NR 565 Week 6 Study Guide , NR 565: Advanced Pharmacology Fundamentals

WEEK 6: CHAPTER 24: Drugs used in treating infectious disease

ANTIMYCOBACTERIALS
 Mycobacteria- among the most difficult to cure (e.g. tuberculosis [TB])
o They grow slowly and are relatively resistant to drugs that are largely dependent on how rapidly
cells are dividing
o Have a lipid-rich cell wall relatively impermeable to many drugs
o Are usually intracellular and inaccessible to drugs that does not have good intracellular
penetration
o Have the ability to go into a dormant state
o Easily develop resistance to any single drugs
o Pregnancy categories:
 Isoniazid: Pregnancy category A
 Streptomycin: Pregnancy category D
 The rest: Pregnancy category C
 Fetal death- d/t TB: isoniazid + rifampin + ethambutol for TB tx if pregnant and
if drug resistance is a possibility.

 Spectrum of coverage for various organisms/Pharmacodynamics
o Isoniazid - most active drug for tx of TB
 Bactericidal- against susceptible mycobacteria (intracellular and extracellular
organisms)
 Interferes with lipid and nucleic acid biosynthesis in growing organisms.
 Isoniazid and ethambutol- inhibits synthesis of mycolic acid (important
constituents for mycobacteria cell walls and are not found in mammalian cells).
o Rifamycins – rifampicin, rifabutin, rifapentine
 Bactericidal- against susceptible mycobacteria
 Bind to the beta subunit of mycobacteria DNA-dependent RNA polymerase and
inhibit RNA synthesis -> destruction of both multiplying and inactive bacilli.
 Readily penetrate most tissues and can kill bacteria that are poorly accessible to
many drugs.
 Rifampin and rifabutin: N. gonorrhoeae, staphylococci, streptococci,
Mycobacterium leprae, MAC, and H. influenzae type B.
 Rifampin-resistance develop rapidly when used as monotherapy- should be
combined with another active abx for tx of established infections.
o Ethambutol
 Bacteriostatic- against susceptible mycobacteria (M. tuberculosis, M. avium, M.
kansasii)
 Inhibits synthesis of arabinogalactan (an essential component of mycobacteria
cells walls).
 Arrests cell multiplication -> cell death
 Enhances the activity of lipophilic drugs (rifampin and ofloxacin) that cross the
mycobacteria cell wall primarily in lipid portions of this cell wall.
o Pyrazinamide- an analogue of nicotinamide
 Bactericidal – against M. tuberculosis in an acidic environment (pH <5.6).
 Useful in tx of TB

,  Exhibits good activity within macrophages and plays a key role in killing
intracellular organisms.
 Shortening therapy and preventing relapses
 Exact action is UNKNOWN.
o Streptomycin – aminoglycoside, used now almost exclusively to treat M. tuberculosis
infections.
 Bactericidal in alkaline extracellular environment
 Added as the 4th drug to the regimen for TB
 Sensitive to M. avium and M. kansasii; resistant to all mycobacterium
 Irreversible inhibitor of protein synthesis.
 Penetrates cells poorly
o Ethionamide- similar binding site and mechanism of action as isoniazid.
 Ultimately blocks the synthesis of mycolic acids.
 Bacteriostatic – M. tuberculosis
 Can inhibit some other Mycobacterium species.
o Capreomycin – peptide abx
 Bactericidal to susceptible mycobacteria.
 Inhibits RNA synthesis -> decreasing replication of M. tuberculosis.
 Resistance easily develops when given as monotherapy (should be given as part
of multidrug regimen)
o Bedaquiline – unique antimycobacterial, approved by FDA in 2012
 For tx of multidrug resistant TB
 Inhibits mycobacterial adenosine triphosphate (ATP) synthesis
 Active against replicating and dormant mycobacteria
 Black-box warning: increased mortality as compared with a placebo tx group.
 Only to be used when an effective tx regimen cannot otherwise be provided.
o Para-aminosalicylic acid- structurally similar to PABA and sulfonamides
 Folate synthesis antagonist
 Active almost exclusive against M. tuberculosis.
 Bacteriostatic
 Not used frequently – primary resistance is common, and other drugs are better
tolerated and less expensive.

 Pharmacokinetics
o Oral antimycobacterials are rapidly and well absorbed in GI tract after PO
administration.
o Isoniazid- 90% bioavailable but should be taken on an empty stomach
 Readily diffuses into all body fluids including CSF (90% of serum levels), pleural,
and ascitic fluids
 Readily diffuses into tissues, organs, saliva, sputum, and feces
 Crosses placenta and breastmilk
 Metabolism is extensive and highly variable and dependent on acetylator status.
 Primarily acetylated by the liver
 50% of both blacks and whites are slow acetylators
 Alaskan and Asians- majority are rapid acetylators
 Rate of acetylator does not affect effectiveness but may increase risk for
toxic reactions with slow acetylators.

,  Excreted in the urine- metabolites, and unchanged drug
 Elimination is largely dependent on renal function

o Rifamycins and ethambutol penetrate and concentrate in most body fluids.
 Adequate CSF penetration occurs only in the presence of inflamed meninges.
 Potent inducers of liver metabolism
 Rifampin and rifapentine- metabolized in the liver by deacetylation.
 Metabolites are active against M. tuberculosis.
 t1/2 life decreases with repeated administration
 excreted primarily in the bile -> enterohepatic recirculation -> feces, urine (small
amount)
 hepatic insufficiency and age slightly affect metabolism of rifabutin only.
 Renal insufficiency- reduced drug distribution and faster drug elimination ->
decreased drug concentrations.
 Food slow the rate of absorption of rifamycins but not the extent of absorption
(may be taken with or without food)
o Pyrazinamide- widely distributed in body tissues and fluids including the liver and lung.
 Reaches high concentrations in CSF
 Crosses the placenta and enter breastmilk in small amounts
 Poor CSF penetration (good penetration if meninges are inflamed)
 70% excreted in urine by glomerular filtration
 Hydrolyzed by the liver to as a metabolite
 Prolonged t1/2 - significant on impaired hepatic and renal functions.
o Ethionomide- widely distributed to body tissues and fluids- CSF and serum
concentrations are equal
 35% metabolized by the liver
 Majority of the drug excreted in the urine as inactive metabolites
o Ethambutol- mainly excreted as unchanged drug in the urine.
 20% metabolized by the liver
 Marked accumulation may occur in renal failure

 Pharmacotherapeutics
o Isoniazid- careful monitoring for hepatotoxicity (ETOH drinkers, chronic liver disease,
severe renal function, >35y/o, drug abuse, pregnant, immediately postpartum)
 Peripheral neuropathy, neurotoxicities may occur
 Special caution: patients with preexisting peripheral neuropathy,
pregnancy, and (+) HIV.
o Ethambutol, streptomycin, capreomycin
 Cautious use for patient with renal impairment
 Dose adjustments may be required
o HEPATOTOXIC: R-ifamycins, I-soniazid, P-yrazinamide, E-thionamide (RIPE)
o Thrombocytopenia and anemia: rifampin and isoniazid
o Gouty arthritis attacks: ethambutol and pyrazinamide
o Visual disturbances, irreversible blindness- ethambutol (cautious use with eye disorders
such as diabetic retinopathy, cataracts, optic neuritis)
o CYP enzyme:
 Rifamycins- potent inducers of liver metabolism