pharmacology of antituberculosis drugs chizoba anozie ......sep 13, 2017 · o second-line anti-tb...
TRANSCRIPT
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EXCELLENCE EXPERTISE INNOVATION
PharmacologyofAntituberculosisDrugs
Chizoba Anozie, PharmDSeptember13,2017
TB Nurse Case ManagementSeptember 12‐14, 2017
• No conflict of interests
• No relevant financial relationships with any commercial companies pertaining to this educational activity
Chizoba Anozie, PharmD hasthefollowingdisclosurestomake:
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Chizoba Anozie, PharmD
Pharmacology of
o First-line anti-tuberculosis drugs
o Second-line anti-TB drugs
o Discuss Adverse reactions
o Drug Interactions
o New and Investigational drugs
Objectives
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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
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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
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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 Children: 10 – 15mg/kg/day
o Administration: Best absorbed on empty stomach (about 50% reduction with fatty meal)
Isoniazid (INH)
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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
Common
Isoniazid (INH)Adverse Effects
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)
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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
Children: 15 – 25mg/kg
Administration: • May be taken with or
without food• Avoid aluminum containing
antacid within 4hrs of admin.
Ethambutol
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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
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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
Levofloxacin (Levaquin)
How SuppliedAdministration:
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).
Levofloxacin
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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 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 (Avelox)
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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)
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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)
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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
o Class - Salicylic acid – anti-folate
o Activity - Bacteriostatic
Dose:
Adult: 8 – 12grams/day (usually 4 grams 2 – 3 x daily)
Children: 200 – 300mg/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)
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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
Dose:
- Adult: 15mg/kg/day
- Children: 15 – 20mg/kg/day
Administration: IM or IV
Amikacin/Streptomycin/Capreomycin
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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
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)
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o Myelosuppression
o Lactic acidosis
o Peripheral neuropathy
o Optic neuritis
o Serotonin syndrome
Serious
o Diarrhea
o Nausea
o Headache
Common
LinezolidAdverse Effects
o Clofazimine
o Bedaquiline
New and Investigational Drugs
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o Not commercially available in the US.
o For cases with very few treatment options
Adult Dose: 100 – 200mg/day
Administration:
o PO only
o Take with food
Clofazimine (Lamprene)
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
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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
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 tablet whole with water
o Avoid alcohol
Bedaquiline
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o QT prolongation
o Hepatotoxicity
o Increase mortality
Serious
o Nausea
o Arthralgia
o Headache
o Elevated AST/ALT
Common
BedaquilineAdverse Effects
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
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o Potent inhibitor of several CYP450 isoenzymes
o Increases concentration of some drugs to point of toxicity• Phenytoin• Carbamazepine• Diazepam• Triazolam
Drug-drug InteractionsIsoniazid
Drug-drug InteractionsRifamycins
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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
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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