tuberculosis. tb is an ancient infectious disease caused by mycobacterium tuberculosis. it has been...
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TUBERCULOSIS
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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
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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
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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 slow-growing granulomatous lesions that are responsible for major tissue destruction.
The most widely encountered mycobacterial infection is tuberculosis but can also cause leprosy
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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.
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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)
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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),
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INH interferes with metabolism of phenytoin, therefore increasing the activity of phenytoin and potentiating the adverse effect of phenytoin.
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Mechanism of Action Rifampin inhibits DNA dependent RNA
polymerase of the bacilli thereby affecting transcription.
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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
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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.