TB Drugs - Pharm Flashcards
“Cidal” antibiotics require the organism to do what?
Organism must be growing in order to have an effect
Significant therapy type and duration for treating TB?
Combination therapy for a prolonged course of therapy
Why must combination therapy be used?
Myobacterium will become resistant to single agent therapy
List 3 rafamycins?
Rifampin, Rifabutin, rifapentine
Compare CYP induction b/t and rifampin, rifabutin, & rifapentine
Induction potency: Rifampin > Rifapentine > Rifabutin
Compare 1/2 life b/t rifampin, rifabutin, & rifapentine
1/2 life: Rifapentine > rifampin or rifabutin
can be given 1x a week.
1st line therapy for M. tuberculosis?
Isoniazid + rifampin + pyrazinamide + ethambutol/streptomycin
1st line therapy for M. avium complex?
Clarithromycin + ethambutol/clofazimine/ciprofloxacin/amikacin
In HIV patients, rifabutin can decrease drug interactions b/t?
decrease drug interaction with PIs (protease inhibitors) and NNRTIs
List the possible treatment methods for latent TB infection. Which has been proven to be most effective? Why?
- Isoniazid 9 months
- isoniazid 6 months
- Isoniazid & Rifapentine 3 months (best option, increased likelihood of compliance/shortest duration of treatment but with Directly Observed Therapy (DOT))
- Rifampin 4 months
Which 2 drugs should not be combined for treatment of latent TB? Why?
Rifampin and pyrazinamide, due to reports of severe liver injury and deaths
Isoniazid & Rifapentine not recommended for what subset of patients (4) ?
- Children less than 2 y/o
- HIV-infected pts receiving antiretroviral treatment - druginteractions
- pregnant women or women expecting to become pregnant
- pts who have LTBI w/ presumed INH or RIF resistance
2 phases of ACTIVE TB treatment. Duration of each phase?
Initial (8 weeks) and continuation phase (18 weeks)
Preferred treatment regimen of ACTIVE TB (initial and continuation phase)
Initial phase (8 weeks w/ 56 doses) - Daily Isoniazid, Rifampin, pyrazinamide, & Ethambutol Continuation phase (18 weeks) - Daily isoniazid and rifampin for 126 doses or twice weekly Isoniazid & rifampin for 36 doses
MOA of isoniazid in mycobacterial cells?
Interferes with mycolic acid synthesis, disrupting the bacterial cell wall synthesis
Isoniazid is bactericidal against what?
Bactericidal against rapidly dividing bacilli, such as those found in extracellular cavitary lesions
Isoniazid is bacteriostatic against what?
Bacteriostatic against:
- organisms found within closed caseous lesions
- macrophages that divide slowly and intermittently
Isoniazid alone and active TB? Good, bad, ugly? why?
Isoniazid not used alone against active TB, bc resistant organisms rapidly emerge. Similar resistance can be seen with pyrazinamide, ethambutol and rifampin
Describe route of administration of isoniazid
Rapidly absorbed from GI tract with oral dose, can be given IM too
Describe distribution of isoniazid. Where specifically can it distribute to (2 locations)?
- Distributed throughout all tissue and fluids.
- Penetrates inflamed meninges and achieves therapeutic levels in CSF
- Crosses placenta and can get into breast milk
Where is isoniazid metabolized? How? Key feature of metabolization? 1/2 life features?
- Metabolized in liver via acetylation (primarily)
- polymorphisms in acetylation capacity (“fast” vs “slow”) cause considerable interpatient variability in plasma concentration.
- 1/2 life can vary 1 - 4 hours
Isoniazid and CYPs, what about them?
Isoniazid induces CYPs; this can impact concurrent CYP substrate therapy
Route of elimination of isoniazid?
75% of drug and inactive metabolites excreted in urine
Adverse effects of isoniazid?
Peripheral neuropathy, hepatotoxicity
“stocking glove” associated with adverse effects of which drug? As a result of competition with what other drug?
Isoniazid. competition with pyridoxal phosphate
How to you correct “stocking glove” symptoms seen with isoniazid?
Vitamin B6 supplementation
Hepatitis occurs in what % of patients receiving isoniazid?
2%
Caution should be administered if going isoniazid with what other types of drugs?
Other drugs that are also hepatotoxic, like rifampin
What decreases drug absorption of isoniazid?
Antacids (especially aluminum salts)
What drug can worsen parkinson’s? MOA?
Isoniazid, inhibits dopadecarboxylase, reducing effectiveness of LEVODOPA therapy and worsening parkinsons
Isoniazid specifically induces which CYP? Which drug can this affect?
Induces CYP2E1, can increase acetaminophen toxicity
MOA of Rafamycins?
Inhibits RNA synthesis (binds Beta subunit of the Mb RNA polymerase)
Describe resistance mechanism seen with rafamycins
alteration in Beta subunit of the RNA polymerase prevents drug from binding to it.
Are rafamycins bactericidal or bacteriostatic?
Bactericidal
Giving a rafamycin alone increases what?
resistance to drug
Rifampin absorption impaired by what?
food or para-aminosalicylic acid
Distribution of rifampin?
penetrates all tissues well, including CSF. 75-85% is protein bound
Method of metabolism of rifampin? Key feature of this type of metabolism
Deacetylated in liver. Deacetylated rifampin still retains full antibacterial activity; however, it is not reabsorbed following elimination into the GI tract
Route of excretion of rifampin? Important point regarding route of excretion?
Primarily in bile. 30% unchanged, which will be reabsorbed via enteroehaptic circulation.
Which drug has a shortened 1/2 life in the 1st two weeks of treatment? Mechanism behind this
Rifampin. Hepatic microsomal enzymes are auto induced, leading to increased deacetylation, shortening the 1/2 life
Patient has orange-red tears, urine, and/or saliva? What drug causes this
Rifampin. will discolor body fluids orange-red
Hepatotoxicity seen in what drugs?
- Isoniazid (in addition to peripheral neuropathy)
- rifampin
- pyrazinamide (at larger doses)
- ethionamide
Rifampin induces what enzyme?
cytochrome p450
Which drug is only effective against actively dividing bacilli?
ethambutol
Is ethambutol bactericidal or bacteriostatic?
low doses - bacteriostatic
higher doses - bactericidal
MOA of ethambutol?
inhibits arabinosyl transferase preventing synthesis of peptidoglycan cell wall, causing increased cell permeability
Where in body does ethambutol distribute to?
concentrates in kidneys, lungs, saliva. Also in CSF with inflamed meninges and cross placenta(like isoniazid)
Route of elimination of ethambutol? Consequence of this?
Excreted in urine (50% of dose unchanged) - can cause renal dysfunction
Optic neuritis is an adverse reaction of what drug?
Ethambutol
Optic neuritis as a result of ethambutol causes what to occur in patients? Reversibility?
decreased visual acuity, loss of color discrimination. Reversible. Must prevent by giving monthly visual exams during therapy
Patient begins experiencing gout symptoms. Which drug (s) are you thinking might have caused this?
Ethambutol or pyrazinamide can cause hyperuricemia, leading to gout
Best environment for pyrazinamide to work in?
Most effective at intracellular sites where M. tuberculosis replicates slowly, such as within macrophages
Which drug (s) can be given IM?
Capremycin and Isoniazid (more likely given orally)
Pyrazinamide route of elimination?
metabolized in liver and excreted in the urine (70%); therefore dose adjustment should be considered in severe renal dysfunction
Arthralgia’s reported in 40% of patients taking what medication?
Pyrazinamide
Which drug (s) are used in multi drug resistant therapy?
cycloserine, & Ethionamide,
MOA of cycloserine
Blocks cell wall synthesis
Route of excretion of cycloserine
excreted unchanged by renal mechanism
Adverse effects of cycloserine?
Involve CNS - headaches, tremors, vertigo, confusion
Patient has epilepsy, which drug do you not give?
Cycloserine
MOA of ethionamide?
inhibits peptide synthesis
Which drug is reserved as a last line agent due to its toxicity? What type of toxicities?
Ethionamide. cause GI, neurologic and hepatotoxicity
Which drug(s) are reserved for Extensively drug resistant TB
Any fluoroquinolone and at least 1 of 3 other injectable drugs (amikacin, kanamycin, or capremycin)
Nephrotoxicity and ototoxic, which drug?
Capreomycin
Patient may develop eosinophilia after taking this drug
Capreomycin
Testing for visual disturbances prior to and during therapy are recommended for which drug?
Ethambutol, due to potential of developing optic neuritis
