Lecture 8 - Antitubercular agents Flashcards
1st line Antitubular Agents
RIPE
Rifamycins
Isoniazid
Pyrazinamide
Ethambutol
Rifamycins
Rifampin
Rifabutin
Rifapentine
Rifamycins MOA
Inhibit DNA dependent RNA polymerase
Bind to b-subunit of enzyme complex
Rifampin ADME properties
Widely distributed, highly lipophilic
Hepatic metabolism, 3-4hrs 1/2 life
mostly feces excreted some in urine
Rifabutin ADME properties
Widely distributed
Hepatic metabolism, 45hrs 1/2life
5 metabolites its metabolized to
Rifapentime ADME properties
High fat meals inc AUC & Max
Widely distributed
Hepatic metabolism, 17hr 1/2 life
Excreted mostly in feces 70/30
Big reason for choosing one Rifamycin over another?
DI
Rifampin DI
has a bunch
Warfarin = inc clot risk
Cyclosporine, Tacrolimus
HIV protease inhibitors + NNRT inhib
Rifabutin DI
way less DI, 50% of induction seen w/ rifampin
still has CYP3A4 tho
Rifapentine DI
more potent inducer than rifabutin but less than rifampin
rarely used
Rifampin Adverse Reactions
Hepatitis main issue
GI, rash, Genitourinary = change colors
Rifabutin Adverse Reactions
Rash, Urine discoloration, GI, some Hematologic
higher incidence
Rifapentine Adverse Reactions
Hepatic, Hematologic, Genitourinary
Rifampin role in therapy
1st line in pulmonary + extra pulmonary TB
resistance rapidly evolves if used alone
Rifabutin role in therapy
Rifampin alternative, as effective in drug susceptible TB
** used in pts w/ HIV if using protease inhibitors **
Rifapentine role in therapy
approved for once weekly use in INH in continuation phase of therapy w/ HIV neg patients
** Avoid in HIV + patients on antiretroviral therapy
Isoniazid (INH) MOA
- inhibit synthetic pathways of mycelia acid
- inhibit catalase-peroxidase enzyme
- Bactericidal ( against activity growing) and bacteriostatic (against non-replicating organisms0
Isoniazid (INH) ADME
well distributed, rapid absorption
excreted mostly in urine
Fast acetylators = lower 1/2 life
Slow acetylators = higher 1/2 life
Isoniazid (INH) Adverse effects
Hepatitis
Neurotoxic - peripheral neuropathy ~ 17% ( give Vit B to prevent)
Hypersensitivity reactions
Isoniazid Hepatitis risk factors
Alcoholics Preexisting liver damage Reg women + women 3 months postpartum Concomitant hepatotoxic agents Active Hep B HIV-seropositve pts on HAART
Isoniazid DI
Phenytoin
Theophylline
Clopidogrel
Isoniazid Role in therapy
1st line, indicated for all clinical forms of TB, used in combo
Used alone for latent TB
Pyrazinamide (PZA) MOA
Converted to pyrazinoic acid, lowering pH of environment
Inhibits fatty acid synthetase, involved in mycelia acid which are important for cell well
Pyrazinamide (PZA) ADME
well absorbed, widely distributed
crosses inflamed meninges
Hepatic metabolism, 9-10hr 1/2 life
Pyrazinamide (PZA) Adverse Reactions
Hepatotoxicity ~ 15% in trials in early trials at higher doses
GI - N/V
Urine retention ~ 50%
Gout
Pyrazinamide (PZA) DI
Doesn’t have any really
BUT enhances hepatitis effects of Rifampin
Pyrazinamide (PZA) Role in therapy
1st line, essential component of multi drug 6month therapy
** Pts have to be on PZA for 1st 2 months **
Primary resistance is low, but if resistant to INH/Rifampin will probs be resistant to PZA
Ethambutol MOA
Interferes with cell wall biosynthesis
Inhibits arabinosyl transferase (EmbB)
Ethambutol ADME
Well absorbed
Widely distributed
Hepatic metabolsim
excreted urine and feces
Ethambutol Adverse Reactions
Neuropathy ** Retrobulbar optic neuritis** GI Hyperuricemia Hypersensitivity
Retrobulbar optic neuritis
Bilateral blurry vision and red/green color vision
Slowly reversible
TIW admin reduces the risk
Ethambutol DI
None
Ethambutol Role in therapy
1st line, 4th drug of combo
protects against rifampin resistance, dropped once susceptibilities results are back
TB Treatment Algo
If think they have TB, start on RIPE
Once susceptibilities back, E can be d/x if no drug resistance
P has to be on of 1st 2 months, can take off after for rest
**If dont get P in 1st 2 months, have to stay on therapy for 9 **
Bedaquiline ( Diarylquinoline) MOA
Inhibits ATP synthase through inhibition of proton transfer chain required for energy generation
Bedaquiline ( Diarylquinoline) ADME
Absorption inc w/ food
Large Vd
Hepatic metabolism
Bedaquiline ( Diarylquinoline) Adverse effects
** Nausea ~ 38%
QTc prolongation
Black box for Cardiac toxicity/sudden death
Bedaquiline ( Diarylquinoline) Black Box
“Only use when an effective treatment regime cannot otherwise be provided”
Clofazimine MOA
Prodrug, originally anti-leporsy
exactly mechanism not well understood
causes accumulation of ROS radicals and cause cell death basically
Clofazimine ADME
Absorption variable, inc w/ food
Highly Lipophilic
No hepatic metabolism
Clofazimine Adverse effects
** Pigmentation changes = pink/brown/black color
GI = abdominal pain
Clofazimine DI
QTc prolonging effects
Cycloserine MOA
Inhibit bacterial cell wall synthesis by competing w/ amino acid (D-alanine) for incorporation into bacterial cell wall
Cycloserine ADME
Mostly GI absorption
Widely distributed most body fluids
Hepatic metabolism
Highly urine excretion
Cycloserine Adverse effects
Cardiac effects
CNS
Skin
Hepatic
Cycloserine DI
Minimal
Ethinamide MOA
Inhibits Peptide synthesis
results in impairment of cell wall synthesis
Ethionamide ADME
essentially complete absorption
Widely distributed, Vd 93.5L
Prodrug, extensive hepatic metabolism
Ethionamide Adverse effects
Cardiovascular- ortho hypotension CNs SKin Hepatic GI
Ethionamide DI
minimal
Streptomycin MOA
Interferes w/ translation of mRNA transcripts
Bind to S12 protein, part of 30S complex
inhibits synthesis of mycobacterial proteins
Streptomycin ADME
Usually given IM, PO poorly absorbed
Distributes into tissues/fluids except CNS
No hepatic metabolism
Urine excretion
Streptomycin Adverse effects
Nephrotoxicity
Auditory + Vestibular toxicity
Hypersensitivity reactions
Pretomanid MOA
Cell-wall lipid biosynthesis inhibitor
inhibition of mycelia acid synthesis
Formation of nitrogen reactive species
Pretomanid ADME
Well absorbed
Distributes throughout body + CSF
Urine excretion
Pretomanid Adverse effects
Pretty high change of Peripheral neuropathy Headache GI Musculoskeletal increased LFTs
Therapy for MDR-TB
- pick 1 later-get Fluoroqinolone (Levo-/Moxifloxacin)
- Both Bedaquiline + Linezolid
- Both Clofazimine + Cycloserine/terizidone
- If cant get those 5 + susceptible, do Amikacin + Streptomycin
- If cant do injectable, do Delamanid, Pyrazinamide, Ethambutol
