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ANTI TB DRUGS
TUBERCULOSIS OR TB
• Deadly infectious disease
Transmission:
• Attacks the lungs but can also affect other parts of
the body.
Pulmonary tuberculosis:-
• Symptoms:• A
chronic
cough
with
blood-tinged
sputum, fever, night sweats, and weight loss.
Cause:• Mycobacterium tuberculosis ,
• A small aerobic non motile bacillus.
• M. tuberculosis complex includes TB
causing mycobacteria :
• M. bovis, M. africanum, M. Canetti and M. microti.
Epidemiology:
• Currently 3.1 billion is infected with Mycobacterium
tuberculosis.
• Mycobacterium avium complex is associated with
AIDS related TB.
• A disease of respiratory transmission.
• 75% of the cases are pulmonary TB
• Patients with the active disease (bacilli)
expel them into the air by:
• Coughing, sneezing, shouting or any
other way that will expel bacilli into
the air
Symptoms:• Chest pain, coughing up blood, and a
productive, prolonged cough for more
than three weeks.
• Systemic symptoms include:• Fever, chills, night sweats, appetite
loss, weight loss, pallor, and often a
tendency to fatigue very easily.
EXTRAPULMONARY
TUBERCULOSIS
• 25% of active cases
• Infection moves from the
lungs, causing other kinds of
TB.
• Occurs more commonly
in immunosuppressed persons
and young children.
SITES OF INFECTION INCLUDE:-
• Pleura in tuberculosis
pleurisy
• Central nervous system
in meningitis,
• Lymphatic system
in scrofula (a disease with
glandular swellings) of the
neck
• Genitourinary system in
urogenital tuberculosis, and
• Bones and joints in Pott's
disease of the spine.
PATHOPHYSIOLOGY:Infection via inhalation of droplet
nuclei.
↓
Transport of bacilli to terminal alveoli
(especially lower segments of lungs)
↓
Ingestion of organisms by macrophages
followed by multiplication within
macrophages
↓
Transport of organisms to regional
lymph nodes by infected macrophages
with continue multiplication and
minimal inflammatory response
↓
Extension of organisms( within 4-6
weeks after inhalation) into the
bloodstream from the regional nodes
↓
Cell mediated immunity /
hypersensitivity reaction
↓
Development of clinical infection
Diagnosis of TB:• Diagnosis by X-ray
• Diagnosis by sputum investigation
• Diagnosis by tuberculin test
• Skin test:- PPD (purified protein
derivative) antigens are injected
intradermally. A positive reaction
is a helpful adjunct in diagnosis.
CLASSIFICATION:• According to their clinical utility:
First line:
• Have high antitubercular efficacy
• Low toxicity
• Used routinely
First line drugs
• 1. Isoniazid (H)
• 2. Rifampin (R)
• 3. Pyrazinamide (Z)
• 4. Ethambutol (E)
• 5. Streptomycin (S)
Second line:
• Have either low antitubercular efficacy
• Higher toxicity or both
• Used as reserve drugs.
Second line drugs
•
•
•
•
•
•
•
Ethionamide (Eto)
Prothionamide (Pto)
Cycloserine (Cs)
Terizidone (Trd)
Para-aminosalicylic acid (PAS)
Rifabutin
Thiacetazone (Thz)
• Fluoroquinolones
•
•
•
•
Ofloxacin (Ofx)
Levofloxacin (Lvx/Lfx)
Moxifloxacin (Mfx)
Ciprofloxacin (Cfx)
• Injectable drugs
• Kanamycin (Km)
• Amikacin (Am)
• Capreomycin (Cm)
• Group I: most potent and best tolerated oral drugs used routinely.
• Group II: potent and bactericidal, but injectable drugs.
• Group III: includes fluoroquinolones (FQs):- well tolerated bactericidal
oral drugs; all patients with drug resistant TB should receive one FQ.
• Group IV: less effective, bacteriostatic/more toxic oral drugs for resistant
TB.
• Group V: drugs with uncertain efficacy; not recommended for MDR-TB;
may be used in extensively resistant TB (XDR-TB).
Isoniazid (INH) (Isonicotinic acid hydrazide, H)
• Primarily tuberculocidal
• Tuberculocidal for rapidly
multiplying bacilli
• Acts on extracellular as well as on
intracellular TB
• Equally active in acidic or alkaline pH
• Cheapest anti-tubercular drugs
Mechanism of Action
• Inhibition of synthesis of mycolic
acids
• Two gene products labelled ‘InhA’ and
‘ KasA’ , - which function in mycolic
acid synthesis are targets of INH
action.
• INH enters sensitive mycobacteria
which convert it by a catalaseperoxidase enzyme into a reactive
metabolite.
• Then forms adduct with NAD that
inhibits InhA and KasA.
• Other products of KatG activation of
INH include superoxide,H2O2 , alkyl
hydroperoxides and NO radical may
also contribute to INH bactericidal effect
INH enters bacilli by passive diffusion
Drug is not directly toxic to the bacillus but
must be activated to its toxic form within
the bacillus by KatG (multifunctionary ,
catalase –peroxidase)
KatG catalyzes the production from INH of
an isoNicotinoyl radical that subsequently
interacts with mycobacterial NAD and
NADP to produce a dozen adducts
A nicotinoyl-NAD isomer, inhibits the
activities of enoyl acyl carrier protein
reductase (InhA) and β-ketoacyl acyl
carrier protein synthase (KasA)
Inhibition of these enzymes inhibits
synthesis of mycolic acid -- bacterial cell
death
Another Adduct, a nicotinoyl-NADP isomer ,
potently inhibits mycobacterial DHFRase
,thereby interfering with nucleic acid
synthesis
Mechanism of resistance
• Emerge rapidly if the drug is used alone.
• Resistance can occur due to either
1.
2.
High-level resistance is
associated with deletion in the
katG gene that codes for a
catalase peroxidase involved in
the bioactivation of INH.
Low-level resistance occurs via
deletions in the inhA gene that
encodes “target enzyme” an acyl
carrier protein reductase.
PHARMACOKINETICS
Absorption
• Rapid and complete; slowed with food
Distribution
• All body tissues and fluids including CSF;
crosses placenta; enters breast milk
• Protein Bound: 10-15%
Metabolism
• Hepatic ( fast, slow acetylators)
Elimination
• Excretion: Urine (75-95%); feces
INTERACTIONS :ADVERSE EFFECTS:• Peripheral neuritis and a variety of
•Aluminium hydroxide
neurological manifestations are the
most important dose-dependent toxic
inhibits
INH
effects.
absorption
• INH neurotoxicity
• Hepatitis is major adverse effect
•INH retards phenytoin,
• Lethargy (a lack of energy and
carbamazepine,
enthusiasm)
• Rashes.
diazepam, theophylline
• Fever acne.
and
warfarin
• Arthralgia.
• Respiratory syndrome:
metabolism
by
breathlessness.
inhibiting CYP2C19
• Purpura, haemolysis, shock and renal
failure.
and CYP3A4,and may
• Cutaneous syndrome : flushing,
raise their blood levels.
pruritis + rash.
• Flu like syndrome : fever, headache,
•PAS inhibits INH
bone pain.
metabolism
and
prologs its half life.
Rifampin (Rifampicin , R)
• Semisynthetic derivative of Rifamycin B obtained from streptomyces
mediterranei
• Bactericidal to M. Tuberculosis and many other gram(+) and gram (-)
bacteria like staph.aureus , N.meningitidis, H.influenza, E.coli,Kleibsella ,
Pseudomonas,Proteus and legionella
• Against TB bacilli , it is as efficacious as INH and better than all other drugs
• Bactericidal actions covers all subpopulations of TB bacilli , but acts best on
slowly or intermittenly dividing ones (spurters)
• Both extra and intracellular organisms are affected
• Good sterilizing and resistance preventing actions
MECHANISM OF ACTION OF RIFAMPIN
• Rifampin interrupts RNA synthesis by binding to beta
subunit of mycobacterial DNA-dependent RNA
polymerase encoded by rpoB gene and blocking its
polymerizing function
• The basis of selective toxicity is that mammalian RNA
polymerase does not avidly bind rifampin
MECHANISM OF ACTION -
MOA OF RIFAMPIN:
 D.N.A

RIFAMPIN

DNA dependent R.N.A.polymerase
R.N.A

Protein Syn.

Cell multiplication
Rifampin bind to β S.U of D.D.R.P

Drug –Enz Complex

Supression of chain initiation
Rifampin resistance
• Mycobacteria and other organisms develop resistance to rifampin rather
rapidly.
• Rifampin resistance is nearly always due to mutation in rpoB gene
reducing its affinity for the drug.
• No cross resistance with any other antitubercular drug,except rifampin
congeners,has been noted.
Pharmacokinetics • Well absorbed orally
• Bioavailability ~ 70% , food decreases absorption
• Rifampin is to be taken in empty stomach
• Widely distributed in the body;
• penetrates intracellularly , enters tubercular cavities and
placenta
• It crosses meninges , largely pumped out of CNS by P–
glycoprotein
• Metabolized in liver – active deacetylated metabolite –
excreted mainly in Bile , some in urine
• Rifampin and its deacetylated metabolite undergoes
enterohepatic circulation
• T1/2 – 2-5 hrs
Interactions with rifampin
• Rifampin is a microsomal enzyme inducer-increases severalCYP3A4,
CYP2D6,CYP1A2 and CYP2C subfamily.
• It thus enhances its own metabolism as well as that of many drugs
including warfarin, oral contraceptives, corticosteroids, sulfonyl ureas,
steroids, HIV protease inhibitors, non nucleoside reverse transcriptase
inhibitors(NNRTIs), theophylline, metaprolol, fluconazol,ketoconazole,
clarithromycin, phenytoin etc.
• Contraceptive failures have occurred.
• It is advisable to switch over to an oral contraceptive containing higher
dose (50 microgram) of
• Estrogen or use alternative method of contraception.
Adverse effects of Rifampin
oIncidence of adverse effects is similar to INH
oHepatitis , a major adverse effect, generally occurs in pts with pre-existing
liver disease and is dose related
oJaundice – discontinuation of drug – reversible
• Minor reactions, usually not requiring drug withdrawal and more common
with intermittent regimens, are:
oCutaneous syndrome: flushing, pruritus + rash (especially on face and
scalp),redness and watering of eyes.
oFlu syndrome: with chills ,fever, headache, malaise (a general feeling of
discomfort) and bone pain.
oAbdominal syndrome :nausea, vomiting, abdominal cramp with or without
diarrhoea.
• Urine and secretions may become orange-red—but this is harmless.
• Other serious but rare reactions are:
oRespiratory syndrome: breathlessness which may be associated with shock
and collapse.
oPurpura, haemolysis, shock and renal failure.
Other uses of rifampin
1.
2.
3.
4.
Leprosy
Prophylaxis of Meningococcal and H.influenza meningitis and
carrier state
Second/third choice drug for MRSA, Diptheroids and legionella
infections
Combination of doxycycline and rifampin is first line therapy of
brucellosis
PYRAZINAMIDE (Z)
• Chemically similar to INH
• Weak cidal action
• More active
MECHANISM OF ACTION
• Similar to INH
• Converted
inside
mycobacterial into active
• In acidic medium
metabolite
(pyrazinoic
• On slowly replicating bacteria
acid)
by
• More lethal
(pyrazinamidase)
enzyme
• To intracellular bacilli
encoded by pncA gene.
• To the sites showing inflammatory
• Gets accumulated in acidic
response
medium.
• Highly effective during the first 2
• By interacting with a different
months of therapy
fatty acid synthase
ADVANTAGES :• Inhibits mycolic acid synthesis.
• Duration of treatment shortened
• Also disrupt mycobacterial cell
• Risk of relapse to be reduced
membrane and its transport
function
PZA : MECHANISM OF ACTION
PZA enter through passive diffusion
Bac. Pyrazinamidase
Pyrazinoic acid
inhibit myobacterial fatty acid synthase -I
INTERFERANCE IN CELL WALL SYSNTHESIS
RESISTANCE:-
ADVERSE EFFECTS:• Develops rapidly if it is
• Hepatotoxicity is the
used alone
most important
• Mostly due to mutation
• Hyperuricaemia
is
in pncA gene.
common (due to
inhibition of uric acid
secretion in kidneys)
PHARMACOKINETICS:• Penetration in CSF
• Abdominal distress
• Metabolized in liver
• Arthralgia
• Excreted ion urine
• Flushing,
rashes,
• Plasma t½ is 6-10 hours.
fever.
USES:-
• Highly useful
meningeal TB
in
ETHAMBUTOL (E)
• Tuberculostatic
• Active against MAC as well as some
other mycobacteria
• Fast multiplying bacilli – more
susceptible
• Added to triple regime of RHZ
ADVANTAGES:• Hastens the rate of sputum conversion
• Prevents development of resistance
MECHANISM OF ACTION
• By inhibiting arabinogalactan
synthesis.
• Drug
targets
arabinosyl
tranferases
(encoded
by
embAB genes) involved in
arabinogalactan synthesis.
• Arabinogalactan required for
mycolic acid incorporation in
mycobacterial cell wall.
RESISTANCE:-
• Develops slowly
• Mutation in embB gene
• Reducing the affinity of the
target enzyme.
• No cross resistance with any
other antitubercular drug.
EXACT MECHANISM : NOT KNOWN
PROBABILITIES :
ETHAMBUTOL
BLOCKS
ARABINOSYL TRANSFERASE (ENCODED BY emb)
NO POLYMERIZATION REACTION OF ARABINOGLYCAN
(Essential component of Myco. Cell wall)
INTERFERANCE IN CELL WALL SYSNTHESIS
PHARAMACOKINETICS
•
•
•
•
•
•
•
•
¾ of an oral dose is absorbed.
Distributed widely
Penetrates meninges
Temporarily stored in RBCs.
Less metabolized.
Excreted in urine
Plasma t½ is ~4 hrs.
Caution is required in its use in patients
with renal disease.
ADVERSE EFFECTS
• Few Side effects
• Loss of visual acuity/colour
vision,
• Optic neuritis- most important
toxicity.
• Nausea
• Rashes
• Fever
• Rarely peripheral neuritis.
• Hyperuricemia (due to
interference with urate
excretion)
• Safe during pregnancy.
USE:• In MAC infection
STREPTOMYCIN
• From a strain of Streptomyces griseus.
• Aminoglycoside antibiotic.
• First clinically useful anti TB drug.
• Tuberculocidal
• Less effective than INH or rifampin
• Acts only on extracellular bacilli.
• Penetrates tubercular cavities
• Poor action in acidic medium.
LIMITATION OF ITS USE
I) Dose related toxicity
II) Development of resistant org.
III) Pt compliance is poor due to i. m
MECHANISM OF ACTION:
• Inhibits bacterial protein synthesis.
• Inhibited in at least three ways:
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.
RESISTANCE
• Developed rapidly
• If used alone in tuberculosisrelapse.
PHARMACOKINETICS
• Absorption: IM: well absorbed;
• Distribution: To extracellular
fluid
including
serum,
abscesses, ascitic, pericardial,
pleural, synovial, lymphatic, &
peritoneal fluids;
• Crosses placenta;
• Small amounts enter breast milk
• Protein Bound: 34%
• Half-life elimination: 2-5 hr,
• Excretion: urine (90%); feces,
saliva, sweat, & tears (<1%)
SIDE EFFECTS:
• Ototoxicity
• Nephrotoxicity
• Paralysis
USE
• Because of need for i.m. injections
and lower margin of safety
• Used only as an alternative to or in
addition to other first line anti-TB
drugs
• Use is restricted to maximum of 2
months.
• It is thus also labelled as a
‘supplemental’ first line drug.
Second line drugs in TB
• Less effective
• More toxic
• Used only if organism is resistant to first line drugs
• Ethionamide , PAS, cycloserine : bacteriostatic
• Amikacin, capromycin, fluoroquinolones are used in Multi Drug
Resistant TB
SECOND LINE DRUGS
Para amino salicylic acid
Mechanism of action
Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively
against mycobacterium tuberculosis.
It is structurally similar to p-amino benzoic acid(PABA) and the sulfonamides.
Adverse Reactions
GI
• Nausea; vomiting; diarrhea; abdominal pain.
Metabolic
• Goiter with or without myxedema.
Miscellaneous
• Hypersensitivity (eg, fever, skin eruptions, leukopenia, thrombocytopenia, hemolytic
anemia, jaundice, hepatitis, vasculitis).
Ethionamide
Mechanism of Action:
Ethionamide, like pyrazinamide, is a nicotinic acid derivative related to isoniazid. It is
thought that ethionamide undergoes intracellular modification and acts in a similar
fashion to isoniazid.
ADRS
>10%
• Disorder of gastrointestinal tract (50%)
Frequency Not Defined
• Postural hypotension
• Dizziness
• Drowsiness
• Headache
• Peripheral neuropathy
• Psychosis
CYCLOSERINE
Cycloserine is an antibiotic produced by streptomyces
orchidaceus.
Mechanism of action :
• It inhibits the incorporation of D- alanine into peptidoglycan
pentapeptide by inhibiting alanine racemase, which converts Lalanine to D- alanine, and D- alanyl-D –alanine ligase (finally
inhibits mycobacterial cell wall synthesis).
• Cycloserine used exclusively to treat tuberculosis caused by
mycobacterium tuberculosis resistant to first line agents
ADR
Frequency Not Defined
• Confusion
• Dizziness
• Headache
• Seizure
• Psychosis
Thioacetazone
Mechanism of action: Bacteriostatic- inhibits cyclopropanaton of cell wall mycolic
acids.
Uses: It continues to be used as a convenient low cost drug to prevent emergence of
isoniazid resistance, streptomycin & ethambutol.
ADR: hepatitis, exfoliative dermatitis, SJS, bone marrow depression rarely
Common: Abdominal discomfort, loose motions, rashes, mild anemia, anorexia.
Azithromycin
Mechanism of Action
Binds to 50S ribosomal subunit of susceptible microorganisms and blocks
dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent
protein synthesis to arrest; does not affect nucleic acid synthesis
ADRS
>10%: Diarrhea (52.8%), Nausea (32.6%), Abdominal pain (27%), Loose stool
(19.1%)
1-10%: Cramping (2-10%), Vaginitis (2-10%), Dyspepsia (9%), Flatulence (9%),
Vomiting (6.7%), Malaise (1.1%)
<1%: Agitation, Allergic reaction, Anemia, Anorexia, Candidiasis, Chest pain,
Conjunctivitis, Constipation, Dermatitis (fungal), Dizziness
Clarithromycin
Mechanism of Action
Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S
ribosomal subunit of susceptible organisms and may inhibit RNAdependent protein synthesis by stimulating dissociation of peptidyl tRNA from ribosomes, thereby inhibiting bacterial growth
ADR
• >10%: Gastrointestinal (GI) effects
• 1-10%: Abnormal taste (adults, 3-7%, Diarrhea (3-6%), Nausea (adults, 3-6%),
Vomiting (adults, 1%; children, 6%), Abdominal pain (adults, 2%; children, 3%),
Rash (children, 3%), Dyspepsia (2%), Headache (2%), Elevated prothrombin time
(PT; 1%)
• <1%: Anaphylaxis, Anxiety, Clostridium difficile colitis, Dizziness, Dyspnea,
Elevated liver function tests
AMIKACIN
Mechanism of Action
Irreversibly binds to 30S subunit of bacterial ribosomes; blocks recognition step in
protein synthesis; causes growth inhibition. For gram-negative bacterial coverage
of infections resistant to gentamicin and tobramycin
ADR
• 1-10%
• Neurotoxicity
• Nephrotoxicity (if trough >10 mg/L)
• Ototoxicity
• <1%: Hypotension, Headache, Drug fever, Rash, Nausea, Vomiting,
Eosinophilia, Tremor, Arthralgia
Contraindications
• Documented hypersensitivity
Cautions
• Renal impairment
• Risk of neurotoxicity, ototoxicity, nephrotoxicity - risk of ototoxicity increase
with concurrent loop diuretics
KANAMYCIN
Mechanism of Action
Bactericidal and believed to inhibit protein synthesis
by binding to 30 S ribosomal subunit.
ADR
Agranulocytosis, Anorexia, Diarrhea, Dyspnea, Enterocolitis, Headache, Incr
salivation, Muscle cramps, Nausea, Nephrotoxicity, Neurotoxicity, Ototoxicity,
Pruritus.
Contraindications
• Documented hypersensitivity
Cautions
• Auditory toxicity more common with kanamycin than with streptomycin and
capreomycin;
• renal toxicity occurs at a frequency similar to that of capreomycin; regular
monitoring of serum creatinine recommended
• Renal impairment
• Myasthenia gravis
• Nephrotoxic agents
RIFABUTIN
Mechanism of Action
Inhibits DNA-dependent RNA polymerase
ADR:
>10%: Discoloration of urine (30%), Neutropenia (25%), Leukopenia
(17%), Rash (11%)
1-10%: Incr AST/ALT (7-9%), Thrombocytopenia (5%), Abdominal pain
(4%), Diarrhea (3%), Headache (3%), Nausea/vomiting (3%), Anorexia
(2%), Flatulence (2%)
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.
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
supercoiled DNA that is required for normal transcription and
replication.
• Inhibition of topoisomerase IV interferes with separation of
replicated chromosomal DNA into the daughter cells during cell
division.
Adverse effects
Nausea, vomiting,diarrhoea(most common). Headache, dizziness,
insomnia, skin rash, photosensitivity.
Damage growing cartilage and cause an arthropathy. Tendinitis,
tendon rupture.
Chemotherapy
DOTS:
To control tuberculosis requires:
• Effective, inexpensive, simple and standardised technology.
The success of the DOTS strategy depends on:
• Government commitment to a national tuberculosis programme.
• Case detection –finding by smear microscopy examination of TB
susceptible in general health services.
• Regular uninterrupted supply of essential anti-TB drugs.
• Monitoring system for programme supervised and evaluation.
Short Course Chemotherapy:
• These are regimens of 6-9 month duration.
• All regimens have an initial intensive phase lasting 2-3 months to kill the
TB bacilli and afford symptomatic relief.
• This is followed by continuation phase for 4-6 months so that relapse
does not occur.
REGIMENS :
Type of patient
Duration of treatment
Regimen
Category-1
1.New sputum positive
2.Seriously ill, sputum negative,
Pulmonary
3.Seriously ill
Intensive phase(2months)
INH+RMP+ETB+PZA
Continuation phase(4months)
INH+RMP
Category-2
Retreatment group
1.Relapse
2.Treatment failure
Intensive phase(3months)
INH+RMP+ETB+PZA
Continuation phase(5months)
INH+RMP+ETB
Category-3
1.New smear negative
pulmonary
2.extrapulmonary
Intensive phase(2months)
INH+RMP+PZA
Continuation phase(4months)
INH+RMP
Multiple Drug Resistance(MDR):
• Resistance to both Isoniazid and Rifampin and number of other anti-TB
drugs . MDR-TB has a more rapid course ,(some die in 4-16 weeks).
• Treatment is difficult as second line drugs
are less efficacious, less convenient, more expensive and toxic.
• Therapy depends on drugs used in earlier regimen, dosage and
regularity with which they have been taken.
• In India>200,000patients have been treated under DOTS by early 2001
with cure rate of 75-80%.
• In other countries 80-93%cure rates have been obtained.
Chemotherapy
Treatment of TB is categorised by:
• Site of disease (pulmonary or extra pulmonary), its severity: the bacillary
load and acute threat to life are taken into consideration.
• Sputum smear positivity/negativity :positive cases are infectious.
• History of previous treatment: risk of drug resistance is more in
irregularly treated patients.
THANK YOU
-PHARMA STREET