Tuberculosis by dungrani.mukesh19

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									   Introduction
   Transmission
   Types
   Diagnosis
   Symptoms
   Pathogenesis
   Treatment
   Category and type of pateints
   DOT therapy
It is abbreviated as TB .

It is common deadly infectious disease (contagious disease)
caused by Mycobacterium tuberculosis, M bovis, M.
africanum.

TB remains a leading infectious killer globally.

Most commonly attacks the lungs, but also affects central
nervous system, bones, joints & skin etc.

Co-infection with HIV and TB accelerates the progression of
both diseases. The mycobacteria are slow-growing intracellular
bacilli that cause tuberculosis
.
In the past decade, tuberculosis cases have significantly increased,
chiefly among AIDS and the homeless
  TRANSMISSION
Pulmonary TB is a disease of respiratory
transmission, Patients with the active disease
(bacilli) expel them into the air by:

   coughing,

   sneezing,

   shouting,

   singing
   Types of infection
Latent TB infection.
 Bacteria become inactive, but alive in body & become
  active later.
 No symptoms.
 Can’t spread bacteria.
 Normal chest x-ray & negative sputum smear.

Active TB infection.
 Become active, multiply fast in the body and cause
  disease.
 Symptoms occur.
 Spread bacteria.
 Abnormal chest x-ray & positive sputum smear.
  DIAGNOSIS
Medical history

                   Physical
                   examination

Chest radiography

                   Tuberculin skin test

Laboratory investigation

              Microbiological studies

Histology
SYMPTOMS
   Weight loss
   Fatigue
   Cough that lasts more than 2 weeks
   Fever
   Night sweats
   Hemoptysis
   Chest pain
         Patogenesis
  TB infection begins when the mycobacteria reach
                the pulmonary alveoli


       where they invade and replicate within
      the endosomes of alveolar macrophages



It happened in the lungs                       Ghon focus
   (i.e. primary side of
         infection)


            Ghon focus is generally located in either the
          upper part of the lower lobe, or the lower part of
                           the upper lobe
Cont…

        Bacteria are picked up by dendritic cells which do
                       not allow replication,


            these cells can transport the bacilli to local
                    (mediastinal) lymph nodes.




               It take over by bloodstream



        From it transfer into tissue and orgen i.e.spread of
                           secondary T.B.
The potential causes for the development of drug
resistance are

 Use of unreliable combination with an appreciable
failure rate.
 Misuse of specific drugs like rifampicin for other
diseases.
 Free availability of anti-TB drug over the counter.
 Use of single drug instead of combination.
 Failure of public health system.
 Economic constrain.
 Delay in diagnosis.
 Ignorance.
   General Principles

Four-drug initial therapy is routinely recommended for all
patients with a clinical or laboratory diagnosis of TB
disease.
Never treat active TB with a single drug.
Never add a single drug to a failing TB treatment regimen.
All TB medications should be administered by directly
observed therapy (DOT) to ensure adherence to the
prescribed treatment regimen and reduce the emergence of
resistant disease.
First Line agent   Second line agent
Rifampicin         Streptomycin,   Kanamycin
Isoniazid          Cycloserine,    Levofloxacin
Rifabutin          Capreomycin,    Moxifloxacin
Rifapentene        Viomycin,       Gatifloxacin
Ethambutol         PAS,            Amikacin
Pyrazinamide       Thiacetazone,   Clofazimine
                   Ethionamide
   Isoniazid (INH)

 It is the most active drug for the treatment of
tuberculosis

After orally administered, well absorbed, widely
distributed in body, including cerebrospinal fluid. INH
can also penetrate into macrophages and caseous foci.

Most INH is metabolized in the liver.
   Mechanism of action
Isoniazid is a prodrug and must be activated by bacterial
catalase.

It is activated by catalase-peroxidase enzyme to form
isonicotinic acyl anion or radical.

These forms will then react with a NMDA radical or anion to
form isonicotinic acyl-NADH complex.

This complex will bind tightly to ketoenoylreductase and
prevents access of the natural enoyl-AcpM substrate.

 This mechanism inhibits the synthesis of mycolic acid in
the mycobacterial cell wall.
It is bactericidal for actively growing tubercle bacilli. But, for
resting tubercle bacilli, it is bacteriostatic.

Isoniazid is able to penetrate into phagocytic cells and thus is
active against both extracellular and intracellular organisms.

This drug is not effective against atypical mycobacteria.

Side effects:
     Elevation of serum transaminases, overt hepatitis
    necessitating discontinuation of therapy, severe hepatitis
    leading to the need for liver transplantation or even fatal
    hepatitis.
     Interfere with pyridoxine metabolism and thus produce
    peripheral neuropathy.(Dose related toxicity) (treated by
    vitamin B6 supplements.)
Cont…

    Hypersensitivity Reactions:
   Fever, skin eruptions (morbilliform, maculopapular,
   purpuric, or exfoliative),lymphadenopathy, and
   vasculitis.

   Metabolic and Endocrine:
   pyridoxine deficiency,pellagra, hyperglycemia,
   metabolic acidosis, and glynecomasia.

    Miscellaneous:
   Rheumatic syndrome and systemic lupus
   erythematosus-like syndrome.
Rifampin (rifampicin)

Mechanism of action:
Rifampin is a potent agent against actively dividing intracellular
and extracellular organisms and has activity against
semidormant bacilli.

It works primarily by inhibiting DNA-dependent RNA
polymerase, blocking RNA transcription.

 It is mainly effective against tubercle bacili resist to other
standard drugs.
 Mycobacterial infections
It often uses in combination with other agents
Tuberculosis, rifampin) in order to prevent emergence of
drug-resistant mycobacteria.


 Leprosy

 Other infections
  Rifampin can be used in a variety of gram-positive
  coccal infections, especially the serious cases that
  cannot be effectively treated with other drugs.
  It is also used as prophylaxis for meningitis caused by
  highly penicillin-resistant strains of pneumococci
 Adverse effects
 Urine, sweat, tears, and contact lenses may take on an
  orange color because of rifampin administration, this effect
  is harmless.

 Light-chain proteinuria and impaired antibody response
  may occur.

 Rifampin induces hepatic microsomal enzymes and
  therefore, affects the half-life of a number of drugs.

 When taken erratically in large doses, a febrile “flu-like”
  syndrome can occur.
Interection:

Rifampin is known to induce certain cytochrome P450 enzymes.

Rifampin has been reported to accelerate the metabolism of the
following drugs:

anticonvulsants (eg, phenytoin),
antiar-rythmics (eg, disopyramide, mexiletine, quinidine,
tocainide), anticoagulants,
 antifungals (eg, fluconazole, itraconazole, ketoconazole),
 barbiturates,
beta-blockers,
calsium channel blockers (eg, diltiazem, nifedipine)

Rifampin also interacts strongly with protease inhibitors and non-
nucleoside reverse transcriptase inhibitors (NNRTIs).
Pyrazinamide
   Pyrazinamide is a pyrazine analogue of nicotinamide. At
    neutral pH, it is inactive, but at pH 5.5 it inhibits tubercle
    bacilli and some other mycobacteria.
   Quickly absorbed after orally administered
   Widely distributed in body tissues,including inflamed
    meninges.
   Excreted mainly by glomerular filtration It is used in
    combination with INH and RFP in multiagent short-term
    therapy to exert its activity against residual intracellular
    organisms that may cause relapse.
   Tubercle bacilli develop resistance to pyrazinamide fairly
    readily,    but     no      cross-resistance     with      other
    antimycobacterial drug.
Side effect:

Hepatotoxicity :
      hyperuricemia
      gout
Gastrointestinal:
      nausea,
      vomiting,
      Anorexia
Hypersensitivity reactions
       urticaria, and pruritus
       angioedema
       Fever, acen, photosensitivity, porphyeia, dysuria, and
      interstitial nephritis
Cont…




    Hematologic and Lymphetic:

            Thrombocytopenia and sideroblastic anemia with
    erythroid hyperplsia,

           vacuolation of erythrocytes and increased serum
    concentration have occurred rarely with this drug.

            Adverse effects on blood clotting mechanisms have
    also been rarely reported.
Ethambutol
 Inhibits many strains of M. tuberculosis, bacteriostatic

 Well absorbed from the gut and widely distributed in all body
  tissues and fluids.

 As with all antituberculotic drugs, resistance to ethambutol
  emerges rapidly when the drug is used alone.

 The most common serious adverse effect is dose-related optic
  neuritis, causing loss of visual acuity and red-green color-
  blindness, but are reversible.
Streptomycin
 Streptomycin is an aminoglycoside antibiotic that
  interferes with bacterial protein synthesis.
 It is effective against most tubercle bacilli, but its
  activity is weaker than that of INH and RFP.
 Streptomycin penetrates into cells poorly, and
  drug-resistance is produced easily.
 At present, streptomycin is employed when an
  injectable drug is needed or desirable, principally
  in individuals with severe, possibly life-threatening
  forms of tuberculosis , and in treatment of
  infections resistant to other drugs.
 It is always given together with other drugs to
  prevent emergence of resistance.
Side effect:
•Ototoxicity and nephrotoxicity
•Vestibular dysfunction
•auditory damage.
SECOND-LINE DRUGS
         Cycloserine


 Inhibitor of cell wall synthesis.
 Cleared – renaly (dose is red. to ½ if creatinine
 clearance is less than 50ml/min).

S/E:
 Peripheral neuropathy.
 CNS dysfunction-Psychosis, depression.
Capreomycin
 Protein synthesis inhibitor
 1g-i/m- MDR strains
 Inj. treatment for MDR-TB
S/E:
 nephrotoxic
 Ototoxic- tinnitus, deafness, vestibular disturbance.
 Inj. site- local pain, sterile abscesses.
Ethionamide
  Chemically related to INH.
  Blocks synthesis of mycolic acids.
  Available in oral form
 S/E:
  gastric irritation ( 1g/d)
  neurological symptoms( Rx-pyridoxine)
  hepatotoxicity
  Resistance- single agent.
     Kanamycin & Amikacin
 Inc. used due to MDR.
 For streptomycin resistant or MDR.
 Combination with two or three drugs.


MOA: Protein synthesis inhibitor by binding to specific 30S-
 subunit ribosomal protein.

S/E: ototoxic & nephrotoxic.
      Aminosalicylic acid
 Folate synthesis antagonist.
 Structurally similar to PABA & sulfonamides.
 Widely distributed in fluids & body tissue except
 CSF.

S/E:
 Peptic ulcers, hemorrhages(give with meals)
 Hypersensitivity reactions- fever, joint pain, skin
  rashes, hepatosplenomegaly, hepatitis,
  adenopathy, granulocytopenia,
 Thiacetazone

• Bacteriostatic

• Skin reactions, including rash and Stevens-Johnson
syndrome, may occur.

• Thiacetazone must be discontinued permanently as
soon as a rash appears.

• Similar to trimethoprim-sulfamethoxazole, the incidence
of skin reactions is much higher in AIDS patients.
  Fluoroquinolones

 Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin.
 For resistant strains against first-line drugs.
 Used in the combined regimen HIV infected patients
 Mutations in gyrase A subunit ( if used as single agent)



  Clofazimine
• Bacteriocidal and anti-inflammatory action
• GI distress, skin colouration, deposition of
crystals.
Category and type of     Duration of treatment   Drug regimen
patient
Category 1               For all such cases    INH + RMP + PZA +
 New                    intensive phase (2    ETB
  (untreated)smear       months) followed by:
  positive pulmonary     continuation phase (4 INZ + RMP
  TB)                    months) total 6
 New                    months
  (untreated)smear
  negative pulmonary
  TB but seriously ill
 New cause of
  seriously ill extra
  pulmonary TB
Category 2              For all such causes      2 months: INH +
Smear positive          intensive phase (2 + 1   RMP + PZA + ETB +
retreatment group       = 3 months)              SM
due to:                 followed by:
                        Continuation phase       1 months: INH +
 Treament failure      (5 months)               RMP + PZA + ETB
 Relapse/defult        Total 8 months           INZ + RMP +ETB

Category 3              For all such cases       INZ + RMP + PZA
 New untreated         intensive phase (2       INZ + RMP
  smear negative        months) followed
  pulmonary TB but      by: continuation
  not seriously ill     phase (4 months)
 Less sever cases of   total 6 months
  extra pulmoary TB
                          DOTS
It stands for "Directly Observed Therapy, Short-course"
 and is a major plank in the WHO global TB eradication
 programme.

It helps patients to take their drugs regularly and
 complete treatment, thus achieving cure and preventing
 the development of drug resistance.

It also reduces the development of drug resistance by
 ensuring that the full course of treatment is followed.

DOTS is used with intermittent dosing (thrice weekly).
    Elements of DOTS :
1.   Government commitment with increase and sustained
     financing.
2.   Case detection through quality assured bacteriology.
3.   Standardized treatment,with supervision and patient
     support.
4.   A regular uniterrupted supply of all essential drugs.
5.   A standarized recording and reporting system.

    The DOTS strategy only works if infrastructure and
     organization are adequate.
    Compliance to therapy is one of the important factors that
     affect the outcome of therapy.
    Patients undergoing DOT therapy will be observed by health
     care professional.
• DOT IS recommended for:

1. All cases resistant to rifampicin.

2. All MDR-TB and XDR-TB cases.

3. All relapses/reactivation.

4. All cases that clearly demonstrate an inability or
   unwillingness
   towards self medication.

5. All cases that has been placed under close supervision.
        References
 F.S.K. Barar, “essential of pharmacotherapeutics”, 10th edition
2005, S. chand and company Ltd, Pg no. 434.
 Harsh Mohan, “essential Pathology for dental students”, 3rd
edition, Jaypee brothers, Pg. no.116.
 KD tripathi, “essential of medical pharmacology”, sixth
edition, Jaypee brothers medical publishers (p) LTD,pg. no.739.
 H.L.Sharma, “principle of pharmacology”
 www.wickkepidia.org

								
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