Lesson_7_antimycobacterial_agents[1].pptx

CLINICAL PHARMACOLOGY I Mitheu kilemi Anti-mycobacterial agents (anti-tuberculosis, anti-leprosy) Introduction Mycobacteria are intrinsically resistant to most antibiotics. Because they grow more slowly than other bacteria, antibiotics that are most active against rapidly...

CLINICAL PHARMACOLOGY I Mitheu kilemi Anti-mycobacterial agents (anti-tuberculosis, anti-leprosy) Introduction Mycobacteria are intrinsically resistant to most antibiotics. Because they grow more slowly than other bacteria, antibiotics that are most active against rapidly growing cells are relatively ineffective. Mycobacterial cells can also be dormant and, thus, resistant to many drugs or killed only very slowly. The lipid-rich mycobacterial cell wall is impermeable to many agents. Mycobacterial species are intracellular  Mycobacteria are notorious for their ability to develop resistance thus combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used. Anti mycobacterial agents (anti- tuberculosis) The main mycobacterial infection are the tuberculosis and leprosy. The treatment of tuberculosis assumes the principle of combination therapy for two main reasons, I. To prevent emergence of resistance (tubercle bacilli develops resistant very fast when monotherapy is used). II. To reduce the rate of spread by reducing bacterial population rapidly. For this reason the available tablets contain multiple drugs in a fixed dose combination (FDC). anti-TB conti’ Anti TB are divided into two first line and second line I. First line; this is not a universal principle but depends on local scientific evidence. The drugs include isoniazid, ethambutol, Rifampicin, pyrazinamide and streptomycin. ii Second line drugs include capreomycin, cycloserine, clarithromycin and ciprofloxacin First-line anti-mycobacterial agents Isoniazid 300 mg/d Rifampin 600 mg/d Pyrazinamide 25 mg/kg/d Ethambutol 15–25 mg/kg/d Once weekly Streptomycin 15 mg/kg/d Second line anti-mycobacterials agents Amikacin 15 mg/kg/d, Aminosalicylic acid 8–12 g/d Bedaquiline 400 mg/d Capreomycin 15 mg/kg/d Clofazimine 200 mg/d Cycloserine 500–1000 mg/d, Divided Ethionamide 500–750 mg/d Levofloxacin 500–750 mg/d Linezolid 600 mg/d Moxifloxacin 400 mg/d Rifabutin2 300 mg/d Rifapentine3 600 mg Anti TB cont.’ Anti mycobacterial treatment/therapy is divided into phases First initial phase (Intensive Phase): takes two months and four drugs are used concomitantly. These includes Isoniazid (H), Rifampicin (R) Pyrazinamide (Z) plus (Ethambutol or streptomycin) if resistant organism are suspected. This combination reduces bacterial population rapidly. The addition of pyrazinamide during this intensive phase allows the total duration of therapy to be reduced to 6 months without loss of efficacy from the initial 8- 12 months duration. Continuation phase takes four months and two ISONIAZID Expected Pharmacological Action This medication is highly specific for mycobacteria. Isoniazid inhibits growth of mycobacteria by preventing synthesis of mycolic acid which are essential components of mycobacterial cell wall. Therapeutic Uses; Indicated for active and latent tuberculosis Latent: INH only – 6 to 9 months Active: Multiple medication therapy including INH, for a minimum of 6 months The initial phase (induction phase) focuses on eradicating the active tubercle bacilli, which will result in non infectious sputum. The second phase (continuation phase) works toward eliminating any other pathogens in the body. Isoniazid cont.’ Isoniazid penetrates into macrophages and is active against both extracellular and intracellular organisms Length of treatment varies and may be as short as 6 months for medication-sensitive tuberculosis (2 months for the initial phase and 4 months for the continuation phase) or as long as 24 months for medication-resistant infections. Complications Side/Adverse Effects Nursing Interventions/Client Education Allergic skin eruptions are the commonest side effects Others are fever, GIT disturbance Peripheral neuropathy (tingling, numbness, burning, and pain resulting from deficiency of pyridoxine, vitamin B6 ). Instruct clients to observe for symptoms and to notify the provider if symptoms occur. Administer 50 to 200 mg of vitamin B6 daily.  Hepatotoxicity (anorexia, malaise, fatigue, nausea, and yellowish discoloration of skin and eyes). Instruct clients to observe for symptoms and notify the provider if symptoms occur. Monitor liver function tests. Instruct clients to avoid consumption of alcohol. Medication may need to be discontinued if liver function test results are elevated.  Contraindications/Precautions INH is contraindicated for clients with liver disease. Interactions Medication/Food Interactions Nursing Interventions/Client Education INH inhibits metabolism of phenytoin, leading to buildup of medication and toxicity. Ataxia and incoordination may indicate toxicity. Monitor the client’s levels of phenytoin. Dosage of phenytoin may need to be adjusted based on phenytoin levels. Interactions cont.’ Concurrent use of alcohol, rifampin, and pyrazinamide increases the risk for hepatotoxicity. Instruct clients to avoid alcohol consumption. Monitor liver function. Interactions cont.’ Induce liver enzymes ,hence affect the metabolism of warfarin, glucocorticoids, narcotics, oral anti diabetes, dapsone and estrogens and oral contraceptives. Advice clients on oral contraceptives to change method of family planning or use a back up method. Nursing Administration Administer by oral route For active tuberculosis, direct observation therapy (DOT) is done to ensure adherence. Advise clients to take INH 1 hours before meals or 2 hours after. If gastric discomfort occurs, the client may take INH with meals. Instruct clients to complete the prescribed course of antimicrobial therapy, even though symptoms may resolve before the full course is completed.  Rifampicin Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Amycolatopsis rifamycinica. This is one of the most active anti TB. It is also active against chlamydiae and gram positive and gram negative bacteria, such as Neisseria and Haemophilus species. Mechanism of action: Rifampin is bactericidal as a result of inhibition of protein synthesis. It binds to the β subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis  Indications: Rifampin is a broad-spectrum antibiotic effective for gram-positive and gram-negative bacteria, M. tuberculosis, and M. Leprae. pharmacokinetics Given orally Has a wide distribution It causes orange tinge coloration to saliva ,sputum, tears, sweat and urine. It is excreted in urine and under goes enterohepatic recycling. Metabolism is in the liver and the metabolites has anti bacterial activity but poorly absorbed from the gut. Half life is one to five hours but reduces during treatment since it induces microsomal enzymes, Side/adverse effects i) Discoloration of body fluids. Inform clients of expected orange color of urine, saliva, sweat, and tears. ii)Hepatotoxicity (jaundice, anorexia, and fatigue) Monitor the client’s liver function. Inform clients regarding symptoms of anorexia, fatigue, and malaise, and instruct them to notify the provider if symptoms occur. Avoid alcohol. iii) Mild gastrointestinal discomfort associated (anorexia, nausea, and abdominal discomfort. Abdominal discomfort is mild and usually does not require intervention Contraindications/Precautions Use cautiously in clients with liver dysfunction.  Interactions Medication/Food Interactions Nursing Interventions/Client Education Rifampin accelerates metabolism of warfarin (Coumadin), oral contraceptives, protease inhibitors, and NNRTIs (medications for HIV), resulting in diminished effectiveness. Increased dosages of HIV medications may be necessary. Monitor PT (prothrombin time) and INR (international normalized ratio) Clients may need to use alternative form of birth control. Concurrent use with INH and pyrazinamide increases risk of hepatotoxicity. Instruct clients to avoid alcohol consumption. Monitor liver function. Nursing Evaluation of Medication Effectiveness Depending on therapeutic intent, effectiveness may be evidenced by: Improvement of tuberculosis symptoms such as clear breath sounds, no night sweats, increased appetite, no afternoon rises of temperature 3 negative sputum cultures for tuberculosis, usually taking 3 to 6 months to achieve.  Ethambutol Ethambutol is a synthetic, water-soluble, heat-stable compound Pharmacodynamics; Ethambutol inhibits mycobacterial arabinosyl transferases, involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Resistance emergence occurs rapidly if used on its own. Pharmacokinetic good absorption from GIT. Metabolism is in the liver. Excretion in urine. It can reach therapeutic concentration in CSF for tuberculosis. Unwanted effects These are common. Optic neuritis dose related especially if renal function decreases. this leads to visual disturbances, red/ green color blindness followed by decreased visual acuity. Monitor color vision in long treatments Contraindication Patients with known optic neuritis Patients who are unable to appreciate and report visual side effects or changes in vision e.g. young children and unconscious patients  Pyrazinamide Pyrazinamide (PZA) is a relative of nicotinamide, and it is used only for treatment of tuberculosis. It is stable and slightly soluble in water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli at concentrations of approximately 20 mcg/mL. The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes. Pharmacodynamics. Pyrazinamide is converted to pyrazinoic acid—the active form of the drug—by mycobacterial pyrazinamidase. Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions. Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA that impair conversion of PZA to its active form It is tuberculostatic at acidic PH. it is very effective against intracellular organism in macrophages since after phagocytosis, in which PH is low. Pharmacokinetic it has good gut absorption. it is widely distributed in that it crosses the BBB Excretion occurs in the liver excreted in the kidneys Streptomycin The mechanism of action and other pharmacologic features of streptomycin is just like that of an aminoglycoside,. The typical adult dosage is 1 g/d (15 mg/kg/d). Most tubercle bacilli are inhibited by streptomycin, 1–10 mcg/mL, in vitro. Nontuberculous species of mycobacteria other than Mycobacterium avium complex (MAC) and Mycobacterium kansasii are resistant.  Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. The drug crosses the blood brain barrier and achieves therapeutic concentrations with inflamed meninges. Clinical Use in Tuberculosis Streptomycin sulfate is used when an injectable drug is needed or desirable and in the treatment of infections resistant to other drugs. The usual dosage is 15 mg/kg/d intramuscularly or intravenously daily for adults (20–40 mg/kg/d for children, not to exceed 1 g) for several weeks, followed by 15 mg/kg two or three times weekly for several months Adverse Reactions Streptomycin is ototoxic and nephrotoxic.: Vertigo and hearing loss are the most common adverse effects and may be permanent. Toxicity is dose-related, and the risk is increased in the elderly. As with all aminoglycosides, the dose must be adjusted according to renal function. Toxicity can be reduced by limiting therapy to no more than 6 months whenever possible First-line anti-mycobacterial agents Isoniazid 300 mg/d Rifampin 600 mg/d Pyrazinamide 25 mg/kg/d Ethambutol 15–25 mg/kg/d Once weekly Streptomycin 15 mg/kg/d SECOND-LINE DRUGS FOR TUBERCULOSIS The alternative drugs termed as second line are usually considered only (1) in case of resistance to first-line agents; (2) in case of failure of clinical response to conventional therapy; and (3) in case of serious treatment-limiting adverse drug reactions. Expert guidance is desirable in dealing with the toxic effects of these second-line drugs. Second line ant-mycobacterials agents Amikacin 15 mg/kg/d, Aminosalicylic acid 8–12 g/d Bedaquiline 400 mg/d Capreomycin 15 mg/kg/d Clofazimine 200 mg/d Cycloserine 500–1000 mg/d, divided Ethionamide 500–750 mg/d Levofloxacin 500–750 mg/d Linezolid 600 mg/d Moxifloxacin 400 mg/d Rifabutin2 300 mg/d Rifapentine3 600 mg Ethionamide: Pharmacodynamics: Ethionamide is chemically related to isoniazid and similarly blocks the synthesis of mycolic acids. Pharmacokinetics: It is poorly water soluble and available only for oral use. It is metabolized by the liver. Ethionamide is also hepatotoxic. Neurologic symptoms may be alleviated by pyridoxine. Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo. Capreomycin: Pharmacodynamics: Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus Pharmacokinetics: Given as an intramuscular injection Toxicity: Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular disturbances occur. The injection causes significant local pain, and sterile abscesses may develop. The intermittent dosing regimen may minimize Others antimycobacterias against M. Tuberculae Cycloserine Aminosalicylic Acid (PAS) Kanamycin & Amikacin Fluoroquinolones Linezolid Rifabutin Bedaquiline Drugs active against nontuberculous mycobacteria Some mycobacterial infections are caused by nontuberculous mycobacteria (NTM), formerly known as “atypical mycobacteria.” Mycobacterium kansasii- Mycobacterium avium complex (MAC)- Drugs active against nontuberculous mycobacteria cont.. These organisms have distinctive laboratory characteristics, are present in the environment, and are generally not communicable from person to person. As a rule, these mycobacterial species are less susceptible than M tuberculosis to antituberculous drugs Antibiotics such as macrolides, sulfonamides, and tetracyclines, which are not active against M tuberculosis, may be effective for infections caused by NTM Drugs active against nontuberculous mycobacteria cont.. Mycobacterium kansasii- Resembles tuberculosis managed with Amikacin, clarithromycin, ethambutol, isoniazid, moxifloxacin, rifampin, streptomycin, trimethoprim-sulfamethoxazole Mycobacterium avium complex (MAC)- Pulmonary disease in patients with chronic lung disease; disseminated infection in AIDS managed with Amikacin, azithromycin, clarithromycin, ethambutol, moxifloxacin, rifabutin DRUGS USED IN LEPROSY Leprosy caused by Mycobacterium leprae is a rare disease. Mycobacterium leprae has never been grown in vitro, but animal models, such as growth in injected mouse footpads, have permitted laboratory evaluation of drugs. Only those drugs with the widest clinical use are presented here. Because of increasing reports of dapsone resistance, treatment of leprosy with combinations of Rifampin and Clofamizine has proved very useful.  DAPSONE pharmacodynamics DAPSONE is chemically related to sulphonamides and acts by inhibiting synthesis of dihydrofolic acid by competing with para-aminobenzoic acid for the active site of dihydropteroate synthetase. Its action is antagonized by PABA. resistance to this drug has increased, hence it ‘s combined with other drugs during treatment. Pharmacokinetic Good oral absorption. It under goes enteral hepatic recycling. It has a half life of 24 to 48 hours it is excreted in feces Clinical use The combination of dapsone, rifampin, and clofazimine is recommended for initial therapy of lepromatous leprosy. A combination of dapsone plus rifampin is commonly used for leprosy with a lower organism burden. Dapsone may also be used to prevent and treat Pneumocystis jiroveci pneumonia in AIDS patients especially for patients allergic to sulphur where Clotrimoxazole (sulphamethaxazole plus trimethoprim) is normally used to prevent nosocomial infections.. Unwanted effects Hemolysis of white blood cells. Anorexia , nausea and vomiting. Fever and allergic dermatitis, neuropathy Leprareation where there is exacerbation of lepromatous lesions can occur and a syndrome resembling infectious mononucleosis which can be fatal. Rifampin Rifampin in a dosage of 600 mg daily is highly effective in leprosy and is given with at least one other drug to prevent emergence of resistance. Even a dose of 600 mg per month may be beneficial in combination therapy. Clofazimine Clofazimine is a phenazine dye used in the treatment of multibacillary leprosy, which is defined as having a positive smear from any site of infection. Pharmacodynamics: Its mechanism of action has not been clearly established. Pharmacokinetics: Absorption of clofazimine from the gut is variable, and a major portion of the drug is excreted in feces. Clofazimine is stored widely in reticuloendothelial tissues and skin, and its crystals can be seen inside phagocytic reticuloendothelial cells. It is slowly released from these deposits, so the serum half-life may be 2 months.  A common dosage of clofazimine is 100 mg/d orally. Toxicity: The most prominent untoward effect is discoloration of the skin and conjunctivae. Gastrointestinal side effects are also common Video+Treatment Guidelines Kenya https://www.youtube.com/watch?v=yC7g2LCFa8c https://chskenya.org/wp-content/uploads/2022/04/GUID ELINES-ON-THE-PROGRAMMATIC-MANAGEMENT-OF-TUBE RCULOSIS-PREVENTIVE-THERAPY-PMTPT-2020.pdf  Questions??? Recap