Pharmacology of Antituberculosis Drugs

Transcription

1 Pharmacology of Antituberculosis Drugs Chizoba Anozie, PharmD September 8, 2016 TB Nurse Case Management September 7-9, 2016 San Antonio, TX EXCELLENCE EXPERTISE INNOVATION Chizoba Anozie, PharmD, has the following disclosures to make: No conflict of interests No relevant financial relationships with any commercial companies pertaining to this educational activity 1

2 Objectives o First-line anti-tuberculosis drugs o Second-line anti-tb drugs o Discuss Adverse reactions o Drug Interactions o New and Investigational drugs Anti tuberculosis Drugs First-Line Drugs o Rifampin o Rifabutin o Isoniazid (INH) o Pyrazinamide (PZA) o Ethambutol 2

3 Rifampin o Class : Rifamycin o Activity: Bactericidal o Dose Adult: 10mg/kg/dose (usually 600mg IV or PO) o Children: 10 to 20mg/dose Administration: Take without food May mix contents of capsule with applesauce or jelly Rifampin o Reddish-orange body fluids o Nausea, vomiting, diarrhea o Rash, Pruritus o Flu-like syndrome o Elevated LFTs o Hepatitis o Renal failure o Hematological (thrombocytopenia, hemolytic anemia) o Vision changes 3

4 Rifabutin Class: Rifamycin Activity: Bactericidal Dose Adult: 5mg/kg/dose (usually 300mg) Children: Appropriate dose not known. Estimated at 5mg/kg/day May be taken with or without food Rifabutin o Reddish-orange body fluids o Rashes, skin discoloration (bronzing or pseudojaundice) o Arthralgia o Taste changes o Hepatotoxicity o Leukopenia, Neutropenia, thrombocytopenia o Anterior uveitis and other eye toxicities 4

5 Isoniazid (INH) o Class: Isonicotinic acid hydrazide o Activity: Bactericidal o Dose (Adult): 5mg/kg/day (PO or IV) (usual dose 300mg daily o Children: 10 15mg/kg/day o Administration: Best absorbed on empty stomach (about 50% reduction with fatty meal) Isoniazid (INH) o Paresthesia o Pyridoxine deficiency o Epigastric discomfort o Cramping with oral solution o Hepatotoxicity o Hypersensitivity reactions o Drug-induced lupus o CNS changes o Peripheral neuropathy 5

6 Pyrazinamide (PZA) o Class: Synthetic derivative of nicotinamide o Activity: Bactericidal o Dose (Adult): 25mg/kg/day (max 2gm) o Children: 20-40mg/kg/day o May be taken with or without food Pyrazinamide (PZA) o Gout (contraindicated in patients with severe gout) o Elevated LFTs o Arthralgia o Rash o GI symptoms o Photosensitivity o Hepatotoxicity o Anemia o Drug-induced myopathy 6

7 Ethambutol Class: Unspecified Activity: Bacteriostatic Dose(Adult): 15-25mg/kg/day Children: 15 25mg/kg Administration: May be taken with or without food Avoid aluminum containing antacid within 4hrs of admin. Ethambutol o Nausea, vomiting o Abdominal discomfort o Blurred vision o Rash o Psychiatric symptoms (mania, hallucinations, psychosis) o Optic neuritis o Peripheral neuropathy o Blindness (irreversible) 7

8 Second-Line Drugs o Levofloxacin o Moxifloxacin o Cycloserine o Ethionamide o Para-aminosalicylic acid (Paser) o Amikacin o Streptomycin o Capreomycin o Linezolid Levofloxacin (Levaquin) o Class: Fluoroquinolone o Activity: Bactericidal o Dose (Adult): 500mg 1000mg daily o Children: Optimal dose is not known, clinical data suggest 15 20mg/kg 8

9 Levofloxacin Administration: Do not administer within 2 hrs after ingestion of milkbased products, antacids or drugs containing divalent cations (iron, magnesium, calcium, zinc, vitamins, sucralfate, didanosine). How Supplied Levofloxacin o Nausea and bloating o Headache o Dizziness` o Insomnia o Arthralgia o Tendinitis o Tendon rupture (rare) o QT prolongation o Arthralgia o Peripheral neuropathy o Photosensitivity 9

10 Moxifloxacin (Avelox) o Class: Fluoroquinolone o Activity: Bactericidal o Dose (Adult): 400mg/day o Children: No established dose o Administration: o Do not administer within 2 hrs after ingestion of milk-based products, antacids or drugs containing divalent cations ( iron, magnesium, calcium, zinc, vitamins, sucralfate, didanosine). Moxifloxacin o Nausea, diarrhea o Headache, dizziness o Arthralgia o Tendinitis o Hepatotoxicity (rare) o Tendon rupture (rare) o QTc prolongation o Peripheral neuropathy 10

11 Cycloserine (Seromycin) o Class: Analog of D-alanine o Activity: Bacteriostatic o Dose (Adult): 15 20mg/kg/day (usually mg once or BID) o Children: 15 20mg/kg/day in 1 to 2 divided doses o Administration: - Take on empty stomach - Give Vitamin B6 supplement Cycloserine o CNS toxicity (behavioral changes, headache, dizziness, lethargy) o Peripheral neuropathy o Skin changes o Skin rash (lichenoid eruptions) o Seizure o Depression o Psychosis o Suicidal ideation o Steven-Johnson syndrome 11

12 Ethionamide (Trecator) o Derivative of Isonicotinic acid o Bactericidal Dose: Adult: 15 20mg/kg/day (usually mg once or BID) Children: 15 20mg/kg/day in 1 to 2 divided doses Ethionamide o GI upset, anorexia o Metallic taste o Endocrine effects(gynecomastia, hair loss, acne, impotence, menstrual irregularity, reversible hypothyroidism) o Hepatotoxicity o Neurotoxicity o Optic neuritis 12

13 Para-aminosalicylic acid (Paser) o Class - Salicylic acid antifolate o Activity - Bacteriostatic Dose: Adult: 8 12grams/day (usually 4 grams 2 3 x daily) Children: mg/kg/day 2 4 times per day o Administration: Take with food Store in refrigerator May sprinkle on applesauce or yogurt Para-aminosalicylic acid (Paser) o GI symptoms (titrate dose over 2 weeks) o Hypothyroidism (reversible) o Hepatoxicity (rare) o Coagulopathy (rare) 13

14 Amikacin/Streptomycin/Capreomycin Aminoglycoside - Amikacin, Streptomycin Cyclic polypeptide - Capreomycin Activity: Bactericidal Dose: - Adult: 15mg/kg/day - Children: 15 20mg/kg/day Administration: IM or IV Amikacin/Capreomycin/Steptomycin o Local pain with IM injections o Electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia) o Nephrotoxicity o Ototoxicity o Vestibular toxicity 14

15 Linezolid (Zyvox) o Class: Oxazolidinones o Activity: Bactericidal o Dose (Adult): 600mg/day o Children: 10mg/kg/dose every 8hours Administration: o Take with or without food o Take Vitamin B6 supplement o Avoid tyramine containing food (aged chees, dried meat, soy sauce, sauerkraut, red wine, tap beer; avoid drug that increase serotonin conc.) Linezolid o Diarrhea o Nausea o Headache o Myelosuppression o Lactic acidosis o Peripheral neuropathy o Optic neuritis o Serotonin syndrome 15

16 New and Investigational Drugs o Clofazimine o Bedaquiline Clofazimine (Lamprene) o Not commercially available in the US. o Usually as last alternative for cases with very few treatment options Adult Dose: mg/day Administration: o PO only o Take with food 16

17 Clofazimine o Pink or red discoloration of skin, conjunctiva, cornea, and body fluids o GI intolerance o Photosensitivity o Dry skin, rash, pruritus o GI bleeding o Bowel obstruction o Retinopathy Bedaquiline (Sirturo) o Not commercially available in the US o FDA indicated for multi-drug resistant pulmonary TB in adults 18 yrs old and older o Use only when other treatment options cannot be utilized Do not use for - Latent TB - Extra-pulmonary TB - Drug sensitive TB Use with at least 3 other susceptible drugs 17

18 Bedaquiline Dosing: o Weeks 1 2: 400mg daily then, o Weeks 3 24: 200mg 3 times per week (at least 48 hrs between doses) Administration: o Take with food o Swallow tablet whole with water o Avoid alcohol Bedaquiline o Nausea o Arthralgia o Headache o Elevated AST/ALT o QT prolongation o Hepatotoxicty o Increase mortality 18

19 Drug-drug Interactions o Most clinically relevant drug-drug interactions involve Rifamycins (Rifampin > Rifabutin) o Rifamycins are inducers of several metabolic pathways especially involving various isoenzymes of the cytochrome P450 (CYP) system o Rifamycins can decrease serum concentrations of many drugs (eg., most of HIV 1 protease inhibitors) to subtherapeutic levels Drug-drug Interactions Isoniazid o Potent inhibitor of several CYP450 isoenzymes o Increases concentration of some drugs to point of toxicity Phenytoin Carbamazepine Diazepam Triazolam 19

20 Drug-drug Interactions Rifamycins Food-drug Interactions Best on Empty Stomach o Rifampin o Isoniazid o Cycloserine o Moxifloxacin o Levofloxacin Best with food o Paser o Clofazimine o Ethionamide o Bedaquiline 20

21 Questions References 1. American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. Treatment of Tuberculosis. MMWR Recomm Rep. 2003; 52(RR-11): Micormedex 2.0, Drugdex Evaluations, Greenwood Village, CO: Truven Health Analytics, Inc. 3. Francis J. Curry National Tuberculosis Center and California Department of Public Health, 2008: Drug-Resistant Tuberculosis: A survival Guide for Clinicians, Second Edition. 4. Epocrates Rx Online (database on the Internet). San Francisco, CA: Epocrates, Inc Retrieved at Web-based; continuous content updates. 21