Anti-tuberculous agents week 4 Flashcards
Define the following terms:
Multi-drug resistant TB (MDR-TB)
Extensively drug resistant TB (XDR-TB)
First line vs second line agents for TB treatment
a. MDR-TB: the infecting organism is resistant to at least isoniazid (INH) and rifampin (RIF).
b. XDR-TB: organism is resistant to at least INH, RIF, fluoroquinolones, and either aminoglycosides or capreomycin, or both.
C. Traditionally, antimicrobials for tuberculosis have been classified as first-line drugs, having superior efficacy with acceptable toxicity, and second-line drugs, having either less efficacy, greater toxicity, or both.
Isoniazid (INH)
MOA
Clinical use
Toxicites
What is given to reduce one of the toxicities?
Mechanisms of resistance. Differentiate btwn low and high level resistance
Coadministration with what drug inactivates INH?
Administration, distribution
Pharmacokinetics
Elmination
MOA: bactericidal against actively growing M. tuberculosis and bacteriostatic against non replicating organisms. Inhibits synthesis of mycolic acid. Bacterial catalase peroxidase (encoded by KatG) required to convert INH to active metabolite
Clinical use: Mycobacterium tuberculosis. The only agent used as solo prophylaxis against TB.
Toxicities: Hepatotoxicity, Neurotoxicity (peripheral neuropathy). INH Injures Neruons and Hepatocytes. INH increases urinary excretion and depletion of vit B6 which is needed for proper nerve function. Coadminister with vitamin B6 supplements.
Systemic lupus erythematosus (SLE), fever, rash
Mechanisms of resistance: Mutation of inhA gene which is involved in mycolic acid synthesis—low level resistance. Mutation or deletion of katG gene that codes for KatG, catalase-peroxidase that activates isoniazid—high level resistance
INH is well absorbed orally or intramuscularly and is distributed throughout the body. Cerebrospinal fluid (CSF) levels are about 20% of plasma concentrations but approach plasma levels in the presence of meningeal inflammation.
Coadministration with vitamin C appears to inactivate INH suspensions.
iv. Metabolism of INH occurs initially by hepatic N-acetyltransferase. Differences in INH half lives in fast vs slow acetylators.
1. Ten to 15% of Asians are “slow” acetylators, as are 58% of American whites, but acetylator status generally does not affect the outcome with daily therapy
What may result from OD of isoniazid? What is used to reverse these consequences?
What drug interactions exist with INH?
What predisposes one to hepatoxicity and neurotoxicity with INH?
Overdose
- May result in metabolic acidosis, hyperglycemia, seizures, and coma.
- High-dose pyridoxine usually reverses these.
Drug interactions
i. Inhibits metabolism of phenytoin resulting in phenytoin toxicity (mental status changes, nystagmus, and ataxia). More common in slow acetylators.
ii. Theophylline toxicity
iii. Hepatoxicity when co-administered with rifampin
Hepatotoxicity is increased in: elderly patients; alcoholic patients; patients with preexisting liver damage; in pregnant women and women up to 3 months postpartum; in combination with acetaminophen; in patients receiving other potentially hepatotoxic agents such as rifampin; in patients with active viral hepatitis; and HIV-seropositive patients on highly active antiretroviral therapy.
Neurotoxicity: Poor nutrition, alcoholism, diabetes mellitus, or uremia predisposes to neuropathy which is more frequent in slow acetylators who have higher plasma levels of unaltered drug.
Rifampin
MOA
Clinical use
Pharmacokinetics
elimination
Effect of Probenecid on rifampin
Mechanism of resistance
Toxicities
Drug-drug interactions
Use in pregnancy?
Rifampin
MOA: Inhibits DNA dependent RNA polymerase
Clinical use: Bactericidal against actively replicating M. tuberculosis whether intracellular or extracellular. Delay resistance to dapsone when used for leprosy. Used for N. meningitidis and H. influenzae prophylaxis in close contacts.
Pharmacokinetics/elimination:
i. Rifampin is well absorbed orally, yielding peak plasma concentrations of 7 to 8 μg/mL after a dose of 600 mg.
ii. It is widely distributed throughout the body. CSF concentrations range from undetectable to 0.5 μg/mL in healthy persons and reach 50% of plasma concentrations with meningeal inflammation.
iii. Rifampin’s high lipid solubility enhances phagosomal penetration.
iv. Rifampin is deacetylated to an active form that undergoes biliary excretion and enterohepatic recirculation.
vi. Excretion is primarily into the gastrointestinal tract, with lesser amounts in the urine.
vii. The plasma concentration and urinary excretion increase in hepatic failure.
viii. Probenecid blocks hepatic uptake, causing decreased biliary excretion.
ix. Full dosage can be given in renal insufficiency.
x. Rifampin is removed by hemodialysis or peritoneal dialysis.
Mechanism of resistance: Mutations reduce drug binding to RNA Pol: 95% of resistance to rifampin results from a point mutation or deletion within an 81-bp region of the gene encoding the β-subunit of RNA polymerase (rpoB).
Toxicities: Minor hepatotoxicity-hepatitis. drug interactions: increases CYP 450. Red/orange body fluids (urine, feces, saliva, sputum, pleural effusions, tears, semen, etc).
Drug interactions
- Potent inducer of cytochrome P-450 enzymes-interaction and can reduce serum concentrations of over 100 agents.
- Induces metabolism of the protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), so rifampin should not be coadministered with these drugs
Rifampin is a pregnancy category C drug, but it is approved for use in pregnant patients with active tuberculosis.
Rifampin’s 4 R’s:
RNA Polymerase inhibitor
Ramps up microsomal CYP 450
Red/orange body fluids
Rapid resistance if used alone
Compare the use, oral bioavailability, peak serum concentration, and drug interactions of Rifabutin to Rifampin.
Why might Rifabutin be used over Rifampin?
Why might Rifapentene be used over rifampin?
Rifabutin more effective in treatment of Mycobacterium avium-intracellulare. Oral bioavailabilty only 20%-less than rifampin.
Rifabutin induces hepatic CYP 450 system 50 % less than rifampin. Because of this, rifabutin is used in pts with HIV infection that are on protease inhibitors.
Rifapentene has same MOA, resistance, activity, toxicity, drug-drug interactions as rifampin. However, it has prolonged half-life of 13 hours allowing for less frequent dosing.
Rifamp ramps up CYP 450, but rifabutin does not.
Pyrazinimide
MOA
Clinical use
Toxicity
Pharmacokinetics
elimination
MOA— Pyrazinoic acid, a metabolite formed after enzymatic conversion of the parent compound by mycobacterial pyrazinamidase, is the active form of the drug. The exact mechanism of action is unknown.
Clinical use: Bactericidal against semi-dormant intracellular Mycobacterium tuberculosis. Rapid development of resistance when used as monotherapy
Toxicities: Hyperuricemia-joint pain, may precipiate flares of gout, hepatotoxicity
Pharmacokinetics:
i. Well-absorbed orally, PZA is widely distributed throughout the body,
ii. Half-life 12 hours
iii. Penetrates inflamed meninges
iv. Hepatic metabolism, but metabolites renally cleared so moderate dose adjustment with renal insufficiency
v. Partially cleared by hemodialysis so dose after dialysis
Ethambutol
MOA
Clinical use
Pharmacokinetics
Elimination
Toxicities
Mechanisms of resistance
Ethambutol
MOA: decrease carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase
Clinical use: bacteriostatic for M. tuberculosis
Pharmacokinetics:
i. 75-80% absorbed after oral administration
ii. Good penetration into tissues including CSF
iii. 25% converted to inactive metabolite
iv. Parent compound and metabolite excreted in urine so **dose adjustment necessary for renal insufficiency**
Toxicities: Optic neuropathy leading to red-green color blindness. Pronounce eyethambutol
Mechanism of resistance: Primary resistance about 2% and is due to to point mutations in the arabinosyltransferase enzyme EmbB, which is coded for by the embB gene.
List second line agents in treatment of TB
Quinolones
capreomycin
para-aminosalycylic acid (PAS)
cycloserine
ethionamide
bedaquiline
Capreomycin
MOA
toxicities
administration
Capreomycin
a. A polypeptide antibiotic obtained from Streptomyces capreolus, is active against M. tuberculosis, including most MDR-TB strains
b. Mechanism of action; inhibits protein synthesis
c. Mechanism of resistance unknown
d. Toxicity includes hearing loss, tinnitus, and decreased renal function
e. No drug interactions
f. No oral absorption, must be given IV or IM
g. Excreted unchanged in the urine
Para-aminosalycylic acid (PAS)
MOA
Uses
administration
excretion
Toxicities
C. Para-aminosalycylic acid (PAS)
a. A synthetic compound that inhibits the growth of tubercle bacilli by blocking folate synthesis.
b. Incompletely absorbed after oral administration
c. 85% excreted in urine- may result in crystalluria
d. Adverse reactions
i. GI intolerance (severe)
ii. Drug induced lupus-like syndrome
iii. Lymphoid hyperplasia and mononucleosis-like syndrome (fever, rash, hepatosplenomegaly, occasionally toxic hepatitis, and adenopathy).
iv. Hypersensitivity common
e. Limited to treatment of MDR-TB and XDR-TB
Cycloserine
MOA
Uses
administration
Toxicities
Cycloserine
a. Inhibits cell wall synthesis
b. Pharmacology
i. Readily absorbed after oral administration
ii. Widely distributed
iii. Crosses blood-brain barrier
iv. Not metabolized.
c. Adverse reactions
i. Peripheral neuropathy (pyridoxine lessens neurotoxicity)
ii. CNS dysfunction (including confusion and seizures)
iii. Suicidal ideation
d. Usage
i. Drug of last resort for susceptible strains of MDR-TB and XDR-TB
ii. Should be avoided in pregnancy (category C)
Ethionamide
MOA
Uses
administration
Toxicities
Ethionamide
a. Derivative of nicotinic acid
b. Bacteriostatic-inhibits oxygen-dependent mycolic acid synthesis.
c. Mechanism of resistance unknown
d. Pharmacology
i. Well absorbed orally
ii. Widely distributed including CSF
iii. Undergoes hepatic metabolism and interferes with INH acetylation
iv. Metabolites renally cleared
e. Adverse reactions
i. GI distress
ii. Psychiatric disturbances and peripheral neuropathy (may be treatable with pyridoxine or nicotinamide)
iii. Reversible hepatotoxicity in about 5%
f. Usage—susceptible strains of MDR-TB
Bedalaquine
MOA
Uses
Pharmacokinetics
administration
Toxicities
Bedalaquine
a. A diaryl-quinoline
b. MOA—blocks c-subunit of ATP synthase, an enzyme needed by M. tuberculosis to replicate
i. Must be ingested with meals to improve bioavailability
ii. Protein binding over 99%
iv. CYP3A4 is the major CYP isoenzyme involved in vitro in the monodesmethyl metabolite (M2), which is 4 to 6-times less active
in terms of antimycobacterial potency.
v. Bedaquiline is mainly eliminated in feces.
vi. Terminal half-life about 5.5 months
e. Adverse reactions
i. Increased mortality (11.4% in treatment group and 2.5% in placebo
ii. Prolonged QT interval
iii. Hepatotoxicity
iv. Nausea, arthralgia, headache
v. Use only for MDR-TB when no other agent available
group)
metabolism of bedaquiline and the formation of the N-
