Escolar Documentos
Profissional Documentos
Cultura Documentos
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Revised 2009. for comments Ahmedshaker21@yahoo.com
This handout is made to help our undergraduate students, its not comprehensive, many issues are
simplified, the students are responsible to see details in text books ;
any item marked by # (opinion ); clinical relevance is indicated by √
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Introduction : Tuberculosis (TB ) as old disease ; it continues to be one of the deadliest
disease in the world. TB is caused by Mycobacteria. tuberculosis , an aerobic , non-spore forming
bacilli ( called acid - fast bacilli: resist decolonization by acid alcohol after staining with basic
fuchsin ) . M. TB grows slowly and may be dormant in the host for long periods. They have the
ability to develop resistance to single chemotherapeutic agents
General principles of treatment : Always use multiple drug regimen; Never add a
single drug to a failing regimen; consider directly observed therapy (DOT) for all
patients. The basis for modern short course (6 month ) are the first four members of the
FIRST LINE DRUG LIST. ( see below ). Patient compliance is an essential issue for
success of therapy.
Principles of treatment
A decision to initiate treatment should be made based on epidemiologic information
clinical, pathological and radiographic findings; results of microscopic examination &
cultures for mycobacterium.
There are international & national guidelines for treatment regimens which involve an
initial phase , followed by a continuation phase, all guidelines make emphases on direct
observation therapy (DOT).
Treatment aims to cure pts. with least interference to their lives; avoid relapse /
recurrence; prevent development of drug resistance & decrease transmission to others
Second Line drugs include: Rifabutin ; fluroquinolones ( Levo-; moxi- &; gati-floxcacin );
Ethionamide; P-amino salicylic acid ; Amikacin, Kanamycin, , linzolid & others..
RIF STM
1
PROPOSED MECHANISM OF ACTION
Drug Mechanism of action ( simplified )
INH Inhibit biosynthesis of mycolic acid ( essential cell wall component)
*note INH is converted by the M.TB to an active metabolite.
PZA ? Inhibition of mycolic acid biosynthesis.
through inhibition of mycobacterial fatty acid synthase gene I ;
* it is only active in acidic pH
EMB Disturb bacterial cell wall barrier
Inhibits arabinosyl transeferases, leads to inhibition of arbinoglycan can
* enhance effect of other drugs such as RIF or ofloxacin .
RIF Inhibits DNA dependent RNA polymerase
binds specifically to the Beta subunit to form a stable drug- enzyme complex; leading to
suppression of chain formation of RNA synthesis.
SM Inhibit protein synthesis.
by binding to the 30s subunit of the bacterial ribosome.
#Note the first three drugs which have simple structure; seemed to affect cell wall.
# The last two drugs with complex structure have different mechanisms.( DNA or Ribosome )
.
PHARMACOKINETICS √√
Drug Absorption CSF Metabolism Elimination
INH enzymatic acetylation
All theses Diffuse readily into most in the liver is under
drugs are tissues including genetic control (Fast Mainly as
PZA inflamed meningies
well and slow acetylators). metabolites in
Adequate
absorbed urine
EMB from GIT Metabolized in liver
RIF
# Penetration intro CSF is Partially metabolized 20 % unchanged
questionable. in feces
Penetrate into RBC 50 % unchanged
in urine
Excellent diffusion to Deacylated in liver, 30 % in urine
most tissues ,strongly undergoes enter hepatic 65 % in the
bound to plasma protein circulation feces.
SM Not Poor penetration , No significant Mainly
absorbed metabolism unchanged by
glomerualr
filtration
Note : Rifampin is enzyme inducer interaction with drugs used by ADIS patients. INH : enzyme
inhibitor ; may increase level of phenytoin ( monitor the level &adjust the dose of phenytoin )
Characteristic adverse effects √√√√ { miscellaneous ADE are many }
Adverse effect Drug(s) most likely Adverse effect Drug(s) most
likely
Hepatitis PZA> RMP,>INH Thrombocytopenia RIF
Neuropathy: INH or PZA Vertigo STM
Visual problems EMB nephrotoxicity
Gout (↑ uric acid ) PZA Orange urine (harmless) RIF
2
Rash PAZ, RIF; EMB
Below we summarize the most clinically relevant issues regarding 2nd line drugs.
Ethanolamine : very close structure to INH but have, low cross resistant with INH,
heptotoxic, neurotoxin, more troublesome GIT adverse effects .
OPTIONAL (PBL ) : how you could mange a patient who have chronic hepatitis C virus
and recently get TB infection.