NR 565 WEEK 6 CHAPTER 24 Drugs used in treating infectious disease.

NR i565 iWEEK i6: iCHAPTER i24: iDrugs iused iin itreating iinfectious idisease


ANTIMYCOBACTERIALS
➢ Mycobacteria- iamong ithe imost idifficult ito icure i(e.g. ituberculosisi[TB])
o They igrow islowly iand iare irelatively iresistant ito idrugs ithat iareilargely idependent ion
ihow irapidly icells iare idividing


o Have ia ilipid-rich icell iwall irelatively iimpermeable ito imanyidrugs
o Are iusually iintracellular iand iinaccessible ito idrugs ithat idoesinot ihave igood
iintracellular ipenetration


o Have ithe iability ito igo iinto ia idormant istate
o Easily idevelop iresistance ito iany isingle idrugs
o Pregnancy icategories:
▪ Isoniazid: iPregnancy icategory iA
▪ Streptomycin: iPregnancy icategory iD
▪ The irest: iPregnancy icategory iC
▪ Fetal ideath- id/t iTB: iisoniazid i+ irifampin i+ iethambutolifor iTB itx iif
pregnant iand iif idrug iresistance iis ia
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possibility.

• Spectrum iof icoverage ifor ivarious iorganisms/Pharmacodynamics
o Isoniazid i - imost iactive idrug ifor itx iof iTB
▪ Bactericidal-iagainst isusceptible imycobacteriai(intracellular
and iextracellular iorganisms)
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▪ Interferes iwith ilipid iand inucleic iacid ibiosynthesis iinigrowing
organisms.
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▪ Isoniazid iand iethambutol- iinhibits isynthesis iof imycolic iacid i(important
constituents ifor imycobacteria icell iwalls
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and iare inot ifound iin imammalian icells).
o Rifamycins i– irifampicin, irifabutin, irifapentine

, ▪ Bactericidal- iagainst isusceptible imycobacteria
▪ Bind ito ithe ibeta isubunit iof imycobacteria iDNA- idependent iRNA
polymerase iand iinhibit iRNA isynthesis
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-> idestruction iof iboth imultiplying iand iinactive ibacilli.
▪ Readily ipenetrate imost itissues iand ican ikill ibacteriaithat iare ipoorly
i accessible ito imany idrugs.
▪ Rifampin iand irifabutin: iN. igonorrhoeae, istaphylococci,istreptococci,
Mycobacterium ileprae, iMAC, iand iH.
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influenzae itype iB.
▪ Rifampin-resistance idevelop irapidly iwhen iused ias
monotherapy- ishould ibe icombined iwith ianother iactiveiabx ifor itx iof
iestablished iinfections.


o Ethambutol
▪ Bacteriostatic- iagainst isusceptible imycobacteria i(M.ituberculosis, iM.
avium, iM. ikansasii)
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▪ Inhibits isynthesis iof iarabinogalactan i(an iessential
component iof imycobacteria icells iwalls).
▪ Arrests icell imultiplication i-> icell ideath
▪ Enhances ithe iactivity iof ilipophilic idrugs i(rifampin iandiofloxacin) ithat
cross ithe imycobacteria icell iwall
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primarily iin ilipid iportions iof ithis icell iwall.
o Pyrazinamide- ian ianalogue iof inicotinamide
▪ Bactericidal i– iagainst iM. ituberculosis iin ian iacidicienvironment
i (pH i<5.6).
▪ Useful iin itx iof iTB
▪ Exhibits igood iactivity iwithin imacrophages iand iplays iaikey irole iin ikilling
intracellular iorganisms.
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▪ Shortening itherapy iand ipreventing irelapses
▪ Exact iaction iis iUNKNOWN.
o Streptomycin i– iaminoglycoside, iused inow ialmost iexclusivelyito itreat iM.
ituberculosis i infections.


▪ Bactericidal iin ialkaline iextracellular ienvironment
▪ Added ias ithe i4th idrug ito ithe iregimen ifor iTB

, ▪ Sensitive ito iM. iavium iand iM. ikansasii; iresistant ito iallimycobacterium
▪ Irreversible iinhibitor iof iprotein isynthesis.
▪ Penetrates icells ipoorly
o Ethionamide- isimilar ibinding isite iand imechanism iof iactionias iisoniazid.
▪ Ultimately iblocks ithe isynthesis iof imycolic iacids.
▪ Bacteriostatic i– iM. ituberculosis
▪ Can iinhibit isome iother iMycobacterium ispecies.
o Capreomycin i– ipeptide iabx
▪ Bactericidal ito isusceptible imycobacteria.
▪ Inhibits iRNA isynthesis i-> idecreasing ireplication iof iM.ituberculosis.
▪ Resistance ieasily idevelops iwhen igiven ias imonotherapy
(should ibe igiven ias ipart iof imultidrug iregimen)
o Bedaquiline i– iunique iantimycobacterial, iapproved iby iFDA iini2012
▪ For itx iof imultidrug iresistant iTB
▪ Inhibits imycobacterial iadenosine itriphosphate i(ATP)isynthesis
▪ Active iagainst ireplicating iand idormant imycobacteria
▪ Black-box iwarning: iincreased imortality ias icomparediwith ia iplacebo itx
i group.
▪ Only ito ibe iused iwhen ian ieffective itx iregimen icannot
otherwise ibe iprovided.
o Para-aminosalicylic iacid- istructurally isimilar ito iPABA iandisulfonamides
▪ Folate isynthesis iantagonist
▪ Active ialmost iexclusive iagainst iM. ituberculosis.
▪ Bacteriostatic

, ▪ Not iused ifrequently i– iprimary iresistance iis icommon,iand iother idrugs iare
better itolerated iand iless
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expensive.

• Pharmacokinetics
o Oral iantimycobacterials iare irapidly iand iwell iabsorbed iin iGIitract iafter iPO
iadministration.


o Isoniazid- i90% ibioavailable ibut ishould ibe itaken ion ian iemptyistomach
▪ Readily idiffuses iinto iall ibody ifluids iincluding iCSF i(90%
of iserum ilevels), ipleural, iand iascitic ifluids
▪ Readily idiffuses iinto itissues, iorgans, isaliva, isputum,iand ifeces
▪ Crosses iplacenta iand ibreastmilk
▪ Metabolism iis iextensive iand ihighly ivariable iandidependent ion
iacetylator istatus.
⟶ i Primarily iacetylated iby ithe iliver
i 50% iof iboth iblacks iand iwhites iare islowiacetylators
Alaskan iand iAsians- imajority iare irapid
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acetylators
⟶ i Rate i of i acetylator i does i not i affect i effectiveness
but imay iincrease irisk ifor itoxic ireactions iwith islowiacetylators.
▪ Excreted iin ithe iurine- imetabolites, iand iunchanged
drug
▪ Elimination iis ilargely idependent ion irenal ifunction

o Rifamycins iand iethambutol ipenetrate iand iconcentrate iinimost ibody ifluids.
▪ Adequate iCSF ipenetration ioccurs ionly iin ithe ipresence
of iinflamed imeninges.
▪ Potent iinducers iof iliver imetabolism