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TB Nurse Case ManagementSan Antonio, Texas
April 30 – May 02, 2019
Pharmacology of Anti-Tuberculosis Drugs
Chizoba Anozie, PharmDApril 30, 2019
Chizoba Anozie, PharmD has thefollowing disclosures to make:•No conflict of interests
•No relevant financial relationships with any commercial companies pertaining to this educational activity
Chizoba Anozie, PharmD
Pharmacology of
o First-line anti-tuberculosis drugs
o Second-line anti-TB drugs
o Discuss Adverse reactions
o Review Drug Interactions
o Review New and Investigational drugs
Objectives
o Rifampin
o Rifabutin
o Isoniazid (INH)
o Pyrazinamide (PZA)
o Ethambutol
Anti tuberculosis DrugsFirst-Line Drugs
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 Hepatitis
o Renal failure
o Hematological (thrombocytopenia, hemolytic anemia)
Serious
o Reddish-orange body fluids
o Nausea, vomiting, diarrhea
o Rash, Pruritus
o Flu-like syndrome
o Elevated LFTs
o Vision changes
Common
RifampinAdverse Effects
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
o Hepatotoxicity
o Leukopenia, Neutropenia, thrombocytopenia
o Anterior uveitis and other eye toxicities
Serious
o Reddish-orange body fluids
o Rashes, skin discoloration (bronzing or pseudojaundice)
o Arthralgia
o Taste changes
Common
RifabutinAdverse Effects
o Class: Isonicotinic acid hydrazide
o Activity: Bactericidal
o Dose (Adult): 5mg/kg/day (PO or IV) (usual dose 300mg daily
o Administration: Best absorbed on empty stomach (about 50% reduction with fatty meal)
o Avoid Alcohol
Isoniazid (INH)
o Hepatotoxicity
o Hypersensitivity reactions
o Drug-induced lupus
o CNS changes
o Peripheral neuropathy
Serious
o Paresthesia
o Pyridoxine deficiency
o Epigastric discomfort
o Cramping with oral solution
o Elevated LFTs
Common
Isoniazid (INH)Adverse Effects
o Class: Synthetic derivative of nicotinamide
o Activity: Bactericidal
o Dose (Adult): 25mg/kg/day (max 2gm)
o May be taken with or without food
Pyrazinamide (PZA)
o Hepatotoxicity
o Anemia
o Drug-induced myopathy
Serious
o Gout (hyperuricemia)
o Elevated LFTs
o Arthralgia
o Rash
o GI symptoms
o Photosensitivity
Common
Pyrazinamide (PZA)Adverse Effects
Class: Unspecified
Activity: Bacteriostatic
Dose(Adult):
15-25mg/kg/day
Administration: • May be taken with or
without food• Avoid aluminum containing
antacid within 4hrs of admin.
Ethambutol
o Optic neuritis
o Peripheral neuropathy
o Blindness (irreversible)
Serious
o Nausea, vomiting
o Abdominal discomfort
o Blurred vision
o Rash
o Psychiatric symptoms (mania, hallucinations, psychosis)
Common
EthambutolAdverse Effects
o Levofloxacino Moxifloxacino Cycloserineo Ethionamideo Para-aminosalicylic acid (Paser)o Amikacino Streptomycino Capreomycino Linezolid
Second-Line Drugs
o Class: Fluoroquinolone
o Activity: Bactericidal
o Dose (Adult): 500mg – 1000mg daily
Levofloxacin (Levaquin)
Administration:
Do not administer within 2 hrs of ingestion of milk-based products, antacids or drugs containing divalent cations (iron, aluminum, magnesium, calcium, zinc, vitamins, sucralfate, didanosine).
Levofloxacin
o Tendon rupture (rare)
o QT prolongation
o Peripheral neuropathy
Serious
o Nausea and bloating
o Headache
o Dizziness
o Arthralgia
o Tendinitis
o Photosensitivity
Common
LevofloxacinAdverse Effects
o Class: Fluoroquinolone
o Activity: Bactericidal
o Dose (Adult): 400mg/day
o Administration:
o Do not administer within 2 hrs of ingestion of milk-based products, antacids or drugs containing divalent cations ( iron, aluminum, magnesium, calcium, zinc, vitamins, sucralfate, didanosine).
Moxifloxacin (Avelox)
o Hepatotoxicity (rare)
o Tendon rupture (rare)
o QT prolongation
o Peripheral neuropathy
Serious
o Nausea, diarrhea
o Headache, dizziness
o Arthralgia
o Tendinitis
Common
MoxifloxacinAdverse Effects
o Class: Analog of D-alanine
o Activity: Bacteriostatic
o Dose (Adult): 15 – 20mg/kg/day (usually 250 – 500mg 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 (Seromycin)
o Seizure
o Depression
o Psychosis
o Suicidal ideation
o Steven-Johnson syndrome
Serious
o CNS toxicity (behavioral changes, headache, dizziness, lethargy)
o Peripheral neuropathy
o Skin changes
o Skin rash (lichenoid eruptions)
Common
CycloserineAdverse Effects
o Derivative of Isonicotinic acid
o Bactericidal
Dose:• Adult: 15 – 20mg/kg/day
(usually 250 – 500mg once or BID)
• Children: 15 –20mg/kg/day in 1 to 2 divided doses
Ethionamide (Trecator)
o Hepatotoxicity
o Neurotoxicity
o Optic neuritis
Serious
o GI upset, anorexia
o Metallic taste
o Endocrine effects(Gynecomastia, hair loss, acne, impotence, menstrual irregularity, reversible hypothyroidism)
Common
EthionamideAdverse Effects
image courtesy: healthline.com
o Class - Salicylic acid; anti-folate
o Activity - Bacteriostatic
Dose:
Adult: 8 – 12grams/day (usually 4 grams 2 – 3 x daily)
o Administration: • Take with food • Store in refrigerator • May sprinkle on applesauce
or yogurt
Para-aminosalicylic acid (Paser)
o Hepatotoxicity (rare)
o Coagulopathy (rare)
Serious
o GI symptoms (titrate dose over 2 weeks)
o Hypothyroidism (reversible)
Common
Para-aminosalicylic acid (Paser)Adverse Effects
o Amikacin, Streptomycin
- Class: Aminoglycoside
o Capreomycin
- Class: Cyclic polypeptide
Activity: Bactericidal
Amikacin/Streptomycin/Capreomycin
Dose:
- Adult: 15mg/kg/day
- Children: 15 – 20mg/kg/day
- Administration: IM or IV
Amikacin/Streptomycin/Capreomycin
o Nephrotoxicity
o Ototoxicity
o Vestibular toxicity
Serious
o Local pain with IM injections
o Electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia)
Common
Amikacin/Capreomycin/StreptomycinAdverse Effects
image courtesy: pinterest.com
o Class: Oxazolidinones
o Activity: Bactericidal
o Dose (Adult): 600mg/day
o Children: 10mg/kg/doseAdministration:
o Take with or without food
o Take Vitamin B6 supplement
o Avoid tyramine containing food (aged cheese, dried meat, soy sauce, sauerkraut, red wine, tap beer; avoid drug that increase serotonin conc.)
Linezolid (Zyvox)
o Myelosuppression
o Lactic acidosis
o Peripheral neuropathy
o Optic neuritis
o Serotonin syndrome
Serious
o Diarrhea
o Nausea
o Headache
Common
LinezolidAdverse Effects
images: courtesy of unitedintegratedhealth.com
o Clofazimine
- Investigational Drug - FDA
o Bedaquiline
- Restricted use in the US
o Delamanid
o - Conditional approval by European medicines agency (EMA)
- Not yet approved by FDA
New and Investigational Drugs
o Not commercially available in the US.
o Available from FDA via single-patient INDs for TB
o Adult Dose: 100 – 200mg/day
Administration:
o PO only
o Take with food
Clofazimine (Lamprene)Investigational Drug
o GI bleeding
o Bowel obstruction
o Retinopathy
Serious
o Pink or red discoloration of skin, conjunctiva, cornea, and body fluids
o GI intolerance
o Photosensitivity
o Dry skin, rash, pruritus
Common
ClofazimineAdverse Effects
image courtesy: mdpi.com
o Restricted use 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
Bedaquiline (Sirturo)
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 whole tablet with water
o Avoid alcohol
Bedaquiline
o QT prolongation
o Hepatotoxicity
o Increase mortality
Serious
o Nausea
o Arthralgia
o Headache
o Elevated AST/ALT
Common
BedaquilineAdverse Effects
image courtesy: https://medicalguidelines.msf.org/viewport/TUB/files/
Drug-drug Interactions
images courtesy: aidsinfo.nih.gov
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 (e.g., most of HIV – 1 protease inhibitors) to sub therapeutic levels
Drug-drug InteractionsRifamycins
o Potent inhibitor of several CYP450 isoenzymes
o Increases concentration of some drugs to point of toxicity• Phenytoin• Carbamazepine• Diazepam• Triazolam
Drug-drug InteractionsIsoniazid
o Paser
o Clofazimine
o Ethionamide
o Bedaquiline
Best with food
o Rifampin
o Isoniazid
o Cycloserine
o Moxifloxacin
o Levofloxacin
Best on Empty Stomach
Food-drug Interactions
Questions
• Bactericidal - Capable of killing bacteria outright
• Bacteriostatic - Capable of inhibiting the growth or reproduction of bacteria
• DOT – Directly observed therapy
• Paresthesia - A burning or prickling sensation that is usually felt in the hands, arms, legs, or feet, but can also occur in other parts of the body.
• Serotonin syndrome - A group of symptoms that may occur following use of certain serotonergic medications or drugs. Symptoms include; high body temperature, agitation, increased reflexes, tremor, sweating, dilated pupils, and diarrhea.
• IND – Investigational New Drug
Glossary of Terms
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): 1 – 77.
2. 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. 2014. Retrieved at www.epocrates.com. Web-based; continuous content updates.
References
