Distribution in the Body 23 thelium with brush border epitheliu sq A. External barriers of the body LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Distribution in the Body 23 A. External barriers of the body Nonkeratinized squamous epithelium Ciliated epithelium Keratinized squamous epithelium Epithelium with brush border Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
24 Distribution in the body Blood-Tissue Barriers e.g, proteins such as insulin(G storage granules. Penetrability Drugs are transported in the blood to romolecules is determined by me ifferent tissues of ar size and electrical charge reach their sites of action, they must ed endothelia are found in the capillar- tion occurs largely in the capillary bed. In the central nervou here both surface area and time av ble for exchange are maximal (exten- thel and there is little trans ive vascular branching. low velocity of cytotic activity. In order to cross th w). The capillary wall forms the blood-brain barrier, drugs must diffuse consists of an endothelial cell layer and nal and basal membrane of endothelial a basement membrane enveloping the cells. Drug movement along this path latter(solid black line in the schematic requires specific physicochemical prop drawings). The endothelial cells are h other by tight -dopa, p. 188). tions or occluding zonulae(labelled Z in Thus, the blood-brain barrier is perme he electron micrograph, top left)such able only to certain types of drugs. that no clefts, gaps, or pores remain that Drugs exchange freely between would permit drugs to pass unimpeded blood and interstitium in the liver. from the blood into the interstitial fluid. where endothelial cells exhibit large e blood-tissue barrier is devel- fenestrations(100 nm in diameter) fac- oped differently in the various capillary ing Disses spaces(D)and where neithe eds. Permeability to ry wall is determined by the structural and functional characteristics of the en- riers are also presen dothelial cells. In many capillary beds, lary wall: e.g. placental barrier of fused As those of cardiac muscle, endothe. syncytiotrophoblast cells; blood: testi- tions and vesicles (arrows in the EM mi- eper crograph, top right). Transcytotic activ (Vertical bars in the EM micro ity entails transport of fluid or macro- graphs represent molecules from the blood into the inter oned erythrocyte: AM: actomyosin stitium and vice versa. Any solutes insulin-containing granules pped in the fluid, including drugs. ay traverse the blood-tissue barrier. In his form of transport, the phys chemical properties of drugs are of little capillary beds (e. g. in the dothelial cells exhibit fen. estrations. Although the cells are tight- they possess pores(arrows in EM mi- bottom right) that are closed diaphragms. Both the dia- nd basement membrane eadily penetrated by substances of low molecular weight- the majority of drugs- but less so by macromolecules. LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Blood-Tissue Barriers Drugs are transported in the blood to different tissues of the body. In order to reach their sites of action, they must leave the bloodstream. Drug permeation occurs largely in the capillary bed, where both surface area and time available for exchange are maximal (extensive vascular branching, low velocity of flow). The capillary wall forms the blood-tissue barrier. Basically, this consists of an endothelial cell layer and a basement membrane enveloping the latter (solid black line in the schematic drawings). The endothelial cells are “riveted” to each other by tight junctions or occluding zonulae (labelled Z in the electron micrograph, top left) such that no clefts, gaps, or pores remain that would permit drugs to pass unimpeded from the blood into the interstitial fluid. The blood-tissue barrier is developed differently in the various capillary beds. Permeability to drugs of the capillary wall is determined by the structural and functional characteristics of the endothelial cells. In many capillary beds, e.g., those of cardiac muscle, endothelial cells are characterized by pronounced endo- and transcytotic activity, as evidenced by numerous invaginations and vesicles (arrows in the EM micrograph, top right). Transcytotic activity entails transport of fluid or macromolecules from the blood into the interstitium and vice versa. Any solutes trapped in the fluid, including drugs, may traverse the blood-tissue barrier. In this form of transport, the physicochemical properties of drugs are of little importance. In some capillary beds (e.g., in the pancreas), endothelial cells exhibit fenestrations. Although the cells are tightly connected by continuous junctions, they possess pores (arrows in EM micrograph, bottom right) that are closed only by diaphragms. Both the diaphragm and basement membrane can be readily penetrated by substances of low molecular weight — the majority of drugs — but less so by macromolecules, e.g., proteins such as insulin (G: insulin storage granules. Penetrability of macromolecules is determined by molecular size and electrical charge. Fenestrated endothelia are found in the capillaries of the gut and endocrine glands. In the central nervous system (brain and spinal cord), capillary endothelia lack pores and there is little transcytotic activity. In order to cross the blood-brain barrier, drugs must diffuse transcellularly, i.e., penetrate the luminal and basal membrane of endothelial cells. Drug movement along this path requires specific physicochemical properties (p. 26) or the presence of a transport mechanism (e.g., L-dopa, p. 188). Thus, the blood-brain barrier is permeable only to certain types of drugs. Drugs exchange freely between blood and interstitium in the liver, where endothelial cells exhibit large fenestrations (100 nm in diameter) facing Disse’s spaces (D) and where neither diaphragms nor basement membranes impede drug movement. Diffusion barriers are also present beyond the capillary wall: e.g., placental barrier of fused syncytiotrophoblast cells; blood: testicle barrier — junctions interconnecting Sertoli cells; brain choroid plexus: blood barrier — occluding junctions between ependymal cells. (Vertical bars in the EM micrographs represent 1 µm; E: cross-sectioned erythrocyte; AM: actomyosin; G: insulin-containing granules.) 24 Distribution in the Body Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Distribution in the Body 25 CNS Liver A. Blood-tissue barriers LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Distribution in the Body 25 A. Blood-tissue barriers CNS Heart muscle Liver G Pancreas AM D E Z Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
26 Distribution in the body Membrane permeation trate of a carrier will exhibit affinity for An ability to penetrate lipid bilayers is a Finally, membrane penetration prequisite for the absorption of drugs, ay occur in the form of small mem their entry into cells or cellular orga- brane-covered vesicles. Two different nelles, and passage across the blood- systems are considered nscytosis(vesicular C) When new vesicles are pinched off, bstances dissolved in the extracellu- drophobic interior(p. 20). Substances lar fluid are engulfed, and then ferried ay traverse this membrane in three through the cytoplasm, vesicles(phago different ways. ergo fusion with lysosomes Diffusion(A). Lipophilic substanc- to form phagolysosomes, and the trans es(red dots)may enter the membrane ported substance is metabolized. Alte from the extracellular space (area natively, the vesicle may fuse with the membrane, and exit into the cytosol eceptor-mediated endocytosis (blue area). Direction and speed of per- (C). The drug first binds to membran leaton depend on the relative conce surface receptors(1, 2)whose cytosol trations in the fluid phases and the domains contact special proteins(adap- membrane. The steeper the gradient tins, 3). Drug-receptor complexes mi (concentration difference), th rate laterally in the membrane and ag drug will be diffusing per unit of time gregate with other complexes by Ficks Law ). The lipid membrane repre- clathrin-dependent process(4). The af- sents an almost insurmountable obsta- fected membrane region invaginates and eventually pinches off to form a de- tached vesicle(5). The clathrin coat is Transport(B). Some drugs may shed immediately (6) followed by the penetrate membrane barriers with the adaptins(7). The remaining vesicle then help of transport systems(carriers), ir h requisite, the drug must have affin- associates and the recepto turms into the cell membrane. the early"endosome delivers its content hen bound to the latter, be capable of to predetermined destinations, e. g. the eing ferried across the membrane. Golgi complex, the cell nucleus, lysoso- membrane passage via transport mech. les, or the opposite cell membrane anisms is subject to competitive inhibi anscytosis) Unlike simple endocyte- s lacking in affinity(blue circles) are tors and operates independently of con- ot transported Drugs utilize carriers cer or physiological substances, e. g, L-do take by L-amino acid rriers(p. 188), and uptake of amin glycosides by the carrier transporting lypeptides through the luminal rane of kidney tubular cells(p Only drugs bearing sufficient emblance to the physiological sub- LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Membrane Permeation An ability to penetrate lipid bilayers is a prerequisite for the absorption of drugs, their entry into cells or cellular organelles, and passage across the bloodbrain barrier. Due to their amphiphilic nature, phospholipids form bilayers possessing a hydrophilic surface and a hydrophobic interior (p. 20). Substances may traverse this membrane in three different ways. Diffusion (A). Lipophilic substances (red dots) may enter the membrane from the extracellular space (area shown in ochre), accumulate in the membrane, and exit into the cytosol (blue area). Direction and speed of permeation depend on the relative concentrations in the fluid phases and the membrane. The steeper the gradient (concentration difference), the more drug will be diffusing per unit of time (Fick’s Law). The lipid membrane represents an almost insurmountable obstacle for hydrophilic substances (blue triangles). Transport (B). Some drugs may penetrate membrane barriers with the help of transport systems (carriers), irrespective of their physicochemical properties, especially lipophilicity. As a prerequisite, the drug must have affinity for the carrier (blue triangle matching recess on “transport system”) and, when bound to the latter, be capable of being ferried across the membrane. Membrane passage via transport mechanisms is subject to competitive inhibition by another substance possessing similar affinity for the carrier. Substances lacking in affinity (blue circles) are not transported. Drugs utilize carriers for physiological substances, e.g., L-dopa uptake by L-amino acid carrier across the blood-intestine and blood-brain barriers (p. 188), and uptake of aminoglycosides by the carrier transporting basic polypeptides through the luminal membrane of kidney tubular cells (p. 278). Only drugs bearing sufficient resemblance to the physiological substrate of a carrier will exhibit affinity for it. Finally, membrane penetration may occur in the form of small membrane-covered vesicles. Two different systems are considered. Transcytosis (vesicular transport, C). When new vesicles are pinched off, substances dissolved in the extracellular fluid are engulfed, and then ferried through the cytoplasm, vesicles (phagosomes) undergo fusion with lysosomes to form phagolysosomes, and the transported substance is metabolized. Alternatively, the vesicle may fuse with the opposite cell membrane (cytopempsis). Receptor-mediated endocytosis (C). The drug first binds to membrane surface receptors (1, 2) whose cytosolic domains contact special proteins (adaptins, 3). Drug-receptor complexes migrate laterally in the membrane and aggregate with other complexes by a clathrin-dependent process (4). The affected membrane region invaginates and eventually pinches off to form a detached vesicle (5). The clathrin coat is shed immediately (6), followed by the adaptins (7). The remaining vesicle then fuses with an “early” endosome (8), whereupon proton concentration rises inside the vesicle. The drug-receptor complex dissociates and the receptor returns into the cell membrane. The “early” endosome delivers its contents to predetermined destinations, e.g., the Golgi complex, the cell nucleus, lysosomes, or the opposite cell membrane (transcytosis). Unlike simple endocytosis, receptor-mediated endocytosis is contingent on affinity for specific receptors and operates independently of concentration gradients. 26 Distribution in the Body Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Distribution in the Body 2 ordo+0 o ○△ ○ ○ 4 o。o○ >oO ○ A Membrane permeation: diffusion B Membrane permeation: transport lysosome Phagolysosome O◎ Extracellular Intracellula Extracellular LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Distribution in the Body 27 C. Membrane permeation: receptor-mediated endocytosis, vesicular uptake, and transport A. Membrane permeation: diffusion B. Membrane permeation: transport Vesicular transport Lysosome Phagolysosome Extracellular Intracellular Extracellular 1 2 3 4 5 7 8 9 6 Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license