1. ANTI TB DRUGS

2. TUBERCULOSIS OR TB Transmission: Pulmonary tuberculosis:-
Deadly infectious disease
Attacks the lungs but can also affect other parts of the body. 
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.
Transmission:
Pulmonary tuberculosis:-
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.

3. Infection moves from the lungs, causing other kinds of TB.
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
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.

4. Diagnosis by sputum investigation Diagnosis by tuberculin test
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)
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)

5. 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).

6. 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 catalase- peroxidase 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

7. 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
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

8. Aluminium hydroxide inhibits INH absorption
INTERACTIONS :-
Aluminium hydroxide inhibits INH absorption
INH retards phenytoin, carbamazepine, diazepam, theophylline and warfarin metabolism by inhibiting CYP2C19 and CYP3A4,and may raise their blood levels.
PAS inhibits INH metabolism and prologs its half life.
ADVERSE EFFECTS:-
Peripheral neuritis and a variety of neurological manifestations are the most important dose-dependent toxic effects.
INH neurotoxicity
Hepatitis is major adverse effect
Lethargy (a lack of energy and enthusiasm)
Rashes.
Fever acne.
Arthralgia.
Respiratory syndrome: breathlessness.
Purpura, haemolysis, shock and renal failure.
Cutaneous syndrome : flushing, pruritis + rash.
Flu like syndrome : fever, headache, bone pain.

9. 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

10. 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

11. MECHANISM OF ACTION -

12. MOA OF RIFAMPIN:  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

13. 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.

14. 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

15. 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.

16. Adverse effects of Rifampin
Incidence of adverse effects is similar to INH
Hepatitis , a major adverse effect, generally occurs in pts with pre-existing liver disease and is dose related
Jaundice – discontinuation of drug – reversible
Minor reactions, usually not requiring drug withdrawal and more common with intermittent regimens, are:
Cutaneous syndrome: flushing, pruritus + rash (especially on face and scalp),redness and watering of eyes.
Flu syndrome: with chills ,fever, headache, malaise (a general feeling of discomfort) and bone pain.
Abdominal 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:
Respiratory syndrome: breathlessness which may be associated with shock and collapse.
Purpura, haemolysis, shock and renal failure.

17. Other uses of rifampin 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

18. PYRAZINAMIDE (Z) Similar to INH
Chemically similar to INH
Weak cidal action
More active
In acidic medium
On slowly replicating bacteria
More lethal
To intracellular bacilli
To the sites showing inflammatory response
Highly effective during the first 2 months of therapy
ADVANTAGES :-
Duration of treatment shortened
Risk of relapse to be reduced
MECHANISM OF ACTION
Similar to INH
Converted inside mycobacterial into active metabolite (pyrazinoic acid) by (pyrazinamidase) enzyme encoded by pncA gene.
Gets accumulated in acidic medium.
By interacting with a different fatty acid synthase
Inhibits mycolic acid synthesis.
Also disrupt mycobacterial cell membrane and its transport function

19. PZA : MECHANISM OF ACTION
PZA enter through passive diffusion
Bac. Pyrazinamidase
Pyrazinoic acid
inhibit myobacterial fatty acid synthase -I
INTERFERANCE IN CELL WALL SYSNTHESIS

20. Highly useful in meningeal TB
RESISTANCE:-
Develops rapidly if it is used alone
Mostly due to mutation in pncA gene.
PHARMACOKINETICS:-
Penetration in CSF
Metabolized in liver
Excreted ion urine
Plasma t½ is 6-10 hours.
ADVERSE EFFECTS:-
Hepatotoxicity is the most important
Hyperuricaemia is common (due to inhibition of uric acid secretion in kidneys)
Abdominal distress
Arthralgia
Flushing, rashes, fever.
USES:-
Highly useful in meningeal TB

21. ETHAMBUTOL (E) MECHANISM OF ACTION ADVANTAGES:- RESISTANCE:-
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.

22. 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

23. PHARAMACOKINETICS ADVERSE EFFECTS USE:- Few Side effects
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

24. STREPTOMYCIN MECHANISM OF ACTION: LIMITATION OF ITS USE
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:
Interference with the initiation complex of peptide formation.
Misreading of mRNA, which causes incorporation of incorrect aminoacids into the peptide, resulting in a nonfunctional or toxic protein.
Breakup of polysomes into nonfunctional monosomes.
RESISTANCE
Developed rapidly
If used alone in tuberculosis- relapse.

25. Absorption: IM: well absorbed;
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.

26. 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

27. 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.

28. 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).

29. 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.

30. ADRS >10% Disorder of gastrointestinal tract (50%)
Frequency Not Defined
Postural hypotension
Dizziness
Drowsiness
Headache
Peripheral neuropathy
Psychosis

31. 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 L- alanine 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

32. ADR Frequency Not Defined Confusion Dizziness Headache Seizure
Psychosis

33. 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.

34. 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

35. 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

36. Clarithromycin
Mechanism of Action Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA- dependent protein synthesis by stimulating dissociation of peptidyl t- RNA from ribosomes, thereby inhibiting bacterial growth

37. 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

38. 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

39. 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

40. KANAMYCIN
Mechanism of Action Bactericidal and believed to inhibit protein synthesis by binding to 30 S ribosomal subunit.

41. 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

42. Mechanism of Action Inhibits DNA-dependent RNA polymerase
RIFABUTIN
Mechanism of Action Inhibits DNA-dependent RNA polymerase

43. 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%)

44. Fluoroquinolones Mechanism of action:
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.

45. Adverse effects
Nausea, vomiting,diarrhoea(most common). Headache, dizziness, insomnia, skin rash, photosensitivity.
Damage growing cartilage and cause an arthropathy. Tendinitis, tendon rupture.

46. 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.

47. 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.

48. 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)
Continuation phase(4months)
INH+RMP+ETB+PZA
INH+RMP
Category-2
Retreatment group
1.Relapse
2.Treatment failure
Intensive phase(3months)
Continuation phase(5months)
INH+RMP+ETB
Category-3
1.New smear negative pulmonary
2.extrapulmonary
INH+RMP+PZA

49. 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 with cure rate of 75-80%.
In other countries 80-93%cure rates have been obtained.

50. 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.

51. THANK YOU -PHARMA STREET