Antimycobacterial Drugs - Pharmacology 3 PDF

Pharmacology 3 Antimycobacterial drugs Dr. Lina Tamimi  Mycobacteria Mycobacteria are intrinsically resistant to most antibiotics. are Gram-positive, non-motile, non-spore forming rod- shaped bacteria intracellular pathogens organisms residing w...

Pharmacology 3 Antimycobacterial drugs Dr. Lina Tamimi  Mycobacteria Mycobacteria are intrinsically resistant to most antibiotics. are Gram-positive, non-motile, non-spore forming rod- shaped bacteria intracellular pathogens organisms residing within macrophages are inaccessible to drugs that penetrate poorly develop resistance  Response to treatment The response to chemotherapy is slow treatment must be Administered for months to years, depending on which drugs are used.  Tuberculosis Tuberculosis (TB) Mycobacterium tuberculosis. attack the lungs can also damage other parts of the body. spreads through the air coughs, sneezes, or talks Inhalation of Mycobacterium tuberculosis and deposition in the lungs leads to one of four possible outcomes: immediate clearance of the organism primary disease (rapid progression to active disease) latent infection (with or without subsequent reactivation disease) reactivation disease (onset of active disease many years following a period of latent infection)  Organs to be infected : Lungs (90% of the cases) Genitourinary tract Skeleton Meninges 7  1st line of drugs: 1.1. Isoniazid (INH) 1.2. Rifamycin’s: Rifampin, Rifabutin, Rifapentine, Rifampicin 1.3. Ethambutol 1.4. Pyrazinamide 1.5. Streptomycin In practice therapy In practice, therapy is initiated with four-drug regimen of: 1. isoniazid 2. rifampin 3. pyrazinamide plus: 4- ethambutol or 4- streptomycin The fourth medication is included until susceptibility of the clinical isolate has been determined.  Ethambutol or streptomycin: Don’t add substantially to the overall activity of the regimen (ie, the duration of treatment cannot be reduced if either drug is used). BUTTTT They provide additional coverage if the isolate proves to be resistant to isoniazid, rifampin, or both.  1.1. Isoniazid Bacteriostatic at low conc. Bactericidal at high conc. Especially against actively growing bacteria. MOA: Inhibits synthesis of mycolic acid is an essential components of mycobacterial cell wall. It is less effective against atypical mycobacterial Species (other than TB). Isoniazid penetrates into macrophages active against both extracellular and intracellular organisms.  Isoniazid is a prodrug …………. activated by mycobacterial catalase-peroxidase (KatG) The activated form of isoniazid forms a covalent complex with : acyl carrier protein (AcpM) a beta-ketoacyl carrier protein synthetase (KasA) which blocks mycolic acid synthesis and kills the cell.  PK Readily absorbed from GIT. Diffuse into all body fluids and tissues. Penetrates caseous material and macrophages so it is effective against intra and extracellular organisms. Metabolized in liver by acetylation. Excreted mainly in urine.  Dosing The typical dosage of isoniazid is 5 mg/kg/d; a typical adult dose is 300 mg given once daily. Up to 10 mg/kg/d may be used for: serious infections if malabsorption is a problem. A 15 mg/kg/d dose, or 900 mg, may be used in a twice- weekly dosing regimen in combination with a second anti tuberculous agent (eg, rifampin 600 mg)  Pyridoxine(B6), 25–50 mg/d, is recommended for those with conditions predisposing to neuropathy. Isoniazid is usually given orally…. can be given parenterally latent tuberculosis: Isoniazid as a single agent is also indicated. The dosage is: 300 mg/d (5 mg/kg/d) or 900 mg twice weekly for 9 months.  Adverse effects Optic neuritis. Peripheral neuritis Allergic reactions ( fever, skin rash, systemic lupus erythematosus ) Hepatitis -Development of isoniazid hepatitis contraindicates further use of the drug. Gastric upset. Hemolytic anemia. CYP inhibitor.  Peripheral neuropathy High in Slow acetylators are people whose liver cannot completely detoxify reactive drug metabolites patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Isoniazid promotes excretion of pyridoxine administration of pyridoxine in a dosage as low as 10 mg/d. CNS toxicity, which is less common includes: memory loss Psychosis seizures.  These effects may also respond to pyridoxine.  1.2. RIFAMPIN Bactericidal. Rifapentine is an analog of rifampin MOA binds strongly to β subunit of bacterial DNA-dependent RNA polymerase leading to inhibition of RNA synthesis. Rifamycin's are : active against many “typical” bacteria added to other therapies, particularly to treat difficult MRSA infections.  PK Well absorbed orally. Excreted mainly through liver into bile. Highly protein bind. Penetrates macrophages so affect extra and intracellular organisms. Adequate CSF conc. Only in meningeal inflammation  Clinical use 1. Mycobacterial infections 2. Prophylaxis in contacts of children with Hemophilus influenzae type B disease. 3. Treatment of serious staphylococcal infections as osteomyelitis ( infection of the bone) and endocarditis. 4. Meningitis by highly penicillin- resistant pneumococci. 5. Latent TB.  Adverse effects Harmless red-orange color to urine, sweat, tears, contact lenses. Rashes. Thrombocytopenia. Nephritis. Cholestatic jaundice. Hepatitis. Flu-like syndrome. Induce cytochrome p-450.  Why rifabutin in HIV? Rifampin is a drug of choice for TB Rifabutin is a drug of choice for MAC Mycobacterium avium complex: lung disease (not TB) both drugs have activity against both pathogens. MAC infections are most common in patients with HIV.  1.3. Pyrazinamide Prodrug …………….converted to pyrazinoic acid ,the active form MOA specific drug target is unknown, but it disrupts: 1. mycobacterial cell membrane metabolism 2. Transport functions. The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes.  PK Bactericidal. Acting on intracellular organisms. Well absorbed orally. metabolized in liver. excreted mainly through kidney.  Clinical uses It is important in short –course (6 months) regimens with isoniazid and rifampicin. Prophylaxis of TB in combination with ciprofloxacin.  Adverse effects Majorly hepatotoxicity (in 1–5% of patients) nausea, vomiting, drug fever. Hyperuricemia: hyperuricemia may provoke acute gouty arthritis.  1.4. ETHAMBUTOL MOA inhibits mycobacterial arabinosyl transferases. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall.  PK Well absorbed from gut. 20% excreted in feces 50% excreted in urine in unchanged form. Crosses BBB only in meningitis.  Clinical uses always given in combination with other anti tuberculous drugs……………(isoniazid or rifampin) Ethambutol HCl: 15–25 mg/kg, is usually given as a single daily dose The dose of ethambutol is 50 mg/kg when a twice-weekly dosing schedule is used. The higher dose is recommended for treatment of tuberculous meningitis.  Adverse effects The most common serious adverse event is: retrobulbar neuritis resulting in loss of visual acuity and red-green color blindness. dose-related adverse effect is more likely to occur at dosages of 25 mg/kg/d continued for several months. At 15 mg/kg/d or less, visual disturbances are very rare. Periodic visual acuity testing is desirable if the 25 mg/kg/d dosage is used.  Contraindication contraindicated in children too young to permit assessment of: 1. visual acuity 2. red green color discrimination Hypersensitivity to ethambutol is rare. 1.5. Streptomycin MOA Aminoglycosides: PSI Against: TB species Mycobacterium avium complex (MAC) Mycobacterium kansasii Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. Streptomycin crosses the BBB and achieves therapeutic concentrations with inflamed meninges.  Clinical use Streptomycin sulfate is used when an injectable drug The usual dosage is 15 mg/kg ……. IV and IM Adverse effects Toxicity is dose-related, and the risk is increased in the elderly. can be reduced by limiting therapy to no more than 6 months ototoxic and nephrotoxic. Vertigo and hearing loss are the most common adverse effects and may be permanent. As with all aminoglycosides, the dose must be adjusted according to renal function. 2nd line drugs  The alternative drugs listed are usually considered only: (1) In case of resistance to first-line agents. (2) In case of failure of clinical response to conventional therapy. (3) In case of serious treatment-limiting adverse drug reactions.  2.1. Ethionamide nicotinamide derivative As isoniazid blocks synthesis of mycolic acid. Used in TB & leprosy. Available only in oral form. Metabolized by the liver ,excreted by kidney. It is poorly tolerated because of : 1. Intense gastric irritation. 2. Neurologic symptoms. 3. Hepatotoxicity.  2.2. Capreomycin aminoglycoside It is an important injectable agent for treatment of drug-resistant tuberculosis Resistant to streptomycin or amikacin………. usually susceptible. Adverse effects It is nephrotoxic and ototoxic. Local pain & sterile abscesses may occur.  2.3. Cycloserine GABA transaminase inhibitor Inhibitor of cell wall synthesis. Cleared renally. The most serious side effects are: 1. peripheral neuropathy 2. CNS dysfunction: depression & psychotic reaction. Pyridoxine should be given Contraindicated in epileptic patients.  2.4. Kanamycin & Amikacin Aminoglycosides Used in multidrug- resistance tuberculosis. Kanamycin is rarely used. Used as alternative to streptomycin. No cross resistance between streptomycin and amikacin.  2.5. Ciprofloxacin & levofloxacin fluoroquinolone antibiotic Effective against typical and atypical mycobacteria. Used against resistant strains. Used in combination with other drugs……???  2.6. Rifapentine As rifampicin , it is RNA polymerase inhibitor. Cross resistance with rifampicin. Potent inducer of cytochrome p450. Effective against typical and atypical mycobacteria. 2.7. P-Aminosalicylic Acid (PAS). Similar in structure to sulfonamide and p-aminobenzoic acid. Folate synthesis inhibitor. MOA Mycobactin synthesis inhibitor ( cell wall component) Well absorbed from GIT. Widely distributed in tissues except CSF. Excreted in urine as active and as metabolic products. Adverse effects Crystalluria anorexia nausea, diarrhea, epigastric pain. Peptic ulcer and hemorrhage can occur. Hypersensitivity reactions. 2.8. Bedaquiline approved by the US Food and Drug Administration (FDA) in 2012 Bedaquiline inhibits adenosine 5′triphosphate (ATP) synthase in mycobacteria. Crossresistance has been reported between bedaquiline and clofazimine 2.9. Pretomanid Approved by the FDA in 2019 drug approved, for the treatment of multi drug resistant tuberculosis  Leprosy Leprosy (also known Hansen's disease) is an infectious disease caused by: Mycobacterium leprae Mycobacterium lepromatosis involves the skin and peripheral nerves  Leprosy affects: 1.The nerves of the extremities 2.The lining of the nose 3.The upper respiratory tract. 4.Skin Leprosy produces: skin sores, nerve damage, and muscle weakness  Treatment First-line medications include: Dapsone : anti-infectives Rifampin : antimycobacterial Clofazimine: antimycobacterial Used in combination, these have proven to be effective Adverse effects skin discoloration ranging from red-brown to nearly black).  M kansasii M kansasii: Mycobacterium Kansasii sensitivity susceptible to rifampin and ethambutol partially resistant to isoniazid Resistance completely resistant to pyrazinamide. Drugs conventional treatment : three-drugs: isoniazid, rifampin, ethambutol  MAC MAC : Mycobacterium Avium Complex drugs Azithromycin, 500 mg once daily or clarithromycin, 500 mg twice daily plus ethambutol, 15–25 mg/kg/d Use of a third agent, such as: ciprofloxacin, 750 mg twice daily or rifabutin, 300 mg once daily…………. HIV