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endothelium is discontinuous, allowing free passage between trapping within the cell of a small vesicle containing extracellular
cells. In the liver, hepatocytes form the barrier between intra- and constituents. The vesicle contents can then be released within the
extravascular compartments and take on several endothelial cell cell, or extruded from its other side. This mechanism appears to
functions. Fenestrated endothelium occurs in glands where be important for the transport of some macromolecules (e.g.
hormones or other molecules need to enter or leave the insulin, which crosses the blood–brain barrier by this process),
bloodstream easily through pores in the endothelium. but not for small molecules. Diffusion through lipid and carrier-
Angiogenesis of fenestrated endothelium is controlled by a mediated transport will now be discussed in more detail.
specific endocrine gland-derived vascular endothelial growth
factor (dubbed EG-VEGF). Endothelial cells lining postcapillary
venules have specialised functions relating to leucocyte migration
DIFFUSION THROUGH LIPID
and inflammation: the sophistication of the intercellular junction
can be appreciated from the observation that leucocyte migration Non-polar substances (i.e. substances with molecules in which
can occur without any detectable leak of water or small ions (see electrons are uniformly distributed) dissolve freely in non-polar
Ch. 18). solvents, such as lipids, and, therefore, penetrate cell membranes
There are four main ways by which small molecules cross cell very freely by diffusion. The number of molecules crossing the
membranes (Fig. 7.1): membrane per unit area in unit time is determined by the
permeability coefficient, P, and the concentration difference
• by diffusing directly through the lipid
across the membrane. Permeant molecules must be present within
• by diffusing through aqueous pores formed by special
the membrane in sufficient numbers and must be mobile within
proteins (‘aquaporins’) that traverse the lipid
the membrane if rapid permeation is to occur. Thus two
• by combination with a transmembrane carrier protein that
physicochemical factors contribute to P, namely solubility in the
binds a molecule on one side of the membrane then changes
membrane (which can be expressed as a partition coefficient for
conformation and releases it on the other
the substance distributed between the membrane phase and the
• by pinocytosis.
aqueous environment) and diffusivity, which is a measure of the
Of these routes, diffusion through lipid and carrier-mediated mobility of molecules within the lipid and is expressed as a
transport are particularly important in relation to pharmacokinetic diffusion coefficient. Among different drug molecules the
mechanisms. Diffusion through aquaporins (membrane diffusion coefficient varies only slightly, as noted above, so the
glycoproteins that can be blocked by mercurial reagents such as most important variable is the partition coefficient (Fig. 7.2).
para-chloromercurobenzene sulfonate) is probably important in Consequently, there is a close correlation between lipid solubility
the transfer of gases such as carbon dioxide, but the pores are too and the permeability of the cell membrane to different substances.
small in diameter (about 0.4 nm) to allow most drug molecules For this reason, lipid solubility is one of the most important
(which usually exceed 1 nm in diameter) to pass through. determinants of the pharmacokinetic characteristics of a drug, and
Consequently, drug distribution is not notably abnormal in many properties—such as rate of absorption from the gut,
patients with genetic diseases affecting aquaporins. Pinocytosis penetration into the brain and other tissues, and the extent of renal
involves invagination of part of the cell membrane and the elimination—can be predicted from knowledge of a drug’s lipid
solubility.
pH and ionisation
Diffusion One important complicating factor in relation to membrane
Diffusion through permeation is that many drugs are weak acids or bases and,
through aqueous
lipid channel Carrier therefore, exist in both unionised and ionised form, the ratio of
the two forms varying with pH. For a weak base, the ionisation
reaction is:
EXTRACELLULAR
Ka
BH+ B + H+
and the dissociation constant pKa is given by the
MEMBRANE
Henderson–Hasselbalch equation:
[BH+]
pKa = pH + log10
INTRACELLULAR [B]
For a weak acid:
Ka
Fig. 7.1 Routes by which solutes can traverse cell AH A − + H+
membranes. (Molecules can also cross cellular barriers by
pinocytosis.) [AH]
pKa = pH + log10
92 [A−]
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> 400
Aspirin pH
ka line
Weak acid ta t al
tes Anion
pKa 3.5 rea
tion
g A−
isa
Ion
100
Undissociated
Relative concentration
acid
< 0.1 AH
6
> 10
Ion
isa
tion
gre
ate
Pethidine st a
t ac
id p
H
Weak base
pKa 8.6
Free
100 Protonated base B
base
BH+ 30
Fig. 7.3 Theoretical partition of a weak acid (aspirin) and a weak base (pethidine) between aqueous compartments (urine,
plasma and gastric juice) according to the pH difference between them. Numbers represent relative concentrations (total plasma
concentration = 100). It is assumed that the uncharged species in each case can permeate the cellular barrier separating the
compartments and, therefore, reaches the same concentration in all three. Variations in the fractional ionisation as a function of pH give
rise to the large total concentration differences with respect to plasma.
means to alkalinise urine in treating aspirin overdose (see p. passively, without any energy source; in this case they merely
365): bicarbonate and acetazolamide each increase urine pH facilitate the process of transmembrane equilibration of the
and hence increase salicylate elimination, but bicarbonate transported species in the direction of its electrochemical gradient
reduces whereas acetazolamide increases distribution of and the mechanism is called facilitated diffusion. Alternatively,
salicylate to the CNS. they may be coupled to the electrochemical gradient of Na+; in
this case transport can occur against an electrochemical gradient
and is called active transport. Carrier-mediated transport,
CARRIER-MEDIATED TRANSPORT
because it involves a binding step, shows the characteristic of
Many cell membranes possess specialised transport mechanisms saturation. With simple diffusion, the rate of transport increases
that regulate entry and exit of physiologically important directly in proportion to the concentration gradient, whereas with
molecules, such as sugars, amino acids, neurotransmitters and carrier-mediated transport the carrier sites become saturated at
metal ions. Generally, such transport systems involve a carrier high ligand concentrations and the rate of transport does not
molecule, i.e. a transmembrane protein which binds one or more increase beyond this point. Furthermore, competitive inhibition
molecules or ions, changes conformation and releases them on of transport can occur in the presence of a second ligand that
94 the other side of the membrane. Such systems may operate purely binds the carrier.
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Bases Acids
Strong pKa Weak
Chloroquine
12
Desmethylimipramine Ascorbic acid
Amphetamine 11
Atropine
Histamine 10
Propranolol 9
Chlorpromazine
Phenytoin
Mepyramine 8
Thiopental
Dopamine
Phenobarbital
Noradrenaline (norepinephrine) 7
Chlorothiazide
Morphine 6
Sulphamethoxazole
Ergometrine
5 Warfarin
Trimethoprim
Methotrexate
Chlordiazepoxide 4
Aspirin
Diazepam Probenecid
3
Penicillins
2
Levodopa Fig. 7.4 pKa values for some acidic and
Weak 1 Strong basic drugs.
As a first approximation, the binding reaction can be regarded as Fig. 7.5 Binding of phenylbutazone to plasma albumin.
a simple association of the drug molecules with a finite The graph shows the disproportionate increase in free
concentration as the total concentration increases, owing to the
population of binding sites, exactly analogous to drug–receptor
binding sites approaching saturation. (Data from: Brodie B,
binding (see Ch. 2). Hogben C A M 1957 J Pharm Pharmacol 9: 345.)
D + S DS
free binding complex
drug site
The usual concentration of albumin in plasma is about 0.6 mmol/l been made of binding interactions of this kind as a source of
(4 g/100 ml). With two sites per albumin molecule, the drug- untoward drug interactions in clinical medicine, but this type of
binding capacity of plasma albumin would, therefore, be about competition is less important than was once thought (see Ch. 51).
1.2 mmol/l. For most drugs, the total plasma concentration
required for a clinical effect is much less than 1.2 mmol/l, so with
PARTITION INTO BODY FAT AND OTHER
usual therapeutic doses the binding sites are far from saturated,
TISSUES
and the concentration bound [DS] varies nearly in direct
proportion to the free concentration [D]. Under these conditions Fat represents a large, non-polar compartment. In practice, this is
the fraction bound, [DS]/([D] + [DS]), is independent of the drug important for only a few drugs, mainly because the effective
concentration. However, some drugs, for example tolbutamide fat:water partition coefficient is relatively low for most drugs.
(Ch. 25) and some sulfonamides (Ch. 44), work at plasma Morphine, for example, though quite lipid soluble enough to
concentrations at which the binding to protein is approaching cross the blood–brain barrier, has a lipid:water partition
saturation (i.e. on the flat part of the binding curve). This means coefficient of only 0.4, so sequestration of the drug by body fat is
that addition of more drug to the plasma will increase the free of little importance. Thiopental, by comparison (fat:water
concentration disproportionately. Doubling the dose of such a partition coefficient approximately 10), accumulates substantially
drug can, therefore, more than double the free (pharmacologically in body fat. This has important consequences that limit its
active) concentration. This is illustrated in Figure 7.5. usefulness as an intravenous anaesthetic to short-term initiation
Binding sites on plasma albumin bind many different drugs, so (‘induction’) of anaesthesia (Ch. 35).
competition can occur between them. Administration of drug B The second factor that limits the accumulation of drugs in body
can thereby reduce the protein binding, and hence increase the fat is its low blood supply—less than 2% of the cardiac output.
free plasma concentration, of drug A. To do this, drug B needs to Consequently, drugs are delivered to body fat rather slowly and
occupy an appreciable fraction of the binding sites. Few the theoretical equilibrium distribution between fat and body
therapeutic drugs affect the binding of other drugs because they water is approached slowly. For practical purposes, therefore,
occupy, at therapeutic plasma concentrations, only a tiny fraction partition into body fat when drugs are given acutely is important
of the available sites. Sulfonamides (Ch. 45) are an exception only for a few highly lipid-soluble drugs (e.g. general
because they occupy about 50% of the binding sites at therapeutic anaesthetics; Ch. 35). When lipid-soluble drugs are given
concentrations and so can cause unexpected effects by displacing chronically, however, accumulation in body fat is often
96 other drugs or, in premature babies, bilirubin (Ch. 50). Much has significant (e.g. benzodiazepines; Ch. 36). Furthermore, there are
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Bile
Portal
Liver Kidney Urine
system Metabolites
Oral or rectal Gut Faeces
Percutaneous Skin
Milk,
Intravenous PLASMA Breast, sweat glands
sweat
Intramuscular Muscle
Brain
Placenta
Intrathecal CSF
Fetus
Expired
Inhalation Lung air
20
Particle size and formulation have major effects on absorption.
Acids Bases In 1971, patients in a New York hospital were found to require
10 unusually large maintenance doses of digoxin (Ch. 17). In a study
on normal volunteers, it was found that standard digoxin tablets
5 from different manufacturers resulted in grossly different plasma
concentrations (Fig.7.8) even though the digoxin content of the
2 tablets was the same, because of differences in particle size.
0 2 4 6 8 10 12 Because digoxin is rather poorly absorbed, small differences in
pKa the pharmaceutical formulation can make a large difference to the
extent of absorption.
Fig. 7.7 Absorption of drugs from the intestine as a
function of pKa, for acids and bases. Weak acids and bases Therapeutic drugs are formulated pharmaceutically to produce
are well absorbed; strong acids and bases are poorly absorbed. desired absorption characteristics. Capsules may be designed to
(Redrawn from: Schanker L S et al. 1957 J Pharmacol 120: remain intact for some hours after ingestion in order to delay
528.) absorption, or tablets may have a resistant coating to give the
98 same effect. In some cases, a mixture of slow- and fast-release
F07145-07-rang.qxd 7/1/03 10:57 PM Page 99
Bioavailability
0 To get from the lumen of the small intestine into the systemic
0 1 2 3 4 5
Hours circulation, a drug must not only penetrate the intestinal mucosa,
it must also run the gauntlet of enzymes that may inactivate it in
Fig. 7.8 Variation in oral absorption among different gut wall and liver. The term bioavailability is used to indicate the
formulations of digoxin. The four curves show the mean
proportion of drug that passes into the systemic circulation after
plasma concentrations attained for the four preparations, each
of which was given on separate occasions to four subjects. The oral administration, taking into account both absorption and local
large variation has caused the formulation of digoxin tablets to metabolic degradation. It is a convenient term for making bland
be standardised since this study was published. (From: generalisations, but the concept creaks badly if attempts are made
Lindenbaum J et al. 1971 N Engl J Med 285: 1344.) to use it with quantitative precision, or even to define it.* One
problem is that it is not a characteristic solely of the drug
preparation: variations in enzyme activity of gut wall or liver, in
gastric pH or intestinal motility all affect it. Because of this, one
cannot speak strictly of the bioavailability of a particular
particles is included in a capsule to produce rapid but sustained preparation, but only of that preparation in a given individual on
absorption. More elaborate pharmaceutical systems include a particular occasion. Even with these caveats, the concept is of
various modified-release preparations (e.g. a long-acting form of limited use because it relates only to the total proportion of the
nifedipine that permits once daily use). Such preparations not drug that reaches the systemic circulation and neglects the rate of
only increase the dose interval but also reduce adverse effects absorption. If a drug is completely absorbed in 30 minutes, it will
related to high peak plasma concentrations following reach a much higher peak plasma concentration (and have a more
administration of a conventional formulation (e.g. flushing dramatic effect) than if it were absorbed more slowly. One rarely
following regular nifedipine). Osmotically driven ‘mini-pumps’ sees a numerical value assigned to ‘bioavailability’, and it is well
can be implanted experimentally, and some oral extended-release to be wary of ostensibly measurable quantities that are used
preparations that are used clinically use the same principle, the impressionistically, but not actually given values. For these
tablet containing an osmotically active core and being bounded reasons, regulatory authorities—which have to make decisions
by an impermeable membrane with a precisely engineered pore to about the licensing of products that are ‘generic equivalents’ of
allow drug to exit in solution, delivering drug at an approximately patented products—lay importance on evidence of
constant rate into the bowel lumen. Such preparations may, bioequivalence, i.e. evidence that the new product behaves
however, cause problems related to high local concentrations of sufficiently similarly to the existing one to be substituted for it
drug in the intestine (an osmotically released preparation of the without causing clinical problems.
anti-inflammatory drug indometacin had to be withdrawn
because it caused small bowel perforation) and are subject to
SUBLINGUAL ADMINISTRATION
variations in small bowel transit time that occur during ageing
and with disease. Absorption directly from the oral cavity is sometimes useful
Physicochemical factors (including some drug interactions; (provided the drug does not taste too horrible) when a rapid
Ch. 50) affect drug absorption. Tetracycline binds strongly to response is required, particularly when the drug is either unstable
Ca2+, and calcium-rich foods (especially milk) prevent its at gastric pH or rapidly metabolised by the liver. Glyceryl
absorption (Ch. 44). Bile acid-binding resins such as
colestyramine (used to treat certain forms of hyper-
cholesterolaemia; Ch. 19) bind several drugs, for example
*The definition of bioavailability offered by the US Food and Drug
warfarin (Ch. 20) and thyroxine (Ch. 28). Administration is: ‘The rate and extent to which the therapeutic moiety is
When drugs are administered by mouth, the intention is usually absorbed and becomes available to the site of drug action’. You may be
that they should be absorbed and cause a systemic effect, but forgiven for finding this confusing. The double use of ‘and’ gives the
definition four possible meanings, two of which are obfuscated by the
there are exceptions. Vancomycin is very poorly absorbed and is uncertain meaning of the phrase ‘becomes available to the site of drug
administered orally to eradicate toxin-forming Clostridium action’. 99
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trinitrate is an example of a drug that is often given sublingually believed to take place through mucosa overlying nasal-associated
(Ch. 17). Drugs absorbed from the mouth pass straight into the lymphoid tissue. This is similar to mucosa overlying Peyer’s
systemic circulation without entering the portal system and so patches in the small intestine, which is also unusually permeable.
escape first-pass metabolism.
Eye drops
RECTAL ADMINISTRATION Many drugs are applied as eye drops, relying on absorption
through the epithelium of the conjunctival sac to produce their
Rectal administration is used for drugs that are required either to effects. Desirable local effects within the eye can be achieved
produce a local effect (e.g. anti-inflammatory drugs for use in without causing systemic side effects; for example, dorzolamide
ulcerative colitis) or to produce systemic effects. Absorption is a carbonic anhydrase inhibitor that is given as eye drops to
following rectal administration is often unreliable, but this route lower ocular pressure in patients with glaucoma. It achieves this
can be useful in patients who are vomiting or are unable to take without affecting the kidney (see Ch. 23), thus avoiding the
medication by mouth (e.g. postoperatively). It is used to acidosis that is caused by oral administration of acetazolamide.
administer diazepam to children who are in status epilepticus Some systemic absorption from the eye occurs, however, and can
(Ch. 39) in whom it is difficult to establish intravenous access. result in unwanted effects (e.g. bronchospasm in asthmatic
patients using timolol eye drops for glaucoma).
APPLICATION TO EPITHELIAL SURFACES
Administration by inhalation
Cutaneous administration Inhalation is the route used for volatile and gaseous anaesthetics
Cutaneous administration is used when a local effect on the skin (see Ch. 35), the lung serving as the route both of administration
is required (e.g. topically applied steroids). Appreciable and elimination. The rapid exchange resulting from the large
absorption may nonetheless occur and lead to systemic effects. surface area and blood flow makes it possible to achieve rapid
Most drugs are absorbed very poorly through unbroken skin. adjustments of plasma concentration. The pharmacokinetic
However, a number of organophosphate insecticides (see Ch. 10), behaviour of inhalation anaesthetics is discussed more fully in
which need to penetrate an insect’s cuticle in order to work, are Chapter 35. Recently, the potential of the lung as a site of
absorbed through skin, and accidental poisoning occurs in farm absorption of peptides and proteins has been appreciated, and
workers. inhaled human insulin is being investigated for use in diabetes
▼ A case is recounted of a 35-year-old florist in 1932. ‘While engaged in mellitus (see Ch 25).
doing a light electrical repair job at a work bench he sat down in a chair Drugs used for their effects on the lung are also given by
on the seat of which some “Nico-Fume liquid” (a 40% solution of free
inhalation, usually as an aerosol. Glucocorticoids (e.g.
nicotine) had been spilled. He felt the solution wet through his clothes to
the skin over the left buttock, an area about the size of the palm of his beclometasone) and bronchodilators (e.g. salbutamol; Ch. 22)
hand. He thought nothing further of it and continued at his work for about are given in this way to achieve high local concentrations in the
15 minutes, when he was suddenly seized with nausea and faintness…and lung while minimising systemic side-effects. However, drugs
found himself in a drenching sweat. On the way to hospital he lost given by inhalation in this way are usually partly absorbed into
consciousness.’ He survived, just, and then 4 days later: ‘On discharge
the circulation, and systemic side-effects (e.g. tremor following
from the hospital he was given the same clothes that he had worn when he
was brought in. The clothes had been kept in a paper bag and were still salbutamol) can occur. Chemical modification of a drug may
damp where they had been wet with the nicotine solution.’ The sequel was minimise such absorption. For example, ipratropium, a
predictable. He survived again but felt thereafter ‘unable to enter a muscarinic receptor antagonist (Chs 10 and 22), is a quaternary
greenhouse where nicotine was being sprayed’. Transdermal dosage ammonium ion analogue of atropine. It is used as an inhaled
forms of nicotine are now used to reduce the withdrawal symptoms that
bronchodilator because its poor absorption minimises systemic
accompany stopping smoking (Ch. 52).
adverse effects.
Transdermal dosage forms, in which the drug is incorporated in a
stick-on patch applied to an area of thin skin, are used
increasingly, and several drugs—for example estrogen for
ADMINISTRATION BY INJECTION
hormone replacement (Ch. 29)—are available in this form. Such
patches produce a steady rate of drug delivery and avoid Intravenous injection is the fastest and most certain route of drug
presystemic metabolism. However, the method is suitable only administration. Bolus injection produces a very high
for lipid-soluble drugs and is relatively expensive. concentration of drug, first in the right heart and lungs and then
in the systemic circulation. The peak concentration reaching the
Nasal sprays tissues depends critically on the rate of injection. Administration
Some peptide hormone analogues, for example antidiuretic by steady intravenous infusion avoids the uncertainties of
hormone (Ch. 23), gonadotrophin-releasing hormone (see Ch. 29) absorption from other sites, while avoiding high peak plasma
and calcitonin, are given as nasal sprays. These peptides are concentrations caused by bolus injection. Drugs given
inactive when given orally as they are quickly destroyed in the intravenously include several antibiotics, anaesthetics such as
gastrointestinal tract, but enough is absorbed through the nasal propofol (Ch. 35), and diazepam for patients with status
100 mucosa to provide a therapeutic effect. Such absorption is epilepticus (Ch. 39).
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Interstitial Intracellular
water water
~16% ~35%
B BB B B B B B B B
Plasma Transcellular
water water
~5% ~2%
Table 7.1 Distribution volumes for some drugs compared with volume of body fluid compartments
Volume (l/kg body weight) Compartment Volume of distribution (Vd; l/kg body weight)
105