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TUBERCULOSIS
Guided By:Dr.Devang B. ShethDepartment of PharmacologyB.K mody Govt. pharmacy college
Prepared By:Krunal A. GoyaniM.Pharm, Sem-IEnrolment No.-152120803008
INDEX Introduction
Epidemiology
Ethology
Risk factor
Transmission
Pathophysiology
Symptoms of tuberculosis
Diagnosis step
Anti-tubercular drug
Treatment and management
INTRODUCTIONTuberculosis is granulomatous disease and major health problem in
developing countries.
As per “WHO” Tuberculosis also call “TB” Is An Infectious Bacterial Disease Caused By Mycobacterium Tuberculosis, Which Most Commonly Affects The Lungs. It Is Transmitted From Person To Person Via Droplets From The Throat And Lungs Of People With The Active Respiratory Disease.
Tuberculosis ancient disease remains a leading infectious killer of mankind.
TB commonly was known as “consumption” because of the pronounced weight loss that it caused Other common names included “wasting disease” and the “white plague.”
To Aggravate The Situation Is The Immunocompromised Patient.
EPIDEMIOLOGY
EPIDEMIOLOGYGlobally In 2013, an estimated 9.0 million people developed TB and 1.5
million died from the disease,360 000 of whom were HIV positive ,480 000 of them being affected by multidrug-resistant (MDR) Mycobacterium tuberculosis strains. On average, an estimated 43,200 of patients with MDR-TB had extensively drug resistant TB (XDR-TB).
There were 80 000 deaths from TB among HIV-negative children in the same year.
TB is slowly declining each year and it is estimated that 37 million lives were saved between 2000 and 2013 through effective diagnosis and treatment.
EPIDEMIOLOGY
EPIDEMIOLOGY India is the second-most population country in the world one fifth of the
global incident TB cases occur in India annually.
WHO statistics for 2013 giving an estimated incidence figure of 1.96 million cases of TB for India out of a global incidence of 9 million.
India’s TB control programme is on track as far as reduction in disease burden is concerned. There is 42% reduction in TB mortality rate by 2012 as compared to 1990 level. Similarly there is 51% reduction in TB prevalence rate by 2012 as compared to 1990 level.
ETIOLOGYTB infection caused by tubercle bacilli, which belong genus to
mycobacterium.
Mycobacterium, from the greek “mycos” refers to mycobacteria’s waxy appearance, which due to highly lipid contain cell wall with slender shape bacillus.
Ziehl-neelson stain or the fluorochrome stain must be used instead gram stain.
Main species of mycobacterium cause tuberculosis.Typical mycobacteria
1. Mycobacterium tuberculosis2. Mycobacterium hominis3. Mycobacterium bovine
Atypical mycobacteria1. Saprophytic mycobacteria 2. Mycobacterium avium
RISK FACTORA healthy immune system can often successfully fight TB bacteria,
but your body can't mount an effective defence if your resistance is low. diseases and medications can weaken your immune system, including :
HIV/AIDSDiabetesChemotherapy MalnutritionAdvanced ageAlcoholism Immunosuppressive medicationsImmigrant (From area with high TB incidence )
TRANSMITTION
Tuberculosis Is Transmitted Mainly By Droplet Infection And Droplet Nuclei. Generated By Sputum-positive Patient With Pulmonary Tuberculosis. To Transmit Infection , The Particles Must Be Fresh Enough To Carry A Viable Organism.
PATHOPYSIOLOGY
Type of tuberculosis infection Pulmonary TB :
1. Primary Tuberculosis :The infection of an individual who has not been previously infected or
immunized is called Primary tuberculosis or Ghon’s complex or childhood tuberculosis.
Lesions forming after infection is peripheral and accompanied by hilar which may not be detectable on chest radiography.
2. Secondary Tuberculosis :
The infection that individual who has been previously infected or sensitized is called secondary or post primary or reinfection or chronic tuberculosis.
SYMPTOMS OF TUBERCULOSIS
coughing Cough with blood Fever
Fatigue Weight loss Chest pain
Chills Night sweats Feel hungerless
DIAGNOSTIC STEPS
BACTERIOLOGIC EVALUATION
HISTORY AND CLINICAL EXAMINATION
RADIOGRAPHIC FEATURES
“The first rule of TB diagnosis: is to think of TB….”
The physician Include TB in his differential diagnosis when history &
symptoms are consistent with TB diagnosis THEN he will recommended
appropriate diagnostic tests to prove the infection.
1
2
Chest X-ray Tuberculosis creates cavities visible in x-rays like this one in the patient's right upper lobe. Abnormalities on chest radiographs may be suggestive, but are never diagnostic of TB. However, chest radiographs may be used to rule out.
BACTERIOLOGIC EVALUATION3
Specimen:
Fresh Sputum ,Gastric Washing , Urine, Pleural Fluid , Cerebrospinal Fluid , Biopsy Material , Blood.
Decontamination & concentration of specimens : Sputum Specimens (Non Sterile) Should Be :
Liquefied with N-acetyl-L-cysteine. Decontaminated with NaOH. Neutralized with buffer. Concentrated By Centrifugation.
Specimens processed in this way can be used for acid fast stains and for culture.
Acid Fast Bacilli “AFB” Smear Test
Specimen examined for acid fast bacilli by staining:
Ziehl-neelson Acid Fast Staining
Auramine-rhodamine Staining
Acid Fast Bacilli “AFB” Culture Test
Löwenstein-Jensen (egg and also contain high concentrations of malachite green to overcome contamination with other bacteria).
Middlebrook 7H10 & 7H11 are ( contain defined vitamins, salts, catalase, glycerol, oleic acid and albumin to neutralize toxic effect of fatty acids).
Acid fast bacilli (AFB) smear microscopy and culture are still the “gold standards” for the diagnosis of active TB but this conventional methods for culture required (6-8) weeks for isolation from media.
Tuberculin skin Test Purified Protein Derivative (PPD) : Is a concentrated filter of broth in which tubercle bacilli have grown for 6 weeks(old). Measuring The Size Of Induration 48-72 Hours. Positive If ≥ 10 mm Induration Size. Standard Method For Screening & Measuring Of A Person’s Cellular
Response.
1 2
Positive Reaction
Person Infected In The Past Or Latent TB Infection.
After BCG Vaccination, But This May Last For Only 3-7 Years .
Persons Are Retested 2 Weeks Later; Their PPD Skin Test “Boosted” By The
Recent Antigen Injection. High Risk Of (Endogenous Infection)
Negative Reaction
Persons Who Have NEVER Been Infected, They Are Not Subject To That
Risk, Though They May Become Infected From An External Source
(Exogenous Infection)
γ-Interferon release assays (GIRA)
Test Rely On The Fact That T-Lymphocytes Will Release γ-interferon
When Exposed To Specific Antigens. These Tests Are Mostly Developed
For The Field Of Tuberculosis Diagnosis, But In Theory, May Be Used In
The Diagnosis Of Other Diseases Which Rely On Cell-mediated
Immunity.
FIRST LINE DRUG
1. Isoniazid (H)
2. Rifampin (R)
3. Pyrazinamide (Z)
4. Ethambutol (E)
5. Streptomycine (S)
SECOUND LINE DRUG
1. Thiacetazone (Tzn)
2. Paraaminosalicylic acid (PAS)
3. Ethionamide (Etm)
4. Cycloserine (Cys)
5. Kanamycine (Am)
6. Capriomycine (Cpr)
NEWER DRUG
1. Ciprofloxacin
2. Ofloxacine
3. Clarithromycine
4. Azithromycine
5. Rifabutine
6. Bedaquiline(Recently)
ANTI-TUBERCULAR DRUG
ANTI-TUBERCULOSIS DRUGS BY GROUP
ISONIAZIDE(H)-Pyridine hydrazide.
Mechanism of Action
Action Bacteriostatic for resting mycobacteria, bactericidal for proliferating
mycobacteria.
Mechanisms of Resistance Mutation or deletion of katG gene. Mutation in kasA gene. Over-expression of the inhA & aphC gene (detoxify organic peroxide)
Dose 5 mg/kg (300 mg),OD Oral / im / iv
Pharmacokinetics Oral BA ~ 100%. Only ~10% is protein bound Metabolised in liver by Arylamine N-acetyltransferase2 (NAT2). Excreted in urine as Acetylisoniazid & Isonicotinic acid.
Adverse reaction Peripheral neuritis Liver damage. Optic neuritis, Convulsions, Hypersensitivity reactions
RIFAMPICINE(R)-RifamycineAction
Bactericidal for mycobacteria; also effective against most Gram-positive and many Gram-negative bacteria.
Mechanism of Action
Binds to the β subunit of DNA-dependent RNA polymerase (rpoB) .
Inhibit RNA synthesis
Mechanisms of Resistance
Mutation at codons site of rpoB gene.
Dose 10 mg/kg (600 mg),OD Oral
Pharmacokinetic
Absorption is variable-Oral bioavailability Rifampicin (68%) &
Rifabutin (20%)
Food- ↓Rifampicin absorbtion but no effect on Rifabutin.
High fat diet- ↑Rifapentin absorption.
Half life - Rifampicin→2-5hrs, Rifabutin →32-67hrs, Rifapentine →14-18hrs
Adverse reaction
Flu like symptoms.
Thrombocytopenic purpura.
GIT disturbances &
Harmless orange tint to saliva, sweat & tears
PYRAZINAMIDE(Z)-Nicotinamide analogueAction
Bactericidal for actively dividing intracellular mycobacteria. Main effect occur in first few months.
Mechanism of Action
PYRAZINAMIDE
Enter M.tuberculosis
Pyrazinoic acid (POA+)
Kill the mycobacteria
Pyrazinamidase/Nicotinamidase
Inhibit FAS
Inhibit growth mycobacteria
Go extra-cellular
Mechanisms of Resistance
Point mutation in pncA gene (encodes Pyrazinamidase)
Dose 1,000 mg (40–55 kg) 1,500 mg (56–75 kg) 2,000 mg (76–90 kg)
Abs/Distrb/ElimGiven orally, widely distributed, crosses into the CSF, excreted in urine.
Adverse reaction Sideroblastic Anemia.
Hepatotoxic &
Joint pains
STREPTOMYCINE(S)-aminoglycosideAction
Bactericidal for actively dividing intracellular mycobacteria.
Mechanism of ActionBind 30S ribosomes.
False pair of codon:anticodone
False reading of genetic cord
Inhibit protein synthesis
Dose 1,000 mg (40–55 kg)
Pharmacokinetics Very poor oral bioavailability hence given in injectable form.
Distributed extracellularly mainly.
Excreted unchanged in urin
Adverse reaction Ototoxicity
Nephrotoxicity
Neuromuscular blockade- ↓release of Ach by inhibiting fusion of
vesicles with terminal membrane
ETHAMBUTOL(E)-Ethylenediamine derivativeAction
Tuberculostatic drug.Mechanism of Action
Inhibit Arabinosyl transferase-Ш enzyme
Disrupt the transport of Arabinose sugar
Arbinogalactan biosynthesis impaired
Disruption in mycobacterial cell wall formation
Dose 1,000 mg (40–55 kg)
Mechanisms of Resistance Mainly by mutation in codon of embB gene. KatG mutation Co-occurance of Ethambutol & Isoniazid resistance.
Pharmacokinetics
Oral bioavailability ~80%.
~10-40% bound to plasma proteins
Adverse reaction Optic neuritis
Colour blindness
Hyperuriceamia
FLASH CARD OF ANTITUBERCULAR DRUG
TRATMENT & MANAGMENTDOTS (Directly Observed Treatment, Short-Course)
DOTS is the name given to the tuberculosis control strategy recommended by the World Health Organization.
According to WHO, “The most cost-effective way to stop the spread of TB in communities with a high incidence is by curing it. The best curative method for TB is known as DOTS.
DOTS is an interventional strategy developed by Dr. Karel Styblo and is recommended by the WHO as the strategy that ensures cure of TB.
A DOT Lay Worker meets with clients to help with TB medication, and provide support and education. Watching clients swallow each dose of anti-TB medication.
The five elements of DOTS
1. Political will.
2. Case detection through quality-assured bacteriology.
3. Standardized treatment, with supervision and patient support.
4. An effective drug supply and management system. &
5. Systematic monitoring and accountability for every patient
diagnosed.
Medication
1. INTENSIVE PHASE ( 2-3 months)
Under direct supervision of a health worker or trained person
2. CONTINUATION PHASE (4-6 months)
A multiblister combipack with drugs for 1 week is given of which the first dose is taken under supervision
H: Isoniazid (300 mg), R: Rifampicin (600 mg), Z: Pyrazinamide (1500 mg), E: Ethambutol (1000 mg), S: Streptomycin (1000 mg)
1. Patients who weigh 60kg or more receive additional Rifampicin
150mg.2. Patients who are more than 50 years old receive Streptomycin
500mg. 3. Patients who weigh less than 30kg receive drugs as per Paediatric
weight band boxes according to body weight.
Category Type of Patient Regimen Duration in monthsCategory IColor of box: RED
New Sputum Positive , Seriously ill sputum negative, Seriously ill extra pulmonary,
2 (HRZE)3,4 (HR)3
6
Category IIColor of box: BLUE
Sputum Positive relapse, Sputum Positive failureSputum Positive treatment after default
2 (HRZES)3,1 (HRZE)3
5 (HRE)3
8
ADVANTAGES
The client is supported to successfully complete the full course of
medication
The client is monitored closely for side effects of medications and supported
to work through the side effects appropriately
The client is encouraged and support.
Reduces the possibility of tuberculosis germs becoming resistant to the
medication.
DRUG RESISTANT TB
1. Multiple drug resistance TB (MDR-TB) An MDR-TB suspect who is sputum culture positive and whose TB
is due to Mycobacterium tuberculosis that are resistant in-vitro to at
least isoniazid and rifampicin.
2. Extensively Drug Resistant TB (XDR–TB) is a subset of MDR-TB where the bacilli, in addition to being
resistant to R and H, are also resistant to any fluoroquinolones and
any one of the second-line injectable drugs (namely Kanamycin,
Capreomycin, or Amikacin).
TREATMENT
STANDARDISED TREATMENT REGIMEN For the treatment of MDR-TB cases
6 drugs
- kanamycin - ofloxacin - ethionamide - pyrazinamide
- ethambutol - cycloserine
for 6-9 months of the Intensive Phase
TREATMENT
CONTINUATION PHASE- 4 drugs
Ofloxacin Ethionamide
Ethambutol Cycloserine
for 18 months.
DOTS DOTS PLUS1. Standardised treatment throughout
the duration of treatment1. Individualised treatment regimens
when mycobacterial culture and anti-tuberculosis drug sensitivity reports become available
2. Diagnosis by microscopy 2. Diagnosis by DSC
3. Reliable supply of a limited number of reliable first-line drugs
3. Provision of a wide-range of second-line anti-tuberculosis drugs.
4. Continuous evaluation of patient notifications, smear results, and outcome
4. Three monthly culture and anti-tuberculosis drug susceptibility testing and more extensive programmatic reviews
5. Commitment from the local government
5. Additional support from external governments and agencies.
REFERENCE1. Dipiro T. Joseph , Talbert L. Talbert , Yee C. Gary , Chales A. Peloquin , Matzke R. Gary ;
Pharmacotherapy Pathophysiological Approach ; 7th Edition ; Page No.-1839.2. Walker Rogger , Whittleses Cate ; Clinical Pharmacy & Therapeutics ; 4th Edition ; Chepter-
40.3. Harsh Mohan ; Taxt Book Of Pathophysiology ; 6th Edition ; Page No.-148.4. Tripathi KD ;Essentials Of Medical Pharmacology ; 6th Edition ; Page No-739.5. Laurence L. Brunton , Bruce A. Chabner , Björn C. Knollmann , Tawanda Gumbo ; Goodman
& Gilman’s The Pharmacological Basis of THERAPEUTICS ; 12th edition ; chapter-56.6. Sharma SK, A mohan ;”Directly Observed Treatment, Short-Course (DOTS)”; Journal,
Indian Academy of Clinical Medicine ; April-June, 2004.7. Lia D’Ambrosio , Rosella Centis , Giovanni Sotgiu , Emanuele Pontali , Antonio Spanevello ,
and Giovanni Battista Migliori1 ; “New anti-tuberculosis drugs and regimens: 2015 update” ; “European respiratory society” ; April 3 2015.
8. Annabel Baddeley , Anna Dean , Hannah Monica Dias , Dennis Falzon, Katherine Floyd, Inés Garcia Baena , Christopher Gilpin , Philippe Glaziou ;”Global tuberculosis report 2014” ; world health organization.
9. TB india 2014 ;RNTCP annual status report. Publised by Ministry of Health and Family Welfare, Nirman Bhavan, New Delhi–110108.
10. G.Brooks , K.Carrroll , J.Butel , S.Melnicks ; Medical Microbiology ; 24th Edition Jawetz , Melnicks Dahlberg's .
THANK YOU
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