TUBERCULOSIS

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TUBERCULOSIS : 

TUBERCULOSIS BY: SHASHANK THAMMISHETTY

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CONTENTS: INTRODUCTION EPIDEMIOLOGY CAUSES PATHOGENESIS DIAGNOSIS TREATMENT

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Tuberculosis or TB  is a common and often deadly infectious disease caused by mycobacteria, usually Mycobacterium tuberculosis in humans. Tuberculosis usually attacks the lungs but can also affect other parts of the body.  The classic symptoms are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss.

CAUSES: : 

The primary cause of TB, Mycobacterium tuberculosis , is a small  aerobic  non-motile  bacillus. The M. tuberculosis complex includes four other TB-causing  mycobacteria: M. bovis, M. africanum, M. canetti  and M. microti.  M. africanum is not widespread, but in parts of Africa it is a significant cause of tuberculosis. CAUSES:

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Acyl lipid Porin Lipoarabinomannan(LAM) Mycolates Arabinoglycan Peptidoglycan Lipid Bilayer Mycobacterial cellwall

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It is currently estimated that 1/2 of the world's population (3.1 billion) is infected with Mycobacterium tuberculosis. Mycobacterium avium complex is associated with AIDS related TB.  The proportion of people who become sick with tuberculosis each year is stable or falling worldwide but, because of population growth, the absolute number of new cases is still increasing. EPIDEMIOLOGY:

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In 2007 there were an estimated 13.7 million chronic active cases, 9.3 million new cases, and 1.8 million deaths, mostly in  developing countries. The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5-10% of the US population test positive.

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Per 1,000,00 10 - 24 < 10 25 - 49 50 - 99 100 - 299 300 or more No estimate Highest estimated TB rates per capita were in Africa

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Pulmonary tuberculosis is a disease of respiratory transmission, 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 Transmission is dependent on closeness and time of contact Transmission:

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Once inhaled by a tuberculin free person, the bacilli multiply 4 -6 weeks and spreads throughout the body. The bacilli implant in areas of high partial pressure of oxygen: lung renal cortex reticuloendothelial system

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PATHOGENISIS:

Signs and symptoms: : 

When the disease becomes active, 75% of the cases are pulmonary TB, that is, TB in the lungs.  Symptoms include  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. Signs and symptoms:

Signs and symptoms: : 

In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB, collectively denoted extrapulmonary tuberculosis. This occurs more commonly in immunosuppressed persons and young children. Extrapulmonary infection sites include the  pleura in tuberculosis pleurisy, the central nervous system in  meningitis, the lymphatic system in  scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine. Signs and symptoms:

Diagnosis by X-ray: : 

Diagnosis by X-ray: Chest x-rays: Multi nodular infiltrate above or behind the clavicle with or without pleural effusion unilaterally or bilaterally.

Diagnosis sputum investigation: : 

Diagnosis sputum investigation: Cultures will reveal the presence of mycobacterium tuberculosis Patients stay infectious for as long as the bacilli are excreted in the sputum

Diagnosis by tuberculin test: : 

Diagnosis by tuberculin test: Skin test. PPD (purified protein derivative) antigens are injected intradermally. A positive reaction is a helpful adjunct in diagnosis. Tuberculin test positivity indicated hypersentivity to bacterial protein

Classification of drugs: : 

According to their clinical utility the drugs are: First line drugs : High antitubercular efficacy and low toxicity which are used routinely. Second line drugs: Either low antitubercular efficacy or high toxicity or both, used in special circumstances only. Classification of drugs:

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First line drugs include: -ISONIAZIDE - PYRAZINAMIDE - ETHAMBUTOL -RIFAMPICIN -STREPTOMYCIN HIGH EFFICACY AND LOW TOXICITY

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Second line drugs include: -THIACETAZONE -CAPREOMYCIN -P-AMINOSALICYLIC ACID -ETHIONAMIDE -CYCLOSERINE -KANAMYCIN -AMIKACIN LOW EFFICACY AND HIGH TOXICITY

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NEWER SECOND LINE DRUGS: Flouroquinolones are active against M.tuberculosis. Ciproflaxacin, Oflaxacin, Newer macrolides and some rifampin congeners are the recent additions. Clarithromycin, Azithromycin, Rifabutin.

ISONIAZIDE[H]: : 

Considered the drug of choice for the chemotherapy of TB. discovered in 1945 a hydrazide of isonicotonic acid bacteriostatic for resting bacilli, bactericidal for growing bacilli. ISONIAZIDE[H]:

ISONIAZIDE[H]: : 

Most active anti-tb drug. Important assets are -potency -infrequent toxicity -low cost Useful for tb meningitis. Effective for both extra cellular & intracellular tb. If combined with other drug it has good resistance preventing action. ISONIAZIDE[H]:

MOA of H: : 

ISONIAZID Kat G( catalase peroxidase in mycobacteria) Active INH AcpM & Kas AcpM- Acyl Carrier protein KasA ( ß ketoAcyl Carrier protein synthetase) Block Mycolic Acid Synthesis MOA of H:

Pharmacokinetics: : 

Abs :complete orally. Oral dose Dist: penetrate all body tissue Placenta Meninges Meta: in liver Excretion:-75-95% excreted in urine -Dose adjustment is not required in Renal Failure C/I - KNOWN HYPERSENSITIVITY -ACUTE HEPATIC DISEASE Pharmacokinetics:

Adverse Effects: : 

Rash Peripheral Neuropathy Hepatitis Transient loss of Memory Seizure Pleural effusion Arthralgia Adverse Effects:

RIFAMPIN[R]: : 

Semisynth. deri of Rifamycin B-from St.meditarranei. Acts both extra &intracellularly. Good sterilising property &resistance preventing action. Bactericidal efficacy ≈ INH &>any other 1st line drug Analogue of RIFAMPIN is RIFABUTIN. obtained from Rifamycin S. RIFAMPIN[R]:

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 MOA OF RIFAMPIN:

Pharmacokinetics: : 

Abs: -Well absorbed from g.i tract -PAS interferes with abs. -Food also interferes with abs. Dist: -wide. Penetration to •Cavities •meningitis •Placenta Met: in liver to an active deacetylated met. Which is excreted in bile. T1/2 varies from 1.5-5 hrs EXCRETION: Urine-30% Faeces 60-65% Pharmacokinetics:

Adverse effects: : 

Hepatitis, a major adverse effect. Respiratory syndrome: breathlessness. Purpura, haemolysis, shock and renal failure. Cutaneous syndrome : flushing, pruritis + rash. Flu like syndrome : fever, headache, bone pain. Adverse effects:

PYRAZINAMIDE[z]: : 

Synthetic analogue of Nicotinamide. Though weakly tuberculocidal  More active in acidic medium. Highly effective during 1st 2months. More effective against Slow Growing. Active both intra & extracellularly. Including Z in combination therapy. -It has potent sterilising action. -Risk of relapse is reduced. PYRAZINAMIDE[z]:

MOA OF PYRAZINAMIDE: : 

Pyrazinamide Mycobacterial Pyrazinamidase Pyrazinoic Acid Inhibits Mycolic Acid Synthesis Resistance due to mutation of gene pncA MOA OF PYRAZINAMIDE:

Pharmacokinetics: : 

Abs : Well absorbed from g . i. tract Dist : good penetration to all body tissue & CSF Meta: extensively in liver. T1/2  6-10hrs Dose: 25mg/D Adverse effects: Arthralgia Flushing Rashes Fever loss of diabetes control Hepatotoxicity Pharmacokinetics:

ETHAMBUTOL[E]: : 

Tuberculostatic ,active against M.tb M.A.C M.intracellularae Rapid Growers are more susceptible. Hastens the rate of sputum conversion. Prevent the emergence of Resistant bacilli. ETHAMBUTOL[E]:

MOA OF E: : 

Mycobact. Arabinosyl Transferase  ETHAMBUTOL  Polymerisation reaction of Arabinoglycan  Essential component of Myco.Cellwall MOA OF E:

Pharmocokinetics: : 

Abs: Well absorbed from g.i.t. Dist : Wide, penetrates the meninges T1/2 ~ 4hrs Excretion :-unchanged in urine(3/4th) -Excreted by G.F& T.S -Dose to be reduced in Renal failure C/I ; Cr. Clearance <50ml/min Doses of Ethambutol : 15mg/kg/day Pharmocokinetics:

Side effects: : 

Loss of visual acuity Color blindness Field Defect Early recognition &stoppage of drug- visual toxicities is largely reversible Contra-indication ;In children <6yrs a) they are unable to report early. b) may not permit the assessment of V.A &red green color blindness discrimination  Renal uric acid excretion Hyperuricemia Pruritus, Joint Pain Side effects:

STREPTOMYCIN : 

First drug used for the treatment of TB. It is aminoglycoside antibiotic. It is tuberculocidal . It acts only on extracelluluar bacilli. Limitation of its use i)dose related toxicity ii)development of resistant org. iii)pt compliance is poor due to i. m STREPTOMYCIN

MOA: : 

acts by protein synthesis inhibitor and decreases the fidelity mRNA and garbles the message, leads to nonsense proteins. Streptomycin only binds to the 30s subunit. Pharmacokinetics: Neither absorbed / destroyed in G.I.Tract. Absorption from inj site is rapid (30-60min) Distributed to Extracellular TB cavities. Not metabolised, Excreted unchanged in urine. MOA:

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SIDE EFFECTS: OTOTOXICITY-drugs get conc. In labrynthine fluid, both vestibular & cochlear damage NEPHROTOXICITY N.M PARALYSIS -Ach release, sensitivity of post.syn. receptors. Sterile abscess at the inj. site

Second line drugs: : 

Aminoglycosides: least effective and more toxic Capreomycin - Viomycin – Kanamycin Adverse effects: These drugs are: Nephrotoxic will cause Proteinuria, Hematuria, Nitrogen metabolism, and Electrolyte disturbances However effect is reversible when drug is stopped Capreomycin has replaced viomycin because of less toxic effects, but all three drugs have the same effects. Second line drugs:

Cycloserine: : 

Can cause CNS disturbances Therapeutic States : Cycloserine should be used when re-treatment is necessary or when the micro-organism is resistant to the other drugs. It must be given in combination with other anti-tuberculosis drugs. Mechanism of Action : An analog of D- alanine synthetase, will block bacterial cell wall synthesis. Cycloserine:

Pharmacokinetics: : 

cys absorbed orally, diffuses all over. About 1/3 of a dose is metabolised the rest is excreted unchanged by kidney. Toxicity: Most common in the CNS: Headache, Tremor, Vertigo, Confusion, Nervousness, Pharmacokinetics:

Thioacetazone & Ethionamide: : 

These are first anti tubercular drugs. It is a tuberculostatic drug. Low efficacy drug. Side effects: hepatitis, optic neuritis, mental disturbences impotence Thioacetazone & Ethionamide:

Para-amino salicylic acid: : 

PAS is a tuberculostatic and one of least active drugs. It inhibits denovo folate synthesis. PAS is completely absorbed by oral route and distributed all over . T1/2 is 1hr. Patient acceptability of PAS is poor. Adverse effects ; Rashes, fever, liver dysfunction Para-amino salicylic acid:

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ChemotherapyDOTS: 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.

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REGIMENS :

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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.

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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.

WORLD TUBERCULOSIS DAY MARCH24 : 

WORLD TUBERCULOSIS DAY MARCH24 MARCH24

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Thank u For your Attention..