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Transcript
ANTI TB DRUGS TUBERCULOSIS OR TB • Deadly infectious disease Transmission: • Attacks the lungs but can also affect other parts of the body. Pulmonary tuberculosis:- • Symptoms:• A chronic cough with blood-tinged sputum, fever, night sweats, and weight loss. Cause:• Mycobacterium tuberculosis , • A small aerobic non motile bacillus. • M. tuberculosis complex includes TB causing mycobacteria : • M. bovis, M. africanum, M. Canetti and M. microti. Epidemiology: • Currently 3.1 billion is infected with Mycobacterium tuberculosis. • Mycobacterium avium complex is associated with AIDS related TB. • A disease of respiratory transmission. • 75% of the cases are pulmonary TB • 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 Symptoms:• Chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks. • Systemic symptoms include:• Fever, chills, night sweats, appetite loss, weight loss, pallor, and often a tendency to fatigue very easily. EXTRAPULMONARY TUBERCULOSIS • 25% of active cases • Infection moves from the lungs, causing other kinds of TB. • Occurs more commonly in immunosuppressed persons and young children. SITES OF INFECTION INCLUDE:- • Pleura in tuberculosis pleurisy • Central nervous system in meningitis, • Lymphatic system in scrofula (a disease with glandular swellings) of the neck • Genitourinary system in urogenital tuberculosis, and • Bones and joints in Pott's disease of the spine. PATHOPHYSIOLOGY:Infection via inhalation of droplet nuclei. ↓ Transport of bacilli to terminal alveoli (especially lower segments of lungs) ↓ Ingestion of organisms by macrophages followed by multiplication within macrophages ↓ Transport of organisms to regional lymph nodes by infected macrophages with continue multiplication and minimal inflammatory response ↓ Extension of organisms( within 4-6 weeks after inhalation) into the bloodstream from the regional nodes ↓ Cell mediated immunity / hypersensitivity reaction ↓ Development of clinical infection Diagnosis of TB:• Diagnosis by X-ray • Diagnosis by sputum investigation • Diagnosis by tuberculin test • Skin test:- PPD (purified protein derivative) antigens are injected intradermally. A positive reaction is a helpful adjunct in diagnosis. CLASSIFICATION:• According to their clinical utility: First line: • Have high antitubercular efficacy • Low toxicity • Used routinely First line drugs • 1. Isoniazid (H) • 2. Rifampin (R) • 3. Pyrazinamide (Z) • 4. Ethambutol (E) • 5. Streptomycin (S) Second line: • Have either low antitubercular efficacy • Higher toxicity or both • Used as reserve drugs. Second line drugs • • • • • • • Ethionamide (Eto) Prothionamide (Pto) Cycloserine (Cs) Terizidone (Trd) Para-aminosalicylic acid (PAS) Rifabutin Thiacetazone (Thz) • Fluoroquinolones • • • • Ofloxacin (Ofx) Levofloxacin (Lvx/Lfx) Moxifloxacin (Mfx) Ciprofloxacin (Cfx) • Injectable drugs • Kanamycin (Km) • Amikacin (Am) • Capreomycin (Cm) • Group I: most potent and best tolerated oral drugs used routinely. • Group II: potent and bactericidal, but injectable drugs. • Group III: includes fluoroquinolones (FQs):- well tolerated bactericidal oral drugs; all patients with drug resistant TB should receive one FQ. • Group IV: less effective, bacteriostatic/more toxic oral drugs for resistant TB. • Group V: drugs with uncertain efficacy; not recommended for MDR-TB; may be used in extensively resistant TB (XDR-TB). Isoniazid (INH) (Isonicotinic acid hydrazide, H) • Primarily tuberculocidal • Tuberculocidal for rapidly multiplying bacilli • Acts on extracellular as well as on intracellular TB • Equally active in acidic or alkaline pH • Cheapest anti-tubercular drugs Mechanism of Action • Inhibition of synthesis of mycolic acids • Two gene products labelled ‘InhA’ and ‘ KasA’ , - which function in mycolic acid synthesis are targets of INH action. • INH enters sensitive mycobacteria which convert it by a catalaseperoxidase enzyme into a reactive metabolite. • Then forms adduct with NAD that inhibits InhA and KasA. • Other products of KatG activation of INH include superoxide,H2O2 , alkyl hydroperoxides and NO radical may also contribute to INH bactericidal effect INH enters bacilli by passive diffusion Drug is not directly toxic to the bacillus but must be activated to its toxic form within the bacillus by KatG (multifunctionary , catalase –peroxidase) KatG catalyzes the production from INH of an isoNicotinoyl radical that subsequently interacts with mycobacterial NAD and NADP to produce a dozen adducts A nicotinoyl-NAD isomer, inhibits the activities of enoyl acyl carrier protein reductase (InhA) and β-ketoacyl acyl carrier protein synthase (KasA) Inhibition of these enzymes inhibits synthesis of mycolic acid -- bacterial cell death Another Adduct, a nicotinoyl-NADP isomer , potently inhibits mycobacterial DHFRase ,thereby interfering with nucleic acid synthesis Mechanism of resistance • Emerge rapidly if the drug is used alone. • Resistance can occur due to either 1. 2. High-level resistance is associated with deletion in the katG gene that codes for a catalase peroxidase involved in the bioactivation of INH. Low-level resistance occurs via deletions in the inhA gene that encodes “target enzyme” an acyl carrier protein reductase. PHARMACOKINETICS Absorption • Rapid and complete; slowed with food Distribution • All body tissues and fluids including CSF; crosses placenta; enters breast milk • Protein Bound: 10-15% Metabolism • Hepatic ( fast, slow acetylators) Elimination • Excretion: Urine (75-95%); feces INTERACTIONS :ADVERSE EFFECTS:• Peripheral neuritis and a variety of •Aluminium hydroxide neurological manifestations are the most important dose-dependent toxic inhibits INH effects. absorption • INH neurotoxicity • Hepatitis is major adverse effect •INH retards phenytoin, • Lethargy (a lack of energy and carbamazepine, enthusiasm) • Rashes. diazepam, theophylline • Fever acne. and warfarin • Arthralgia. • Respiratory syndrome: metabolism by breathlessness. inhibiting CYP2C19 • Purpura, haemolysis, shock and renal failure. and CYP3A4,and may • Cutaneous syndrome : flushing, raise their blood levels. pruritis + rash. • Flu like syndrome : fever, headache, •PAS inhibits INH bone pain. metabolism and prologs its half life. Rifampin (Rifampicin , R) • Semisynthetic derivative of Rifamycin B obtained from streptomyces mediterranei • Bactericidal to M. Tuberculosis and many other gram(+) and gram (-) bacteria like staph.aureus , N.meningitidis, H.influenza, E.coli,Kleibsella , Pseudomonas,Proteus and legionella • Against TB bacilli , it is as efficacious as INH and better than all other drugs • Bactericidal actions covers all subpopulations of TB bacilli , but acts best on slowly or intermittenly dividing ones (spurters) • Both extra and intracellular organisms are affected • Good sterilizing and resistance preventing actions MECHANISM OF ACTION OF RIFAMPIN • Rifampin interrupts RNA synthesis by binding to beta subunit of mycobacterial DNA-dependent RNA polymerase encoded by rpoB gene and blocking its polymerizing function • The basis of selective toxicity is that mammalian RNA polymerase does not avidly bind rifampin MECHANISM OF ACTION - MOA OF RIFAMPIN: D.N.A RIFAMPIN DNA dependent R.N.A.polymerase R.N.A Protein Syn. Cell multiplication Rifampin bind to β S.U of D.D.R.P Drug –Enz Complex Supression of chain initiation Rifampin resistance • Mycobacteria and other organisms develop resistance to rifampin rather rapidly. • Rifampin resistance is nearly always due to mutation in rpoB gene reducing its affinity for the drug. • No cross resistance with any other antitubercular drug,except rifampin congeners,has been noted. Pharmacokinetics • Well absorbed orally • Bioavailability ~ 70% , food decreases absorption • Rifampin is to be taken in empty stomach • Widely distributed in the body; • penetrates intracellularly , enters tubercular cavities and placenta • It crosses meninges , largely pumped out of CNS by P– glycoprotein • Metabolized in liver – active deacetylated metabolite – excreted mainly in Bile , some in urine • Rifampin and its deacetylated metabolite undergoes enterohepatic circulation • T1/2 – 2-5 hrs Interactions with rifampin • Rifampin is a microsomal enzyme inducer-increases severalCYP3A4, CYP2D6,CYP1A2 and CYP2C subfamily. • It thus enhances its own metabolism as well as that of many drugs including warfarin, oral contraceptives, corticosteroids, sulfonyl ureas, steroids, HIV protease inhibitors, non nucleoside reverse transcriptase inhibitors(NNRTIs), theophylline, metaprolol, fluconazol,ketoconazole, clarithromycin, phenytoin etc. • Contraceptive failures have occurred. • It is advisable to switch over to an oral contraceptive containing higher dose (50 microgram) of • Estrogen or use alternative method of contraception. Adverse effects of Rifampin oIncidence of adverse effects is similar to INH oHepatitis , a major adverse effect, generally occurs in pts with pre-existing liver disease and is dose related oJaundice – discontinuation of drug – reversible • Minor reactions, usually not requiring drug withdrawal and more common with intermittent regimens, are: oCutaneous syndrome: flushing, pruritus + rash (especially on face and scalp),redness and watering of eyes. oFlu syndrome: with chills ,fever, headache, malaise (a general feeling of discomfort) and bone pain. oAbdominal syndrome :nausea, vomiting, abdominal cramp with or without diarrhoea. • Urine and secretions may become orange-red—but this is harmless. • Other serious but rare reactions are: oRespiratory syndrome: breathlessness which may be associated with shock and collapse. oPurpura, haemolysis, shock and renal failure. Other uses of rifampin 1. 2. 3. 4. Leprosy Prophylaxis of Meningococcal and H.influenza meningitis and carrier state Second/third choice drug for MRSA, Diptheroids and legionella infections Combination of doxycycline and rifampin is first line therapy of brucellosis PYRAZINAMIDE (Z) • Chemically similar to INH • Weak cidal action • More active MECHANISM OF ACTION • Similar to INH • Converted inside mycobacterial into active • In acidic medium metabolite (pyrazinoic • On slowly replicating bacteria acid) by • More lethal (pyrazinamidase) enzyme • To intracellular bacilli encoded by pncA gene. • To the sites showing inflammatory • Gets accumulated in acidic response medium. • Highly effective during the first 2 • By interacting with a different months of therapy fatty acid synthase ADVANTAGES :• Inhibits mycolic acid synthesis. • Duration of treatment shortened • Also disrupt mycobacterial cell • Risk of relapse to be reduced membrane and its transport function PZA : MECHANISM OF ACTION PZA enter through passive diffusion Bac. Pyrazinamidase Pyrazinoic acid inhibit myobacterial fatty acid synthase -I INTERFERANCE IN CELL WALL SYSNTHESIS RESISTANCE:- ADVERSE EFFECTS:• Develops rapidly if it is • Hepatotoxicity is the used alone most important • Mostly due to mutation • Hyperuricaemia is in pncA gene. common (due to inhibition of uric acid secretion in kidneys) PHARMACOKINETICS:• Penetration in CSF • Abdominal distress • Metabolized in liver • Arthralgia • Excreted ion urine • Flushing, rashes, • Plasma t½ is 6-10 hours. fever. USES:- • Highly useful meningeal TB in ETHAMBUTOL (E) • Tuberculostatic • Active against MAC as well as some other mycobacteria • Fast multiplying bacilli – more susceptible • Added to triple regime of RHZ ADVANTAGES:• Hastens the rate of sputum conversion • Prevents development of resistance MECHANISM OF ACTION • By inhibiting arabinogalactan synthesis. • Drug targets arabinosyl tranferases (encoded by embAB genes) involved in arabinogalactan synthesis. • Arabinogalactan required for mycolic acid incorporation in mycobacterial cell wall. RESISTANCE:- • Develops slowly • Mutation in embB gene • Reducing the affinity of the target enzyme. • No cross resistance with any other antitubercular drug. EXACT MECHANISM : NOT KNOWN PROBABILITIES : ETHAMBUTOL BLOCKS ARABINOSYL TRANSFERASE (ENCODED BY emb) NO POLYMERIZATION REACTION OF ARABINOGLYCAN (Essential component of Myco. Cell wall) INTERFERANCE IN CELL WALL SYSNTHESIS PHARAMACOKINETICS • • • • • • • • ¾ of an oral dose is absorbed. Distributed widely Penetrates meninges Temporarily stored in RBCs. Less metabolized. Excreted in urine Plasma t½ is ~4 hrs. Caution is required in its use in patients with renal disease. ADVERSE EFFECTS • Few Side effects • Loss of visual acuity/colour vision, • Optic neuritis- most important toxicity. • Nausea • Rashes • Fever • Rarely peripheral neuritis. • Hyperuricemia (due to interference with urate excretion) • Safe during pregnancy. USE:• In MAC infection STREPTOMYCIN • From a strain of Streptomyces griseus. • Aminoglycoside antibiotic. • First clinically useful anti TB drug. • Tuberculocidal • Less effective than INH or rifampin • Acts only on extracellular bacilli. • Penetrates tubercular cavities • Poor action in acidic medium. LIMITATION OF ITS USE I) Dose related toxicity II) Development of resistant org. III) Pt compliance is poor due to i. m MECHANISM OF ACTION: • Inhibits bacterial protein synthesis. • Inhibited in at least three ways: 1. Interference with the initiation complex of peptide formation. 2. Misreading of mRNA, which causes incorporation of incorrect aminoacids into the peptide, resulting in a nonfunctional or toxic protein. 3. Breakup of polysomes into nonfunctional monosomes. RESISTANCE • Developed rapidly • If used alone in tuberculosisrelapse. PHARMACOKINETICS • Absorption: IM: well absorbed; • Distribution: To extracellular fluid including serum, abscesses, ascitic, pericardial, pleural, synovial, lymphatic, & peritoneal fluids; • Crosses placenta; • Small amounts enter breast milk • Protein Bound: 34% • Half-life elimination: 2-5 hr, • Excretion: urine (90%); feces, saliva, sweat, & tears (<1%) SIDE EFFECTS: • Ototoxicity • Nephrotoxicity • Paralysis USE • Because of need for i.m. injections and lower margin of safety • Used only as an alternative to or in addition to other first line anti-TB drugs • Use is restricted to maximum of 2 months. • It is thus also labelled as a ‘supplemental’ first line drug. Second line drugs in TB • Less effective • More toxic • Used only if organism is resistant to first line drugs • Ethionamide , PAS, cycloserine : bacteriostatic • Amikacin, capromycin, fluoroquinolones are used in Multi Drug Resistant TB SECOND LINE DRUGS Para amino salicylic acid Mechanism of action Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against mycobacterium tuberculosis. It is structurally similar to p-amino benzoic acid(PABA) and the sulfonamides. Adverse Reactions GI • Nausea; vomiting; diarrhea; abdominal pain. Metabolic • Goiter with or without myxedema. Miscellaneous • Hypersensitivity (eg, fever, skin eruptions, leukopenia, thrombocytopenia, hemolytic anemia, jaundice, hepatitis, vasculitis). Ethionamide Mechanism of Action: Ethionamide, like pyrazinamide, is a nicotinic acid derivative related to isoniazid. It is thought that ethionamide undergoes intracellular modification and acts in a similar fashion to isoniazid. ADRS >10% • Disorder of gastrointestinal tract (50%) Frequency Not Defined • Postural hypotension • Dizziness • Drowsiness • Headache • Peripheral neuropathy • Psychosis CYCLOSERINE Cycloserine is an antibiotic produced by streptomyces orchidaceus. Mechanism of action : • It inhibits the incorporation of D- alanine into peptidoglycan pentapeptide by inhibiting alanine racemase, which converts Lalanine to D- alanine, and D- alanyl-D –alanine ligase (finally inhibits mycobacterial cell wall synthesis). • Cycloserine used exclusively to treat tuberculosis caused by mycobacterium tuberculosis resistant to first line agents ADR Frequency Not Defined • Confusion • Dizziness • Headache • Seizure • Psychosis Thioacetazone Mechanism of action: Bacteriostatic- inhibits cyclopropanaton of cell wall mycolic acids. Uses: It continues to be used as a convenient low cost drug to prevent emergence of isoniazid resistance, streptomycin & ethambutol. ADR: hepatitis, exfoliative dermatitis, SJS, bone marrow depression rarely Common: Abdominal discomfort, loose motions, rashes, mild anemia, anorexia. Azithromycin Mechanism of Action Binds to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest; does not affect nucleic acid synthesis ADRS >10%: Diarrhea (52.8%), Nausea (32.6%), Abdominal pain (27%), Loose stool (19.1%) 1-10%: Cramping (2-10%), Vaginitis (2-10%), Dyspepsia (9%), Flatulence (9%), Vomiting (6.7%), Malaise (1.1%) <1%: Agitation, Allergic reaction, Anemia, Anorexia, Candidiasis, Chest pain, Conjunctivitis, Constipation, Dermatitis (fungal), Dizziness Clarithromycin Mechanism of Action Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNAdependent protein synthesis by stimulating dissociation of peptidyl tRNA from ribosomes, thereby inhibiting bacterial growth ADR • >10%: Gastrointestinal (GI) effects • 1-10%: Abnormal taste (adults, 3-7%, Diarrhea (3-6%), Nausea (adults, 3-6%), Vomiting (adults, 1%; children, 6%), Abdominal pain (adults, 2%; children, 3%), Rash (children, 3%), Dyspepsia (2%), Headache (2%), Elevated prothrombin time (PT; 1%) • <1%: Anaphylaxis, Anxiety, Clostridium difficile colitis, Dizziness, Dyspnea, Elevated liver function tests AMIKACIN Mechanism of Action Irreversibly binds to 30S subunit of bacterial ribosomes; blocks recognition step in protein synthesis; causes growth inhibition. For gram-negative bacterial coverage of infections resistant to gentamicin and tobramycin ADR • 1-10% • Neurotoxicity • Nephrotoxicity (if trough >10 mg/L) • Ototoxicity • <1%: Hypotension, Headache, Drug fever, Rash, Nausea, Vomiting, Eosinophilia, Tremor, Arthralgia Contraindications • Documented hypersensitivity Cautions • Renal impairment • Risk of neurotoxicity, ototoxicity, nephrotoxicity - risk of ototoxicity increase with concurrent loop diuretics KANAMYCIN Mechanism of Action Bactericidal and believed to inhibit protein synthesis by binding to 30 S ribosomal subunit. ADR Agranulocytosis, Anorexia, Diarrhea, Dyspnea, Enterocolitis, Headache, Incr salivation, Muscle cramps, Nausea, Nephrotoxicity, Neurotoxicity, Ototoxicity, Pruritus. Contraindications • Documented hypersensitivity Cautions • Auditory toxicity more common with kanamycin than with streptomycin and capreomycin; • renal toxicity occurs at a frequency similar to that of capreomycin; regular monitoring of serum creatinine recommended • Renal impairment • Myasthenia gravis • Nephrotoxic agents RIFABUTIN Mechanism of Action Inhibits DNA-dependent RNA polymerase ADR: >10%: Discoloration of urine (30%), Neutropenia (25%), Leukopenia (17%), Rash (11%) 1-10%: Incr AST/ALT (7-9%), Thrombocytopenia (5%), Abdominal pain (4%), Diarrhea (3%), Headache (3%), Nausea/vomiting (3%), Anorexia (2%), Flatulence (2%) Fluoroquinolones Ciprofloxacin, Levofloxacin, gatifloxacin, moxifloxacin can inhibit strains M tuberculosis. They are also active against atypical mycobacteria. Moxifloxacin is the most active against M tuberculosis. Mechanism of action: They inhibit bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA Gyrase) and topoisomerase IV. • Inhibition of DNA Gyrase prevents the relaxation of supercoiled DNA that is required for normal transcription and replication. • Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the daughter cells during cell division. Adverse effects Nausea, vomiting,diarrhoea(most common). Headache, dizziness, insomnia, skin rash, photosensitivity. Damage growing cartilage and cause an arthropathy. Tendinitis, tendon rupture. Chemotherapy DOTS: To control tuberculosis requires: • Effective, inexpensive, simple and standardised technology. The success of the DOTS strategy depends on: • Government commitment to a national tuberculosis programme. • Case detection –finding by smear microscopy examination of TB susceptible in general health services. • Regular uninterrupted supply of essential anti-TB drugs. • Monitoring system for programme supervised and evaluation. Short Course Chemotherapy: • These are regimens of 6-9 month duration. • All regimens have an initial intensive phase lasting 2-3 months to kill the TB bacilli and afford symptomatic relief. • This is followed by continuation phase for 4-6 months so that relapse does not occur. REGIMENS : Type of patient Duration of treatment Regimen Category-1 1.New sputum positive 2.Seriously ill, sputum negative, Pulmonary 3.Seriously ill Intensive phase(2months) INH+RMP+ETB+PZA Continuation phase(4months) INH+RMP Category-2 Retreatment group 1.Relapse 2.Treatment failure Intensive phase(3months) INH+RMP+ETB+PZA Continuation phase(5months) INH+RMP+ETB Category-3 1.New smear negative pulmonary 2.extrapulmonary Intensive phase(2months) INH+RMP+PZA Continuation phase(4months) INH+RMP Multiple Drug Resistance(MDR): • Resistance to both Isoniazid and Rifampin and number of other anti-TB drugs . MDR-TB has a more rapid course ,(some die in 4-16 weeks). • Treatment is difficult as second line drugs are less efficacious, less convenient, more expensive and toxic. • Therapy depends on drugs used in earlier regimen, dosage and regularity with which they have been taken. • In India>200,000patients have been treated under DOTS by early 2001 with cure rate of 75-80%. • In other countries 80-93%cure rates have been obtained. Chemotherapy Treatment of TB is categorised by: • Site of disease (pulmonary or extra pulmonary), its severity: the bacillary load and acute threat to life are taken into consideration. • Sputum smear positivity/negativity :positive cases are infectious. • History of previous treatment: risk of drug resistance is more in irregularly treated patients. THANK YOU -PHARMA STREET