Suttle/Cross - TB Flashcards
1
Q
What is BCG also used for?
A
To treat bladder cancer
2
Q
What are the risk factors for TB?
A
- Prison (crowded conditions)
- Immigrant from high burden country
- Malnourished
- Alcoholism
- Poverty
- Debilitating illness
- AIDS
- Elderly
-
Certain diseases: DM, Hodgkin lymphoma, CKD, malnutrition, immunosuppression
1. RA on TNF alpha antagonists
3
Q
What are the basic TB tx regimens (chart: preferred and alternatives)?
A
- Summary: 2-4 drugs taken for at least 26 weeks on different dosing schedules
- NOTE: a continuation phase of once-weekly INH/RPT can be used for HIV- patients who do NOT have cavities on chest film AND who have (-) acid-fast bacilli (AFB) smears at the completion of the initial phase
4
Q
What is this?
A
- MTB acid-fast stain
-
Acid fast bacillus, obligate aerobe
1. Ability to retain carbolfuchsin stain due to high lipid content in waxy cell wall (mycolic acid)
2. Grows very slowly (doubling time of 18 hours) - Cultures held for 6-8 weeks before being finalized
- Stained poorly by the dyes used in gram stain
5
Q
What are the 2 main side effects for INH?
A
- Neuropathy for slow acetylators
- Hepatotoxicity for fast acetylators
6
Q
What is the MOA of Ethambutol?
A
- Inhibition of RNA synthesis
-
Disrupts cell wall synthesis: INH arabinosyl transferase -> mycolic acids usually attach to 5’-hydroxyl groups of D-arabinose residues of arabinogalactan and form mycolyl-arabinogalactyl-peptidoglycan complex in cell wall
1. Disrupts arabinogalactan synthesis (necessary for synthesis of peptidoglycan units of cell wall)
2. Results in increased cell wall permeability - Static effect: possible -cidal at high levels
- Bacilli must be actively dividing
- Slow devo of resistance; no cross resistance
7
Q
What are the first-line and alternative agents for treating TB?
A
-
First-line:
1. Isoniazid (INH) + Rifampin (RIF) + Pyrazinamide (PZA) + Ethambutol (EMB) or Streptomycin -
Alternative:
1. Ofloxacin; cycloserine; capreomycin; kanamycin; amikacin; ethionamide; clofazimine; para-aminosalicyclic acid - NOTE: in HIV+, Rifabutin (instead of Rifampin) can DEC drug interaxns w/PI’s and NNRTI’s
8
Q
Why is the IGRA test important?
A
- IFN-gamma assay (IGRA) can be used for diagnosis of TB, and is specific only to MTB
- Will also not get a false (+) for people who have received the BCG vaccine
9
Q
What is the difference between TB infection and active disease?
A
- Most infections acquired from active case to susceptible host – this is primary infection
- In most cases, primary infections are asymptomatic (only 5% develop clinically significant disease -> peeps with impaired cell-mediated immunity)
1. Only evidence of infection is fibrocalcific nodule at site of infection
2. Viable organisms can remain dormant for years and reactivate to produce 2o infection (active disease)
3. 2o infection usually involves apices of lungs -> cavitation occurs frequently
4. Erosion of cavities into airway is source of infection –> person is expectorating organisms
10
Q
What are some of the new TB drugs in devo (image)?
A
Probably don’t need to know these
11
Q
How is TB related to HIV?
A
- All stages of HIV associated w/INC risk of TB, even with HAART -> but, low CD4 count important risk factor
- Variable pulmonary manifestations (see attached image; others with bilateral infiltrates, pleural effusion)
1. Increased frequency of false negative sputum smears, absence of granulomas in tissues -> may see TB infection in the lower lobes of the lungs - Cavitation/bronchial damage more severe in immuno-competent individuals due to robust immune response
1. With reduced immune response as in HIV, there is no bronchial damage and few AFB in sputum
12
Q
What are the AE’s of Isoniazid?
A
-
Peripheral neuropathy: dose-relsated burning, prickling sensation in hands and feet (stocking-glove)
1. Competition bt INH and pyridoxal phosphate -> corrected w/Vit. B6 supplementation (10-50mg daily)
2. More freq. in malnourished, diabetics, and alcoholics -
Hepatotoxicity: dose-related
1. Major toxic rxn (hepatitis) in 2% due to toxic metabolite from acetylation of INH
2. INC liver enzymes in up to 20% of pts (caution if admin w/other hepatotoxic drugs, like RIF) - Allergic rxns: not dose-related
13
Q
Why is TB difficult to diagnose in HIV+ patients?
A
- Not as much expectoration of bacteria (can’t rely as much on these tests)
- PPD may be (-) because the patient’s immune system is so compromised
14
Q
Briefly describe the MOA’s of the 4 first-line anti-TB drugs (image).
A
- Isoniazid: inhibits cell wall synthesis
- Ethambutol: inhibits cell wall synthesis
- Pyrazinimide: exact target unclear, but 1) disrupts plasma membrane and 2) disrupts energy metabolism
- Rifampin: inhibits RNA synthesis
15
Q
What is the critical cytokine for the control of TB?
A
- TNF from macros is critical to help control TB infection (this is why RA pts on TNF-alpha inhibitors are at an increased risk)
- TNF is important to keep granulomas from falling apart
1. IFN-gamma also critical because if you have mutations in this receptor, you won’t form granulomas at all
16
Q
What are the treatment options for latent TB infection? Which tx is more frequently completed?
A
- 3-mo tx with INH-RPT with DOT is effective and more frequently completed than US standard of INH w/o DOT
- NOTE: due to reports of severe liver injury and death, the CDC recommends that the combo of RIF and PZA should generally NOT be offered for tx of latent TB infection
17
Q
What are the MOA, resistance, and spectrum of Rifampin?
A
-
MOA: inhibition of RNA synthesis via binding of beta subunit of the Mb RNA polymerase (mammalian RNA polymerase not as sensitive, so unaffected except at supra-clinical doses)
1. Bactericidal -
Resistance: DNA-dependent RNA polymerase does not bind drug (becoming widespread)
1. Never give as a single agent bc resistance emerges rapidly - Spectrum: IC and EC mycobacteria
- NOTE: RIF is the most commonly used of the Rafamycins
18
Q
What is resistant TB? What is the main risk factor?
A
- MDR TB: resistance to INH and RIF most common -> AIDS patients
-
XDR TB: resistance to INH, RIF, flouroquinolone, at least one additional drug
1. Emerged in 2005 in south Africa. -
Noncompliance is risk factor for devo of resistance
1. Directly observed therapy (DOT) is used in Shelby County and many other places to prevent this
19
Q
What should you do before treating patients for latent TB?
A
Make sure patients do not have active disease -> get a CXR
20
Q
What are some of the clinical manifestations of miliary/disseminated TB? CXR?
A
- Lymphohematogenous dissemination following 1o inf can result in miliary/disseminated TB (HIV patients at high risk)
-
CXR can look like a bunch of seeds all over (millet seeds)
1. Dyspnea, cough -
Other organ involvement: liver (RUQ pain, nausea and vomiting), bone marrow, spleen
1. Meningitis, Pott’s disease (vertebral osteomyelitis), GI (nausea/vomiting/diarrha), urinary tract (sterile pyuria, hematuria, proteinuria)
2. Adrenal insufficiency, epididymitis (highly convoluted duct behind the testis, along which sperm passes to the vas deferens), prostatitis
21
Q
How is Isoniazid absorbed, distributed, metabolized, and excreted?
A
- Absorption: rapidly from GI tract with oral dose, or IM
-
Distribution: all tissues and fluids
1. W/inflamed meninges, therapeutic levels in CSF
2. Crosses placenta; distributed in breast milk -
Metabolism: acetylated via N-acetyl transferase
1. 2-3x lower plasma conc in fast acetylators vs. slow (half-lives vary from 1-4 hours)
2. Chronic liver disease affects metabolism (DEC dose)
3. Induces CYP -> can influence concurrent CYP substrate therapy - Excretion: drug, inactive metabolites (75%) out in urine
22
Q
How do you diagnose latent TB?
A
-
PPD (purified protein derivative): intradermal injection of tuberculin material stimulates delayed-type hypersensitivity rxn mediated by T lymphos -> induration in 48-72 hours
1. BCG immunization can cause false (+) test -> wanes over time and clinically ignore the fact that someone got the BCG (adults at least; up to 20% will still be (+) 10 yrs or more from time of vaccination)
2. Infection with nontuberculous mycobacteria can also cause false positive results -
IGRA (Quantiferon gold, Quan-TB, T-spot): blood cells from the pt exposed to Ags from MTB -> amt of IFN-gamma released from cells is measured
1. No false positives with BCG or NTM infections - HIV+ patients: false negatives in both tests can occur due to lack of immune response, sometimes called anergy
23
Q
How are Rifabutine and RPT related to RIF?
A
- Rifabutine and RPT are derivatives of RIF
1. Rifabutine: <potent></potent>
<p>2. <u>RPT</u>: longer half-life than Rifabutine and RIF, so it can be given only once weekly (intermediate to RIF and Rifabutine as a CYP inducer) </p>
</potent>
24
Q
What is the main toxicity associated with Ethambutol?
A
Ocular toxicity
25
What are some of the possible clinical manifestations of TB (image)?
26
How do you treat TB?
- **Secondary/primary pulmonary TB**
1. If suspicion is high, don't wait for confirmed dx -\> start treatment
2. _4-drug treatment_ required initially:
a. INH, Rifampin, Pyrazinimide, Ethambutol (RIPE)
b. Once susceptibility is known, and *if susceptible*, can stop Ethambutol
c. After 2 months of RIPE/RIP, can stop PZA and continue INH/Rifampin for 4-7 more months to complete 6-9 months of therapy
- **Miliary TB**: 9-12 months -\> all 4 drugs
27
What are the first-line and alternative treatments for M. Avium complex?
- **First-line**: Clarithromycin + Ethambutol or Clofazimine or Ciprofloxacin or Amikacin
- **Alternative**: Rifabutin; Rifampin (RIF); Ethionamide; Cycloserine; Imipenem; Azithromycin
28
What are the most common symptoms with primary TB infection?
In most cases, primary infection is asymptomatic
29
What is the resistance to Isoniazid?
- When used alone, _resistant organisms rapidly emerge_, so used in combo (1 in 106 orgs have naturally occurring resistance to INH -\> about 100 orgs on day 1 of tx -\> about the same for PZA and EMB; 1 in 108 for RIF)
- _Resistance mechanisms_:
1. Inability to take up the drug
2. Alteration in the target enzyme
3. Overproduction of the target enzyme
30
What is the treatment for latent TB?
- Isoniazid for 9 months
- Isoniazid and Rifapentine for 3 months
31
What is the MOA of Pyrazinomide?
- Exact MOA unkown
- Bacilli convert pyrazinomide to pyrazinoic acid (POA)
- _DEC pH below threshold for growth_
- Resistant strains may lack the pyrazinamidase
- _Cidal or static_ depending on conc in infected site
- _Most active_ against tubercle bacilli in acid envo of lysosome and macro -\> _IC site w/slow replication_
32
What is the likelihood of getting TB on a plane?
- Likelihood of other passengers on plane getting TB actually very low due to the high rate of air exchange on the plane
1. Passed more by contact than aerosol transmission on a plane
33
What is PknG?
- MTB can grow intracellularly in macros -\> effective means of evading the immune system
1. Ab's and complement are ineffective
- Once MTB is phagocytosed, it can **inhibit phagosome-lysosome fusion via the protein PknG** (see attached image)
34
How do you diagnose TB?
- **Acid fast stain** on sputum initial test (see attached image) -\> culture should be done at the same time
1. _Lowenstein-Jensen agar required_ -\> substances to enrich growth and inhibit other flora
2. _3-6 wks_ to grow on solid agar (doubling time 18 hrs)
3. Will not grow on blood agar
- _Culture in liquid media_ can show results in 2 weeks
- _PCR_, or nucleic acid amplification even more rapid
1. Better on smear-positive specimens (initially sputum will come back smear-positive or negative)
35
When is Cycloserine used? What is its MOA?
- Broad spectrum, second-line agent
1. Active _pulm and extra-pulm TB_ -\> only used when others fail, and in re-treatment (i.e., MDR-TB)
2. Used for M. Avium complex when others don't work
3. UTI's (seldom used clinically)
- **MOA**: structural analog of D-alanine; _blocks cell wall syn_
1. Can block enzymes (via competitive INH) required for D-alanine incorporation into pentapeptide of peptidoglycan strands (give wall rigid mech stability): L-alanine racemase and D-alanine synthetase
2. Based on conc at site (and bac susceptibility), will be _static or cidal_
3. Effective in resistant orgs -\> NO cross resistance
36
What is latent TB infection?
- MTB infection is contained initially and infection remains in a prolonged, suppressed state of “latency"
1. Asymptomatic
- Latent infection has the potential to develop into active infection at any time -\> identification and treatment of LTBI protects the health of the individual and the public
- Overall, _w/o treatment, about 5 to 10% of infected persons will develop TB disease_ at some time in their lives
1. About half of those people who develop TB will do so in the first two years of infection
2. For persons whose immune systems are weak, esp. those with HIV infection, risk of devo TB disease is considerably higher than for peeps with normal immune systems
37
What can't you have when you are on INH?
Can’t drink alcohol when you are on INH
Sorry, no shots of tequila
38
How can we prevent TB?
- Prompt ID and adequate treatment immediately
- Use masks and respiratory isolation
- Treat latent converters
- _Screen_: HIV infected, close contacts of pt with TB, low-income populations, alcoholics and IVDU, prison inmates, foreign born from countries with high incidence
39
What is this?
Miliary/disseminated TB
40
What should you give with INH? Why?
- Add B6 to INH
- To prevent peripheral neuropathy
41
What is the ADME of Cycloserine?
- **Absorption**: administered orally w/good absorption
- **Distribution**: distributed widely and NOT protein bound
1. Lungs, pleural, and synovial fluid
2. _CSF conc uninflamed meninges: 50-80%_ (with inflamed, 80-100% of serum conc)
3. Rapidly crosses placenta; distributed in amniotic fluid and breast milk
- **Excretion**: excreted unchanged by renal mech; _dose adjustment required for renal impairment_
42
What is the MOA of Isoniazid?
- Interferes with mycolic acid synthesis -\> disrupts cell wall synthesis
1. Cidal for rapidly dividing bacilli -\> EC cavitary lesions
2. Static for slow-growing -\> closed caseous lesions and macros
- Penetrates host cells, so effective for IC bacilli
43
What is the ADME of Pyrazinamide?
- **Absorption**: well absorbed from GI tract after oral admin, and peak serum levels w/in 2 hours
- **Distribution**: widely distributed -\> therapeutic in CSF w/inflamed meninges
1. Distributes into breast milk, but unknown if crosses into placenta
- **Metabolism**: _hydrolyzed in the liver_ to pyrazinoic acid, its major metabolite, then to hydroxyl-pyrazinoic acid, the main excretory compound
- **Excretion**: Pyrazinamide and its metabolites are excreted in the urine (70%), primarily via glomerular filtration -\> _dose adjustment is recommended in severe renal dysfunction_
44
What is MDR-TB? What are the possible effective treatments?
- MDR TB is a form of drug-resistant TB in which TB _bacteria can no longer be killed by at least the two best antibiotics, isoniazid (INH) and rifampin (RIF)_, most commonly used to cure TB
- As a result, this form of the disease is more difficult to treat than ordinary TB and requires up to 2 additional drugs?
45
What are the AE's of Cycloserine?
- _Involve CNS_: usually reversible w/discontinued therapy
1. Headache, tremor, vertigo, confusion, psychotic states w/suicidal tendencies, paranoid reactions, seizures
2. Contraindicated in peeps w/history of epilepsy
- Symptoms generally appear w/in _first 2 weeks of therapy_
- _Large doses, or concurrent alcohol use INC risk of seizures_
- Use w/caution in pts w/history of depression, as risk of suicide may increase
46
What are the therapeutic uses of Rifampin?
- First-line against M. TB -\> effective for both rapidly (EC cavitary lesions and slowly dividing (closed caseous lesions and macros) cells (but NOT as a single agent)
- Not only for TB:
1. _MRSA and S. epididermis_ (in combo w/Vanc or Gentimicin -\> NOT effective as a single agent)
2. Prophylactically for household members exposed to meningitis caused by meningococci or _H. flu_
3. Eradication of Staph in nasal carriers
4. Most active anti-leprosy drug at present
47
What is the most important determinant of whether over MTB disease occurs?
Adequacy of the host’s cell-mediated immune response
48
What is XDR-TB? What are some tx options?
- Less common form of MDR-TB in which _TB bac have changed enough to circumvent the 2 best AB's, INH and RIF, as well as most of the alternative drugs for MDR-TB_
1. These second-line drugs incl. any fluoroquinolone, and at least one of the other three injectable anti-TB drugs: amikacin or kanamycin (aminoglycosides), or capreomycin
- As a result, XDR TB needs up to _2 years of extensive drug treatment_, and is the most challenging to treat.
49
Describe the drug interaxns of RIF.
- _Induction of CYP 450_: most enzymes, except 2D6 (incl. 1A2, 2C9, 2C19, and 3A4)
1. Reduces half-lives of drugs metabolized by P450: prednisone, propanodol, sulfonamides, dapsone, ketoconazole, HIV protease inhibitors, NNRTI's, etc.
- _Oral anticoags and contraceptives less effective_
1. Significant DEC in efficacy of coumadin-type anticoags
2. Reports of reduced plasma estrogen concs
3. Alternative contraceptive means should be used while taking RIF
- _Probenecid INC serum levels of RIF when taken concurrently_
- **NOTE**: _Rifabutin_ has less effect on metabolism of HIV PI's; polymyalgia, pseudo-jaundice, and anterior uveitis (inflam of middle layer of the eye) unique to Rifabutin
50
What are the clinical manifestations of secondary/reactivated TB?
- _Insidious onset_
- Malaise, anorexia, low-grade fever, weight loss, night sweats, shortness of breath (SOB)
- Cough productive of _blood-streaked and/or purulent sputum_
- Some get pleuritic pain
51
What is the pathogenesis of TB?
- Doesn't have classic bacterial virulence factors, like toxins, capsules and fimbriae
- **Cell wall** contains many waxy-like substances that make it _impermeable to many host defense_ systems: 1) mycolic acids, 2) glycolipids, 3) arabinogalactans, 4) free lipids
- **Virulence factors**:
1. _Cord factor_: virulent strains grow in characteristic cord-like pattern, avirulent strains do not -\> inhibits macro maturation and induces TNF-alpha release
2. _Sulfatides_ (surface glycolipids): once phagocytosed, inhibits phago-lysosomal fusion (protein **PknG**), allowing the bacteria to replicate
- Can **grow IC in macros**: effective means of evading the immune system -\> Ab's and complement are ineffective
- **IFN-γ**: critical mediator allowing macros to contain the infection -\> released by TH1 (after MTB enters macro via endocytosis)
1. Th1 response leads to granuloma formation and caseous necrosis (_IL-12_ released by macros to call Th1)
2. Activated macros secrete TNF and cytokines that recruit more monocytes
- **TNF-α** extremely important –\> RA patients on antagonists at increased risk for TB
52
In which pts is 3-mo tx with INH-RPT for latent TB infection not recommended? Why?
- _Children \<2 y/o_ bc safety and pharmacokinetics of RPT have not been established for them
- _HIV+ patients on ART_ bc drug interaxns have not been studied
- _Pregnant women or women expecting to get pregnant_ during tx bc safety in pregnancy is unkown
- Pts who have LTBI w/presumed INH or RIF resistance
53
Why is TB hard to treat? Why is this important?
- Organism multiplies slowly
- Survives in protected IC location; may be dormant for long periods (resistant to AB's in this state)
- Propensity to devo resistance to antimicrobials
- Compliance issues
- Drug toxicity and interactions (esp. for HIV+)
- **COMBINATION and PROLONGED COURSE OF THERAPY** (can last up to 2 years)
54
What are the 2 fixed mycobacterium drug combos?
- Rifater: 120mg RIF, 50mg INH, 300mg PZA
- Rifamate: 600mg RIF, 300mg INH
55
What are some of the clinical manifestations of progressive primary TB?
- Tubercle can erode into a bronchus, spill its contents and infection spreads to other parts of the lung
- _Resembles acute bacterial pneumonia_
- _CXR_ with infiltrates or lobar consolidation, hilar LAD, pleural effusion (variable)
- **Difficult to diagnose**
56
What are the AE's for RIF?
- Relatively low AE incidence (**\<4%**)
- _Discolors body fluids_ (tears, urine, saliva) -\> turns them orange-red (wear glasses so contact lenses not stained)
- GI disturbances and nervous system complaints
- Fever, chills, and aches
- **Hepatotoxicity** (hepatitis/liver failure): jaundice with chronic liver disease, alcoholics, elderly, or pts receiving other hepatotoxics; more relevant in pts that are slow acetylators -\> _rare in pts w/normal liver function_ (RIF/INH generally safe in such pts)
57
What is a positive PPD?
- _\>15 mm_: no known risk factors
- _10-15 mm_: homeless, IVDU, nursing home resident, recent immigrant, children less than 4 years of age
- _5-10 mm_: HIV, recent contact of someone with TB, person with fibrotic changes on CXR consistent with prior TB, organ transplants, immunosuppressed (prednisone, TNF alpha antagonists)
58
What is Capreomycin?
- **MOA**: unknown, but _bacteriostatic_
1. Strains of TB resistant to Streptomycin or Amikacin (both aminoglycosides) usually susceptible
- IM admin
- **AE's**: nephrotoxicity (incl. _acute tubular necrosis_, ATN), ototoxicity (3% detectable, 11% sub-clinical), eosinophilia, elevated serum BUN
1. Serious AE's incl. ATN, electrolyte disturbances, and acoustic N injury -\> toxicity reduced if given 2-3x wkly after initial response to daily dosing
- Reserved as **last line agent** due to admin route and AE profile: adjunct (parenteral) agent in combo w/at least one other -\> _resistance develops when used alone_
- Effective in MDR therapy; also used in tx of other mycobacterial diseases
59
What factor makes TB virulent?
Cord factor
60
Why is a long course of therapy required for TB?
- Organism grows very slowly
- There are metabolically inactive lesions in the lesion
- Organism is located intracellularly
- Caseous material blocks penetration by drugs
61
What is the ADME of Ethambutol?
- **Absorption**: 75% of oral dose
- **Distributio****n**: widely, but concentrates in kidneys, lungs, and saliva
1. Therapeutic levels in CSF w/inflamed meninges
2. Crosses placenta -\> levels 30% of maternal
3. Distributes into breast milk: no reports of AE's to fetus or infant
- **Metabolism**: partially metabolized in the liver
- **Excretion**: excreted in urine (50% as unchanged drug); T(1/2) of 3.5 hrs, but extends up to 15 hours w/renal disease -\> _REDUCE DOSE w/renal disease_
62
What are the epi, transmission for MTB?
- Mycobacterium tuberculosis (MTB) _causes more deaths than any other single microbial agent worldwide_
1. 1.7 million people die each year
2. 9 million new infections occur each year
3. 500,000 are infected with a MDR strain of TB
- _Humans are the natural reservoir_, and disease is spread person-to-person
1. Most transmission via aerosols generated by coughing of people who have the disease
- _90% of people who become infected with MTB do not develop the disease_
- Things are getting better -\> mortality has decreased significantly in the last 25 years
63
Describe the ADME of RIF.
- **A**: well absorbed orally; impaired by food or para-aminosalicylic acid (TB AB: separate use by 8-12 hrs)
- **D**: penetrates all tissues well, incl. CSF; 75-85% protein bound
- **M**: deacetylated in liver (retains full AB activity, but not reabsorbed) -\> half-life INC by hepatic dysfunction (auto-induction of hepatic microsomal enzymes in first 2 wks = shorter half-life)
- **E**: primarily in bile (30% unchanged -\> undergoes hepatic recirculation); sm. amt. via renal tubular secretion
1. No adjustment needed for renal insufficiency
64
What are the AE's and drug interactions associated with Ethambutol?
- **AE's**: dose-related _optic neuritis_ (\<1%)-\> DEC visual acuity, loss of color discrimination, constriction of visual fields monthly visual exams during therapy (bc duration relative to length of tx after sxs noticed), _reversible_ weeks to months after end of therapy (unilateral or bilateral)
1. Allergic reactions
2. Increase in serum urate (_hyperuricemia_; w/ or w/o precipitation of gout) -\> about 50% of pts, and possibly enhanced by INH and pyridoxine (Vit. B6)
- **Drug interactions**: Al++-containing acids reduce absorption -\> allow 3-4 hrs after antacids b4 Etham dose
65
What are the AE's of Pyrazinamide?
- Dose-related _hepatotoxicity_: typically seen w/large doses for long periods (40-50mg/kg/d; most severe rxn)
1. Transient INC in serum aminotransferase also observed
- Mild, non-gouty arthralgias
- _Hyperuricemia_: due to INH of urate excretion; often asymptomatic, but if discontinue use if acute gout devos
1. **Arthralgia** (non-gouty) reported in about 40% of pts, and appears to be secondary to hyperuricemia
66
What is Ethionamide? What are its AE's?
- _Inhibits peptide synthesis_: structural analog of INH
1. Works via different mech, but result the same
2. Resistance can devo rapidly when used as a single agent; can induce low-level resistance to isoniazid
3. Inactive _pro-drug_ activated by mycobac redux system
- Oral admin, and wide distribution, incl. CSF
- Extensive _hepatic metabolism_
- _Static or cidal_, depending on concentration
- Reserved as **last-line agent due to toxicity**: GI, hepatic, neurologic
1. About 50% of pts can't tolerate a single does above 500 mg bc of GI disturbance -\> best taken w/meals in divided doses so GI disturbance is minimized
a. Most common _GI effects_ are anorexia, nausea, gastric irritation
3. _Neurologic effects_: depression, asthenia (abnormal physical weakness or lack of energy), blurred vision, diplopia, dizziness, tremors and others -\> relieved by pyroxidine (Vit. B6)
3. Signs and symptoms of _hepatotoxicity_ resolve when treatment stopped -\> hepatic function should be checked at regular intervals
67
What are the drug interactions with INH?
- _Antacids_ (esp. w/aluminum salts): DEC drug absorption, possibly by gastric emptying (take at least 1 hr pre-INH)
- _Levodopa_: inhibits dopa decarboxylase, reducing effectiveness of tx and worsening Parkinson's symptoms
- _Inhibits CYP's_: that metabolize phenytoin (anti-convulsant), diazepam (anxiety, muscle spasms, seizures), fluoxetine (SSRI), nelfinavir (PI), and others, DEC efficacy
- _Induces CYP2E1_: worsening production of toxic metabolite of acetaminophen produced by this pathway
