Drugs are transported in the blood todifferent tissues of the body. In order toreach their sites of action, they mustleave the bloodstream. Drug permea-tion occurs largely in the capillary bed,where both surface area and time avail-able for exchange are maximal (exten-sive vascular branching, low velocity offlow). The capillary wall forms theblood-tissue barrier. Basically, thisconsists of an endothelial cell layer anda basement membrane enveloping thelatter (solid black line in the schematicdrawings). The endothelial cells are“riveted” to each other by tight junc-tions or occluding zonulae (labelled Z inthe electron micrograph, top left) suchthat no clefts, gaps, or pores remain thatwould permit drugs to pass unimpededfrom the blood into the interstitial fluid.
The blood-tissue barrier is devel-oped differently in the various capillarybeds. Permeability to drugs of the capil-lary wall is determined by the structuraland functional characteristics of the en-dothelial cells. In many capillary beds,e.g., those of cardiac muscle, endothe-lial cells are characterized by pro-nounced endo- and transcytotic activ-ity, as evidenced by numerous invagina-tions and vesicles (arrows in the EM mi-crograph, top right).
Transcytotic activ-ity entails transport of fluid or macro-molecules from the blood into the inter-stitium and vice versa. Any solutestrapped in the fluid, including drugs,may traverse the blood-tissue barrier. Inthis form of transport, the physico-chemical properties of drugs are of littleimportance.In some capillary beds (e.g., in thepancreas), endothelial cells exhibit fen-estrations. Although the cells are tight-ly connected by continuous junctions,they possess pores (arrows in EM mi-crograph, bottom right) that are closedonly by diaphragms. Both the dia-phragm and basement membrane canbe readily penetrated by substances oflow molecular weight — the majority ofdrugs — but less so by macromolecules,e.g., proteins such as insulin (G: insulinstorage granules. Penetrability of mac-romolecules is determined by molecu-lar size and electrical charge.
Fenestrat-ed endothelia are found in the capillar-ies of the gut and endocrine glands.In the central nervous system(brain and spinal cord), capillary endo-thelia lack pores and there is little trans-cytotic activity. In order to cross theblood-brain barrier, drugs must diffusetranscellularly, i.e., penetrate the lumi-nal and basal membrane of endothelialcells. Drug movement along this pathrequires specific physicochemical prop-erties (p. 26) or the presence of a trans-port mechanism (e.g., L-dopa, p. 188).Thus, the blood-brain barrier is perme-able only to certain types of drugs.Drugs exchange freely betweenblood and interstitium in the liver,where endothelial cells exhibit largefenestrations (100 nm in diameter) fac-ing Disse’s spaces (D) and where neitherdiaphragms nor basement membranesimpede drug movement.
Diffusion bar-riers are also present beyond the capil-lary wall: e.g., placental barrier of fusedsyncytiotrophoblast cells; blood: testi-cle barrier — junctions interconnectingSertoli cells; brain choroid plexus: bloodbarrier — occluding junctions betweenependymal cells.
Thursday, January 15, 2009
External Barriers of the Body
Prior to its uptake into the blood (i.e.,during absorption), a drug has to over-come barriers that demarcate the bodyfrom its surroundings, i.e., separate theinternal milieu from the external mi-lieu. These boundaries are formed bythe skin and mucous membranes.When absorption takes place in thegut (enteral absorption), the intestinalepithelium is the barrier. This single-layered epithelium is made up of ente-rocytes and mucus-producing gobletcells. On their luminal side, these cellsare joined together by zonulae occlu-dentes (indicated by black dots in the in-set, bottom left).
A zonula occludens ortight junction is a region in which thephospholipid membranes of two cellsestablish close contact and becomejoined via integral membrane proteins(semicircular inset, left center). The re-gion of fusion surrounds each cell like aring, so that neighboring cells are weld-ed together in a continuous belt. In thismanner, an unbroken phospholipidlayer is formed (yellow area in the sche-matic drawing, bottom left) and acts asa continuous barrier between the twospaces separated by the cell layer – inthe case of the gut, the intestinal lumen(dark blue) and the interstitial space(light blue).
The efficiency with whichsuch a barrier restricts exchange of sub-stances can be increased by arrangingthese occluding junctions in multiplearrays, as for instance in the endotheli-um of cerebral blood vessels. The con-necting proteins (connexins) further-more serve to restrict mixing of otherfunctional membrane proteins (ionpumps, ion channels) that occupy spe-cific areas of the cell membrane.This phospholipid bilayer repre-sents the intestinal mucosa-blood bar-rier that a drug must cross during its en-teral absorption. Eligible drugs are thosewhose physicochemical properties al-low permeation through the lipophilicmembrane interior (yellow) or that aresubject to a special carrier transportmechanism.
Absorption of such drugs proceeds rapidly, because the absorbingsurface is greatly enlarged due to theformation of the epithelial brush border(submicroscopic foldings of the plasma-lemma). The absorbability of a drug ischaracterized by the absorption quo-tient, that is, the amount absorbed di-vided by the amount in the gut availablefor absorption.In the respiratory tract, cilia-bear-ing epithelial cells are also joined on theluminal side by zonulae occludentes, sothat the bronchial space and the inter-stitium are separated by a continuousphospholipid barrier.With sublingual or buccal applica-tion, a drug encounters the non-kerati-nized, multilayered squamous epitheli-um of the oral mucosa.
Here, the cellsestablish punctate contacts with eachother in the form of desmosomes (notshown); however, these do not seal theintercellular clefts. Instead, the cellshave the property of sequestering phos-pholipid-containing membrane frag-ments that assemble into layers withinthe extracellular space (semicircular in-set, center right). In this manner, a con-tinuous phospholipid barrier arises alsoinside squamous epithelia, although atan extracellular location, unlike that ofintestinal epithelia. A similar barrierprinciple operates in the multilayeredkeratinized squamous epithelium of theouter skin. The presence of a continu-ous phospholipid layer means thatsquamous epithelia will permit passageof lipophilic drugs only, i.e., agents ca-pable of diffusing through phospholipidmembranes, with the epithelial thick-ness determining the extent and speedof absorption. In addition, cutaneous ab-sorption is impeded by the keratinlayer, the stratum corneum, which isvery unevenly developed in various are-as of the skin.
A zonula occludens ortight junction is a region in which thephospholipid membranes of two cellsestablish close contact and becomejoined via integral membrane proteins(semicircular inset, left center). The re-gion of fusion surrounds each cell like aring, so that neighboring cells are weld-ed together in a continuous belt. In thismanner, an unbroken phospholipidlayer is formed (yellow area in the sche-matic drawing, bottom left) and acts asa continuous barrier between the twospaces separated by the cell layer – inthe case of the gut, the intestinal lumen(dark blue) and the interstitial space(light blue).
The efficiency with whichsuch a barrier restricts exchange of sub-stances can be increased by arrangingthese occluding junctions in multiplearrays, as for instance in the endotheli-um of cerebral blood vessels. The con-necting proteins (connexins) further-more serve to restrict mixing of otherfunctional membrane proteins (ionpumps, ion channels) that occupy spe-cific areas of the cell membrane.This phospholipid bilayer repre-sents the intestinal mucosa-blood bar-rier that a drug must cross during its en-teral absorption. Eligible drugs are thosewhose physicochemical properties al-low permeation through the lipophilicmembrane interior (yellow) or that aresubject to a special carrier transportmechanism.
Absorption of such drugs proceeds rapidly, because the absorbingsurface is greatly enlarged due to theformation of the epithelial brush border(submicroscopic foldings of the plasma-lemma). The absorbability of a drug ischaracterized by the absorption quo-tient, that is, the amount absorbed di-vided by the amount in the gut availablefor absorption.In the respiratory tract, cilia-bear-ing epithelial cells are also joined on theluminal side by zonulae occludentes, sothat the bronchial space and the inter-stitium are separated by a continuousphospholipid barrier.With sublingual or buccal applica-tion, a drug encounters the non-kerati-nized, multilayered squamous epitheli-um of the oral mucosa.
Here, the cellsestablish punctate contacts with eachother in the form of desmosomes (notshown); however, these do not seal theintercellular clefts. Instead, the cellshave the property of sequestering phos-pholipid-containing membrane frag-ments that assemble into layers withinthe extracellular space (semicircular in-set, center right). In this manner, a con-tinuous phospholipid barrier arises alsoinside squamous epithelia, although atan extracellular location, unlike that ofintestinal epithelia. A similar barrierprinciple operates in the multilayeredkeratinized squamous epithelium of theouter skin. The presence of a continu-ous phospholipid layer means thatsquamous epithelia will permit passageof lipophilic drugs only, i.e., agents ca-pable of diffusing through phospholipidmembranes, with the epithelial thick-ness determining the extent and speedof absorption. In addition, cutaneous ab-sorption is impeded by the keratinlayer, the stratum corneum, which isvery unevenly developed in various are-as of the skin.
Potential Targets of Drug Action
Drugs are designed to exert a selectiveinfluence on vital processes in order toalleviate or eliminate symptoms of dis-ease. The smallest basic unit of an or-ganism is the cell. The outer cell mem-brane, or plasmalemma, effectively de-marcates the cell from its surroundings,thus permitting a large degree of inter-nal autonomy. Embedded in the plas-malemma are transport proteins thatserve to mediate controlled metabolicexchange with the cellular environment.
Theseincludeenergy-consumingpumps (e.g., Na, K-ATPase, p. 130), car-riers (e.g., for Na/glucose-cotransport, p.178), and ion channels e.g., for sodium(p. 136) or calcium (p. 122)
(1).Functional coordination betweensingle cells is a prerequisite for viabilityof the organism, hence also for the sur-vival of individual cells. Cell functionsare regulated by means of messengersubstances for the transfer of informa-tion. Included among these are “trans-mitters” released from nerves, whichthe cell is able to recognize with thehelp of specialized membrane bindingsites or receptors. Hormones secretedby endocrine glands into the blood, theninto the extracellular fluid, representanother class of chemical signals. Final-ly, signalling substances can originatefrom neighboring cells, e.g., prostaglan-dins (p. 196) and cytokines.The effect of a drug frequently re-sults from interference with cellularfunction. Receptors for the recognitionof endogenous transmitters are obvioussites of drug action (receptor agonistsand antagonists, p. 60). Altered activityof transport systems affects cell func-tion (e.g., cardiac glycosides, p. 130;loop diuretics, p. 162; calcium-antago-nists, p. 122). Drugs may also directlyinterfere with intracellular metabolicprocesses, for instance by inhibiting(phosphodiesterase inhibitors, p. 132)or activating (organic nitrates, p. 120)an enzyme.
(2).In contrast to drugs acting from theoutside on cell membrane constituents, agents acting in the cell’s interior needto penetrate the cell membrane.The cell membrane basically con-sists of a phospholipid bilayer (80Å =8 nm in thickness) in which are embed-ded proteins (integral membrane pro-teins, such as receptors and transportmolecules). Phospholipid moleculescontain two long-chain fatty acids in es-ter linkage with two of the three hy-droxyl groups of glycerol. Bound to thethird hydroxyl group is phosphoric acid,which, in turn, carries a further residue,e.g., choline, (phosphatidylcholine = lec-ithin), the amino acid serine (phosphat-idylserine) or the cyclic polyhydric alco-hol inositol (phosphatidylinositol). Interms of solubility, phospholipids areamphiphilic: the tail region containingthe apolar fatty acid chains is lipophilic,the remainder – the polar head – is hy-drophilic. By virtue of these properties,phospholipids aggregate spontaneouslyinto a bilayer in an aqueous medium,their polar heads directed outwards intothe aqueous medium, the fatty acidchains facing each other and projectinginto the inside of the membrane.
(3).The hydrophobic interior of thephospholipid membrane constitutes adiffusion barrier virtually imperme-able for charged particles. Apolar parti-cles, however, penetrate the membraneeasily. This is of major importance withrespect to the absorption, distribution,and elimination of drugs.
Theseincludeenergy-consumingpumps (e.g., Na, K-ATPase, p. 130), car-riers (e.g., for Na/glucose-cotransport, p.178), and ion channels e.g., for sodium(p. 136) or calcium (p. 122)
(1).Functional coordination betweensingle cells is a prerequisite for viabilityof the organism, hence also for the sur-vival of individual cells. Cell functionsare regulated by means of messengersubstances for the transfer of informa-tion. Included among these are “trans-mitters” released from nerves, whichthe cell is able to recognize with thehelp of specialized membrane bindingsites or receptors. Hormones secretedby endocrine glands into the blood, theninto the extracellular fluid, representanother class of chemical signals. Final-ly, signalling substances can originatefrom neighboring cells, e.g., prostaglan-dins (p. 196) and cytokines.The effect of a drug frequently re-sults from interference with cellularfunction. Receptors for the recognitionof endogenous transmitters are obvioussites of drug action (receptor agonistsand antagonists, p. 60). Altered activityof transport systems affects cell func-tion (e.g., cardiac glycosides, p. 130;loop diuretics, p. 162; calcium-antago-nists, p. 122). Drugs may also directlyinterfere with intracellular metabolicprocesses, for instance by inhibiting(phosphodiesterase inhibitors, p. 132)or activating (organic nitrates, p. 120)an enzyme.
(2).In contrast to drugs acting from theoutside on cell membrane constituents, agents acting in the cell’s interior needto penetrate the cell membrane.The cell membrane basically con-sists of a phospholipid bilayer (80Å =8 nm in thickness) in which are embed-ded proteins (integral membrane pro-teins, such as receptors and transportmolecules). Phospholipid moleculescontain two long-chain fatty acids in es-ter linkage with two of the three hy-droxyl groups of glycerol. Bound to thethird hydroxyl group is phosphoric acid,which, in turn, carries a further residue,e.g., choline, (phosphatidylcholine = lec-ithin), the amino acid serine (phosphat-idylserine) or the cyclic polyhydric alco-hol inositol (phosphatidylinositol). Interms of solubility, phospholipids areamphiphilic: the tail region containingthe apolar fatty acid chains is lipophilic,the remainder – the polar head – is hy-drophilic. By virtue of these properties,phospholipids aggregate spontaneouslyinto a bilayer in an aqueous medium,their polar heads directed outwards intothe aqueous medium, the fatty acidchains facing each other and projectinginto the inside of the membrane.
(3).The hydrophobic interior of thephospholipid membrane constitutes adiffusion barrier virtually imperme-able for charged particles. Apolar parti-cles, however, penetrate the membraneeasily. This is of major importance withrespect to the absorption, distribution,and elimination of drugs.
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