Antituberculotics Flashcards
Latent TB infection
TB bacilli dormant in lungs, don’t cause destruction
No s/sx
Not infectious
TB disease
TB bacilli invade and damage parts of body
S/sx of disease disappear
can be infectious
TB sx
Cough x 3 weeks tired weight loss sweating at night fever no appetite
Transmission of TB
droplet nuclei; expelled when a person with INFECTIOUS TB sneezes, speaks, sings, or coughs
Other names for mycobacterium tuberculosis
Captain of death white death white plague consumption tuberculosis
Mycobacterium tuberculosis (Mtb)
acid-fast
slow generation time, 15-20 hours (drug resistance - time to mutate)
facultative intracellular parasite, usually of macrophages
Mtb structure
acid fast cell wall: mycolic acid + arabinogalactan + peptidoglycan
Tx path for TB
always use first-line drugs IN COMBO; then result to second-line (not as good, more toxic)
1st line TB drugs
Isoniazid, rifampin, pyrazinamide, ethambutol; (streptomycin, rifabutin) - alternates
MDR TB tx
INH, Rif
XDR TB tx
INH, Rif, any fluoroquinolone, and one injectable
Tx TB
Initial: INH, Rif, Pyrazinamide (PZA), Ethambutol (EMB) x 2 months
Continuation: INH, Rif x 4 months
Tx for latent TB
INH or Rif as monotherapy daily
Isoniazid (INH) MOA
Inhibits biosynthesis of mycolic acid; produg that required KatG
Spectrum of INH
MOST NARROW DRUG (inhibits only mycolic acid)
Resistance to INH
mutated KatG (required to activate INH
Prodrugs
INH (KatG), PZA
INH use
prophylaxis (alone) - liver damage esp. >35 yo
Active TB (give with Rif, EMB, PXA) Latent TB- monotherapy
can reach intracellular bacilli, advantage
static; INH and Rif is cidal
INH Pharmacokinetics
Oral
Good GI absorption
Metabolism by acetylation (liver) inactivates drug (fast vs. slow)
Excreted through urine
Who are slow metabolizers of INH
whites and blacks
Who are fast metabolizers of INH
Eskimos, Native Am, Asians
INH toxicities
HEPATITIS (abnormal LFT, jaundice, hep in older people, more common in fast acetyltors)
PERIPHERAL NEURITIS (slow acetylators, antagonized by pyridoxine)
HEMOLYSIS (in G6PD- not contra)
LUPUS LIKE SYNDROME (HIP drugs)
CNS stimulations
Others: H/A, vertigo, constipation, micturition, orthostatic HTN, eosinophilia, albuminuria, skin rashes, allergy, bone marrow depression
Rifampin MOA
inhibits DNA dependent RNA polymerase (rpoB subunit)- prevents transcription; oral
Rifamycins
group of structurally similar complex macrocyclic abx (rifabutin, rifapentine)
Resistance to Rifampin
rpoB mutation
Rifampin use
Active TB - combo (RIPE)
Latent TB- monotherapy
similar to INH
Additional: leprosy
Rifampin toxicities
not serious (no hepatotoxicity) GI Hypersensitivity HEPATIC ENZYME INDUCTION (P450s) - not recommended for HIV-treated individuals ORANGE urine, sweat, tears, contacts DECREASES BC EFFECTIVENESS
Rifampin drug interactions
induces adrenal, thyroid hormones, vitamin D and HAART (HIV)
Ethambutol MOA
inhibits arabinosyl transferase (embCAB) (involved in AG synthesis; STATIC; just as narrow as INH
Kinetics of Ethambutol
Combo therapy (RIPE) oral, well absorbed, GETS INTO CNS!!! renal elimination, excreted in feces and urine, dose adjustment needed in renal failure
Ethambutol Toxicities
decrease visual acuity and loss of green-red percention*** (usually reversible); no recommended <13 but not contra (opthamology exam)
Allergy, GI, numbness, joint pain, peripheral neuritis
Renal insufficiency- give smaller dose
Pyrazinamide
prodrug; MOA
active at acidic pH**
greatest activity against DORMANT organisms
oral; well absorbed, good tissue penetration (Meninges)
combo tx (RIPE)
Responsible for reducing tx for TB to 6 months
Pyrazinamide
CNS penetration
Ethambutol, Pyrazinamide
Toxicity of PZA
hepatic dysfunction, hyperuricemia, non gouty polyarthralgia, myalgia, GI, porphyria, photosensitivity
Hepatic effecting TB drugs
INH - hepatitis
Rif - hepatic enzyme induction (P450s)
Ethambutol - none
PZA- hepatic dysfunction
Streptomycin
30s inhibitor of protein synthesis; cidal
parenteral, limited tissue penetration, cell penetration poor thereforebest for extracellular Mtb
Renal excretion TB drugs
Ethambutol, Streptomycin (dose adjustment)
Toxicity of Streptomycin
ototoxicity, nephrotoxicity
Rifabutin
inhibits DNA dependent RNA polymerase (rpoB)
oral, well absorbed, enterohepatic cycling, metabolies ORANGE COLORED
Rifabutin use
replaces Rifampin in HIV-TB co-infected individuals to avoid drug interactions; less potent inducer of P450 enzymes
2nd line TB tx
lower potency and/or greater toxicity
Mycobacterium avium complex (MAC) cause
M. avium, M. intracellulare
What is MAC
common environmental pathogen; infection following inhalation (similar to TB) or swallowing (GI, diarrhea)
Sx of MAC
hair loss, ulcers, kidney destruction
MAC resistance
resistant to anti-TB and antimicrobials
Tx for MAC
2-3 Antimicrobials x 12 months
- Clarithromycin or azithromycin
- ethambutol
- Add third oral (rifabutin, rifampin, ciprofloxacin)
IV amikacin in certain cases (resistance to clarithromycin)
Coinfectious HIV
Mtb, MAC
Mycobacterium leprae tx (WHO-MDT) vague
multi-drug therapy (tx w/ one with always confer resistance
PB leprosy sx
1-5 patches
Posi leproxy tx
rifampin and dapsone, 6 mo
Multi leproxy sx
> 5 patches
MB leproxy tx
rifampin, dapsone, 6-12 months
Most widely used and least expensive drug
Dapson
Dapsone MOA
similar to sulfa (PABA antagonist); oral, GI absorption complete and rapid; slow excretion
Dapsone toxicity
N/V, H/A, Dizziness dose-related hemolysis Methemolgobinemia, leukopenia, agranulocytosis, allergic derm, exfoliative derm with concurrent liver damage peripheral neuritis NASAL OBSTRUCTION (IMPROVES 3-6 MONTHS)
Peripheral neuritis
INH
Ethambutol
Dapson
Most heavily regulated drug in US
Thalidomide (STEP) program
Thalidomide toxicity
teratogenic; not be given any time in pregnancy
Thalidomide use
DOC for moderate to severe ENL (erythema nodosum leprosum) in non-childbearing people
Orphan drug status: lepromatous leprosy, tx of mycobacterium infections;
Lupus like syndrom drugs
“HIP”
Hydrazaline, INH, Procainamide
What drug is used in both leprosy and TB
Rifampin
