Pharmacology of Antituberculosis Drugs

Transcription

1 Pharmaclgy f Antituberculsis Drugs Chizba Anzie, PharmD September 13, 2017 TB Nurse Case Management September 12 14, 2017 EXCELLENCE EXPERTISE INNOVATION Chizba Anzie, PharmD has the fllwing disclsures t make: N cnflict f interests N relevant financial relatinships with any cmmercial cmpanies pertaining t this educatinal activity 1

2 Pharmaclgy f Chizba Anzie, PharmD Objectives First-line anti-tuberculsis drugs Secnd-line anti-tb drugs Discuss Adverse reactins Drug Interactins New and Investigatinal drugs 2

3 Anti tuberculsis Drugs First-Line Drugs Rifampin Rifabutin Isniazid (INH) Pyrazinamide (PZA) Ethambutl Rifampin Class : Rifamycin Activity: Bactericidal Dse Adult: 10mg/kg/dse (usually 600mg IV r PO) Children: 10 t 20mg/dse Administratin: Take withut fd May mix cntents f capsule with applesauce r jelly 3

4 Rifampin Cmmn Reddish-range bdy fluids Nausea, vmiting, diarrhea Rash, Pruritus Flu-like syndrme Elevated LFTs Serius Hepatitis Renal failure Hematlgical (thrmbcytpenia, hemlytic anemia) Visin changes Rifabutin Class: Rifamycin Activity: Bactericidal Dse Adult: 5mg/kg/dse (usually 300mg) Children: Apprpriate dse nt knwn. Estimated at 5mg/kg/day May be taken with r withut fd 4

5 Rifabutin Cmmn Reddish-range bdy fluids Rashes, skin disclratin (brnzing r pseudjaundice) Arthralgia Taste changes Serius Hepattxicity Leukpenia, Neutrpenia, thrmbcytpenia Anterir uveitis and ther eye txicities Isniazid (INH) Class: Isnictinic acid hydrazide Activity: Bactericidal Dse (Adult): 5mg/kg/day (PO r IV) (usual dse 300mg daily Children: 10 15mg/kg/day Administratin: Best absrbed n empty stmach (abut 50% reductin with fatty meal) 5

6 Isniazid (INH) Cmmn Paresthesia Pyridxine deficiency Epigastric discmfrt Cramping with ral slutin Serius Hepattxicity Hypersensitivity reactins Drug-induced lupus CNS changes Peripheral neurpathy Pyrazinamide (PZA) Class: Synthetic derivative f nictinamide Activity: Bactericidal Dse (Adult): 25mg/kg/day (max 2gm) Children: 20-40mg/kg/day May be taken with r withut fd 6

7 Pyrazinamide (PZA) Cmmn Gut (hyperuricemia) Elevated LFTs Arthralgia Rash GI symptms Phtsensitivity Serius Hepattxicity Anemia Drug-induced mypathy Ethambutl Class: Unspecified Activity: Bacteristatic Dse(Adult): 15-25mg/kg/day Children: 15 25mg/kg Administratin: May be taken with r withut fd Avid aluminum cntaining antacid within 4hrs f admin. 7

8 Ethambutl Cmmn Nausea, vmiting Abdminal discmfrt Blurred visin Rash Psychiatric symptms (mania, hallucinatins, psychsis) Serius Optic neuritis Peripheral neurpathy Blindness (irreversible) Secnd-Line Drugs Levflxacin Mxiflxacin Cyclserine Ethinamide Para-aminsalicylic acid (Paser) Amikacin Streptmycin Capremycin Linezlid 8

9 Levflxacin (Levaquin) Class: Flurquinlne Activity: Bactericidal Dse (Adult): 500mg 1000mg daily Children: Optimal dse is nt knwn, clinical data suggest 15 20mg/kg Levflxacin Administratin: D nt administer within 2 hrs after ingestin f milkbased prducts, antacids r drugs cntaining divalent catins (irn, magnesium, calcium, zinc, vitamins, sucralfate, didansine). Hw Supplied 9

10 Levflxacin Cmmn Nausea and blating Headache Dizziness Arthralgia Tendinitis Phtsensitivity Serius Tendn rupture (rare) QT prlngatin Peripheral neurpathy Mxiflxacin (Avelx) Class: Flurquinlne Activity: Bactericidal Dse (Adult): 400mg/day Children: N established dse Administratin: D nt administer within 2 hrs after ingestin f milk-based prducts, antacids r drugs cntaining divalent catins ( irn, magnesium, calcium, zinc, vitamins, sucralfate, didansine). 10

11 Mxiflxacin Cmmn Nausea, diarrhea Headache, dizziness Arthralgia Tendinitis Serius Hepattxicity (rare) Tendn rupture (rare) QT prlngatin Peripheral neurpathy Cyclserine (Sermycin) Class: Analg f D-alanine Activity: Bacteristatic Dse (Adult): 15 20mg/kg/day (usually mg nce r BID) Children: 15 20mg/kg/day in 1 t 2 divided dses Administratin: - Take n empty stmach - Give Vitamin B6 supplement 11

12 Cyclserine Cmmn CNS txicity (behaviral changes, headache, dizziness, lethargy) Peripheral neurpathy Skin changes Skin rash (lichenid eruptins) Serius Seizure Depressin Psychsis Suicidal ideatin Steven-Jhnsn syndrme Ethinamide (Trecatr) Derivative f Isnictinic acid Bactericidal Dse: Adult: 15 20mg/kg/day (usually mg nce r BID) Children: 15 20mg/kg/day in 1 t 2 divided dses 12

13 Ethinamide Cmmn GI upset, anrexia Metallic taste Endcrine effects(gynecmastia, hair lss, acne, imptence, menstrual irregularity, reversible hypthyridism) Serius Hepattxicity Neurtxicity Optic neuritis Para-aminsalicylic acid (Paser) Class - Salicylic acid antiflate Activity -Bacteristatic Dse: Adult: 8 12grams/day (usually 4 grams 2 3 x daily) Children: mg/kg/day 2 4 times per day Administratin: Take with fd Stre in refrigeratr May sprinkle n applesauce r ygurt 13

14 Para-aminsalicylic acid (Paser) Cmmn GI symptms (titrate dse ver 2 weeks) Hypthyridism (reversible) Serius Hepattxicity (rare) Cagulpathy (rare) Amikacin/Streptmycin/Capremycin Amikacin, Streptmycin - Class: Aminglycside Capremycin - Class: Cyclic plypeptide Activity: Bactericidal Dse: - Adult: 15mg/kg/day - Children: 15 20mg/kg/day Administratin: IM r IV 14

15 Amikacin/Capremycin/Streptmycin Cmmn Lcal pain with IM injectins Electrlyte abnrmalities (hypkalemia, hypcalcemia, hypmagnesemia) Serius Nephrtxicity Ottxicity Vestibular txicity Linezlid (Zyvx) Class: Oxazlidinnes Activity: Bactericidal Dse (Adult): 600mg/day Children: 10mg/kg/dse Administratin: Take with r withut fd Take Vitamin B6 supplement Avid tyramine cntaining fd (aged cheese, dried meat, sy sauce, sauerkraut, red wine, tap beer; avid drug that increase sertnin cnc.) 15

16 Linezlid Cmmn Diarrhea Nausea Headache Serius Myelsuppressin Lactic acidsis Peripheral neurpathy Optic neuritis Sertnin syndrme New and Investigatinal Drugs Clfazimine Bedaquiline 16

17 Clfazimine (Lamprene) Nt cmmercially available in the US. Fr cases with very few treatment ptins Adult Dse: mg/day Administratin: PO nly Take with fd Clfazimine Cmmn Pink r red disclratin f skin, cnjunctiva, crnea, and bdy fluids GI intlerance Phtsensitivity Dry skin, rash, pruritus Serius GI bleeding Bwel bstructin Retinpathy 17

18 Bedaquiline (Sirtur) Nt cmmercially available in the US FDA indicated fr multi-drug resistant pulmnary TB in adults 18 yrs ld and lder Use nly when ther treatment ptins cannt be utilized D nt use fr - Latent TB - Extra-pulmnary TB - Drug sensitive TB - Use with at least 3 ther susceptible drugs Bedaquiline Dsing: Weeks 1 2: 400mg daily then, Weeks 3 24: 200mg 3 times per week (at least 48 hrs between dses) Administratin: Take with fd Swallw tablet whle with water Avid alchl 18

19 Bedaquiline Cmmn Nausea Arthralgia Headache Elevated AST/ALT Serius QT prlngatin Hepattxicity Increase mrtality Drug-drug Interactins Mst clinically relevant drug-drug interactins invlve Rifamycins (Rifampin > Rifabutin) Rifamycins are inducers f several metablic pathways especially invlving varius isenzymes f the cytchrme P450 (CYP) system Rifamycins can decrease serum cncentratins f many drugs (e.g., mst f HIV 1 prtease inhibitrs) t sub therapeutic levels 19

20 Drug-drug Interactins Isniazid Ptent inhibitr f several CYP450 isenzymes Increases cncentratin f sme drugs t pint f txicity Phenytin Carbamazepine Diazepam Triazlam Drug-drug Interactins Rifamycins 20

21 Fd-drug Interactins Best n Empty Stmach Rifampin Isniazid Cyclserine Mxiflxacin Levflxacin Best with fd Paser Clfazimine Ethinamide Bedaquiline Questins 21

22 References 1. American Thracic Sciety; Centers fr Disease Cntrl and Preventin; Infectius Diseases Sciety f America. Treatment f Tuberculsis. MMWR Recmm Rep. 2003; 52(RR-11): Micrmedex 2.0, Drugdex Evaluatins, Greenwd Village, CO: Truven Health Analytics, Inc. 3. Francis J. Curry Natinal Tuberculsis Center and Califrnia Department f Public Health, 2008: Drug-Resistant Tuberculsis: A survival Guide fr Clinicians, Secnd Editin. 4. Epcrates Rx Online (database n the Internet). San Francisc, CA: Epcrates, Inc Retrieved at Web-based; cntinuus cntent updates. 22