Resp. Pathophys. Tb Drugs

Front 1

Initial Phase

Back 1

- Requires four drug regimen to be maximally effective
o Minimizes development of resistance (most agents given alone will cause rapid resistance)
o High proportion of population has isolates resistance to INH
o Directly observed therapy (DOT) also employed to ensure adherence
- Regimen includes the following four drugs for TWO MONTHS:
o Rifampin
o Isoniazid (INH)
o Pyrazinamide (PZA)
o Ethambutol

Front 2

Continuation Phase

Back 2

- Duration:
o 4 months, OR
o 7 months:
 Cavitary pulmonary TB whose sputum culture at 2 months of treatment is +
 Initial phase did not contain PZA (ie. not used in liver disease or pregnancy)
 Patients receiving once weekly INH and rifapentene whose sputum culture is + after initial phase

- Treatment Options:
o 2 drug regimen (often rifampin or derivative + INH)
o Once weekly or 2-3 times weekly with DOT

 DOT: observe patient as they swallow the medication (preferred management strategy)
 Ensures adherence/completion
 Identification of ADEs early

Front 3

Rifampin

Back 3

First Line Drug for TB

MOA: Binds to bacterial DNA-dependent polymerase to inhibit RNA synthesis
- Specific for bacterial enzyme only (human RNA polymerase synthesis)
- Active against many mycobacterium species
Esp. intracellular organism & other hard to get sites (ie. Abscesses & lung cavities)
- Bactericidal

ADE:
- Discoloration of secretions (orange/red urine, sweat, & tears)
- Hepatotoxicity (results in hyperbilirubinemia & increase in alkaline phosphatase)
More frequently seen in patients receiving INH+Rifampin (additive with other TB drugs)


DI: Potent inducer of CYP-P450 enzymes (result in decreased levels of other drugs)
- HIV protease inhibitor
- Calcinerin inhibitors
- Oral contraceptives
- Warfain

Front 4

Rifabutin

Back 4

First Line Drug for TB

MOA:
- Rifampin derivatives
- more potent (identical MOA)
- cause CYP induction (but only ½ degree of rifampin)
- appears to be as effective for treatment of susceptible TB
- substitute for rifampin in patients being treated w/ proteases inhibitors for HIV co-infection

Front 5

Rifapentene

Back 5

First Line Drug for TB

MOA:
- Rifampin derivatives
- long half life (once weekly dosing in HIV negative patients)
- more cyp P450 induction than rifabutin, but less than riframpin

Metabolism:
CYP 450 induction
Rifampin>rifapentene>rifabutin

Front 6

Isoniazid (INH)

Back 6

First Line Drug for TB

MOA:
Prodrug activated by mycobacterium cells that inhibits synthesis of mycolic acids (component of mycobacterium cell walls)
- Bactericidal against actively growing MTB
- Bacteriostatic against non-replicating organisms
- Min/no activity against other mycobacterial species

Metabolism:
Occurs in liver by N-acetyltransferases
- Slow acetylators (autosomal recessive trait – white & AA) will have decreased drug removal & increased risk of adverse reactions & drug interactions

ADE:
Hepatotoxicity
- 10-20% of patients will develop asymptomatic rises in aminotransferases (eventually resolve w/ continued therapy)
- Clin sign hepatitis <1%
- Most common time of hepatoxicity is week 4-8 weeks therapy
- If patient experience symptoms, discontinue drug
- incidence ↑age & other risk factors (alcoholics, concomitant hepatoxins)
- at risk patients should be closely monitored

Peripheral Neuropathy
- Dose related
- Due to increase excretion of pyridoxine (Vit B6) caused by INH
- Supplement w/ B6 (25-50mg/day) to prevent this effect

DI:
- Increased phenytoin levels (decrease metabolism)
- additive hepatotoxicity

Front 7

Pyrazinamide
(PZA)

Back 7

First Line Drug for TB

MOA:
Unknown, but is a prodrug that requires activation by pyrazinamidase into active form of pyrazinoic acid
- Optimal activity is in acidic environment (ie. In lysosomes)
- Bactericidal

ADE:
- N/V (most common)
- Hepatotoxicity
• Lower doses used today min this
• May w/hold in severe liver disease
- Elevations in serum uric acid (acute gout is rare unless pre-existing gout)
- Non-gouty polyarthralgias (responsive to NSAIDs)
- Potential teratogenicity (not used in pregnancy)

Front 8

Ethambutol

Back 8

First Line Drug for TB

MOA:
Inhibits arabinosyl transferase to decrease the formation of cell wall components
- Helps in the formation of arabinogalactan & liparabinomannan
May be discontinued

ADE:
Retrobullar optic neuritis (dose dependent & usually reversible)
- Bilateral blurry vision
- Impairment of visual acuity & red-green color vision

Front 9

Streptomycin

Back 9

First Line Drug for TB

MOA:
- Aminoglycoside Abx that inhibits protein synthesis by binding the 30S ribosomal unit
- Initial drug utilized for the treatment of TB
- Fallen out of favor due to high resistance rate (only first line if susceptibility confirmed)

ADE:
- Nephrotoxicity (less than other AMGs)
- Ototoxicity ( less than other AMGs)
- Vestibular toxicity (more than other AMGs)
- Patients need to be counseled on monitoring for gait issues

Front 10

Fluoroquinolones
(moxifloxacin & levofloxacin)

Back 10

Second line drug for TB

MOA:
Inhibition of DNA gyrase
- Currently being investigated as first-line agents

ADE:
CNS toxicity
QT prolongation
Tendonitis/tendon rupture in children

DI: Chelation with oral formulations (separate from divalent cations)

Front 11

Linezolid

Back 11

Second line drug for TB

MOA:
Binds 50s ribosomal subunit to inhibit protein synthesis

ADE:
Dose/duration dependent thrombocytopenia/bone marrow suppression (may limit utility)

DI: Weak MAOI (interactions w/ serotonergic agents)

Front 12

Other AMGs
(kanamycin & amikacin)

Back 12

Second line drug for TB

MOA:
Inhibits protein synthesis by binding 30s ribosomal subunit
- Amakacin can be used in some cases of streptomycin resistant strains (appears quite active)


ADE:
Nephrotoxicity
- Ototoxicity (more common w/ kanamycin)
- Vestibular toxicity
- Patients need to be counseled on monitoring for gait issues

Front 13

Capreomycin

Back 13

Second line drug for TB

MOA:
Peptide protein synthesis inhibitor (similar to AMGs beside the fact that it is a peptide)
Only available in injection

ADE:
- Nephrotoxicity
- Ototoxicity
- Vestibular toxicity

Front 14

Ethionamide

Back 14

Second line drug for TB

MOA:
Blocks mycolic acid synthesis (structurally similar to INH)

ADE:
- Hepatotoxicity
- Neuropathies- supplement w/ Vit B6
- GI disturbances ( occur more frequently & lead to significant non-adherence)

Front 15

Cycloserine

Back 15

Second line drug for TB

MOA:
Structural analog of D-alanine that inhibits alanine racemase (leads to inhibition of cell wall synthesis)


ADE:
Limit clinical utility
- CNS effects (headache, tremors, psychosis, convulsions)
- Peripheral neuropathy (supplement with vit B6 150mg/day to prevent)
25% of patients may experience side effects during first 2 weeks

Front 16

Aminosalicyclic Acid (PAS)

Back 16

Second line drug for TB

MOA:
Inhibit folate synthesis (structurally similar to sulfonamides)

ADE:
- GI intolerance
- Hypersensitivity reactions