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MECHANISMS
OF
DRUGPERMEATION/TRANSPORT
Fluidbilayerofphospholipids.
Scatteredmembraneproteinmoleculesembeddedinbilayerserveas
Receptors selectivetargetsfordrugaction
Ionchannels
Transporters
Lipidmoleculesarecapableoflateralmovement.
Itisflexible
Hashighelectricalresistance
Relativelyimpermeabletohighlypolarmolecules
Highlypermeabletolipidsolubledrugmolecules
CELLMEMBRANE
MainMechanismsOfDrugPermeation/Transport
1.Passivediffusion
Lipiddiffusion
Aqueousdiffusion
2.Carriermediatedtransport
Activetransport
Facilitateddiffusion
3.Pinocytosis
Endocytosis
Exocytosis
PassiveDiffusion
Drugs cross the cell membranes along the concentration
and electrical gradient without expenditure of energy according
to Ficks Law.
Ficks Law:
Flux(moleculesperunittime)=(C1 C2)xAreaxPermeabilityCoefficient
Thickness
PermeabilityCoefficient:
Itisameasureofthemobilityofthedrugmoleculesinthe
mediumofdiffusionpath.
Lipid diffusion
The most important mechanism for transport of majority
of drugs in the body. It is the passive movement of lipid
soluble molecules through membranes or other lipid
structures.
CharacteristicsofLipidDiffusion:
Passiveprocess,governedbyFicks Law.
Alongaconcentrationgradient.
Onlylipidsolubledrugmoleculescancross.
Itoccursthroughthecells,bydissolvinginthelipidmatrixof
themembrane.
Energynotrequired.
Notsaturable orcapacitylimited
Notinhibitable byothersubstances.
Example: Mostofthedrugs
FactorsAffectingtheLipidDiffusion
1. ConcentrationgradientFromhigherlower
2. SurfaceAreaLargertheSAgreaterthediffusion
3. LipidsolubilityThemostimportantfactor.Itisdependentupon:
a) Lipidaqueouspartitioncoefficient.
b) Degreeofionization.Itdependson
pKaofdrug(Ionizationconstant)
pHofthemedium.
Lipidaqueouspartitioncoefficient
Itdetermineshowreadilythedrugmoleculescanmovebetween
aqueous&lipidmedia,.
GreaterthecoefficientFasterthediffusion
DegreeofIonization :Itdependson
pKa ofadrug: WhenpHissameaspKa ,50%drugisionizedand
50%isunionized.
Aspirin3.5,Morphine7.9
pHofthemedium:IonizationofweakelectrolytesispH
dependent.
Ionizationofweakelectrolytedrugs(weakacidicorweakbasic)
ispHdependent,theylose/gainprotonsasfollows:
Weakacidicdrug:
Neutralaspirin Aspirinanion+Proton
_
HA A +H+
weakbasicdrug:
Pyrimethamine cation NeutralPyrimethamine +Proton
BH+ B +H+
AtlowpH Reactionmovestowardsleft
AthighpH Reactionmovestowardsright
SoWeakAcidicdrugsaremostlynonionizedatlowpH &
weakbasicdrugsarenonionizedathighpHorviceversa.
Non - nionized drug: Ionized drug:
Uncharged , Non polar Charged , Polar
Lipid soluble Lipid insoluble, Water soluble
Permeates membrane rapidly Does not permeates rapidly by
by lipid diffusion. lipid diffusion
Specificreceptors fortransportproteinsmustbepresentforthis
processtowork.
Endocytosis: Drugswhichhaveverylargemolecules
(macromolecules)canbeengulfedbythecellmembraneina
vesicle&carriedintothecell&releasedwithinthecellby
pinchingoffthevesicle&breakdownofitsmembrane.
Examples:
TransportofvitaminB12withabindingprotein(intrinsic
factor)acrossgutwall.
IronistransportedintohemoglobinsynthesizingRBCs
precursorswithtransferrin.
Exocytosis:
Exocytosis istheeverse ofendocytosis.It is
responsibleforsecretionofmanysubstancesfrom
cells.
e.g.Expulsionofneurotransmittersintothesynaptic
cleft.
Theneurotransmittersubstancesarestoredin
membraneboundvesiclesinnerveendingsto
protectthemfrommetabolicdestruction.
Appropriateactivationofnerveendingcauses
expulsionofitscontentsintothesynapticcleft.