TB - LaCount Flashcards
Mycobacterium tuberculosis
- ___ -growing aerobic bacterium - relatively resistant to most antibiotics
- Acid fast bacteria (AFB)
- Lipid rich cell wall contains mycolic acids and is ___ to many drugs
- Causes both latent and active infections
- Facultative ___ parasite
- Obligate aerobe
- slow
- impermeable
- intracellular
Treatment of active Tb infections
Most common: combination of (4) (RIPE)
- Alternative – rifapentine (RPT), INH,
pyrazinamide, and ___ (MOX)
- Different drugs are needed to combat dividing and dormant forms
- Tb rapidly develops resistance to individual drugs
- rifampin, isoniazid (INH), pyrazinamide, and ethambutol
- moxifloxacin
Isoniazid (Nydrazid ® , Laniazid ® )
- Isonicotinic acid hydrazide (INH)
- Specific for M. tb
- Bacteri ___
- Only active against ___ M. tb
- Prodrug – activated by M. tb ___ protein
- bactericidal
- KatG
Isoniazid mechanism of action
- Activation by ___ (catalase-peroxidase)
- Forms adducts with NAD+ and NADP+
- Inhibits enzymes that use NAD+ and
NADP+
Activated isoniazid inhibits ___ :
- Component of ___
- Catalyzes the NADH-dependent reduction of ___ bound to acyl carrier protein
- inhibit synthesis of ___ acid from going past FAS II
- KatG
- InhA
- FAS II
- fatty acids
- mycolic
Isoniazid resistance
- downregulation of ___
- Over-expression of ___
- KatG
- InhA
Isoniazid
Metabolism
- Acetylation by liver ___ (NAT2)
- Rate determined ___
- No therapeutic consequence if dosed daily, but can result in subtherapeutic levels if dosed weekly
- N-acetyltransferase
- genetically
Isoniazid toxicity
- ___ is major concern
- Peripheral ___
- hypersensitivity
- rheumatological conditions
- ___ associated with antinuclear antibodies (disappears when the drug is stopped)
- Arthritic symptoms
- ___ like syndromes
- Hepatitis
- neuropathy
- Vasculitis
- lupus
Isoniazid toxicity mechanism
Acetylisoniazid can be
converted to acetylhydrazine
- ___ converts acetylhydrazine to hepatotoxic metabolites
- NAT2 can acetylate acetylhydrazine to nontoxic diacetylhydrazine
- rapid acetylators will rapidly remove acetylhydrazine
- slower acetylators or induction of CYP2E1 will lead to more ___ metabolites
- ___ induces CYP2E1 & potentiates isoniazid hepatotoxicity
- CYP2E1
- toxic
- Rifampin
Isoniazid toxicity
Isoniazid can cause ___ neuropathy
- More frequent in slow acetylators
- Reversed by administering ___
Two mechanisms
1) Isoniazid resembles pyridoxine (vitamin ___ )
2) Isoniazid ___ inhibits pyridoxine phosphokinase (converts pyridoxine to pyridoxal phosphate (active form))
INH metabolites directly ___ pyridoxine species
- peripheral
- pyridoxine
- B6
- competitively
- inactivate
Pyrazinamide (Aldinamide)
Shortened treatment to __ months
- sterilizing agent against residual intracellular
bacteria (persister bacilli; sometimes referred to as nonreplicating, persistent bacilli (NRPB))
Structurally similar to ___
Activity is pH dependent
- Inactive at neutral pH
- Activated by ___ pH
Prodrug - requires conversion to pyrazinoic acid by ___
- 6
- nicotinamide
- low
- pncA
Pyrazinamide mechanism
inhibition of ___ leading to inhibition of ___ synthesis
- binding affinity is ___
- Increases levels of free ___
- panD
- Coenzyme A
- low
- fatty acids
Pyrazinamide Resistance and Toxicity
Generated easily, but suppressed when used in combination
- Primarily due to mutations in ___
Toxicity
- ___ is most common side effect (approximately 1%)
- ___ is most dangerous (most common out of 4 drug regimen)
- Hydroxylated POA is cause of toxicity
- pncA
- arthralgia
- Hepatitis
Ethambutol
Bacterio ___ inhibitor of M. tb
MOA: Inhibits mycobacterial ___
transferases. Involved in the polymerization of ___
- Results in build up of ___
- Inhibits formation of arabinogalactan and lipoarabinomannan (LAM)
- Bacteriostatic
- arabinosyl
- arabinogalactan
- arabinan
Ethambutol
Synergistic with ___
- Increases penetration into cell
Resistance is due to over-expression of or mutations in ___ transferase
- Not recommended for use alone due to
resistance
Toxicity
- Most important - ___
- Can be irreversible if treatment not discontinued
- Rifampin
- arabinosyl
- optic neuritis
Rifampin
Semisynthetic derivative of rifamycin B - produced by Streptomyces mediterranei
- Reduced length of therapy from 18 to 9 months
Most ___ first line agent
- High sterilizing activity
- rapidly renders patients ___
- Bacteri ___
Penetrates most tissues and phagocytic cells
Active against growing and stationary (non- dividing) cells with low metabolic activity
- Can kill M. tb inaccessible to many other drugs
- Most effective when cell division is occurring
- effective
- non-infectious
- Bactericidal
Rifapentine
Rifapentine - derivative of rifampin
- cyclopentyl ring
- More ___
- ___ half-life (13.5 h vs. 2 - 5 h)
- lipophilic
- longer
Rifampin MOA and AE
Binds to RNA ___ deep within the DNA/RNA channel
- Blocks the path of the elongating RNA
Colors urine, tears and sweat ____
Potent ___ of cytochrome P450s
- Increase in CYP enzymes increases elimination of other drugs metabolized by these enzymes
- polymerase
- orange
- inducer
Fluoroquinolones
___ , ___ , and ___ have activity against M. tb (MOX preferred)
MOA: Mechanism
- Traps ___ on DNA as ternary complex
- prevents resolution of ___ DNA
- Disrupts DNA replication
- bacteri ___
Can replace ___ in 4-month Mtb
treatment regiment
- Moxifloxacin, gatifloxacin and levofloxacin
- gyrase
- supercoiled
- bactericidal
- ethambutol
Toxicity associated with anti
___ : isoniazid, pyrazinamide, rifampin
___ damage: ethambutol
- Loss of visual acuity & red-green color-blindness
- ___ discoloration of the urine: rifampin
- Patients should be monitored at least
monthly for adverse effects
- Hepatitis
- Eye
- Orange
BPaL regimen
Combination therapy
- ___
- ___
- ___ – inhibits protein synthesis
Treatment of
- extensively drug-resistant tuberculosis (XDR TB)
- treatment-intolerant or non-responsive
multidrug-resistant TB (MDR-TB)
- Bedaquiline
- Pretomanid
- Linezolid
Bedaquiline
first in class - diarylquinoline
MOA: Inhibits ATP synthase
- PO
- bacteri ___ against bacilli
- Metabolized by ___
Resistance – mutations in ___
- bactericidal
- CYP3A4
- atpE
Nitroimidazoles
- ____ :nitro-dihydro-imidazooxazole
Delamanid
- similar structure and mechanism
- Approved for use in Europe, Japan and South Korea
- Pretomanid
Pretomanid mechanism
Prodrug - activated by M. tb
deazaflavin-dependent nitroreductase ( ___ )
- Aerobic conditions: Forms reactive intermediate metabolite that inhibits ___ acid production (and likely other pathways)
In anaerobic, nonreplicating, persistent bacilli
- generates reactive nitrogen species such as ___
- direct poisoning of the respiratory complex -> ___ depletion
- Increases killing by innate immune system
- Ddn
- mycolic
- NO, ATP
Second line agents
Active anti-tubercular agents
- ___ well tolerated
- ___ incidence of side effects
Usually considered only if
- ___ / Intolerance to first line agent
- Expert guidance available to deal with toxic side- effects
- less, greater
- Resistance
