Color Atlas of Pharmacology (Part 3): Distribution in the Body

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Color Atlas of Pharmacology (Part 3): Distribution in the Body

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Distribution in the Body proceeds rapidly, because the absorbing surface is greatly enlarged due to the formation of the epithelial brush border (submicroscopic foldings of the plasmalemma). The absorbability of a drug is characterized by the absorption quotient, that is, the amount absorbed divided by the amount in the gut available for absorption. In the respiratory tract, cilia-bearing epithelial cells are also joined on the luminal side by zonulae occludentes, so that the bronchial space and the interstitium are separated by a continuous phospholipid barrier. With sublingual or buccal application, a drug encounters the non-keratinized, multilayered squamous epithelium of the...

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  1. 22 Distribution in the Body External Barriers of the Body proceeds rapidly, because the absorbing surface is greatly enlarged due to the Prior to its uptake into the blood (i.e., formation of the epithelial brush border during absorption), a drug has to over- (submicroscopic foldings of the plasma- come barriers that demarcate the body lemma). The absorbability of a drug is from its surroundings, i.e., separate the characterized by the absorption quo- internal milieu from the external mi- tient, that is, the amount absorbed di- lieu. These boundaries are formed by vided by the amount in the gut available the skin and mucous membranes. for absorption. When absorption takes place in the In the respiratory tract, cilia-bear- gut (enteral absorption), the intestinal ing epithelial cells are also joined on the epithelium is the barrier. This single- luminal side by zonulae occludentes, so layered epithelium is made up of ente- that the bronchial space and the inter- rocytes and mucus-producing goblet stitium are separated by a continuous cells. On their luminal side, these cells phospholipid barrier. are joined together by zonulae occlu- With sublingual or buccal applica- dentes (indicated by black dots in the in- tion, a drug encounters the non-kerati- set, bottom left). A zonula occludens or nized, multilayered squamous epitheli- tight junction is a region in which the um of the oral mucosa. Here, the cells phospholipid membranes of two cells establish punctate contacts with each establish close contact and become other in the form of desmosomes (not joined via integral membrane proteins shown); however, these do not seal the (semicircular inset, left center). The re- intercellular clefts. Instead, the cells gion of fusion surrounds each cell like a have the property of sequestering phos- ring, so that neighboring cells are weld- pholipid-containing membrane frag- ed together in a continuous belt. In this ments that assemble into layers within manner, an unbroken phospholipid the extracellular space (semicircular in- layer is formed (yellow area in the sche- set, center right). In this manner, a con- matic drawing, bottom left) and acts as tinuous phospholipid barrier arises also a continuous barrier between the two inside squamous epithelia, although at spaces separated by the cell layer – in an extracellular location, unlike that of the case of the gut, the intestinal lumen intestinal epithelia. A similar barrier (dark blue) and the interstitial space principle operates in the multilayered (light blue). The efficiency with which keratinized squamous epithelium of the such a barrier restricts exchange of sub- outer skin. The presence of a continu- stances can be increased by arranging ous phospholipid layer means that these occluding junctions in multiple squamous epithelia will permit passage arrays, as for instance in the endotheli- of lipophilic drugs only, i.e., agents ca- um of cerebral blood vessels. The con- pable of diffusing through phospholipid necting proteins (connexins) further- membranes, with the epithelial thick- more serve to restrict mixing of other ness determining the extent and speed functional membrane proteins (ion of absorption. In addition, cutaneous ab- pumps, ion channels) that occupy spe- sorption is impeded by the keratin cific areas of the cell membrane. layer, the stratum corneum, which is This phospholipid bilayer repre- very unevenly developed in various are- sents the intestinal mucosa-blood bar- as of the skin. rier that a drug must cross during its en- teral absorption. Eligible drugs are those whose physicochemical properties al- low permeation through the lipophilic membrane interior (yellow) or that are subject to a special carrier transport mechanism. Absorption of such drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  2. Distribution in the Body 23 Nonkeratinized Ciliated epithelium squamous epithelium Epithelium with Keratinized squamous brush border epithelium A. External barriers of the body Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  3. 24 Distribution in the Body Blood-Tissue Barriers e.g., proteins such as insulin (G: insulin storage granules. Penetrability of mac- Drugs are transported in the blood to romolecules is determined by molecu- different tissues of the body. In order to lar size and electrical charge. Fenestrat- reach their sites of action, they must ed endothelia are found in the capillar- leave the bloodstream. Drug permea- ies of the gut and endocrine glands. tion occurs largely in the capillary bed, In the central nervous system where both surface area and time avail- (brain and spinal cord), capillary endo- able for exchange are maximal (exten- thelia lack pores and there is little trans- sive vascular branching, low velocity of cytotic activity. In order to cross the flow). The capillary wall forms the blood-brain barrier, drugs must diffuse blood-tissue barrier. Basically, this transcellularly, i.e., penetrate the lumi- 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 erties (p. 26) or the presence of a trans- “riveted” to each other by tight junc- port mechanism (e.g., L-dopa, p. 188). tions or occluding zonulae (labelled Z in Thus, the blood-brain barrier is perme- the 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 The blood-tissue barrier is devel- fenestrations (100 nm in diameter) fac- oped differently in the various capillary ing Disse’s spaces (D) and where neither beds. Permeability to drugs of the capil- diaphragms nor basement membranes lary wall is determined by the structural impede drug movement. Diffusion bar- and functional characteristics of the en- riers are also present beyond the capil- dothelial cells. In many capillary beds, lary wall: e.g., placental barrier of fused e.g., those of cardiac muscle, endothe- syncytiotrophoblast cells; blood: testi- lial cells are characterized by pro- cle barrier — junctions interconnecting nounced endo- and transcytotic activ- Sertoli cells; brain choroid plexus: blood ity, as evidenced by numerous invagina- barrier — occluding junctions between tions and vesicles (arrows in the EM mi- ependymal cells. crograph, top right). Transcytotic activ- (Vertical bars in the EM micro- ity entails transport of fluid or macro- graphs represent 1 µm; E: cross-sec- molecules from the blood into the inter- tioned erythrocyte; AM: actomyosin; G: stitium and vice versa. Any solutes insulin-containing granules.) trapped in the fluid, including drugs, may traverse the blood-tissue barrier. In this form of transport, the physico- chemical properties of drugs are of little importance. In some capillary beds (e.g., in the pancreas), 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 closed only by diaphragms. Both the dia- phragm and basement membrane can be readily penetrated by substances of low molecular weight — the majority of drugs — but less so by macromolecules, Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  4. Distribution in the Body 25 CNS Heart muscle E AM Z G D Liver Pancreas A. Blood-tissue barriers Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  5. 26 Distribution in the Body Membrane Permeation strate of a carrier will exhibit affinity for it. An ability to penetrate lipid bilayers is a Finally, membrane penetration prerequisite for the absorption of drugs, may 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. brain barrier. Due to their amphiphilic Transcytosis (vesicular transport, nature, phospholipids form bilayers C). When new vesicles are pinched off, possessing a hydrophilic surface and a substances dissolved in the extracellu- hydrophobic interior (p. 20). Substances lar fluid are engulfed, and then ferried may traverse this membrane in three through the cytoplasm, vesicles (phago- different ways. somes) undergo fusion with lysosomes Diffusion (A). Lipophilic substanc- to form phagolysosomes, and the trans- es (red dots) may enter the membrane ported substance is metabolized. Alter- from the extracellular space (area natively, the vesicle may fuse with the shown in ochre), accumulate in the opposite cell membrane (cytopempsis). membrane, and exit into the cytosol Receptor-mediated endocytosis (blue area). Direction and speed of per- (C). The drug first binds to membrane meation depend on the relative concen- surface receptors (1, 2) whose cytosolic 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), the more grate laterally in the membrane and ag- drug will be diffusing per unit of time gregate with other complexes by a (Fick’s Law). The lipid membrane repre- clathrin-dependent process (4). The af- sents an almost insurmountable obsta- fected membrane region invaginates cle for hydrophilic substances (blue tri- and eventually pinches off to form a de- angles). 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- fuses with an “early” endosome (8), respective of their physicochemical whereupon proton concentration rises properties, especially lipophilicity. As a inside the vesicle. The drug-receptor prerequisite, the drug must have affin- complex dissociates and the receptor ity for the carrier (blue triangle match- returns into the cell membrane. The ing recess on “transport system”) and, “early” endosome delivers its contents when bound to the latter, be capable of to predetermined destinations, e.g., the being ferried across the membrane. Golgi complex, the cell nucleus, lysoso- Membrane passage via transport mech- mes, or the opposite cell membrane anisms is subject to competitive inhibi- (transcytosis). Unlike simple endocyto- tion by another substance possessing sis, receptor-mediated endocytosis is similar affinity for the carrier. Substanc- contingent on affinity for specific recep- es lacking in affinity (blue circles) are tors and operates independently of con- not transported. Drugs utilize carriers centration gradients. for physiological substances, e.g., L-do- pa uptake by L-amino acid carrier across the blood-intestine and blood-brain barriers (p. 188), and uptake of amino- glycosides by the carrier transporting basic polypeptides through the luminal membrane of kidney tubular cells (p. 278). Only drugs bearing sufficient re- semblance to the physiological sub- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  6. Distribution in the Body 27 A. Membrane permeation: diffusion B. Membrane permeation: transport 1 2 3 4 8 9 7 6 5 Vesicular transport Lysosome Phagolysosome Extracellular Intracellular Extracellular C. Membrane permeation: receptor-mediated endocytosis, vesicular uptake, and transport Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  7. 28 Distribution in the Body Possible Modes of Drug Distribution Solid substance and and Solid substance structurally bound structurally bound water Following its uptake into the body, the water drug is distributed in the blood (1) and through it to the various tissues of the body. Distribution may be restricted to 40% the extracellular space (plasma volume 20% plus interstitial space) (2) or may also 40% extend into the intracellular space (3). Certain drugs may bind strongly to tis- sue structures, so that plasma concen- trations fall significantly even before intracellular intracellular extra-cellular extracellular elimination has begun (4). water water water water After being distributed in blood, macromolecular substances remain Potential aqueous Potential aqueous solvent solvent spaces for drugs largely confined to the vascular space, spaces for drugs because their permeation through the blood-tissue barrier, or endothelium, is impeded, even where capillaries are Further subdivisions are shown in fenestrated. This property is exploited the table. therapeutically when loss of blood ne- The volume ratio interstitial: intra- cessitates refilling of the vascular bed, cellular water varies with age and body e.g., by infusion of dextran solutions (p. weight. On a percentage basis, intersti- 152). The vascular space is, moreover, tial fluid volume is large in premature or predominantly occupied by substances normal neonates (up to 50 % of body bound with high affinity to plasma pro- water), and smaller in the obese and the teins (p. 30; determination of the plas- aged. ma volume with protein-bound dyes). The concentration (c) of a solution Unbound, free drug may leave the corresponds to the amount (D) of sub- bloodstream, albeit with varying ease, stance dissolved in a volume (V); thus, c because the blood-tissue barrier (p. 24) = D/V. If the dose of drug (D) and its is differently developed in different seg- plasma concentration (c) are known, a ments of the vascular tree. These re- volume of distribution (V) can be calcu- gional differences are not illustrated in lated from V = D/c. However, this repre- the accompanying figures. sents an apparent volume of distribu- Distribution in the body is deter- tion (Vapp), because an even distribution mined by the ability to penetrate mem- in the body is assumed in its calculation. branous barriers (p. 20). Hydrophilic Homogeneous distribution will not oc- substances (e.g., inulin) are neither tak- cur if drugs are bound to cell mem- en up into cells nor bound to cell surface branes (5) or to membranes of intracel- structures and can, thus, be used to de- lular organelles (6) or are stored within termine the extracellular fluid volume the latter (7). In these cases, Vapp can ex- (2). Some lipophilic substances diffuse ceed the actual size of the available fluid through the cell membrane and, as a re- volume. The significance of Vapp as a sult, achieve a uniform distribution (3). pharmacokinetic parameter is dis- Body weight may be broken down cussed on p. 44. as follows: L llmann, Color Atlas of Pharmacology ' 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  8. Distribution in the Body 29 1 2 3 4 Distribution in tissue Plasma Interstitium 6% 25% 4% 65% Erythrocytes Aqueous spaces of the organism Intracellular space Lysosomes Mito- chondria Nucleus Cell membrane 5 6 7 A. Compartments for drug distribution Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  9. 30 Distribution in the Body Binding to Plasma Proteins drug will enter hepatic sites of metab- olism or undergo glomerular filtration. Having entered the blood, drugs may When concentrations of free drug fall, bind to the protein molecules that are drug is resupplied from binding sites on present in abundance, resulting in the plasma proteins. Binding to plasma pro- formation of drug-protein complexes. tein is equivalent to a depot in prolong- Protein binding involves primarily al- ing the duration of the effect by retard- bumin and, to a lesser extent, !-globu- ing elimination, whereas the intensity lins and acidic glycoproteins. Other of the effect is reduced. If two substanc- plasma proteins (e.g., transcortin, trans- es have affinity for the same binding site ferrin, thyroxin-binding globulin) serve on the albumin molecule, they may specialized functions in connection compete for that site. One drug may dis- with specific substances. The degree of place another from its binding site and binding is governed by the concentra- thereby elevate the free (effective) con- tion of the reactants and the affinity of a centration of the displaced drug (a form drug for a given protein. Albumin con- of drug interaction). Elevation of the centration in plasma amounts to free concentration of the displaced drug 4.6 g/100 mL or O.6 mM, and thus pro- means increased effectiveness and ac- vides a very high binding capacity (two celerated elimination. sites per molecule). As a rule, drugs ex- A decrease in the concentration of hibit much lower affinity (KD approx. albumin (liver disease, nephrotic syn- 10–5 –10–3 M) for plasma proteins than drome, poor general condition) leads to for their specific binding sites (recep- altered pharmacokinetics of drugs that tors). In the range of therapeutically rel- are highly bound to albumin. evant concentrations, protein binding of Plasma protein-bound drugs that most drugs increases linearly with con- are substrates for transport carriers can centration (exceptions: salicylate and be cleared from blood at great velocity, certain sulfonamides). e.g., p-aminohippurate by the renal tu- The albumin molecule has different bule and sulfobromophthalein by the binding sites for anionic and cationic li- liver. Clearance rates of these substanc- gands, but van der Waals’ forces also es can be used to determine renal or he- contribute (p. 58). The extent of binding patic blood flow. correlates with drug hydrophobicity (repulsion of drug by water). Binding to plasma proteins is in- stantaneous and reversible, i.e., any change in the concentration of unbound drug is immediately followed by a cor- responding change in the concentration of bound drug. Protein binding is of great importance, because it is the con- centration of free drug that determines the intensity of the effect. At an identi- cal total plasma concentration (say, 100 ng/mL) the effective concentration will be 90 ng/mL for a drug 10 % bound to protein, but 1 ng/mL for a drug 99 % bound to protein. The reduction in con- centration of free drug resulting from protein binding affects not only the in- tensity of the effect but also biotransfor- mation (e.g., in the liver) and elimina- tion in the kidney, because only free Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  10. Distribution in the Body 31 Drug is Drug is not bound strongly to plasma bound to proteins plasma proteins Effect Effect Effector cell Effector cell Biotransformation Biotransformation Renal elimination Renal elimination Plasma concentration Plasma concentration Free drug Bound drug Free drug Time Time A. Importance of protein binding for intensity and duration of drug effect Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
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