Pharm - Tuberculosis Part 1 Flashcards
true or false
tuberculosis is not caused by bacteria
FALSE
caused by mycobacterium tuberculosis bacteria
true or false
tuberculosis is contagious
true
true or false
tuberculosis is not a significant public health concern
FALSE - it is
global health concern affecting millions worldwide
name 3 types of infections that mycobacterium tuberculosis can cause
silent
latent
active
3 risk factors for tuberculosis infection
immunocompromised
poverty
crowding living conditions
TB is one of the top ___ causes of death worldwide
10
which 2 countries account for majority of tb cases
asia and africa
around how many people are infected with the TB bacterium
2 billion
does the mycobacterium tuberculosis bacterium go into our cells?
YES - it’s an intracellular pathogen. goes into the macrophages specifically
is mycobacterium tb aerobic or anaerobic?
motile or non motile?
aerobic non motile
does mycobacterium tb grow fast or slow
slowly replicates and lies dormant for a long time
how is mycobacterium tb able to be resistant to many antibiotics
it has a very thick hydrophobic (!60% LIPID) cell well that is rich in mycolic acids - hard for drug to get in
also, the antibiotic we design has to go into our body, then into our cells, and then into the bacteria to kill it - lot of steps bc it’s an intracellular pathogen
true or false
mycobacterium tuberculosis has a thicker cell wall than most bacteria
TRUE
mycobacterium TB has a ___- cell wall
waxy - from mycolic acids
~60% lipids
name the 4 layers of the cell wall of mycobacterium tuberculosis
what is the “mycomembrane?”
glycolipids (top)
mycolic acids
arabinogalactan
peptidoglycan (bottom)
4 LAYERS
“mycomembrane” is the glycolipids + mycolic acids
primary TB vs latent TB vs reactivation TB
primary TB = initial infection within the lungs
latent TB = ASYMPTOMATIC infection with no active disease
reactivation = return of active disease (often bc of some immunosuppression)
symptoms of pulmonary tb vs extrapulmonary tb
pulmonary tb symptoms - cough, chest pain, weight loss, fever
extrapulmonary - infection in other organs like lymph nodes bones and kidneys
true or false
mycobacterium tuberculosis can only infect the respiratory system
FALSE
can affect other tissues like lymph nodes, bone, kidneys, and even brain
4 diagnostic ways to test for TB
-tuberculin skin test
-IFNY release assay
-chest XRAY
-sputum culture
what does the tuberculin skin test measure
how the immune system of the patient will respond to tuberculosis proteins
issue with using chest x ray to diagnose TB
may get false positives of TB - just looking at pulmonary abnormalities and not any specific marker
5 first line drugs for tuberculosis
isoniazid
rifampin
pyrazinamide
ethambutol
streptomycin
what is DOT
directly observed therapy - done to ensure that the patient is being compliant with TB therapy
what is MDR-TB
multi-drug resistant TB
challenges to treat - needs specialized treatment
5 SECOND line drugs for TB
capreomycin
ethionamide
cycloserine
kanamycin
PAS (para-amino salicylate)
what is vDOT
VIDEO directly observed therapy for tb
when is the tb bacteria considered to be multi drug resistant in a patient
if it is resistant to 1st line drugs
(isoniazid, ethambutol, rifampin, streptomycin, pyrazinamide)
what is is XDR-TB
VERY resistant
TB that is resistant to at least rifampin and isoniazid
PLUS any quinoline
PLUS 1 of these 2nd lines: kanamycin, capreomycin, or amikacin
explain the profile of patients that are more likely to develop XDR tuberculosis resistance
more likely to be younger
65 and older are actually less likely
name 2 1st line TB agents that work by inhibiting cell wall synthesis and the specific layers they block the formation of
isoniazid and ethambutol
isoniazid - mycolic acid
ethambutol - arabinogalactan
which 1st line TB agent inhibits RNA synthesis and how does it accomplish this
rifampin
inhibits DNA dependent RNA polymerase
if no RNA, can’t make protein
give 2 MOAs of pyrazinamide
disrupts the plasma membrane
disrupts energy (ATP) synthesis
what is the general size of isoniazid and what does this say about its function as an anti TB agent
SMALL MOLECULE
thus, able to penetrate the macrophages where the tb bacteria is located, and also easily absorbed
however, still kinda hard to get into the bacteria itself because of the waxy 4 layer cell wall
is isoniazid bacteriostatic or cidal
CIDAL - for tb bacteria that are actively growing
isoniazid is actually LESS effective for what kind of TB bacteria
atypical species
is isoniazid usually used alone? why or why not
NO
usually used as combo therapy to reduce resistance to it
true or false
isoniazid is a prodrug
TRUE
activated by KatG (mycobacterial catalase peroxidase) + coenzyme NADH into it’s active form
isoniazid inhibits the synthesis of ________
mycolic acids
what does isoniazid inhibit and how
inhibits the enzyme ACYL CARRIER PROTEIN REDUCTASE
does this by forming a complex with Acp and KasA
doing this inhibits the synthesis of the mycolic acid portion of the cell wall
4 methods of isoniazid resistance
-bacteria can overexpress the enzyme (acyl carrier protein reductase - inhA)
-mutate or delete the katG gene that activates isoniazid into its active form
-mutate KasA (complex that forms with isoniazid)
-overexpress ahpC mutant (protects cell from oxidative stress)
can isoniazid:
-be absorbed from GI tract?
-widely distribute in the tissues?
-penetrate the CNS?
yes to all
IT IS A SMALL MOLECULE
Since isoniazid is absorbed from the GI tract, can we give it orally?
yes
4 adverse effects of isoniazid*
drug-induced systemtic lupus erythematosus
hypersensitivity rxns
isoniazid-induced hepatitis
peripheral neuropathy
as mentioned, an adverse effect of isoniazid is peripheral neuropathy
can anything be done to reduce the chance of this happening?
give with vitamin b6
aside from helping to prevent peripheral neuropathy from isoniazid, why else is vitamin b6 good to administer with isoniazid
it can reduce the chance of SEIZURES
(seizures is a potential but rare AE of isoniazid bc it is able to cross BBB)
explain the metabolism of isoniazid and is there any concern with it
phase 2 acetylation happens FIRST – to N-Acetyl INH
then it undergoes phase 1 hydrolysis – to ACETYLHYDRAZINE WHICH IS HEPATO TOXIC!!!
acetylhydrazine can acetylate macromolecules – hepatic proteins
if isoniazid is administered alone, around how long is it until resistence emerges
what is the mechanism of resistance?
2-3 months
the drug can’t get into the organism (bacteria)
rifampin is a semisynthetic derivative of ______
rifamycin
is rifampin static or cidal and what is spectrum
broad spectrum - (+), (-), and enteric
bactericidal
also obviously active against mycobacterium tuberculosis
explain the regimen in which rifampin is given
ALWAYS given with isoniazid for cases of active TB
NOT GIVEN ALONE
explain the MOA of rifampin
binds beta subunit (ALLOSTERIC SITE) of DNA dependent RNA polymerase to INHIBIT RNA SYNTHESIS (inhibit mRNA synthesis = no proteins and bacteria can’t survive)
true or false
rifampin does not bind human RNA polymerase
TRUE - only bacterial
explain the resistance mechanism for rifampin
point mutations occur in the RNA polymerase WHICH DECREASES RIFAMPIN BINDING TO IT
what is the name of the enzyme that promotes transcription of DNA to mRNA
DNA-dependent RNA polymerase
(this is the enzyme that rifampin inhibits)
is rifampin given orally?
yes - well absorbed
given as capsules
true or false
rifampin is not well distributed
FALSE
readily distributed in tissues and phagocytic cells (including macrophages where mycobacterium infects!)
significance of how rifampin is metabolized
metabolized by liver into bile, where it undergoes enterhepatic recirculation — this gives it a longer half life
differentiate between the excretion of isoniazid vs rifampin
isoniazid - in urine
rifampin - mainly in feces as deactlyated metabolite
**3 main AE of rifampin
turns urine/sweat/tears orange
nephrotoxicity - nephritis, acute tubular necrosis
cholestatic hepatitis
**MAIN special consideration of rifampin
it is an inducer of CYP450 isoforms!!!
therefore, serum levels of many drugs will decrease bc their metabolism is increased
ie - oral contraceptives may not work
name 6 classes of drugs that are metabolized by CYP system and thus will have a DDI with rifampin and their serum levels will decrease
methadone
oral contraceptives
anticoagulants
anticonvulsants
protease inhibitors
NNRTIs
RIFAMPIN inhibits the synthesis of _____________
mRNA
2 mechanisms rifampin resistance
mutations in rpoB gene (encodes B subunit of RNA polymerase)
ABC transporters such as Dac C (D-ala-D-ala-carboxypeptidase) can pump the drug out
true or false
pyrazinamide is a first line agent for tb
true
explain the MOA of pyrazinamide
diffuses into granuloma of mycobacterium tuberculosis
this is where pyrazinamidase (a tb enzyme) converts pyrazinamide into the ACTIVE FORM – PYRAZINOIC ACID
this pyrazinoic acid BLOCKS THE SYNTHESIS OF COENZYME A —- thus inhibiting ATP synthesis - less energy – inhibits trans-translation
in acidic conditions, acid gets protonated and disrupts cell membrane function to cause cell death
mechanism is not well established – BUT THOUGHT TO COLLAPSE MEMBRANE POTENTIAL AND AFFECT TRANSPORT FUNCTIONS OF THE MEMBRANE
true or false
pryazinamide is a prodrug
TRUE
converted by pyrazinamidase into the active form - pyrazinoic acid
true or false
pyrazinamide does not enter macrophages
FALSE
it does
half life pyrazinamide
6 hours
