Pharmacology of Tuberculosis

Question 1

First line drugs used for TB

Answer 1

Isoniazid (INH)
Rifampin
Ethambutol
Pyrazinamide

Question 2

Second line drugs used to tx TB

Answer 2

Streptomycin
Ethionamide
Capreomycin
Cycloserine
Aminosalicylic acid
Kanamycin & amikacin
Fluoroquinolones
Linezolid
Rifabutin
Rifapentine
Bedaquiline

Question 3

MOA of isoniazid

Answer 3

INH is a structural congener of pyridoxine that inhibits synthesis of mycolic acids (essential components of mycobacterial cell walls)

Question 4

Clinical use of INH

Answer 4

Bactericidal for actively growing tubercle bacilli; less effective against dormant organisms

Single most important drug in tx of TB

Sole drug given in tx of latent infections

Question 5

Mechanisms of resistance to isoniazid

Answer 5

Resistance can emerge rapidly if drug is used alone

High level resistance is associated with deletion of katG gene that codes for catalase-peroxidase involved in bioactivation of INH

Low level resistance occurs via deletions in inhA gene that encodes the target enzyme, an acyl carrier protein reductase

Question 6

Pharmacokinetics of INH

Answer 6

Well absorbed orally, penetrates cells to act on intracellular mycobacteria

Metabolized by the liver

Pts may be fast or slow metabolizers — fast metabolizers exhibit half life of 60-90 mins (Asian, Native American > European, African); slow metabolizers exhibit half life of 3-4 hrs

Question 7

Toxicities associated with INH

Answer 7

Neurotoxic effecs - peripheral neuritis, restlessness, muscle twitching, insomia (can be alleviated by pyridoxine)

Hepatotoxic - may cause abnormal LFTs, jaundice, hepatitis

May inhibit hepatic metabolism of drugs like carbamazepine, phenytoin, warfarin

Hemolysis has occurred in pts with G6PD deficiency

Lupus-like syndrome has also been reported

Question 8

MOA of rifampin

Answer 8

Inhibits DNA-dependent RNA polymerase

Question 9

Clinical use of rifampin

Answer 9

Bactericidal against TB

Almost always used in combo with other drugs, but can be used as sole drug in latent TB in those intolerant or resistant to INH

Also used in MRSA, PRSP, and leprosy to delay resistance to dapsone

Question 10

Primary mechanism of resistance to rifampin

Answer 10

Occurs via changes in drug sensitivity of the polymerase; more rapidly emerging resistance if drug is used alone

Question 11

Pharmacokinetics of rifampin

Answer 11

Well absorbed orally, distributed to many tissues including CNS

Undergoes enterohepatic cycling and is partially metabolized in the liver

Both free drug and metabolites, which are orange colored, are eliminated primarily in feces

Question 12

Toxicities associated with rifampin

Answer 12

Commonly causes light chain proteinuria and may impair antibody responses

Occasionally skin rash, thrombocytopenia, nephritis, liver dysfunction

If given less than 2x/week, may lead to flu-like syndrome and anemia

Question 13

Drug interactions associated with rifampin

Answer 13

Strong inducer of liver enzymes; enhances elimination rate of many drugs including anti-convulsants, contraceptive steroids, cyclosporine, ketoconazole, methadone, terbinafine, warfarin

Question 14

MOA of ethambutol

Answer 14

Inhibits arabinosyltransferases involved in synthesis of arabinogalactan (component of mycobacterial cell wall)

Question 15

Clinical use of ethambutol

Answer 15

Main use is TB; always given in combo with other drugs

Question 16

Mechanism of resistance to ethambutol

Answer 16

Develops rapidly via mutations in emb gene if drug is used alone

Question 17

Pharmacokinetics of ethambutol

Answer 17

Well absorbed orally and distributed to most tissues including CNS; large fraction is eliminated unchanged in the urine - dose reduction is necessary if used in pts with renal impairment

Question 18

Toxicities associated with ethambutol

Answer 18

Most common are dose-dependent visual disturbances: decreased visual acuity, red-green color blindness, optic neuritis, possible retinal damage (most regress when drug is stopped)

Other effects: HA, confusion, hyperuricemia, peripheral neuritis

Question 19

MOA of pyrazinamide

Answer 19

Unknown; but bacteriostatic action appears to require metabolic conversion via pyrazinamidases present in TB; key part of short course treatment

Question 20

Mechanism of resistance associated with pyrazinamide

Answer 20

Occurs via mutations in the gene that encodes enzymes involved in bioactivation of pyrazinamide and by increased expression of efflux systems

Question 21

Pharmacokinetics of pyrazinamide

Answer 21

Well absorbed orally, penetrates most body tissues including CNS

Partly metabolized to pyrazinoic acid, and both parent molecule and metabolite are excreted in urine

Plasma half life is increased in hepatic or renal failure

Question 22

Toxicities associated with pyrazinamide

Answer 22

40% of pts develop nongouty polyarthralgia

Hyperuricemia occurs commonly but is usually asymptomatic

Other: myalgia, GI irritation, maculopapular rash, hepatic dysfunction, porphyria, photosensitivity reactions

Avoid in pregnancy

Question 23

MOA of streptomycin in terms of TB tx

Answer 23

Aminoglycoside used principally in drug combos for tx of life-threatening TB disease, including meningitis, miliary dissemination, and severe organ TB

Bactericidal inhibitor of protein synthesis (via 30S ribosomal subunit)

Question 24

Mechanisms of resistance to streptomycin

Answer 24

Occurs d/t changes in ribosomal binding site

[Multidrug resistant strains of TB that are resistant to streptomycin may be susceptible to amikacin]

Question 25

Pharmacokinetics of streptomycin

Answer 25

Must be given IV or IM for systemic effect

Major mode of excretion is glomerular filtration - watch renal function

Question 26

Toxicities associated with streptomycin

Answer 26

Ototoxic, nephrotoxic, neuromuscular blockade, skin reactions (dermatitis)

Contraindicated in pregnancy

Question 27

Second-line agent for TB that is a congener of INH; major disadvantage is severe GI irritation and adverse neurologic effects at doses need to achieve effective plasma levels

Answer 27

Ethionamide

Question 28

Second line agent for TB that has limited use due to ototoxicity and renal dysfunction

Answer 28

Capreomycin

Question 29

Second line TB agent with limited use d/t peripheral neuropathy and CNS dysfunction

Answer 29

Cycloserine

Question 30

Second line TB agent rarely used because primary resistance is common; toxicities include GI irritation, peptic ulceration, hypersensitivity reactions, and effects on kidney, liver, and thyroid function

Answer 30

p-Aminosalicylic acid (PAS)

Question 31

Fluoroquinolones may be used in TB that is resistant to first-line therapy, but should always be used in combo with 2+ other active agents. What fluoroquinolones are indicated for TB?

Answer 31

Ciprofloxacin

Ofloxacin

Question 32

Second line TB agent indicated for streptomycin-resistant or multidrug-resistant strains

Answer 32

Amikacin

Question 33

Second-line TB drug in rifamycin class that is equally effective as rifampin and less likely to cause drug interactions; it is usually preferred over rifampin in tx of TB or other mycobacterial infections in AIDS pts, especially those already being treated with CYP450 substrates

Answer 33

Rifabutin

Question 34

Second-line TB agent in rifamycin class that is long-acting, but otherwise similar to rifampin

Answer 34

Rifapentine

Question 35

Standard antitubercular drug regimen

Answer 35

Initial 3-drug regimen of INH, rifampin, and pyrazinamide

If organisms are fully susceptible, and pt is HIV negative, discontinue pyrazinamide after 2 mo and continue 2-drug therapy for further 4 mo

Question 36

Alternative antitubercular drug regimen

Answer 36

INH + rifampin for 9 mo

INH + ethambutol for 18 mo

Intermittent (2-3x/week) high-dose 4-drug regimens

Question 37

If TB pt’s resistance to INH is >4%, initial drug regimen should include _____ or _______

Answer 37

Ethambutol; streptomycin

Question 38

How should multidrug resistant organisms (resistant to INH and rifampin) be treated?

Answer 38

Tx with 3+ drugs to which organism is susceptible for a period of 18+ months, including 12 months after sputum culture becomes negative