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.

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