Anti-TB Agents Flashcards
What kind of bacilli is Mycobacterium tuberculosis?
Obligate aerobe, acid-fast bacilli
When is the highest risk of progression to active TB?
In the first 2 years after initial infection
Which population is most susceptible to progression to active TB?
Immunocompromised patients, elderly, HIV positive patients
What is STEP and their strategies to control TB?
Singapore Tuberculosis Elimination Programme (STEP)
1. Direct Observation Therapy (DOT)
2. Monitoring
3. Contact investigation
First line Anti-TB agents
Rifampicin, Isoniazid, Pyrazinamide, Ethambutol, Streptomycin
Why is monotherapy of active TB avoided and why must it be prolonged treatment?
Reduce transmission
Ensure killing of slow growing semi-dormant organisms that can cause relapse
Clinical diagnosis that prompts treatment initiation
Sputum obtained from Ziehl Neelsen stain for acid fast bacilli is positive (Red)
What to check before initiating TB treatment?
- Baseline liver enzymes
- Visual acuity & color vision (for ethambutol)
- Weight loss and dose adjustments
Standard TB Regimen duration and phases? What is the endpoint at each phase
6 Month Regimen
- 2 month Intensive Phase (RIPE) daily
»> Majority elimination - 4 month Continuous Phase (RI) 3x/wk to daily
»> Cure
Cutaneous reactions (Pruritus and rash) are adverse effects present in ________
All first-line TB drugs
Gastrointestinal symptoms (Nausea, anorexia, abdominal discomfort) are adverse effects of _____________ and you should administer _____________
Rifampicin, Isoniazid, Pyrazinamide
after light meals or before bedtime
Rifampicin: Administration? MOA?
Oral
Bactericidal effect on metabolically active bacilli / bacilli in stationary phase
Inhibition of DNA-dependent RNA polymerase and thus halting gene transcription (mRNA synthesis) and protein synthesis
Rifampicin Resistance mechanism
Mutation in gene coding for RNA polymerase beta chain
Rifampicin clinical indications
Active and latent TB; Leprosy (Mycobacterium leprae)
Rifampicin is cleared by?
Hepatic metabolism and Biliary excretion
Rifampicin should be used with caution in which patients?
Pregnancy - Cat C but not teratogenic
Breastfeeding - Monitor for jaundice
Liver failure - Monitor LFT
For pregnant women, what else should be administered with Rifampicin and why?
Vitamin K - To avoid postpartum hemorrhage (ADR: Thrombocytopenia)
How does rifampicin affect CYP450 enzymes? Which drugs have DDI with rifampicin?
Inducer of CYP450 to increase metabolism
- Warfarin, corticosteroids, contraceptives, HIV protease inhibitors
Hepatotoxicity potential increased
- Isoniazid
5 ADRs of Rifampicin
- Cutaneous Syndrome (Flush, pruritus)
- Hepatitis
- Flu-like Syndrome (Fever, chills)
- Respiratory Syndrome (SOB)
- Immune reactions (Thrombocytopenia)
Patient counselling point for rifampicin ADR
Orange discoloration of body fluids (tears, sweat, urine)
Isoniazid: Administration? MOA?
Oral Prodrug
Bactericidal effect mainly on rapid growing bacilli
Catalase-peroxidase enzyme produced by Mycobacterium Tuberculosis activates isoniazid to form oxidative-derived free radicals that can inhibit mycolic acid formation in bacterial cell wall and DNA damage
Isoniazid Resistance mechanism
Mutations in (regulatory) genes coding for:
1. Mycolic acid synthesis
2. Catalase-oxidase enzyme
Isoniazid is clinically indicated in ________
Active/Latent TB and Prophylaxis
Isoniazid is cleared by _______ and how does genetic polymorphism affect it?
Hepatic metabolism by N-acetyltransferase 2 that converts isoniazid to acetylhydrazine by NAT2 pathway. Hydrazine, a reactive metabolite, can also be formed through amidase pathway.
Different people - Slow acetylators vs Rapid acetylator phenotype affect acetylation rate
Isoniazid should be used with caution in _______________________ and why?
Pregnancy - Peripheral neuropathy ADR risk
Breastfeeding - Monitor jaundice
Liver failure - Monitor LFT
What should be given with isoniazid and why?
Pyridoxine; Avoid vitamin B6 deficiency leading to peripheral neuropathy
How does isoniazid cause vitamin B6 deficiency?
Competitive interference with pyridoxine metabolism results in the inhibition of active vitamin B6 formation
How is pyridoxine used by the body?
Pyridoxine is converted to pyridoxal phosphate cofactor (active form) involved in many metabolic processes
Isoniazid food interactions?
Carbohydrates decrease absorption
Tyramine and histamine rich food (MAO and histaminase inhibition by isoniazid)
Antacids increase pH, reduce absorption
Isoniazid affects CYP450 by acting as a ________
Inhibitor that increases phenytoin anticonvulsant and anticoagulant concentrations
Isoniazid ADRs?
- Hypersensitivity (Rare) - Lupus-like syndrome, psychosis, hematologic reactions
- Hepatitis
- Peripheral Neuropathy
What is responsible for bacteriological relapse? Which drug can solve this problem?
Persistent bacilli; Pyrazinamide
Comment on Pyrazinamide molecular structure and derivative
Similar to isoniazid; Nicotinic acid derivative
But no cross-resistance to isoniazid
Comment on the effect of pyrazinamide action on bacteria and macrophages
- Bactericidal
- Potent sterilizing effect
- In acid medium within macrophages and at site of acute inflammation
Pyrazinamide: Administration? MOA?
Oral Prodrug
Converted to active form by pyrazinamidase upon entering bacteria into pyrazinoic acid which reduces the pH level in the bacterial cell, inactivating critical pathways needed for bacterial survival
Pyrazinamide Resistance Mechanism?
Mutation in gene coding for pyrazinamidase
Pyrazinamide is clinically indicated for ________
Active TB
Can TB drugs penetrate CSF fluid?
Rifampicin - 10-20% of serum concentration found in CNS & increases with meningitis
Pyrazinamide - Same concentration in CNS as in plasma and crosses BBB
Ethambutol - Does not cross unless meningitis where therapeutic concentration is achieved
Are all TB drugs safe in pregnancy? What category?
Cat C
Rifampicin - Give with Vitamin K (Hemorrhage)
Isoniazid - Give with Pyridoxine (Peripheral Neuropathy)
Pyrazinamide - Safe
Ethambutol - Not teratogenic
Pyrazinamide cautions in which patients?
Pregnancy
Breastfeeding - Monitor jaundice
Liver failure - Hepatotoxicity of drug should warrant avoidance in liver diseases
Kidney failure - Dose adjustment
Pyrazinamide DDI with _________
Probenecid, Rifampicin, Isoniazid
Pyrazinamide ADR
- GI effect N/V
- Hepatotoxicity
- Photosensitivity
- Hyperuricemia & Arthralgia (Gout-like symptoms)
- Exanthema (Rash) & Pruritus
How does pyrazinamide cause gout-like symptoms?
Pyrazinoic acid inhibits renal tubular secretion of uric acid
Ethambutol effect on bacilli and what bacilli?
Bacteriostatic, Rapid growing bacilli
Ethambutol Administration, MOA?
Oral
Inhibits arabinosyltransferase from polymerising the arabinose into arabinogalactan (principal polysaccharide of mycobacterial cell wall)
This affects the cell wall integrity and facilitate lipophilic abx entry (rifampicin & levofloxacin)
Ethambutol Resistance Mechanism
Mutation in embB gene encoding arabinosyltransferase
Ethambutol is cleared by?
Urine excreted unchanged (50%)
Liver metabolism (25%)
Feces unchanged (25%)
Ethambutol ADRs?
- Visual toxicity (Acuity, color, blurring)
- Hyperuricemia/Gout (Less than pyrazinamide)
Who has greater risk of visual toxicity taking ethambutol?
Kidney failure, elderly, prolonged treatment (> 2 months)
Caution in young children
What drug can replace ethambutol in the intensive phase?
Streptomycin
