1.  TUBERCULOSIS

2.  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

3.  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

4.  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

10.  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.

11.  Seen in pts who have had prior therapy  Those who fail to comply  Treatment with a single drug

12.  Multi drug therapy with a minimum of two drugs preferably bactericidal.  Direct observed therapy (DOT) to address the problem of noncompliance

13.  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.

14.  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)

15.  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.

17.  Organism eventually develops resistance.  The mechanism of resistance is related to mutation or deletion of KatG leading to inability to activate the prodrug.

18.  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)

19.  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),

20.  INH interferes with metabolism of phenytoin, therefore increasing the activity of phenytoin and potentiating the adverse effect of phenytoin.

21. Mechanism of Action  Rifampin inhibits DNA dependent RNA polymerase of the bacilli thereby affecting transcription.

22.  Due to alteration of the target enzyme(DNA dependent RNA polymerase) of the drug

23.  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

24.  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.

25.  Treatment of leprosy  Prophylaxis for individuals exposed to meningitis caused by meningococci or H. influenza

26.  Capreomycin  Viomycin  Kanamycin  STREPTOMYCIN

27.  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

28.  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.

29.  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

30.  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)

31. .  Aminosalicylic acid  Capreomycin  Cycloserine  Ethionamide  Fluoroquinolones  macrolides

32.  a structural analog of PABA (p-aminobenzoic acid) is bacteriostatic inhibits de novo folate synthesis

33.  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 

34.  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.

35.  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

36.  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

37.  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

38.  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.