Suttle Treatment of Tb Flashcards by Robert Ellis

bactericidal treatments require…

bacteria to be actively growing

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Tb can survive within

macophages–> making them resistant to AB’s

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general course of tx for TB infection

multi-agents (will become resisitant to single therapy) and for a protracted course of tx.

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First line therapy against M. tuberculosis

INH + RIF+ pyrazinamide + (ethambutol or streptomycin)

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First line tx for MAC

Clarithromycin + ethambutol or clofazamine or cipro or amikacin

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why is rifabutin better than rifampin

less potent CYP inducer

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why is rifampentene better than rifampin

longer half-life (once weekly dosing)

*intermediate CYp inducer

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best LATENt therapy

IND-RPT under DOT

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who does not get INH-RPT

, 2, pregnant, HIV, LTBI with INH or RIF resistance

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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

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how to ensure compliance

DIRECT OBSERVED THERAPY

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HIV NEGATIVE PT’S WITH NEGATIVE AFB SPUTUM AND CHEST X RAY CAN GET
*AFTER INHITIAL PHASE

CONTINUATION PHASE OF OCE WEEKLY INH/RPT

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ISONIAZID TARGETS

cell wall synthesis

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ethambutol targets

cell wall synthesis

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pryazinamide targets

unknown–> disrupts plasma membrane and enables energy metabolism

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MOA for isoniazid

interferes with mycolic acid synthesis

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cidal for rapidly dividing bacilli

* static for latent/ slow growing

isoniazid

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resistance to isonizaid

inability to take up the drug, alteraiton of taret enzyme, overproduction of target enzyme,
*rapid resistance, never as mono thereapy

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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)

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excretion of isoniazid

75% in the urine

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can isoniazid reach therapeutic levels in the brain

yes, rapidly absorbed from GI (oral or IM) cna distributes to all tissues

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Adverse effects of isoniazid

peripheral neuropathy
B6 depletions (competes with pyridoxal phosphate)
hepatotoxicity
allergic rxns )not dose rleated)

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drug interactions

drugs with Al+ salts, give 1 hour prior to antacids
corticosteroids decrease efficacy
CYP inhibitors–> caution with phenytoin, diazepam, fluoxetine, nelfavir,

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MOA for rifampin

inhibitio of RNA synthesis bind RNA pol beta subunit)

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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