Pulmonology Medications Part 5.pdf

Pulmonary Medications Part 5 Debra Forzese, Pharm. D. Anti-Mycobacteria Medications Background q Mycobacteria grow slowly, resistant to many antibiotics q Anti-mycobacteria drugs are diverse compounds q Activity against mycobacterial infections which include tuberculosis, leprosy, and mycobacte...

Pulmonary Medications Part 5 Debra Forzese, Pharm. D. Anti-Mycobacteria Medications Background q Mycobacteria grow slowly, resistant to many antibiotics q Anti-mycobacteria drugs are diverse compounds q Activity against mycobacterial infections which include tuberculosis, leprosy, and mycobacterium avium complex (MAC) q Monotherapy usually not recommended due to risk of drug resistance q Treatment takes months, requires check of sputum Tuberculosis(TB) Treatment Phases Intensive Phase qUsed to kill active growing TB bacilli qCrucial for preventing emergence of drug resistance and determining ultimate regimen outcome qFour drugs should be included during the intensive phase until results of drug – susceptibility tests are available – Isoniazid, Rifampin, Pyrazinamide, Ethambutol qEach drug in this intensive phase plays a key role • Isoniazid and Rifampin are bactericidal against M. tuberculosis • Pyrazinamide has potent sterilizing activity • Ethambutol helps prevent emergence of Rifampin resistance (when primary Isoniazid resistance is present) Tuberculosis Treatment Phases Continuation Phase q Eliminate remaining TB bacilli q Reduce treatment failure and relapse q This phase lasts 4 or 7 months q 7 months for patients with cavitary pulmonary TB caused by drug susceptible organisms, whose sputum culture at time of completion of 2 months of treatment continues to be positive, intensive phase did not include Pyrazinamide, patients with HIV who are not receiving antiviral therapy during TB treatment Treatment of Tuberculosis (TB) q Standard of care for initiating treatment of TB is a four- drug regimen q Nonadherence is a major problem in controlling TB, can lead to drug resistance • To improve adherence DOT (directly observed therapy) – in person or electronically q Multiple treatment regimens in the US for TB and can take 4, 6, or 9 months depending on the regimen q Choice of appropriate TB treatment regimen is based on drug-susceptibility results, coexisting medical conditions (HIV, diabetes), and potential drug interactions First line agents Isoniazid (Nydrazid) Rifampin (Rifadin) Pyrazinamide (Rifater) Ethambutol (Myambutol) Isoniazid q Bactericidal q Prophylaxis against TB, monotherapy for latent TB q MOA – inhibits biosynthesis of mycolic acid, an essential component of bacterial cell wall q Well absorbed, widely distributed q Hepatic metabolism via acetylation q Renal excretion Isoniazid Adverse effects q Hepatotoxicity q Peripheral neuropathy (use prophylactic B6 supplement) q Seizures q Hemolytic anemia in patients with G-6-P dehydrogenase deficiency q Drug-induced lupus erythematosus Drug interactions – carbamazepine, phenytoin, theophylline- increased levels Isoniazid Black Box Warning q Severe and sometimes fatal hepatitis q Age related risk q Daily alcohol consumption increases risk q Monitor liver enzymes Rifampin q Macrolide antibiotic q Rapid resistance if used alone q MOA- inhibits DNA dependent RNA polymerase enzyme, bactericidal q Lipophilic, widely distributed in all tissues/fluids q Metabolized in liver q Eliminated mainly in bile/feces, some in urine <30% Rifampin Adverse effects qHepatotoxicity – especially alcoholics, other hepatotoxic drugs qRash qDiscoloration of body fluids- orange red colored urine, sweat, tears, feces qHemolytic anemia, neutropenia, thrombocytopenia qNephritis qFlu like symptoms Rifampin Drug Interactions Strong inducer CYP450 – decreased bioavailability of co-administered drugs – cardiac medications, anticoagulants, some anticonvulsants Pyrazinamide q Metabolized to active form q Mechanism of action – not completely understood, thought to inhibit electron transport and cell membrane metabolism in mycobacteria q Used in combination with isoniazid and rifampin for short course regimens against residual organisms that may cause relapse q Resistance develops quickly when used as monotherapy, most effective when used in combination with other drugs Pyrazinamide q Well absorbed q Widely distributed to body tissues and fluids q Bacteriostatic or bactericidal depending on drug concentration at infection site q Renally excreted (dose reduction needed with renal impairment) q Drug interactions • Rifampin increases hepatoxicity, can be fatal • Cyclosporine levels reduced Pyrazinamide Adverse Effects qHepatotoxicity qNausea, vomiting qHyperuricemia qNon-gouty polyarthralgia qThrombocytopenia, sideroblastic anemia qRash qPhotosensitivity Ethambutol q Bacteriostatic q Mechanism of Action – inhibits essential component of mycobacterial cell wall q Well absorbed q Widely distributed q Partially metabolized in liver q Primarily excreted renally – dose reduction in renal impairment q Always given in combination with other anti-TB drugs to prevent resistance Ethambutol Drug Interactions q Aluminum hydroxide may reduce serum level of ethambutol Adverse Effects qOptic neuropathy causes changes in visual acuity, red – green color blindness qHepatotoxicity qGI effects – abdominal pain, nausea, vomiting qNeutropenia, thrombocytopenia qDizziness, confusion Second Line Agents Bedaquiline Clofazimine Streptomycin CyCloserine Ethionamide Bedaquiline (Sirturo) q Classified as a diarylquinoline q Important option to treat drug resistant pulmonary TB q Mechanism of Action – inhibits mycobacterial ATP synthase q Metabolized through CYP450 system q Excreted primarily in feces q Used in combination with at least 3 other medications to treat multi drug resistant TB Bedaquiline Limitations – q Not for use in extrapulmonary TB or latent TB or drug sensitive TB q Not for use in treatment of other mycobacteria q limited clinical data on safety/effectiveness with HIV or multidrug resistant TB coinfection Drug Interactions – many serious interactions, avoid alcohol and other hepatoxic drugs Bedaquiline Adverse Effects qQT prolongation qHepatotoxicity, elevated enzymes qNausea qHeadache qArthralgia