ANTITUBERCULOUS DRUG

Situation in Bangladesh

• Major public health problem in Bangladesh.

• The country ranks sixth among 22 highest burden TB countries in the world.

• It is estimated that about 70,000 people die every year due to TB.

• In 2009, 160,735 TB cases were notified to Nation Tuberculosis Control Program (NTP).

• Only 30 % of expected new cases are detected by national tuberculosis control program (NTP)

• Other receive treatment from private sectors

• One person get sick in every 2 minutes

• One person dies in every 10 minutes

Drug of Neglected Diseases (DNDs)

• Last 25 years, NO anti- TB drug has been developed

• No anti- TB drugs even in the pipe line

• Whereas, a number of drugs for diseases like

Baldness

Obesity

Erectile dysfunction

Why???

• Orphan Disease:Any disease that affects a small percentage of the population. condition that affects less than 200,000 people in the United Statese.g. ribose-5-phosphate isomerase deficiency

• Orphan Receptor:an apparent receptor that has a similar structure to other

identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan.

• Orphan Drug:a pharmaceutical agent that has been developed

specifically to treat a rare medical conditioncondition that affects less than 200,000 people in the

United States,"[2] or about 1 in 1,500 people.

Tuberculosis• Tuberculosis is an infectious disease caused by

Mycobacterium tuberculosis

• Mycobacterium tuberculosis can lead to seriousinfections of the lungs, genitourinary tract, skeleton, &meninges

• The disease may have to be treated for six months totwo years

• Resistant organisms readily emerge, particularly inpatients who have had prior therapy or who fail to

adhere to the treatment protocol.

• Mycobacteria are intrinsically resistant to mostAntibiotic, Because they grow slowly comparedwith other bacteria, antibiotics that are mostactive against growing cells are relativelyineffective

• Mycobacterial cells can also be dormant & thuscompletely resistant to many drugs or killed onlyvery slowly

• The lipid-rich mycobacterial cell wall isimpermeable to many agents

• Mycobacterial species are intracellular pathogens, & organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly

• Finally, mycobacteria are notorious for their ability to develop resistance

• Combinations of two or more drugs are required to overcome these obstacles & to prevent emergence of resistance during the course of therapy

• The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used

• Five first-line antimicrobial agents are currently recommended for antituberculosis therapy

• Second-line medications are more toxic, or have not been studied as extensively.

• The second-line medications are useful in patients who cannot tolerate the first-line drugs or who are infected with mycobacteria that are resistant to the first-line agents

• First-line drugs –

Isoniazid (bactericidal)

Rifampicin (bactericidal)

Pyrazinamide (bactericidal)

Ethambutol (bacteriostatic)

Streptomycin (bactericidal)

• Second-line drugs –

Amikacin Capreomycin Cycloserine

Kanamycin ThioacetazoneClarithromycin

Paraamino salicylic acid (PAS) Ciprofloxacin

Levofloxacin Rifabutin Clofazimine

Justification of combination therapy• Different mechanism of action provide additive

antibacterial effect

• Compliance –Early clinical improvement leads to

discontinuation,duration of therapy reduced as aresult of combination

• Emergence of resistance can be delayed –– Intracellular, long metabolic inactivity tends to

develop early resistance

• Individual dose reduction –– Theoretically suppose to minimize the possibility of

adverse effects, however spectrum of adverseeffects has increased

• Some obstacles that can be overcome by combination therapy –

– Most antibiotics are more effective against rapidly growing organism than against slowly growing ones. Because mycobacterium are very slowly growing organisms, they are relatively resistant to antibiotics. INH inhibit growth of resting microbe & kills multiplying

– Mycobacterial cells can also be dormant & thus completely resistant to many drugs – or killed only very slowly by the few drugs that are active. INH passes freely into mammalian cells, effective against intracellular organism. Rifampicin, pyrazinamide can kill semidormant within cells

– The lipid rich mycobacterial cell wall is impermeable to many agents

– A substantial proportion of mycobacterialorganisms are intracellular, resting within macrophages, & inaccessible to drugs that penetrate poorly. INH can penetrate caseousTB lesion.

–Mycobacteria are notorious for their ability to develop resistance to any single drug. Combination of drugs are required to overcome these obstacles & to prevent emergence of resistance during the course of therapy

• Steps of TB management –

–Step 1 BCG Vaccination: 80% world children vaccinated relatively effective in preventing serious but non-infective childhood TB

–Step 2 Chemoprophylaxis: Treating infected TB people before they get sick.

– INH 5mg/kg by mouth daily for 1 year in –

»Immuno-suppressed patient

»Unvaccinated contact (tuberculin positive)

»Adolescents with high degree of tuberculin sensitivity

–Step 3 Different Treatment Regimens

Treatment Regimens• DOTS (Directly Observed Treatment, Short-course

chemotherapy)

• Health workers observe patient taking medicine

• A national TB control programme to monitor progress

• Unsupervised daily regimen (6 months regimen)– Initial phase 2 months

• Pyrazinamide• Isoniazid• Rifampicin• Ethambutol (Likelihood of drug resistance or seriously

ill)– Continuation phase 4 - 5 months

• Isoniazid• rifampicin

Treatment Regimens & Success rate• 9 months regimen

– Initial phase 2 months• Isoniazid Rifampicin Ethambutol

– Continuation phase 7 months• Isoniazid Rifampicin

• 12 month regimen: inexpensive & reasonably effective– Twice weekly: nearly 100% effective

• Streptomycin 1 gm I.M.• INH 15 mg/kg plus pyridoxin 10 mg orally

– Daily: very cheap regimen which is 80-95% effective• INH 300 mg & thiacetazone 150 mg – single doses by

mouth• Comparative success rates in Bangladesh

– Smear positive cases with DOTS 80%– Unsupervised daily regimen 57%

TB Diagnostic Category

TB patient TB Treatment

Initial phase (daily)

Regimens

Continuation phase(3 times weekly)

I New smear positive;New smear negative PTB with extensive parenchymal involvement or severe forms of extra PTB (e.g. meningial, miliary, pericardial, peritonial, massive unilateral/bilateral pleural effusion, spinal, intestinal, genitourinary & multi organ TB)

2 (HRZE)

4 fixed-dose combination daily for 1st 2 months followed by

4 Fixed drug combinations R – 150 mg

INH – 75 mg

Pyraz -400 mg

Etham-275 mg

4 (HR)3

2 fixed drug combination thrice weekly for another 4 months

2 FDC contains

Rifam 150mg

INH – 75mg

TB Diagnostic Category

TB patient TB Treatment

Initial phase (daily)

Regimens

Continuation phase(3 times weekly)

II Previously treated for > 1 month with sputum smear positive PTB with- Relapse/-Treatment after interruption/-Treatment failure

2 (HRZE)S/

1 (HRZE)

4 FDC daily for 1st 3 month plus streptomycin injection 500 mg daily for 1st 2 months followed by The dose of Streptomycin should not exceed 750 mg daily after the age of 50 years

5 (HR)3 E3

2 FDC + Ethambutol (400 mg) thrice weekly for next 5 months

TB Diagnostic Category

TB patient TB Treatment

Initial phase (daily)

Regimens

Continuation phase (3 times weekly)

III New smear negative PTB (other than category I),

Less severe form of extra PTB

(e.g. lymph node, pleural effusion {unilateral}, bone {excluding spine}, peripheral joint, skin TB)

2 (HRZ)

3FDC daily for 1st

2 months followed by

4 (HR)3

2 FDC thrice weekly for another 4 months

Drug Clinical setting Daily dose

Rifampicin CHILD 10-20 mg/kg

Adults weighing <50 kg & in the elderly

450 mg

Adults weighing >50 kg 600 mg

Isoniazid CHILD 10 mg/kg

Adults 200 – 300 mg

Ethambutol CHILD & adults: Initial 8 weeks 25 mg/kg

CHILD & adults: Subsequently 15 mg/kg

Pyrazinamide CHILD & adults 20-35 mg/kg

Streptomycin CHILD 30 mg/kg

Adult 1 gm

Isoniazid

• Antibacterial activity limited against mycobacteria

• Inhibits growth of resting microbes, kills multiplying

• Passes freely into mammalian cells, effective against intracellular organisms

• For bacilli in the stationary phase, isoniazid is bacteriostatic, but for rapidly dividing organisms, it is bactericidal

• Mechanism of action:

– not very clear.

– INH is a prodrug that is Isoniazid is a prodrug that is activated by mycobacterial catalase-peroxidase(KatG) which forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase,

–which blocks mycolic acid synthesis, an important constituent of the cell wall of mycobacteria & kills the cell.

Mechanism of action:

Isoniazid is a prodrug

↓

activated by mycobacterial catalase-peroxidase(KatG)

↓

forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase

↓

blocks mycolic acid synthesis(an important constituent of the cell wall of mycobacteria) & kills the cell.

• Pharmacokinetics:

–Rapidly & completely absorbed from GIT.

–Wide distribution including CSF

–Penetrates & accumulates into caseous tuberculouslesion

–Minimum tuberculostatic concentration is 25 – 30 ng/ml

–Metabolized through N-acetylation

• Slow acetylator half-life would be 3 hour

(Drug causes toxicity, so peripheral neuropathy itself )

• Rapid acetylator ( by drug metabolite) half-life would be 1 hour (metabolite causes toxicity, so hepatotoxicity)

• Adverse effects:

– Commonest – allergic skin eruption

– Drug fever

– Hepatitis in elderly & patients with liver

disease & in rapid acetylators

– Hemolytic anemia in G6PD deficiency

– Arthritic symptoms

– Decreased metabolism of anti-epileptic drugs

like phenytoin, carbamazepine &

ethosuximide. So their effects are increased

– Peripheral neuropathy particularly common in

malnourished patients due to deficiency of

pyridoxine

• Explanation – INH is structurally analogue

to pyridoxine & form a hydrazone ( a highly

water soluble) with pyridoxal with no

vitamin activity & the complex rapidly

excreted in the urine

• Measure to prevent – Pyridoxine 10 mg/day

to prevent anticipated neuropathy

Rifampicin• A semisynthetic derivatives of rifampicin, an antibiotic

produced by streptomyces mediterranei.• Most active antituberculosis agent

• Effective against–Different mycobacteria - staphylococci–N. meningitidis - H. influenzae

• It is a powerful hepatic enzyme inducer - its own metabolism as well as other drugs like – phenytoin, OCP, glucocorticoids, – clarithromycin, ketoconazole, theophyllline,– clarithromycin

• Two Rifampicin derivatives available

– Rifampicin Rifabutin

• Mechanism of action:

Rifampin binds to the subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis.

• Resistance

Mutation to the β subunit of bacterial RNA polymerase this result in binding of Refampicin to RNA polymerase .

• Human RNA polymerase does not bind rifampinand is not inhibited by it.

• Rifampin is bactericidal for mycobacteria.

• It readily penetrates most tissues and intophagocytic cells & Can kill both extracellular &intracellular microorganisms

• It can kill organisms that are poorly accessible tomany other drugs, such as intracellularorganisms and those sequestered in abscessesand lung cavities.

• Attains effective concentration in CSF

• Pharmacokinetics:

–Used orally, IV formulations available.

–Well absorbed from GIT

–Widely distributed throughout the whole body including

CSF when meninges are inflammed

– 80 – 90% protein bound

–Will cross placenta & distribute into the breast milk

– t½ 3 hours

–Metabolized in the liver. Undergoes enterohepatic

cycling

–Parent drug & metabolites are excreted via the bile &

urine

• Adverse effects:–Rash, Thrombocytopenia, Flu like syndrome, Dizziness,

Confusion, Hemolysis–Red discoloration of urine, tear & sputum is a useful

indication that patient is taking the drug– Fatal hepatitis mainly being associated with prior liver

disease• Indications:

– TB– Leprosy– Pneumonia–Gonorrhoea–Chemoprophylaxis of meningococcal meningitis– Staphylococcal endocarditis(staphylococcal

infections )–Osteomylitis

Pyrazinamide • Synthetic, orally effective, bactericidal, antitubercular agent

used in combination with INH & rifampicin

• Prodrug, converted to pyrazinoic acid by pyrazinamindaseof the m. tuberculosis

• Inactive in neutral pH, tuberculostatic in acidic pH

• It is bactericidal to actively dividing organisms, but the mechanism of its action is unknown

• Can kill persisters, i.e., semidormantmycobacteria within the cell lysosome as well asin macrophages after phagocytosis because pHof phagolysosome is low.

• Distribute throughout the body, penetrateadequately to CSF, hence the drug is valuable intuberculous meningitis

• an important front-line drug used in conjunctionwith isoniazid and rifampin in short-course (ie,6-month) regimens as a "sterilizing" agent activeagainst residual intracellular organisms that maycause relapse.

• Safe to use in pregnancy

• Adverse effects:-hepatotoxicity (v.high dose -in 1–5% of

patients), –Arthralgia–Urate retention can also occur & may precipitate a

gouty attack–GI upset – anorexia, nausea, vomiting–Malaise–Fever–Urticaria, skin rash

Ethambutol

• Dextroisomer, has antitubercular effect

• Bacteriostatic & specific for most strains of M.tuberculosis & M. kansasaii

• M/A:

Inhibits mycobacterial arabinosyl transferaseswhich involved in the polymerization reaction ofarabinoglycan, an essential component of themycobacterial cell wall.

• Used as an alternative to streptomycin

• Resistance emerges rapidly if used alone, always given in combination with other antituberculous drugs.

• well absorbed from the gut.

• Taken up by the erythrocytes & slowly released.

• About 20% of the drug is excreted in feces and 50% in urine in unchanged form.

• Ethambutol crosses the blood-brain barrier only if the meninges are inflamed & Can penetrate CSF , use in TB meningitis.

• Adverse effects:–Optic neuritis (retrobulbar neuritis):

dose related side effect, initially red/green color blindness followed by a in visual acuity. Disappear following withdrawal of drug

So,baseline opthalmic assesment is required.

–Other adverse effects: Arthralgia, GI disturbance, Headache & mental disturbance

– Peripheral neuritis: rare–Hypersensitivity: skin rash, fever, itching

Streptomycin

• First antibiotic effective in the treatment of tuberculosis

• Penetrates into cells poorly & is active mainly against extracellular tubercle bacilli

• Crosses the BBB & achieves therapeutic concentrations with inflamed meninges

• Nontuberculosis species of mycobacteriaother than M. avium complex (MAC) & M. kansasaii are resistant to streptomycin

• Used when an injectable drug is needed or desired, principally in individuals with severe, possibly life-threatening forms of TB, e.g. meningitis & disseminated disease, & in treatment of infections resistant to other drugs

• Adverse effect: dose related, & the risk is in elderly–Ototoxicity & nephrotoxicity. Vertigo &

hearing loss are most common & may be permanent.

2nd line drug for tuberculosis

Recommended In case of

• Resistance to first-line agents;

• Failure of clinical response to conventional therapy;

• Serious treatment-limiting adverse drug reactions; and

• When expert guidance is available to deal with the toxic effects.

• MDR –TB : is a form of TB caused by bacteria that do not respond to at least INH & refampicin, the @ most powerful anti TB drug

• Extensively Drug Resistant( XDR-TB) is a form of MDR TB that respond to even fewer available medicine , including the most effective 2nd line anti TB drug.