Drug Treatment of Pulmonary TB PDF

# Drug treatment of Pulmonary TB ## Year III ### Respiratory System Block ## Important features of Mycobacteria tuberculosis * Tubercle bacilli are resistant to most antibiotics as they 1. Are intracellular organism residing within macrophages inaccessible to drugs that poorly penetrate...

# Drug treatment of Pulmonary TB ## Year III ### Respiratory System Block ## Important features of Mycobacteria tuberculosis * Tubercle bacilli are resistant to most antibiotics as they 1. Are intracellular organism residing within macrophages inaccessible to drugs that poorly penetrate macrophages 2. Have Thicker Cell wall that is impermeable to many drugs 3. Have Efflux pump ability to develop resistance 4. Can be present in dormant state 5. Grow slowly & Respond slowly to chemotherapy 6. Require Long term therapy (months to years) 7. Require Combinations therapy (≥ 3 drugs) to prevent resistance ## Classification of anti-tuberculous drugs | Classification | Description | Examples | | ----------------------- | ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ----------------------------------------------------------------------------------------------------- | | 1- First line drugs | High effective (against IC and EC M tuberculosis) & Less toxic | 1) Isoniazid (INH) 2) Rifampin 3) Pyrazinamide 4) Ethambutol | | 2- Second line drugs | Less effective & more toxic Reserved For patients a. in whom 1st line drugs are ineffective or contraindicated b. With available expert guidance to deal with their toxic effects | 1) Para-aminosalicylic acid 2) Linezolid 3) Amikacin 4) Cycloserine 5) Capreomycin 6) Ethionamide 7) Streptomycin | | 3-Newer Drugs | Can be used in specific situations | 1-Floruquinolones a) Gatifloxacin b) Moxifloxacin c) Levofloxacin 2) Macrolides (Clarithromycin & Azithromycin) 3-Rifabutin 4- Bedaquiline, Delamanid & Pretomanid | ## 1. First line anti-TB drugs ## 1. Isoniazid = isonicotinic acid hydrazide (INH) * The single most important drug used in ttt of TB. * It is a component of most drug combination regimens for ttt of TB. * Active only against Mycobacterium Tuberculosis (Tubercle Bacillus). * Has equal efficacy against IC, EC bacilli & bacilli in Caseous granuloma. * It has structural similarity to pyridoxine (vitamin B6). ### MOA: * Bactericidal against active bacilli * Bacteriostatic against resting bacilli * Pro-drug activated inside bacteria by catalase-peroxidase (KatG) * inhibit mycolic acids synthesis (important constitutes of mycobacteria cell wall) → Cell wall disruption → bacterial cell death ### Pharmacokinetics: * Well absorbed from oral (but fatty meal its oral absorption) or IM routes. * Widely distributed to all tissues including CSF. * Metabolized in liver by 1. Hydrolysis → isonicotinic acid 2. Acetylation → acetyl isoniazid * Acetyltransferase enzymatic activity is under genetic control (Slow, intermediate & Rapid acetylators?). * Plasma concentration ↑ in slow acetylator & ↓ in rapid acetylator. * t1/2 is 1 hour in fast acetylators, but ↑ in slow acetylators, hepatic or renal disease. * Excreted in urine (75-95%), feces, saliva. ### Therapeutic uses of INH: 1. Treatment of active TB: 300 mg/d (5 mg/kg/day) orally with anti-TB drugs to resistant 2. Prophylaxis of TB: can be used alone (300 mg/day for 6 months) in a) Close contact to infected patient???? b) Baby born to infected mother c) Immunodeficient individuals (life long or at least 9 months) ### Adverse drug reactions (ADR): 1. Hepatoxicity: the most common Toxic effect in 1% of isoniazid recipients * More common in rapid acetylators, elderly & alcoholics. * C/P: Anorexia, nausea, vomiting, jaundice, and right upper abdominal quadrant pain. * Can be fatal if the drug is not stopped immediately. * The drug is discontinued if Serum transaminases (ALT & AST) are a) > 5 times the upper limit of normal with asymptomatic liver disease or b) > 3 times normal with symptomatic liver disease 2. Neuropathy: the most common ADR why? due to relative pyridoxine deficiency * Peripheral neuropathy "pins and needles" sensation in his feet. * Central neuropathy: Memory loss, Psychosis, Ataxia, & Seizures. * More common in Slow acetylators, elderly, alcoholics, DM, uremia, and pregnancy. * Due to relative pyridoxine deficiency why? as INH↑ pyridoxine excretion & interfere with pyridoxine (vit metabolism * Prevented & treated by concurrent administration of pyridoxine (vitamin B6) 10-50 mg/day 3. Drug induced Lupus: Skin rash, fever, arthritis in Slow acetylators 4. Microsomal enzyme inhibitor: ↓ metabolism of Phenytoin, diazepam, carbamazepine and warfarin→ Toxicity 5. Resistance Why? due to ↓ activity of Catalase-peroxidase (Prodrug?) ## 2. Rifampin * Bactericidal for most of gram +ve and gram -ve bacteria. * Effective against mycobacteria at all sites. ### Pharmacokinetics: * Well absorbed from GIT. * Distributed to all tissues INCLUDING CSF (particularly in inflammed meninges). * Partially deacetylated in liver. * Excreted mainly in bile in deacetylated and unchanged forms. * The unchanged form undergoes enterohepatic circulation → prolong its effect. * Excreted mainly in feces and little is excreted in urine. ### MOA: * It inhibits RNA synthesis by inhibiting DNA dependent RNA polymerase. ### Adverse drug reactions (ADR): 1. Red orange to brown coloration of all body secretions. 2. impaired liver function with jaundice (Hepatoxic). 3. impairment of immune response, Rash. 4. inducer of microsomal enzyme (Potent) ↓ Effectiveness of hormonal contraceptives so, Fertile women should not rely on hormonal contraceptives alone for birth control Why? as rifampin is potent enzyme inducer ↓ effectiveness → Failure of hormonal contraceptives by rifampicin. 5. influenza like syndrome, acute tubular necrosis with proteinuria, thrombocytopenia & hemolytic anemia (in daily dose > 1200 mg). ### Therapeutic uses: A. in combination with 1. INH 600 mg/d (10 mg/kg/day) orally for ttt of TB 2. Sulphones(Dapsone) for ttt of Leprosy. 3. Co-trimoxazole for ttt of nasopharynx staph. Carrier. 4. Vancomycin or Floxacillin for ttt of Serious staph infections e.g., osteomyelitis & prosthetic valve endocarditis. B. Chemoprophylaxis in meningococcal & H. influenza meningitis 600 mg twice/day for 2 days. ## 2. Rifabutin * Less potent Microsomal enzyme inducer. * indicated in place of (preferred to) Rifampin for treatment of Tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or non-nucleoside Reverse Transcriptase inhibitors (cytochrome P450 substrates) Why? Because it is a less potent enzyme inducer than Rifampin. * Dose: 5 mg/kg/day=300mg/day). ### N.B. * Rifamycins a) are macrocyclic antibiotics b) include Rifampin, Rifabutin & Rifapentine ## 3. Pyrazinamide(PZA) ### Bactericidal ### MOA: * Pyrazinamide is most effective against Tubercle Bacilli in acidic environment within the macrophage or areas of tissue necrosis Why? As At acidic pH, PZA is converted in mycobacteria by pyrazinamidase → Pyrazinoic acid (active metabolite) inhibit fatty acid synthesis disrupts mycobacterial Cell membrane metabolism and transport functions. ### Pharmacokinetics: * Well absorbed orally and widely distributed including CSF. * Metabolized in liver & metabolites excreted in urine (4% is excreted as unchanged form). ### ADR: 1. Hepatoxic. 2. Hyperuricemia (↑ serum uric acid) Why? due to ↑ urates excretion→ acute episodes of gout (gouty arthritis). 3. Nausea, vomiting, fever. ### Therapeutic uses: * Treatment of TB (1.5-2g/d=20 mg/kg/day) in combination with other anti-TB drugs. ## NB: Rifampicin, isoniazid and pyrazinamide * All are Potentially Hepatotoxic drugs. * Liver function tests (LFTs) should be checked before their uses. * Recheck LFTs periodically throughout treatment. * They should be stopped immediately If transaminases rise a) > 5 times the upper limit of normal with asymptomatic liver disease or b) > 3 times the upper limit of normal with symptomatic liver disease ## 4. Ethambutol * Bacteriostatic and Bacteriocidal in large doses. * Active against mycobacteria only. * Moderately effective against the fast-growing bacilli. * Its main indication is to delay emergence of drug resistance. ### MOA: * Inhibit mycobacterial arabinosyl transferase → Inhibits incorporation of mycolic acid into mycobacteria cell wall. ### Pharmacokinetics: * Well absorbed orally & Low CSF penetration even in inflamed meninges. * 80% excreted unchanged in urine (✓ dose from daily to 3 times weekly if CrCl <30 mL/min). ### ADR: 1. Optic neuritis: * Dose related & Reversible color perception (red-green), visual field or ↓ visual acuity. * EYE examination should be done before administration and then periodically why? * Should be avoided in infant and young children Why? as they are unable to report visual defects. 2. Hyperuricemia: due to decrease excretion of uric acid→ gouty arthritis. 3. Others: GI upset, headache, dizziness, confusion, hallucination. ### Therapeutic uses: * Treatment of TB orally 1g/d (15 mg/kg/day) in combination therapy. ## II) Second line anti-TB drugs * Most of them are bacteriostatic. * There is a limitation for the use of 2nd line drugs because of their toxicities. ## 1. Streptomycin * Bactericidal for EC mycobacteria as it penetrates poorly into living cells. ### MOA: * Binds to 30S bacterial subunit → inhibits protein synthesis by Interference with initiation complex of peptide formation, misreading of the genetic code in mRNA and break up of polysomes into non-functioning monosomes. ### Pharmacokinetics * given IM (Poorly absorbed orally administration) & its CSF concentration is not adequate. * Not metabolized, renally excreted unchanged. ### Therapeutic uses: * With other drugs (5 or 6 drugs) in severe or disseminated TB (1g/d IM) (15mg/kg). ### ADR: dose-related, and the risk is increased in elderly. 1. Ototoxic (Vertigo and hearing loss). 2. Nephrotoxic 3. Neuromuscular paralysis. ### Contraindication * in Pregnancy (ototoxic) ### Avoid in pregnancy ## 2. Amikacin: IM, injectable (15 mg/kg/24 hour) * MOA: inhibit protein synthesis by binding to the 30S ribosomal unit. * ADR: Ototoxicity ## 3. Linezolid: * MOA: inhibits protein synthesis 50S ribosomal unit. * Is not a preferred drug due to the risk of serious hematologic and neurologic toxicity. * Reserved for treatment of infections due to drug-resistant organisms. ## 4. Capreomycin: injectable * MOA: inhibit protein synthesis by binding to the 70S ribosomal unit. * ADR: Nephrotoxicity & Ototoxicity ## 5. Ethionamide: chemically related to isoniazid * MOA: inhibit mycolic acid synthesis. * ADR: Depression, drowsiness (can be relieved by pyridoxine), GI irritation, Hepatotoxicity. ## 6. Cycloserine: It is an analog of the amino acid D-alanine. * MOA: It interferes with an early step in bacterial cell wall synthesis (inhibit alanine racemase inhibits incorporation of D-alanine into peptidoglycan pentapeptide). * ADR: Psychosis, suicidal tendency, convulsions. ## 7. Para-aminosalicylic acid (PAS): * MOA: it inhibits folic acid synthesis and may inhibit the synthesis of the cell wall component (mycobactin). * ADR: GI irritation, hypersensitivity. ## N.B. There is no cross resistant between amikacin and streptomycin. ## III) New anti-TB Drugs ### i) Floroquinolons: * MOA: inhibits DNA synthesis by it inhibiting DNA gyrase. 1. Moxifloxacin (400 mg/day) or 2. Gatifloxacin (400 mg/day it is associated with dysglycemia). 3. Levofloxacin 1000 mg/day. * Moxifloxacin and Gatifloxacin are 4 - 10 fold more potent than Levofloxacin. * In Rats models of TB: * Moxifloxacin, in combination with Rifampin and pyrazinamide, has been shown to reduce the time to negative lung cultures by up to 2 months and produce stable cure compared with Isoniazid, Rifampin, and pyrazinamide. ### ii) Macrolides: Clarithromycin / Azithromycin * MOA: Inhibits protein synthesis by binding with 505 ribosomal subunits ### iii) Bedaquiline, Delamanid & Pretomanid: * Approved for tttof MDR-TB in combination with other TB drugs. #### A- Bedaquiline: approval by US (FDA). * Dosing consists of 400 mg orally once daily for two weeks. * Followed by 200 mg orally three times weekly for a total treatment duration of 24 weeks. * It is given with food and in combination with other TB drugs. #### MOA * Bactericidal anti-tuberculous * inhibits ATP synthase in mycobacteria → 1. ↓ energy production 2. Depletes cellular energy stores #### Side Effects: 1. Cardiotoxicity → QT prolongation (Torsade de Pointes arrhythmia) so, baseline ECG and regular ECG every (2-4 weeks) should be performed during intake of this drug. 2. Hepatotoxicity 3. Arthralgia 4. Nausea, Headache #### A. Delamanid: Approved by the European Medicines Agency (EMA). #### B. Pretomanid (related to Delamanid) Approved in 2019 by US (FDA) #### MOA * Pro-drug activated only within Replicating aerobic & Latent anaerobic mycobacteria → 1. mycolic acid synthesis → inhibits cell wall synthesis (aerobic & actively replicating TB). 2. ↑ release of nitric oxide → toxic effects on intracellular mycobacteria → killing under (anaerobic & non-replicating TB). * Used with bedaquiline and linezolid for extensively -drug-resistant tuberculosis (XDR-TB). * Taken by mouth. #### Common side effects : 1. Headache 2. Acne 3. Vomiting, Diarrhea 4. Nerve damage 5. Low blood sugar 6. Liver inflammation # Thank Yoυ