Drug Distribution.pdf

At the end of this e-learning session you are able to…
A. Explain factor affecting drug distribution.
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1. Prof. Shaikh Abusufiyan
Assistant Professor,
AIKTC-School of Pharmacy,
New Panvel-410206
Drug Distribution
Pharma Learning Forever

2. At the end of this e-learning session you are able to…
A. Explain factor affecting drug distribution.

3. Distribution
•Theextentofdistributionofadrugdependsonits
•Lipidsolubility
•IonizationatphysiologicalpH
•Extentofbindingtoplasmaandtissueproteins
•Presenceoftissue-specifictransporters
•anddifferencesinregionalbloodflow.

4. •Movementofdrugproceeds
Untilanequilibriumisestablished
betweenunbounddruginplasmaand
tissuefluids.

5. Apparent volume of distribution (V)
•Assumingthatthebodybehavesasa“singlehomogeneous
compartmentwithvolume“V”
•Itmeansitisthatvolume-->thatwouldaccommodateall
thedruginthebody.

6. Factor affecting volume of distribution (V)
•Lipid-insolubledrugs-->donotentercells-
Therefore“V”isapproximatelyequaltovolumeof
extracellularfluide.g.streptomycin,gentamicin
0.25L/kg.
•Drugsextensivelyboundtoplasmaproteins-->
arelargelyrestrictedtothevascularcompartment
andhavelowvaluese.g.diclofenacandwarfarin
(99%bound),V=0.75L/kg.

7. •Drugssequestratedinothertissues-->mayhave
Vmuchmorethantotalbodywaterorevenbody
masse.g.digoxin6L/kg.
•Mostofthedrugsarepresentinothertissues
plasmaconcentrationislow.
Incaseofpoisoning,drugswithlargevolumesof
distributionarenoteasilyremovedbyhaemodialysis.

8. •Pathologicalstatese.g.congestiveheartfailure,
uraemia,cirrhosisofliveretc.-->canalterthe
“V”ofmanydrugsbyaltering:
•distributionofbodywater
•permeabilityofmembranes
•bindingproteins
•accumulationofmetabolitesthatdisplacethedrug
frombindingsites.

9. Illustration of concept of V

10. Redistribution
•Redistribution:Highlylipid-solubledrugsgetinitiallydistributed
toorgans-->withhighbloodflowi.e.brain,heart,kidneyetc.
•Later,itisredistributedintolessvascularbutmorebulkytissues
(muscle,fat)&itleadto-->fallinplasmaconcentration.

11. •Ifthesiteofactionofthedrugwasin
oneofthehighlyperfusedorgans
Redistributionresultsinterminationofdrug
action.
Greaterthelipidsolubilityofthedrug
Fasterisitsredistribution.

12. •Eg.Anaestheticactionofthiopentonesod.injected
i.v.is-->terminatedinfewminutesdueto
redistribution.
Solution:
•However,whenthesamedrugisgivenrepeatedly
orcontinuouslyoverlongperiods
thesitesgetsaturated
Andthedrugbecomeslongeracting.

13. PenetrationintobrainandCSF:
•Thecapillaryendothelialcellsinbrainhavetight
junctions-->lacklargeintercellularpores.
•Further,neuraltissue-->coversthecapillaries.
•Togethertheyconstitute-->blood-brainbarrier.

14. Usual capillaries & brain capillaries

15. •Asimilarblood-CSFbarrieris-->locatedinthechoroid
plexus:tightjunctions.
•Boththesebarriersarelipoidal-->limittheentryof
nonlipid-solubledrugse.g.Streptomycin,neostigmineetc.

16. •Therefore,Onlylipid-solubledrugs-->abletopenetrate
andhaveactiononthecentralnervoussystem.
•Inflammationofmeninges-->increasesthepermeabilityof
thesebarriers.
•Somedrugsaccumulateinthebrain-->byutilizingthe
transportersforendogenoussubstances.

17. Enzymaticblood-brainbarrier:
•Someenzymessuchas
•Monoamineoxidase(MAO)
•Cholinesterase
•Andsomeotherenzymesarepresentinthe
capillarywallsorinthecellsliningthebrain.
Donotallowcatecholamines,5-HT,acetylcholineetc.to
enterbrainintheactiveform.

18. Othersitesfordistributionoflipidinsolubledrugsinbrain:
•Theblood-brainbarrierisdeficientatthe
•CTZinthemedullaoblongata
•Andatcertainperiventricularsites(anteriorhypothalamus).
Therefore,evenlipid-insolubledrugsareemetic

19. Q&A
Q.1 Enlist distribution dependent factors.
Q.2 What is apparent volume of
distribution?.
Q.3 Blood-brainbarrier and brain-CSF
barrierslimit entry of……………..drugs.
Q4. Name part of brain where even lipid
insoluble drugs can also penetrate.
Copyright @shaikhabusufiyan2021

20. Distribution across placenta
•Passageacrossplacenta
•Placentalmembranes(lipoidal)
freepassagerestrict
•lipophilicdrugshydrophilicdrugs.

21. •Placentacontaintwotypeoftransporter
1.TheplacentaleffluxP-gp(effluxtransporter)
limitfoetalexposuretomaternallyadministereddrugs.
2.Influxtransporters-
Drugistransportedintotheplacenta.

22. Non-lipid-solubledrugs,whenpresentin
1.highconcentrationor
2.forlongperiodsinmaternalcirculation
Enterintothefoetus
Placentaisanincompletebarrierandalmostanydrugtaken
bythemothercanaffectthefoetusorthenew-born.

23. Plasma-protein drug binding
•Drugspossessphysicochemicalaffinityforplasmaproteins.
•Itbindto
•Acidicdrugsplasmaalbumin
•Basicdrugsalpha1acidglycoprotein.
•Albuminbindingisquantitativelymoreimportant.

24. •It is an Saturable process.
•Binding may be lower
when large amounts of the drugare given.

25. Clinical implication of plasma protein binding
1.Highlyplasmaproteinbounddrugs
restrictedtothevascularcompartment
Smallervolumeofdistribution
v

26. Drugs highly bound to plasma protein

27. (ii)Theboundfractionisnotavailableforaction,unlessitisfree.
•BounddrugFreedrug
•Thereforeplasmaproteinbinding-->providetemporarystorageto
thedrugsinvascularcompartment.

28. (iii)Highdegreeofproteinbindinggenerallymakesthe
druglongacting,because
boundfractionisnotavailableformetabolismorexcretion,
unlessitisactivelyextractedbyliverorkidneytubules.

29. iv. Plasma concentrations of the drug=
Concentration of bound+ Concentration of free drug.

30. Displacement interactions
V.Onedrugcanbindtomanysitesonthealbuminmolecule.
Conversely,morethanonedrugcanbindtothesamesite.
Itleadtodisplacementinteractions:drugboundwithhigher
affinitywilldisplacethatboundwithloweraffinity.

31. •Twohighlybounddrugsdonotnecessarilydisplaceeachother.
•e.g.probenecidandindomethacinarehighlyboundtoalbuminbut
donotdisplaceeachother.
•Similarly,acidicdrugsdonotgenerallydisplacebasicdrugsand
viceaversa

32. Clinically important displacement interactions
•Salicylatesdisplacesulfonylureas.
•Indomethacin,phenytoindisplacewarfarin.
•SulfonamidesandvitKdisplace
•bilirubin
•(kernicterusinneonates).
•Salicylatesdisplacemethotrexate

33. (vi)Inhypoalbuminemia
bindingisreduced
highconcentrationsoffreedrug
e.g.phenytoinandfurosemide.

34. •Somediseasesmayalsoalterdrugbinding
•Eg.propranololbindingisincreasedin
•Pregnantwomen
•Andinpatientswithinflammatorydisease.

35. Tissue storage
•Drugsmayalsoaccumulateinspecificorgansbyactive
transportorgetboundtospecifictissueconstituents.
•Drugssequestratedinvarioustissues
largevolumeofdistributionlongdurationofaction.

36. Storage toxicity
•Somemayexertlocaltoxicityduetohighconcentration
•e.g.Tetracyclinesonboneandteeth
Chloroquineonretina.
•Drugsmayalsoselectivelybindtospecificintracellular
organelle
e.g.Tetracyclinetomitochondria

37. Drug concentrated in tissue

38. Reference:
•KDTripathi.EssentialsofMedical
Pharmacology.SeventhEdition.Jaypee
Publication.Pageno:18-22.

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