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Transcript

TUBERCULOSIS

TB is an ancient infectious disease caused by
Mycobacterium tuberculosis. It has been known since
1000 B.C., so it not a new disease. Since TB is a
disease of respiratory transmission, optimal
conditions for transmission include:
 overcrowding
 poor personal hygiene
 poor public hygiene

Pulmonary tuberculosis is a disease of respiratory
transmission, Patients with the active disease
(bacilli) expel them into the air by:
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coughing,
sneezing,
shouting,
or any other way that will expel bacilli into the
air
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Are slender, rod-shaped bacteria with lipid-rich
cell wall that stain poorly with Gram stain, but
once stained, the walls cannot be easily
decolorized. Hence are termed “acid-fast”
Mycobacterial infections are intracellular and
generally results in the formation of slowgrowing granulomatous lesions that are
responsible for major tissue destruction.
The most widely encountered mycobacterial
infection is tuberculosis but can also cause
leprosy


Treating tuberculosis as well as other
mycobacterial infection poses therapeutic
problems.
The organism grows slowly, thus the disease may
have to be treated for six moths to two years.
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Seen in pts who have had prior therapy
Those who fail to comply
Treatment with a single drug
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Multi drug therapy with a minimum of two drugs
preferably bactericidal.
Direct observed therapy (DOT) to address the
problem of noncompliance
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Based on degree of effectiveness and potential
side effect.
FIRST-LINE DRUGS: Ethambutol, isoniazid,
rifampin, streptomycin and pyrazinamide
Most effective and less toxic
SECOND-LINE DRUGS: Fluoroquinolones,
macrolides, aminosalicylic acid, cycloserine,
ethionamide etc.
Second line drugs are less effective and more toxic.


Considered the first drug of choice for the
chemotherapy of TB. discovered in 1945 the
hydrazide of isonicotonic acid, therefore called
INH
Is a synthetic analog of pyridoxine (vit B6)

INH is a prodrug that is activated by a
mycobacterial catalase-peroxidase (KatG) which
inhibits the synthesis of mycolic acid which is
part of the bacteria cell wall structure.
 is bacteriostatic for resting bacilli,
 bactericidal for growing bacilli.

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Organism eventually develops resistance.
The mechanism of resistance is related to
mutation or deletion of KatG leading to inability
to activate the prodrug.
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Absorption: INH rapidly absorbed either oral or
parenteral route.
Drug is metabolized via acetylation resulting in
the production of inactive but toxic metabolite
called monoacetylhydrazine that is excreted in the
urine and then hydrolysis
This acetylation is genetically regulated resulting
in two types of acetylators: fast and slow
acetylators.
fast-acetylators: have a short half-life(~1 hr)
Slow-acetylators: have a long half-life (~3hrs)
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Induced Hepatitis (2% of Population) due to the
buildup of toxic metabolic products of
acetylisoniazid --> acetylhydrazine. Common in
fast acetylators.
Hepatic reactions to Isoniazid ↑es with age.
Peripheral neuritis: the most common adverse
effect is due to vit B6 def. and thus can be corrected
by supplementation with B6
Others: sideroblastic anemia, SLE(slow
acetylators),

INH interferes with metabolism of phenytoin,
therefore increasing the activity of phenytoin
and potentiating the adverse effect of
phenytoin.
Mechanism of Action
 Rifampin inhibits DNA dependent RNA
polymerase of the bacilli thereby affecting
transcription.

Due to alteration of the target enzyme(DNA
dependent RNA polymerase) of the drug
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Does not cause many side effects in any great
frequency.
G.I. upset: Anorexia, Nausea ,Vomiting Mild
abdominal pain,
Hepatitis
Red-orange discoloration of body fluid(
sweat, saliva, stool, urine) etc
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Is an inducer of cytP450, so can decrease the half
life of certain drugs that require P450 for their
metabolism e.g., warfarin, sulfonyurea, oral
contraceptives etc.
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Treatment of leprosy
Prophylaxis for individuals exposed to meningitis
caused by meningococci or H. influenza
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Capreomycin
Viomycin
Kanamycin
STREPTOMYCIN
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The first drug used clinically for treatment of TB
1947-1952; was the only drug available at that time.
is an aminoglycoside antibiotic
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
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These drugs are: Nephrotoxic - will cause
Proteinuria, Hematuria, Nitrogen
metabolism, and Electrolyte disturbances
Ototoxic: involving both hearing and
balance.
Hearing is irreversible but balance is
reversible once drug is stopped.
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Bactericidal antitubercular drug.
mechanism of action is not understood. Used in
combination with isoniazid and rifampin.
Must be enzymatically hydrolyzed to pyrazinoic
acid(active form) by pyrazinamidase
Active against tubercle bacilli in lysosomes and in
macrophages.
Adverse effect: gout
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MOA: Inhibition of arabinogalactan, a component of
the bacteria cell wall
Adverse effect: inhibits urate excretion – GOUT
OPTIC NEURITIS - vision changes (e.g., blurring,
inability to distinguish between red-green color
blindness)
.
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Aminosalicylic acid
Capreomycin
Cycloserine
Ethionamide
Fluoroquinolones
macrolides
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a structural analog of PABA (p-aminobenzoic
acid) is bacteriostatic inhibits de novo folate
synthesis
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GI irritation due to the amount of drug given
(high doses) nausea, vomiting, bleeding, occurs
in 30-40% of the patients.
Hypersensitivity reactions Rash, Fever
hepatotoxicity
All will disappear when the drug is stopped
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Structural analog of isoniazid but not believed to
act by the same mechanism
Oral administration
Widely distributed throughout the body
Adverse effects- hepatotoxicity, optic neuritis,
Peripheral neuropathy.
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Also called Hansen disease
Caused by mycobacteria
leprae
Treated with a triple drug
regimen of dapsone,
clofazimine and rifampin for
6 to 24 months to decrease
prevalence

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Structurally related to sulfonamides
It is bacteriostatic
MOA; acts as a PABA antagonist to inhibit folate
synthesis
Undergoes hepatic acetylation
Excreted through urine
Adverse effects: hemolysis in pts with G6PD def,
metHb, peripheral neuropathy and erythema
nodosum leprosum


A serious and severe skin complication of leprosy
which is due to inflammation of fat cells in the
face, arms and shins of pts treated with dapsone
Treatment: corticosteroid or thalidomide

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MOA: Binds to DNA and prevents it from serving
as a template for future DNA replication.
Also has redox properties → production of
oxygen free radicals.
Is bactericidal
Adverse effect: red-brown discoloration of the
skin, eosinophilic enteritis
No erythema nodosum leprosum.