ANTI-TUBERCULOSIS DRUGS

PRESENTER :CATERINA MUGAMBI

MSCN
I

FEBRUARY 2024

MODERATOR :DR.MOHAMED
scope
 Tuberculosis (TB)

- Tuberculosis (TB) is an infectious disease usually caused by the bacterium Mycobacterium

tuberculosis (MTB).
- 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.
 Tuberculosis
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)
 Anti-tubercular Agents
Synthetic anti tubercular agents:
• Isoniozid,
• Ethionamide,
• Ethambutol,
• Pyrazinamide,
• Para amino salicylic acid
Anti-tubercular antibiotics:
• Rifampicin,
• Rifabutin,
• Cycloserine,
• Streptomycin,
• Capreomycin sulphate
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
 Isoniazid (INH)
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.

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 .
Ethambutol

Mode of action
inhibit RNA synthesis

Pharmacokinetics
- It is well absorbed from the gut and well distributed throughout the body.
- 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.
- It can be used for Tuberculous meningitis.
• Adverse effects
- fever and skin rashes.
- optic neuritis and reduction in visual acuity.
- loss of red and green color discrimination.
 Rifabutin

A broad-spectrum antibiotic that is being used as prophylaxis against

disseminated Mycobacterium avium complex infection in HIV-positive
patients.
It is now recommended as first-line treatment for tuberculosis

Mechanism of action
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.
Adverse effects
o Common side effects:
Gi disturbances.
▪ Itching
▪ 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 .
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
pirazinamide

• Adverse effects
• - The most common (approximately 1%) side effect of
pyrazinamide is joint pains (arthralgia)
• - The most dangerous side effect is hepatotoxicity.
• - Others include nausea and vomiting, anorexia, sideroblastic
anemia, skin rash, urticaria, pruritus, dysuria, interstitial
nephritis, malaise; rarely porphyria, and fever.
 Ethionamide (ETH)

• Ethionamide is an antibiotic used to treat tuberculosis.

• Specifically, it is used, along with other anti tuberculosis medications, to treat active multidrug-
resistant tuberculosis.
• - It is no longer recommended for leprosy
• MOA
• Has an inhibitory effect on the mycolic acid synthesis.

• Adverse effects
• o Most common side effects includes git disturbances.
• o Ethionamide can cause hepatocellular toxicity and is contraindicated in patients with severe liver
impairment
Para-amino-salicylic acid (PAS

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

• It 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.
• is an inhibitor of bacterial folate metabolism thus reducing iron
uptake by M. tuberculosis.
Para-amino-salicylic acid (PAS
Adverse effects

• The most common side effect is gastrointestinal intolerance

manifested by nausea, vomiting, diarrhea, and abdominal pain.
• Hypersensitivity reactions: Fever, skin eruptions, dermatitis
• lymphoma-like syndrome, leucopenia, agranulocytosis,
thrombocytopenia, hemolytic anemia, jaundice, hepatitis,
hypoglycemia, optic neuritis, encephalopathy, and vasculitis and a
reduction in prothrombin.
 Rifampicin

• Rifampicin (Rifampin) is a member of the class of rifamycins that is a semisynthetic

antibiotic.
• It is a broad 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.
• Well absorbed 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
• Rifampin inhibits DNA-dependent RNA polymerase, leading to a suppression of RNA
synthesis and cell death.
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

Adverse effects
• hepatotoxicity.
• common side effects fever, gastrointestinal
disturbances, rashes, and immunological
reactions.
Cycloserine

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.
Cycloserine

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

Capreomycin inhibit
protein synthesis by
binding to the 70S
ribosomal unit
Capreomycin

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.
Streptomycin

• Streptomycin is an aminoglycoside antibiotic indicated to treat multi-

drug resistant mycobacterium tuberculosis and various non-
tuberculosis infections.
• Although streptomycin originally had broad gram-negative and gram-
positive coverage, its spectrum of activity has been significantly
narrowed due to antibiotic resistance
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.

• 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.
Antituberclar agents
Phases in TB TREATMENT
• First phase called the intensive phase
• Lasts for two months

• The second one called the continuous phase

• Lasts for 6-9 months.
First line drugs:
Isoniazid ( H)
Rifampicin (R)
Ethambutol (E)
Pyrazinamide ( Z)
Streptomycin ( S) now reserved drug in
first line
 When are they used
Second line drugs:
They are usually considered only
Para aminosalicylic acid (PAS) 1) in case of resistance to first-line agents;

Ethionamide ( Etm) 2) in case of failure of clinical response to conventional

therapy; and
Kanamycin 3) in case of serious treatment-limiting adverse drug
reactions
Cycloserine Expert guidance to deal with the toxic effects drugs is
Amikacin desirable

Capreomycin
Newer Second Line drugs:
Ciprofloxacin
Ofloxacin
Levofloxacin
Clarithromycin
Azithromycin
Rifabutin
Mechanism of drug resistance
DRUG RESISTANT TB
• Patients with drug resistant TB are categorised by the resistance
pattern of MTB strains isolated in their sputum or other specimen.
• The major reasons for the development of drug resistance:
1. Non-adherence:
• Causes of non adherence are multifactorial such as inadequate
access due distance, implied cost, poor health education,
displacement of persons due hunger, wars and migration.
reasons for the development of drug
resistance
2)Poor quality medicines.
The bioavailability of Rifampicin can easily be
compromised by poor quality FDC.
3) Misuse of mainstay anti-TB drug treatment for treatment of other
ailments.
4) Drug stock outs leading to treatment interruptions
5) High virulence strains of Mycobacterium TB.
Classification of drug resistance
• Drug Resistance is classified in two ways: Based on exposure or the
type of resistance.
1) Exposure:

• Primary resistance - if there was definitely no previous treatment.

• Initial resistance - when previous treatment cannot definitely be
excluded.
• Acquired resistance - if there is a definite history of previous
treatment.
2) Based on the type of resistance expressed by the TB bacilli as

• Mono-resistant TB- TB which is resistant in vitro to exactly one 1st line anti-TB
drug.
• Rifampicin resistant TB with or without resistance to other anti TB drugs.
• Poly resistant TB- TB which is resistant in vitro to more than one anti-TB drug
except both Rifampicin and Isoniazid.
• Multi-Drug Resistant (MDR) TB - resistance to both Rifampicin and Isoniazid
• Extensively Drug Resistant (XDR) TB- is MDR TB (resistance to at least Rifampicin
and Isoniazid), resistance to any fluroquinolone and at least one of the following
2nd line injectable drugs: Kanamycin, Amikacin and Capreomycin.
Treatment and follow up of drug resistant
TB
• The treatment of patients with drug resistant TB is complex and requires trained
TB clinicians.
• Treatment should be offered in settings where infection control measures are in
place.
Mono-resistant TB:
• When there is resistance to any one single drug, only the offending drug should
be substituted;
• Ethambutol replaces Isoniazid; Fluoroquinolone replaces Rifampicin.
Poly-resistant TB:
• When there is resistance to two or more drugs but excluding both Rifampicin and
Isoniazid, the same principle holds. The two offending drugs should be replaced.
Cont’d resistance management
MDR-TB
• This is resistance to both Isoniazid and Rifampicin.
• The duration of treatment is guided by smear and culture
conversion.
• A patient is considered to have sputum conversion after two sets of
consecutive negative smears and cultures taken 30 days apart.
• The date of the first set of negative cultures and smears is used as
the date of conversion.
• The treatment consists of two phases as follows:
Intensive Phase of MDR-TB
• 8 Km-Pto-Lfx-Cs-Z
• This lasts for a minimum of 8 months and the following drugs are
used
• a) Inj. Kanamycin [Km]
• b) Tabs Prothionamide [Pto]
• c) Tabs Levofloxacin [Lfx]
• d) Tabs Cycloserine [Cs]
• e) Tabs Pyrazinamide [Z]
Continuation Phase
• Continuation Phase– 12Pto- Lfx -Cs-Z
• This lasts for 12 months and uses the following drugs
• a) Tabs Prothionamide [Pto]
• b) Tabs Levofloxacin [Lfx]
• c) Tabs Cycloserine [Cs]
• d) Tabs Pyrazinamide [Z]
XDR-TB
XDR TB should be managed by using an individualized regimen based on the
DST(drug susceptibility testing) results and patient drug history
The patient should use at least an injectable, high generation quinolone,
Cycloserine, Proethionamide, Pyrazinamide and add at least two drugs from
group 5
The injectable should be given for at least 12 months
For every culture positive after month 3 of treatment, add 3 months of
injectable after the 12th month of injectable
If the patient becomes culture positive after a period of negative cultures,
repeat the culture and DST
If still culture positive, count the first culture positive as the first month of
treatment and restart treatment
Treatment in pregnancy
• All pregnant women with active TB should be treated with a full
complement of anti-TB drugs.
• give Pyridoxine with Isoniazid to avoid the risk of damaging the
infant’s nervous system.
• Streptomycin should not be used in pregnancy -cause deafness in the
infant.
• When treating drug resistant TB the amino glycosides
(Kanamycin,Amikacin and Capreomycin) and the thionamides
(Ethionamide and Prothionamide) should not be used because of
associated ototoxity.
References
• Katsu G. B. & Trevor J. A. (2015) Basic & clinical pharmacology. 13th
Edition. McGraw-Hill Education
• Ministry of Health Kenya, Division of leprosy, tuberculosis and lung
disease (2013) Guidelines for Management of Tuberculosis and
Leprosy in Kenya. Second Edition. August, 2013 Kenya
• Ritter JM, Lewis LD, Mant TGK, Ferro A; 2008, A textbook of Clinical
Pharmacology and Therapeutics, 5th edition, Italy, Hodder Arnold.