Suttle Treatment of Tb Flashcards
bactericidal treatments require…
bacteria to be actively growing
Tb can survive within
macophages–> making them resistant to AB’s
general course of tx for TB infection
multi-agents (will become resisitant to single therapy) and for a protracted course of tx.
First line therapy against M. tuberculosis
INH + RIF+ pyrazinamide + (ethambutol or streptomycin)
First line tx for MAC
Clarithromycin + ethambutol or clofazamine or cipro or amikacin
why is rifabutin better than rifampin
less potent CYP inducer
why is rifampentene better than rifampin
longer half-life (once weekly dosing)
*intermediate CYp inducer
best LATENt therapy
IND-RPT under DOT
who does not get INH-RPT
, 2, pregnant, HIV, LTBI with INH or RIF resistance
Active cases of TB get what dosing regimine
initial phase –> 8 weeks
continuation phase-> 18 weeks
*2-4 drugs taken for 26 weeks on different dosing schedules
how to ensure compliance
DIRECT OBSERVED THERAPY
HIV NEGATIVE PT’S WITH NEGATIVE AFB SPUTUM AND CHEST X RAY CAN GET
*AFTER INHITIAL PHASE
CONTINUATION PHASE OF OCE WEEKLY INH/RPT
ISONIAZID TARGETS
cell wall synthesis
ethambutol targets
cell wall synthesis
pryazinamide targets
unknown–> disrupts plasma membrane and enables energy metabolism
MOA for isoniazid
interferes with mycolic acid synthesis
- cidal for rapidly dividing bacilli
* static for latent/ slow growing
isoniazid
resistance to isonizaid
inability to take up the drug, alteraiton of taret enzyme, overproduction of target enzyme,
*rapid resistance, never as mono thereapy
metabolism of Isoniazid
acetylated by Nacetyl transferease
*chronic liver disease will decrease metabolism
normal half life 1-4 hours depending on acetylaiton status
(slow vs fast acetylators)
excretion of isoniazid
75% in the urine
can isoniazid reach therapeutic levels in the brain
yes, rapidly absorbed from GI (oral or IM) cna distributes to all tissues
Adverse effects of isoniazid
peripheral neuropathy
B6 depletions (competes with pyridoxal phosphate)
hepatotoxicity
allergic rxns )not dose rleated)
drug interactions
drugs with Al+ salts, give 1 hour prior to antacids
corticosteroids decrease efficacy
CYP inhibitors–> caution with phenytoin, diazepam, fluoxetine, nelfavir,
MOA for rifampin
inhibitio of RNA synthesis bind RNA pol beta subunit)
is rifampin cidal or static
cidal
resistance to RIFAMPIN
DNA dependent RNA polymerase does not bind drug, never given as mono therapy
spectrum of rifampin
intra or extracellular mycobacterium
name the rifamycins
rifampin, rifapentine, rifabutin *RIF is most common
Distribution of rifampin
well absorbed, distributes to tissues well, 75% bound to proteins+ CSF
absorption problems with rifampin
impaired by food of para-aminosalicylic acid
does rifampin get into the CSF
yes
metabolism of Rifampin
deacetylated in the liver–> stil ctive just not re-absorbable (facilitates excertion)
excetion of rifampin
bile (30% unchanged), small amount renal secretion
adjustment for rifampin in renal insufficiency
NONE
impairement of rifampin half life
increased by hepatic dysfunction
adverse effects of rifampin
discolors body fluids, (orange red), hepatotoxicity, Nervous complaints,
Drug interactions with rifampin
induces CYP’s–> reduces half life of pred, ketocon, NNRTI’s etc.
oral contraceptives less effective and anticoags less effective
which drug icreases serum concentration of rifampin
probenacid
rifampin can cuase death from
liver failure–> in pt.’s with hepatitis, and chornic liver diseae, on other hepatotosic drugs and alcohol
only cyp not induced by Rifampin
2d6
Other uses of rifampin
first line for MB TB rapid and slow
–> MRSA, Leprosy, eradiates nasal staph, prophylactics for household members exposed to H flu or meningococcal meningitis
ethambutol MOA
INhibits RNA synthesis ??*
disrupts cell wall (arabinosyl transferase)
spectrum of Ethambutol
static–> cidal at higher concentrations
*bacillia must be actively dividing
resistance to Ethambutol
slow, no cross resistance
Distribution of Ethambutol
wide–> concentrates in (kidneys, lungs, saliva), CSF access +, placenta crossing, breast milk as well
eliminiation of ethambutol
pertially metab. n liver, excerted in urine,
half life of ethambutol
3.5 hours–> up to 15 hours in kidney disease
absorptoin of ethambutol
75%with oral dosing
adverse rxns with ethambutol
optic neuritis (loss of visual accuity, color blind, reversible)
allergic rhinitis
hyperuricemia
interactions with ethambutol
Al++_ antacids reduce absorption
before ehtmabutol therapy begins pt. must have
vision test, and must be monitored throughout treatment
MOA for pyrazinamide
?????
decreases pH below threshold growth
bacilli conver pyrazinamide to
pyrazinoic acid
resistant strains
lack pyrazinamidase
cidal or static for pyrzainamide
depends on cencentration
Is pyrazinamide therapeutic in CSF
yes
metabolism pf pyrazinamide
liver and excreted in urine via Glomerular filtration not secrteion
adverse effects of pyrazinamide
dose related hepatoxocity
- -> non-gouty arthritis
- ->hyperuricemia
MDR TB-> definition
cannot be killed by INH or rifampin
TX for DMR -TB and MAC when other dont work and for UTI’s
cycloserin (broad spectrum)
MOA for cycloserine
cell wall inhibition of synthesis
(strcutural analog od D-alanine–> can block L alanine racemase and D alanine synthase–> required for encorporation into peptidoglycan strands)
Cycloserine cidal or static
depends on concentraiton
Canc cylsoerine penentrate meninges
yes 86% noninflammed, 100% inflammed
can cycloserine cross placenta
yess—immensely
excretion of cycloserine
unchanged by renals (change dose for Renal impairment)
distribution of cycloserine
widely, 70-90% absorbed from GI, NOT PROTEIN BOUND< lungs, pleura, synovial folds)
adverse effects of cycloserine
Central Nervous system (suizide, seizure)
Cycloserine containdicated in pt’s with
epilepsy
ethonamide MOA
inhibits peptide synthesis
structural analog of isoniazid
ethonamide
why is ethonamide reserved as last line agent
GI
Neuro
Hepato-toxicites
given along side Ethonamide
pyridoxine (reverses CNS disturbances)
ethonamide is active or inactive as adinsiteres
inactive, activated by bacerial redux system
resistance to ethonamide
rapid, never a solo drug, can icnrease resistance to isoniazid
XDR-TB
inh and RPt resistance + alternatives (floroquinolones and any one of 1. amikacin, kinamycin, capreomycin)
*aminoglycosides
static drug reserved for last ditch effor to treat XDR TB
cepreomycin
bad side effects–>IM route
side effects of Capreomycin
nephrotoxicity and ototoxicity
