18 Drug Administration From Application to Distribution his route is determined by both th physicochemical properties of the drug and the therapeutic requiremen As arule, drugs reach their target organs (acute vs long-term effe via the blood. Therefore, they must fi enter the blood, usually the venous limb by the route and method of application. the circulation. There are several pos- It is fastest with intravenous injection less fast which intramuscula ction he drug may be injected or infused and slowest with subcutaneous injec atravenously, in which case the drug is tion. When the drug is applied to the ntroduced directly into the blood- oral mucosa(buccal, sublingual um. In us or intramus- plasma levels rise faster than with con- ular injection, the drug has to diffuse ventional oral administration because from its site of application into the the drug preparation is deposited at its blood. Because these procedures entail actual site of absorption and very high jury to the outer skin, strict require- concentrations in saliva occur upon the ments must nique For that reason, the oral route take across the oral epithelium is acce (i.e, simple application by mouth) erated. The same does not hold true fo the blood is chosen much more fre- orally, because both the volume of fluid quently. The disadvantage of this route for dissolution and the absorbing sur- is that the drug must pass through the face are much larger in the small intes liver on its way into the general circula- tine than in the oral cavity tion. This fact assumes prac Bioavailability is defined as the cance with any drug that may be rapidly fraction of a given drug dose that reach- transformed or possibly inactivated in es the circulation in unchanged form the liver(first-pass hepatic elimination; and becomes available for systemic dis- p 42). Even with rectal administration, tribution. The larger the presystemic least a fraction of the drug enters the elimination, the smaller is the bioavail- general circulation via the portal vein, ability of an orally administered drug. because only veins draining the short terminal segment of the rectum com- municate directly with the inferior vena cava. Hepatic passage is circumvented hen absorption occurs buccally or from the oral cavity drains directly into he superior vena cava. The same woul (p. 14) However, with this route, a local ffect is usually intended; a systemic ac lso be applied percutaneously in the form of a transdermal delivery system (p. 12). In this case, drug is slowly re- etrates the epidermis and subepiderr n. leased from the reservoir and the pillaries. Only a very few drugs can be applied transdermally. The feasibility of LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
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 absorbable 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 bioavailability of an orally administered drug. 18 Drug Administration Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Drug Administration 19 Sublingual A. From application to distribution LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug Administration 19 Intravenous Sublingual buccal Inhalational Transdermal Subcutaneous Intramuscular Oral Aorta Distribution in body Rectal A. From application to distribution Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
20 Cellular Sites of action Potential Targets of Drug Action gents acting in the cells interior need penetrate the cell membran Drugs are designed to exert a selective The cell membrane basically ence on vital processes in order to sists of a phospholipid bilayer (8 alleviate or eliminate symptoms of dis- 8nm in thickness)in which are embed- ease. The smallest basic unit of an or ganism is the cell. The outer cell me marcates the cell from its surroundings, contain two long-chain fatty acids in es- ter linkage with two of the three hy- nal autonomy. Embedded in the plas- droxyl groups of glycerol Bound to the malema are transport proteins that third hydroxyl group is phosphoric aci serve to mediate controlled metabolic which, in turn, carries a further residue exchange with the cellular environment. e.g. choline, (phosphatidylcholine= led These includ ithin), the amino acid (phospha pumps(e.g, Na, K-ATPase, p. 130),car- serine)or the cyclic polyhydric alco- 178), and ion channels e.g. for sodium terms of solubility, phospholipids are (p.136) or calcium(p.122)(1) amphiphilic: the tail region containing single cells is a prere of the organism, hence also for the sur- drophilic. By virtue of these properties. vival of individual cells. Cell functions phospholipids aggregate spontaneously are regulated by means of messenger into a bilayer in an aqueous medium. substances for the transfer of informa- their polar heads directed outwards int tion. Included among these are"trans- the aqueous medium, the fatty acid mitters"released from nerves, which chains facing each other and projecting the cell is able to recognize with the into the inside of the membrane( 3 embrane bindir The hydrophobic interior of the sites or receptors. Hormones secreted phospholipi ne blood. then diffusion barrier virtuall to the extracellular fluid, represent able for charged particles. another class of chemical signals. Final- cles, however, penetrate the membrane ly, signalling substances can originate easily. This is of major importance with from neighboring cells, e.g. prostaglan- respect to the absorption, distribution dins(p. 196)and cytokines. The effect of a drug frequently re- ults from interference with cellular function. Receptors for the recognition dogenous transmitters are obvious tes of drug action (receptor agonist of transport systems affects cell func. rocesses, for instance by inh diesterase inhibitors, p. or activating(organic nitrates, p. 120) In contrast to drugs acting from the utside on cell membrane constituents LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
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., prostaglandins (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 (80Å = 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 hydroxyl 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 (phosphatidylserine) 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 hydrophilic. 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. 20 Cellular Sites of Action Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Cellular Sites of Action 21 Recep lon channel Cellular substrates Direct action ①=Dng on metabolism 2 f A. Sites at which drugs act to modify cell function LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Cellular Sites of Action 21 Nerve Transmitter Receptor Enzyme Hormone receptors Neural control Hormonal control Direct action on metabolism Cellular transport systems for controlled transfer of substrates Ion channel Transport molecule Effect Intracellular site of action Choline Phosphoric acid Glycerol Fatty acid A. Sites at which drugs act to modify cell function 1 2 3 D Hormones D D D D = Drug Phospholipid matrix D D Protein Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Distribution in the body External Barriers of the Body proceeds rapidly, because the absorbing rface is greatly enlarged due to th Prior to its uptake into the blood (i.e. formation of the epithelial brush border ome barriers that demarcate the body lemma). The absorbability of a drug is from its surroundings, ie separate the characterized by the absorption quo m the external m tient. that is the amount absorbed di lieu. These boundaries are formed by vided by the amount in the gut available ut(enteral absorption), the intestinal ing epithelial cells are also joined on the oithelium is the barrier. This single- luminal side by zonulae occludentes, so ronchial space and the inter ocytes and mucus-producing goblet stitium are separated by a continuou lls. On their luminal side, these cells phospholipid barrier With sublingual or buccal applica dentes(indicated by black dots in the in- tion, a drug encounters the ne et, bottom left). A zomula 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 of desmosomes(n oined via integral membrane proteins shown): however, these do not seal the (semicircular inset, left center) tercellular clefts. Instead. the cells gion of fusion surrounds each cell like a have the property of sequestering phos- ing, so that neighboring cells are weld- pholip nembrane fray ed together in a continuous belt. In this ments that assemble into layers within ner, an unbroken phospholipid the extracellular space(semicircular in- layer is formed (yellow area in the sche. set, center right). In this manner, a con- tIc it)and 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 he case of the gut, the intestinal lumen intestinal epithelia. A similar barrie dark blue)and the interstitial space principle operates in the multilayered (light blue). The efficiency with which keratinized squamous epithelium of the barrier restricts exchange of uter skin. The presence of a contin tances can be increased by arranging ous phospholipid layer means that hese occluding junctions in multiple squamous epithelia will permit passage rrays, as for instance in the endothel um of cerebral blood vessels. The co able of diffusing through phospholipid cting proteins (connexins)fur embranes, 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 ents the intestinal mucosablood bar. as of the skin er that a drug must cross during its en- whose physicochemical prop membrane interior (yellow)o ubject to a special carrier mechanism. Absorption of such drugs LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
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 singlelayered epithelium is made up of enterocytes and mucus-producing goblet cells. On their luminal side, these cells are joined together by zonulae occludentes (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 endothelium 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 enteral 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 interstitium are separated by a continuous phospholipid barrier. With sublingual or buccal application, a drug encounters the non-keratinized, 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 phospholipid-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. 22 Distribution in the Body Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license