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Perspiration ^j1 ^¡^ impossible possible

Dry, non-oily skin u

Oily, moist skin

Perspiration ^j1 ^¡^ impossible possible

Dry, non-oily skin u

Oily, moist skin

A. Dermatologicals as skin protectants

Lipophilic drug in lipophilic base

Lipophilic drug in hydrophilic base

Hydrophilic drug in lipophilic base

Hydrophilic drug in hydrophilic base

Lipophilic drug in lipophilic base

Lipophilic drug in hydrophilic base

Hydrophilic drug in lipophilic base

Hydrophilic drug in hydrophilic base

B. Dermatologicals as drug vehicles

From Application to Distribution in the Body

As a rule, drugs reach their target organs via the blood. Therefore, they must first enter the blood, usually the venous limb of the circulation. There are several possible sites of entry.

The drug may be injected or infused intravenously, in which case the drug is introduced directly into the bloodstream. In subcutaneous or intramuscular injection, the drug has to diffuse from its site of application into the blood. Because these procedures entail injury to the outer skin, strict requirements must be met concerning technique. For that reason, the oral route (i.e., simple application by mouth) involving subsequent uptake of drug across the gastrointestinal mucosa into the blood is chosen much more frequently. The disadvantage of this route is that the drug must pass through the liver on its way into the general circulation. This fact assumes practical significance with any drug that may be rapidly transformed or possibly inactivated in the liver (first-pass hepatic elimination; p. 42). Even with rectal administration, at least a fraction of the drug enters the general circulation via the portal vein, because only veins draining the short terminal segment of the rectum communicate directly with the inferior vena cava. Hepatic passage is circumvented when absorption occurs buccally or sublingually, because venous blood from the oral cavity drains directly into the superior vena cava. The same would apply to administration by inhalation (p. 14). However, with this route, a local effect is usually intended; a systemic action is intended only in exceptional cases. Under certain conditions, drug can also be applied percutaneously in the form of a transdermal delivery system (p. 12). In this case, drug is slowly released from the reservoir, and then penetrates the epidermis and subepidermal connective tissue where it enters blood capillaries. Only a very few drugs can be applied transdermally. The feasibility of this route is determined by both the physicochemical properties of the drug and the therapeutic requirements (acute vs. long-term effect).

Speed of absorption is determined by the route and method of application. It is fastest with intravenous injection, less fast which intramuscular injection, and slowest with subcutaneous injection. When the drug is applied to the oral mucosa (buccal, sublingual route), plasma levels rise faster than with conventional oral administration because the drug preparation is deposited at its actual site of absorption and very high concentrations in saliva occur upon the dissolution of a single dose. Thus, uptake across the oral epithelium is accelerated. The same does not hold true for poorly water-soluble or poorly absorb-able drugs. Such agents should be given orally, because both the volume of fluid for dissolution and the absorbing surface are much larger in the small intestine than in the oral cavity.

Bioavailability is defined as the fraction of a given drug dose that reaches the circulation in unchanged form and becomes available for systemic distribution. The larger the presystemic elimination, the smaller is the bioavail-ability of an orally administered drug.

Potential Targets of Drug Action

Drugs are designed to exert a selective influence on vital processes in order to alleviate or eliminate symptoms of disease. The smallest basic unit of an organism is the cell. The outer cell membrane, or plasmalemma, effectively demarcates the cell from its surroundings, thus permitting a large degree of internal autonomy. Embedded in the plasmalemma are transport proteins that serve to mediate controlled metabolic exchange with the cellular environment. These include energy-consuming pumps (e.g., Na, K-ATPase, p. 130), carriers (e.g., for Na/glucose-cotransport, p. 178), and ion channels e.g., for sodium (p. 136) or calcium (p. 122) (1).

Functional coordination between single cells is a prerequisite for viability of the organism, hence also for the survival of individual cells. Cell functions are regulated by means of messenger substances for the transfer of information. Included among these are "transmitters" released from nerves, which the cell is able to recognize with the help of specialized membrane binding sites or receptors. Hormones secreted by endocrine glands into the blood, then into the extracellular fluid, represent another class of chemical signals. Finally, signalling substances can originate from neighboring cells, e.g., prostaglan-dins (p. 196) and cytokines.

The effect of a drug frequently results from interference with cellular function. Receptors for the recognition of endogenous transmitters are obvious sites of drug action (receptor agonists and antagonists, p. 60). Altered activity of transport systems affects cell function (e.g., cardiac glycosides, p. 130; loop diuretics, p. 162; calcium-antagonists, p. 122). Drugs may also directly interfere with intracellular metabolic processes, for instance by inhibiting (phosphodiesterase inhibitors, p. 132) or activating (organic nitrates, p. 120) an enzyme (2).

In contrast to drugs acting from the outside on cell membrane constituents, agents acting in the cell's interior need to penetrate the cell membrane.

The cell membrane basically consists of a phospholipid bilayer (80À = 8 nm in thickness) in which are embedded proteins (integral membrane proteins, such as receptors and transport molecules). Phospholipid molecules contain two long-chain fatty acids in ester linkage with two of the three hy-droxyl groups of glycerol. Bound to the third hydroxyl group is phosphoric acid, which, in turn, carries a further residue, e.g., choline, (phosphatidylcholine = lecithin), the amino acid serine (phosphat-idylserine) or the cyclic polyhydric alcohol inositol (phosphatidylinositol). In terms of solubility, phospholipids are amphiphilic: the tail region containing the apolar fatty acid chains is lipophilic, the remainder - the polar head - is hy-drophilic. By virtue of these properties, phospholipids aggregate spontaneously into a bilayer in an aqueous medium, their polar heads directed outwards into the aqueous medium, the fatty acid chains facing each other and projecting into the inside of the membrane (3).

The hydrophobic interior of the phospholipid membrane constitutes a diffusion barrier virtually impermeable for charged particles. Apolar particles, however, penetrate the membrane easily. This is of major importance with respect to the absorption, distribution, and elimination of drugs.

Drug Distribution The Body Ppt Images

External Barriers of the Body

Prior to its uptake into the blood (i.e., during absorption), a drug has to overcome barriers that demarcate the body from its surroundings, i.e., separate the internal milieu from the external milieu. These boundaries are formed by the skin and mucous membranes.

When absorption takes place in the gut (enteral absorption), the intestinal epithelium is the barrier. This single-layered epithelium is made up of ente-rocytes and mucus-producing goblet cells. On their luminal side, these cells are joined together by zonulae occlu-dentes (indicated by black dots in the inset, bottom left). A zonula occludens or tight junction is a region in which the phospholipid membranes of two cells establish close contact and become joined via integral membrane proteins (semicircular inset, left center). The region of fusion surrounds each cell like a ring, so that neighboring cells are welded together in a continuous belt. In this manner, an unbroken phospholipid layer is formed (yellow area in the schematic drawing, bottom left) and acts as a continuous barrier between the two spaces separated by the cell layer - in the case of the gut, the intestinal lumen (dark blue) and the interstitial space (light blue). The efficiency with which such a barrier restricts exchange of substances can be increased by arranging these occluding junctions in multiple arrays, as for instance in the endotheli-um of cerebral blood vessels. The connecting proteins (connexins) furthermore serve to restrict mixing of other functional membrane proteins (ion pumps, ion channels) that occupy specific areas of the cell membrane.

This phospholipid bilayer represents the intestinal mucosa-blood barrier that a drug must cross during its en-teral absorption. Eligible drugs are those whose physicochemical properties allow permeation through the lipophilic membrane interior (yellow) or that are subject to a special carrier transport mechanism. Absorption of such drugs 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 inter-stitium are separated by a continuous phospholipid barrier.

With sublingual or buccal application, a drug encounters the non-kerati-nized, multilayered squamous epithelium of the oral mucosa. Here, the cells establish punctate contacts with each other in the form of desmosomes (not shown); however, these do not seal the intercellular clefts. Instead, the cells have the property of sequestering phos-pholipid-containing membrane fragments that assemble into layers within the extracellular space (semicircular inset, center right). In this manner, a continuous phospholipid barrier arises also inside squamous epithelia, although at an extracellular location, unlike that of intestinal epithelia. A similar barrier principle operates in the multilayered keratinized squamous epithelium of the outer skin. The presence of a continuous phospholipid layer means that squamous epithelia will permit passage of lipophilic drugs only, i.e., agents capable of diffusing through phospholipid membranes, with the epithelial thickness determining the extent and speed of absorption. In addition, cutaneous absorption is impeded by the keratin layer, the stratum corneum, which is very unevenly developed in various areas of the skin.

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 en-dothelial 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 macro-molecules from the blood into the inter-stitium and vice versa. Any solutes 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 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 mac-romolecules is determined by molecular size and electrical charge. Fenestrat-ed endothelia are found in the capillaries 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 the blood-brain barrier, drugs must diffuse transcellularly, i.e., penetrate the lumi-nal 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 |im; E: cross-sectioned erythrocyte; AM: actomyosin; G: insulin-containing granules.)

Lipophilic Hydrophilic Medications

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 blood-brain 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-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 resemblance to the physiological sub strate 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 (phago-somes) 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 (adap-tins, 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, lysoso-mes, or the opposite cell membrane (transcytosis). Unlike simple endocyto-sis, receptor-mediated endocytosis is contingent on affinity for specific receptors and operates independently of concentration gradients.

C. Membrane permeation: receptor-mediated endocytosis, vesicular uptake, and transport

Possible Modes of Drug Distribution

Following its uptake into the body, the drug is distributed in the blood (1) and through it to the various tissues of the body. Distribution may be restricted to the extracellular space (plasma volume plus interstitial space) (2) or may also extend into the intracellular space (3). Certain drugs may bind strongly to tissue structures, so that plasma concentrations fall significantly even before elimination has begun (4).

After being distributed in blood, macromolecular substances remain largely confined to the vascular space, because their permeation through the blood-tissue barrier, or endothelium, is impeded, even where capillaries are fenestrated. This property is exploited therapeutically when loss of blood necessitates refilling of the vascular bed, e.g., by infusion of dextran solutions (p. 152). The vascular space is, moreover, predominantly occupied by substances bound with high affinity to plasma proteins (p. 30; determination of the plasma volume with protein-bound dyes). Unbound, free drug may leave the bloodstream, albeit with varying ease, because the blood-tissue barrier (p. 24) is differently developed in different segments of the vascular tree. These regional differences are not illustrated in the accompanying figures.

Distribution in the body is determined by the ability to penetrate membranous barriers (p. 20). Hydrophilic substances (e.g., inulin) are neither taken up into cells nor bound to cell surface structures and can, thus, be used to determine the extracellular fluid volume (2). Some lipophilic substances diffuse through the cell membrane and, as a result, achieve a uniform distribution (3).

Body weight may be broken down as follows:

Solid substance and structurally bound water

intracellular extracellular water water

Potential aqueeus suivent spaces for drugs

Further subdivisions are shown in the table.

The volume ratio interstitial: intra-cellular water varies with age and body weight. On a percentage basis, interstitial fluid volume is large in premature or normal neonates (up to 50% of body water), and smaller in the obese and the aged.

The concentration (c) of a solution corresponds to the amount (D) of substance dissolved in a volume (V); thus, c = D/V. If the dose of drug (D) and its plasma concentration (c) are known, a volume of distribution (V) can be calculated from V = D/c. However, this represents an apparent volume of distribution (Vapp), because an even distribution in the body is assumed in its calculation. Homogeneous distribution will not occur if drugs are bound to cell membranes (5) or to membranes of intracellular organelles (6) or are stored within the latter (7). In these cases, Vapp can exceed the actual size of the available fluid volume. The significance of Vapp as a pharmacokinetic parameter is discussed on p. 44.

intracellular extracellular water water

Distribution in tissue

Plasma

Interstitium

6%

25%

4%

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