Anti-mycobacterial (TB) Drugs Flashcards
- State the two major principles for antituberculous therapy
slow to reproduce with lipid-rick mycobacterial cell acting as intracellular pathogens are difficult to kill and notorious for their ability to develop resistance
combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance, it must also be administered over a long course
- Discuss the rational for two stages of therapy (active treatment phase and the suppressive treatment phase) and what determines the movement from one stage to the other.
active treatment is to reduce the burden of organisms and prevent transmission of TB
suppressive treatment phase is targeted at eliminating organisms that are intracellular and slowly replicating
3,4,6. Identify which antituberculosis drugs are first-line agents, and where it is known, describe the mechanisms, mechanism of resistance, and toxicities: isoniazid.
mechanism: inhibits synthesis of myoclic acids
prodrug that is activated by KatG and forms a complex of acyl carrier protein and KasA which blocks synthesis
resistance: over expression of inhA which encodes the acyl carrier protein reductase or mutation of katG or KasA genes
metabolism is genetically determined by levels of N-acetyltransferase which can lead to sub therapeutic concentration if admin once weekly; INH is contraindicated if patient develops hepatitis (dependent on age, alcohol and pregnancy); peripheral neuropathy is observed due to pyridoxine deficiency (suggest B6 supplement)
can be used as a single agent for tx. of latent TB or in combination for active TB
3,4,6. Identify which antituberculosis drugs are first-line agents, and where it is known, describe the mechanisms, mechanism of resistance, and toxicities: rifampin.
mechanism: binds to the B sub unite of bacterial DNA-dependent RNA polymerase and inhibits RNA synthesis and is bactericidal for mycobacteria
also indicated in menigococcal, strep carriage and H. flu contacts
resistance?
toxcities: causes harmless orange color to urine, sweat, tears and contact lenses, occasionally rashes, thrombocytopenia, and nephritis, cholestatic jaundice and hepatitis, if administered less often than twice weekly, causes a flu-like syndrome, anemia, thrombocytopenai and acute tubular necrosis.
strongly induces cytochrome P450, increasing the elimination of numerous other drugs
3,4,6. Identify which antituberculosis drugs are first-line agents, and where it is known, describe the mechanisms, mechanism of resistance, and toxicities: pyrazinamide.
mechanism: converted to pyraxinoic acid and targets of action are unknown
resistance may be due to impaired uptake or impaired conversion to active form
adverse reactions: hepatotoxicity, NVD and hyperuricemia which may provoke acute gouty arthritis
3,4,6. Identify which antituberculosis drugs are first-line agents, and where it is known, describe the mechanisms, mechanism of resistance, and toxicities: ethambutol.
mechanism: inhibits mycobacterial arabinosyl transferases involved in cell wall synthesis (polymerization reaction)
concentrations in CNS are highly variable
adverse reactions: retrobulbar neuritis, resulting in loss of visual acuity and red-green color blindness (dose related effect), contraindicated in children and can cause gout flares
- Describe the effect of a genetic polymorphism on the pharmcaokinetics of isoniazid.
metabolism is genetically determined by levels of N-acetyltransferase which can lead to sub therapeutic concentration if admin once weekly; INH is contraindicated if patient develops hepatitis (dependent on age, alcohol and pregnancy); peripheral neuropathy is observed due to pyridoxine deficiency (suggest B6 supplement)
- Discuss the second-line agents that are commonly used when there is resistance to the first-line drugs or when patient-related issues warrant their use, esp. moxifloxacin.
fluoroquinolones: also active against atypical mycobacteria, moxifloxin is most active against TB
(inhibits topoisomerase)
important in resistance to first line treatments
resistance develops with mutations in the DNA gyrase A subunit if used as a single agent
- List the potential drug interactions that can occur with the use of isoniazid or rifampin.
any drugs metabolized by CYP
- Describe the current recommended treatment regimens for TB.
for latent infections: isoniazid alone for 9mo
active disease: INH, RIF, PZA and EMB for 8 weeks,
if orgs susceptible, can dc EMB
if ioniazid resistance add EMB or streptomycin
continuation phase daily to once weekly INH and RIF for 18 weeks
if organisms are isoniazid resistant daily rifampin and pyrazinamide and ehtambuterol for 26 weeks
- List the majors drugs used for the prophylaxis of TB.
rifabutin: similar to rifampin and cross resistance with rifampin but is indicate in HIV infected patients because it is a less potent inducer of P450 and is effective in tx. of disseminated atypical mycobacterial infection in AIDS or preventative therapy of TB
What are the niche applications of streptomycin.
penetrates cells poorly, and is active mainly against extracellular tubercle bacilli, crosses BBB and achieves therapeutic concentrations with inflamed meninges
non tuberculosis species are resistant
used principally in individuals with severe possibly life-thretening forms of TB (meningitis or disseminated disease) and for tx. infections resistant to other drugs
adverse reaction: ototoxic and nephrotoxic causing hearing loss and vertigo, dose must be adjusted according to renal function (limit to 6mo whenever possible)
List other second line treatments and describe why they are not optimal.
ethionamide- poorly water-soluble and available only in oral form
capreomycin: used as an injectable agent for tx. of drug resistant TB, is ottoxic and nephrotoxic (adjust dosing based on kidney function)
cycloserine: adjust with kidney function, toxicities re: peripheral neuropathy and CNS dysfunction
amino salicylic acid: folate synthesis antagonist, other oral drugs are better tolerated because GI symptoms are common and hypersensitivity rxns manifest as fever, joint pain, skin rashes, hepatosplenomegaly, hepatitis, adenopathy and granulocytopenia after 3-8 weeks
kanamycin and amikacin: not used because of less toxic alternatives, used in multi drug resistant TB
fluoroquinolones: also active against atypical mycobacteria, moxifloxin is most active against TB
linezolid: active in murine models of TB, used in MDR strains, but can lead to bone marrow suppression, irreversible peripheral and optic neuropathy
rifabutin: similar to rifampin and cross resistance with rifampin but is indicate in HIV infected patients because it is a less potent inducer of P450 and is effective in tx. of disseminated atypical mycobacterial infection in AIDS or preventative therapy of TB
rifapentin: active against M TB and M avium, potent inducer of P450 enzymes (not to be used with HIV infected patients)
What is the DOC with leprosy tx.
dapsone and other sulfones which inhibits folate synthesis
combination dapsone, rifampin and clofazimine is recommended
many patients develop hemolysis or methemoglobinemia and GI intolerance
