subunit of the bacterial ribosome irreversibly, interfering with the binding of formyl-methionyl-tRNA
to the 30S subunit.
- This leads to codon misreading, eventual inhibition of protein synthesis and ultimately death of
microbial cells.

• Dose:
- For the treatment of brucellosis (Adults Intramuscular dosage): 1-2 g IM per day in divided doses every
6-12 hours.
- For the treatment of gram-negative bacillary bacteremia, meningitis, or lower respiratory tract infections
(Adults Intramuscular dosage): 1-2 g IM per day in divided doses every 6-12 hours.
- For the treatment of urinary tract infection (UTI) due to E. coli, Proteus sp., E. aerogenes, K. pneumoniae,
or E. faecalis (Adults Intramuscular dosage): 1-2 g IM per day in divided doses every 6-12 hours.
- For the treatment of tuberculosis (Adults Intramuscular dosage): 15 mg/kg IM once a day (Daily dosing);
25 to 30 mg/kg IM 2 to 3 times a week (Intermittent dosing).

• Adverse effects
- Common side effects include vertigo, vomiting, numbness of the face, fever, and rash. Fever and rashes
may result.
- The most concerning side effects are kidney toxicity and ear toxicity.
- Use is not recommended during pregnancy.
- It is not recommended in people with myasthenia gravis.

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