When a drug is given at a constant rate continuous or intermittent the time to reach steady state depends only on the t'/ 2 and, for all practical purposes, after 5 x t'/ 2 the amount of
Trang 1Time to reach steady state
If a drug is administered by constant-rate i.v
infusion it is important to know when steady state
has been reached, for maintaining the same dosing
schedule will then ensure a constant amount of
drug in the body and the patient will experience
neither acute toxicity nor decline of effect The t1/2
provides the answer: with the passage of each t1/2
period of time, the plasma concentration rises by
half the difference between the current concentration
and the ultimate steady-state (100%) concentration
Thus:
in 1 x t1/2, the concentration will reach (100/2)
50%,
in 2 x t1/2 (50 + 50/2) 75%,
in 3 x i\ (75 + 25/2) 87.5%,
in 4 x ty2 (87.5 + 12.5/2) 93.75%
in 5 x i\ (93.75 + 6.25/2) 96.875% of the ultimate
steady state
When a drug is given at a constant rate (continuous or
intermittent) the time to reach steady state depends only
on the t'/ 2 and, for all practical purposes, after 5 x t'/ 2 the
amount of drug in the body will be constant and the
plasma concentration will be at a plateau.
Changes in plasma concentration
The same principle holds for change from any
steady-state plasma concentration to a new steady
state brought about by increase or decrease in the
rate of drug administration, provided the kinetics
remain first-order Thus when the rate of
admin-istration is altered to cause either a rise or a fall in
plasma concentration, a new steady-state
concen-tration will eventually be reached and it will take
a time equal to 5 x t l / 2 to reach the new steady
state
Note that the actual level of any steady-state
plasma concentration (as opposed to the time taken
to reach it) is determined only by the difference
between the rate of drug administration (input) and
the rate of elimination (output) If drug elimination
remains constant and administration is increased
by 50%, in time a new steady-state concentration
will be reached which will be 50% greater than the
original
Decline in plasma concentration
Since t1/2 is the time taken for any plasma con-centration to decline by one-half, starting at any steady-state (100%) plasma concentration, in 1 x t1/2 the plasma concentration will fall to 50%, in 2 x t1/2
to 25%, in 3 x t1/2 to 12.5%, in 4 x t1/2 to 6.25% and in
5 x t1/2 to 3.125% of the original steady-state concentration
Hence the i l / 2 can predict the rate and extent of decline in plasma concentration after dosing is discontinued The relation between t/£ and time to reach steady-state plasma concentration applies to all drugs that obey first-order kinetics, as much to dobutamine (t/£ 2 min) when it is useful to know that an alteration of infusion rate will reach a
plateau within 10 min, as to digoxin (i l / 2 36 h) when
a constant (repeated) dose will give a steady-state plasma concentration only after 7.5 days Plasma t1/2 values are given in the text where they seem particularly relevant Inevitably, natural variation within the population produces a range in tl / 2 values for any drug For clarity only, single average t1/2 values are given while recognising that the population range may be as much as 50% from the stated figure
in either direction
A few t1/2 values are listed in Table 7.1 so that they can be pondered upon in relation to dosing in clinical practice
Biological effect t^ is the time in which the biological effect of a drug declines by one half With drugs that act competitively on receptors (a- and (3-adrenoceptor agonists and antagonists) the biological effect t1/2 can be provided with reasonable accuracy
TABLE 7.1 Plasma t'/ 2 of some drugs
adenosine dobutamine benzylpenicillin amoxycillin paracetamol midazolam tolbutamide atenolol dothiepin (dosulepin) diazepam
piroxicam ethosuximide
< 2 s e c
2 min
30 min
1 h
2 h
3 h
6 h
7 h
25 h
40 h
45 h
54 h
Trang 2T I M E C O U R S E O F D R U G C O N C E N T R A T I O N A N D E F F E C T 7
Sometimes the biological effect t l / 2 cannot be
pro-vided, e.g with antimicrobials when the number of
infecting organisms and their sensitivity determine
the outcome
THERAPEUTIC MONITORING
The issues that concern the practising doctor are not
primarily those of changing drug plasma
concen-tration but relate to drug effect: to the onset,
magnitude and duration of action of individual
doses Accurate information about the time course
of drug action is less readily obtained than that
about plasma concentration This immediately raises
implications about the relation between plasma
concentration and drug effect and, particularly, the
extent to which useful response may be predicted
by measuring the concentration of drug in plasma
Experience shows that patients differ greatly in
the amount of drug required to achieve the same
response The dose of warfarin that maintains a
therapeutic concentration may vary as much as
5-fold between individuals, and there are many other
examples This is hardly surprising considering
known variation in rates of drug metabolism, in
disposition and in tissue responsiveness, and it
raises the question of how optimal drug effect can
be achieved quickly in each patient, i.e can drug
therapy be individualised? A logical approach is to
assume that effect is related to drug concentration
at the receptor site in the tissues and that in turn the
plasma concentration is likely to be constantly
related to, though not necessarily the same as, tissue
concentration Indeed, for many drugs, correlation
between plasma concentration and clinical effect is
better than that between dose and effect Yet
monitoring therapy by measuring drug in plasma is
of practical use only in selected instances The
reasons for this repay some thought
Plasma concentration may not be worth measuring.
This is the case where dose can be titrated against a
quickly and easily measured effect such as blood
pressure (antihypertensives), body weight (diuretics),
INR (oral anticoagulants) or blood sugar
(hyp-oglycaemics)
Plasma concentration has no correlation with
effect This is the case with drugs that act
irreversibly and these have been named 'hit and run drugs' because their effect persists long after the drug has left the plasma Such drugs destroy or inactivate target tissue (enzyme, receptor) and restoration of effect occurs only after days or weeks, when resynthesis takes place, e.g some monoamine oxidase inhibitors, aspirin (on platelets), some anticholinesterases and anticancer drugs
Plasma concentration may correlate poorly with effect Inflammatory states may cause misleading results if only total drug concentration is measured Many basic drugs, e.g lidocaine, disopyramide, bind
to acute phase proteins, e.g o^-acid glycoprotein, which are present in greatly elevated concentration
in inflammatory states The consequent rise in total drug concentration is due to increase in bound (inactive) but not in the free (active) concentration and correlation with effect will be poor if only total drug is measured The best correlation is likely to be achieved by measurement of free (active) drug in plasma water but this is technically more difficult and total drug in plasma is usually monitored in routine clinical practice
The assay procedure may not measure metabolites
of a drug that are pharmacologically active, e.g some benzodiazepines, or may measure metabolites that are pharmacologically inactive; in either event correlation between plasma concentration and effect is weakened
Plasma concentration may correlate well with effect.
When this is the case, and when the therapeutic effect is inconvenient to measure, dosage may best
be monitored according to the plasma concentration (in relation to a previously defined optimum range) Plasma concentration monitoring has proved useful in the following situations:
• As a guide to the effectiveness of therapy, e.g plasma gentamicin and other antimicrobials against sensitive bacteria, plasma theophylline for asthma, blood ciclosporin to avoid transplant rejection
• When the desired effect is suppression of infrequent sporadic events such as epileptic seizures or episodes of cardiac arrhythmia
• To reduce the risk of adverse drug effects, e.g otic damage with aminoglycoside antibiotics or
Trang 3adverse CNS effects of lithium, when therapeutic
doses are close to toxic doses (low therapeutic
index)
When lack of therapeutic effect and toxicity may
be difficult to distinguish Digoxin is both a
treatment for, and sometimes the cause of,
cardiac supraventricular tachycardia; a plasma
digoxin measurement will help to distinguish
whether an arrhythmia is due to too little or too
much digoxin
When there is no quick and reliable assessment
of effect, e.g lithium for mood disorder
To check patient compliance on a drug regimen,
when there is failure of therapeutic effect at a
dose that is expected to be effective, e.g
antiepilepsy drugs
To diagnose and treat drug overdose
Interpreting plasma concentration
measurements
The following points are relevant:
• A target therapeutic concentration range quoted
for a drug should be regarded only as a guide to
help to optimise dosing and should be evaluated
with other clinical indicators of progress
• Consider whether a patient has been taking a
drug for a sufficient time to reach steady-state
conditions, i.e when 5 t1/2 periods have elapsed
since dosing commenced or since the last change
in dose In the case of drugs that alter their own
rates of metabolism by enzyme induction, e.g
carbamazepine and phenytoin, it is best to allow
2-4 weeks to elapse between change in dose and
plasma concentration measurement Sampling
when plasma concentrations are still rising or
falling towards a steady state is likely to be
misleading
• Consider whether peak or trough concentration
should be measured As a general rule when a
drug has a short t l / 2 it is desirable to know both;
monitoring peak (15 min after an i.v dose) and
trough (just before the next dose) concentrations
of gentamicin (t1/2 2.5 h) helps to provide efficacy
without toxicity For a drug with a long t1/2, it is
usually best to sample just before a dose is due;
effective immunosuppression with ciclosporin
(t l / 2 27 h) is obtained with trough concentrations
of 50-200 micrograms/1 when the drug is given
by mouth
Recommended plasma concentrations for drugs appear throughout this book where these are relevant
Individual pharmacokinetic processes
This section considers the processes whereby drugs are absorbed into, distributed around, metabolised
by and eliminated from the body
Absorption
Commonsense considerations of anatomy, physio-logy, pathophysio-logy, pharmacophysio-logy, therapeutics and convenience determine the routes by which drugs are administered Usually these are:
• Enteral: by mouth (swallowed) or by sublingual
or buccal absorption; by rectum
• Parenteral: by intravenous injection or infusion,
intramuscular injection, subcutaneous injection
or infusion, inhalation, topical application for local (skin, eye, lung) or for systemic
(transdermal) effect
• Other routes, e.g intrathecal, intradermal,
intranasal, intratracheal, intrapleural, are used when appropriate
The features of the various routes, their advantages and disadvantages are relevant
ABSORPTION FROM THE GASTROINTESTINAL TRACT
The small intestine is the principal site for absorption
of nutrients and it is also where most orally-administered drugs enter the body This part of the gut has two important attributes, an enormous surface area due to the intestinal villi, and an epithelium through which fluid readily filters in response to osmotic differences caused by the
Trang 4presence of food It follows that drug access to the
small intestinal mucosa is important and disturbed
alimentary motility can reduce absorption, i.e if
gastric emptying is slowed by food, or intestinal
transit is accelerated by gut infection The colon is
capable of absorbing drugs and many
sustained-release formulations probably depend on absorption
there
Absorption of ionisable drugs from the buccal
mucosa is influenced by the prevailing pH which is
6.2-7.2 Lipid-soluble drugs are rapidly effective by
this route because blood flow through the mucosa
is abundant and entry is directly into the systemic
circulation, avoiding the possibility of first-pass
(presystemic) inactivation in the liver (see below)
The stomach does not play a major role in absorbing
drugs, even those that are acidic and thus
un-ionised and lipid-soluble at gastric pH, because its
surface area is much smaller than that of the small
intestine and gastric emptying is speedy (t/£ 30 min)
ENTEROHEPATIC CIRCULATION
This system is illustrated by the bile salts, which are
conserved by circulating through liver, intestine
and portal blood about eight times a day A number
of drugs form conjugates with glucuronic acid in
the liver and are excreted in the bile These
glucuronides are too polar (ionised) to be reabsorbed;
they therefore remain in the gut, are hydrolysed by
intestinal enzymes and bacteria, releasing the parent
drug, which is then reabsorbed and reconjugated in
the liver Enterohepatic recycling appears to help
sustain the plasma concentration and thus the effect
of sulindac, pentaerythritol tetranitrate and
ethinyloestradiol (in many oral contraceptives)
SYSTEMIC AVAILABILITY AND
BIOAVAILABILITY
When a drug is injected intravenously it enters the
systemic circulation and thence gains access to the
tissues and to receptors, i.e 100% is available to
exert its therapeutic effect If the same quantity of
the drug is swallowed, it does not follow that the
entire amount will reach first the portal blood and
then the systemic blood, i.e its availability for
therapeutic effect via the systemic circulation may
be less than 100% The anticipated response to a
A B S O R P T I O N
drug may not be achieved unless availability to the systemic circulation is taken into account In a strict sense, considerations of reduced availability apply whenever any drug intended for systemic effect is given by any route other than the intravenous, but
in practice the issue concerns enteral admin-istration The extent of systemic availability is ordinarily calculated by relating the area under the plasma concentration-time curve (AUC) after a single oral dose to that obtained after i.v admin-istration of the same amount (by which route a drug is 100% systemically available) Different pharmaceutical formulations of the same drug can thus be compared Factors influencing systemic availability may be thought of in three main ways:
Pharmaceutical factors 8 The amount of drug that
is released from a dose form (and so becomes
available for absorption) is referred to as its
bio-availability This is highly dependent on its
pharma-ceutical formulation With tablets, for example, particle size (surface area exposed to solution), diluting substances, tablet size and pressure used in the tabletting machine can affect disintegration and dissolution and so the bioavailability of the drug Manufacturers are expected to produce a formulation with an unvarying bioavailability so that the same amount of drug is released with the same speed from whatever manufactured batch or brand the patient may be taking Substantial differences in bioavailability of digoxin tablets from one manufacturer occurred when only the technique and machinery for making the tablets were changed; also tablets containing the same amount
8 Some definitions of enteral dose-forms: Tablet: a solid dose
form in which the drug is compressed or moulded with pharmacologically inert substances (excipients); variants
include sustained-release and coated tablets Capsule: the drug is provided in a gelatin shell or container Mixture: a
liquid formulation of a drug for oral administration.
Suppository: a solid dose-form shaped for insertion into
rectum (or vagina, when it may be called a pessary); it may be
designed to dissolve or it may melt at body temperature (in which case there is a storage problem in countries where the environmental temperature may exceed 37°C); the vehicle in which the drug is carried may be fat, glycerol with gelatin, or macrogols (polycondensation products of ethylene oxide)
with gelatin Syrup: the drug is provided in a concentrated sugar (fructose or other) solution Linctus: a viscous liquid
formulation, traditional for cough.
Trang 5of digoxin but made by different companies, were
shown to produce different plasma concentrations
and therefore different effects, i.e there was neither
bioequivalence nor therapeutic equivalence Physicians
tend to ignore pharmaceutical formulation as a
factor in variable or unexpected responses because
they do not understand it and feel entitled to rely
on reputable manufacturers and official regulatory
authorities to ensure provision of reliable
formu-lations Good pharmaceutical companies reasonably
point out that, having a reputation to lose, they take
much trouble to make their preparations consistently
reliable This is a matter of great importance when
dosage must be precise (anticoagulants, antidiabetics,
adrenal steroids) The following account by Lauder
Brunton in 1897 indicates that the phenomenon of
variable bioavailability is not recent.
A very unfortunate case occurred some time ago in
a doctor who had prescribed aconitine to a patient
and gradually increased the dose He thought he
was quite certain that he knew what he was doing.
The druggist's supply of aconitine ran out, and he
procured some new aconitine from a different
maker This turned out to be many times stronger
than the other, and the patient unfortunately
became very ill The doctor said, Tt cannot be the
medicine', and to show that this was true, he drank
off a dose himself with the result that he died So
you must remember the difference in the different
preparations of aconitine, 9
i.e they had different bioavailability and so lacked
therapeutic equivalence.
Biological factors Those related to the gut include
destruction of drug by gastric acid, e.g
benzyl-penicillin, and impaired absorption due to intestinal
hurry which is important for all drugs that are
slowly absorbed Drugs may also bind to food
constituents, e.g tetracyclines to calcium (in milk),
and to iron, or to other drugs (e.g acidic drugs to
cholestyramine) and the resulting complex is not
absorbed.
Presystemic (first-pass) elimination Despite the
9 The doctor would have died of cardiac arrhythmia and/or
cerebral depression Aconitine is a plant alkaloid and has no
place in medicine.
fact that they readily enter gut mucosal cells, some drugs appear in low concentration in the systemic circulation The reason lies in the considerable extent
to which such drugs are metabolised in a single passage through the gut wall and (principally) the liver This is a significant feature of the oral route, and as little as 10-20% of the parent drug may reach the systemic circulation unchanged By contrast, if the drug is given intravenously, 100% becomes systemically available and the patient is exposed
to higher concentrations with greater, but more predictable, effect If a drug produces active metabolites, differences in dose may not be as great
as those anticipated on the basis of differences in plasma concentration of the parent drug after intravenous and oral administration Once a drug is
in the systemic circulation, irrespective of which route is used, about 20% is subject to the hepatic metabolic processes in each circulation because that
is the proportion of cardiac output that passes to the liver.
As the degree of presystemic elimination differs much between drugs and between individuals, the phenomenon of first-pass elimination adds to variation in systemic plasma concentrations, and thus particularly in initial response to the drugs that are subject to this process When a drug is taken in overdose, presystemic elimination may be reduced, and bioavailability increased; this may explain rapid onset of toxicity with antipsychotic drugs, many of which undergo first-pass elimination.
Drugs for which presystemic elimination is significant include:
Analgesics
dextropropoxyphene morphine
pentazocine pethidine
Adrenoceptor b/ockers labetalol
propranolol metoprolol oxprenolol
Others clomethiazole chlorpromazine isosorbide dinitrate nortriptyline
In severe hepatic cirrhosis with both impaired liver cell function and well-developed channels shunting blood into the systemic circulation without passing through the liver, first-pass elimination is reduced and systemic availability is increased The result of these changes is an increased likelihood of exaggerated response to normal doses of drugs
Trang 6having high hepatic clearance and, on occasion,
frank toxicity
Drugs that exhibit the hepatic first-pass
phenom-enon do so because of the rapidity with which they
are metabolised The rate at which drug is delivered
to the liver, i.e blood flow, is then the main
determinant of its metabolism Many other drugs
are completely metabolised by the liver but at a
slower rate and consequently loss in the first pass
through the liver is unimportant The parenteral
dose of these drugs does not need to be reduced to
account for presystemic elimination Such drugs
include diazepam, phenytoin, theophylline, warfarin
ADVANTAGES AND DISADVANTAGES
OF ENTERAL ADMINISTRATION
By swallowing
For systemic effect Advantages are convenience
and acceptability
Disadvantages are that absorption may be delayed,
reduced or even enhanced after food or slow or
irregular after drugs that inhibit gut motility
(antimuscarinic, opioid) Differences in presystemic
elimination are a cause of variation in drug effect
between patients Some drugs are not absorbed
(gentamicin) and some drugs are destroyed in the
gut (insulin, oxytocin, some penicillins) Tablets
taken with too small a quantity of liquid and in the
supine position, can lodge in the oesophagus with
delayed absorption10 and may even cause ulceration
(sustained-release potassium chloride and
doxy-cycline tablets), especially in the feeble elderly and
those with an enlarged left atrium which impinges
on the oesophagus.11
10 A woman's failure to respond to antihypertensive
medication was explained when she was observed to choke
on drinking Investigation revealed a large pharyngeal
pouch that was full of tablets and capsules Her blood
pressure became easy to control when the pouch was
removed Birch D J, Dehn T C B 1993 British Medical Journal
306:1012.
11 Ideally solid-dose forms should be taken standing up and
washed down with 150 ml (tea cup) of water; even sitting
(higher intra-abdominal pressure) impairs passage At least
patients should be told to sit and take 3 or 4 mouthfuls of
water (a mouthful = 30 ml) or a cupful Some patients do not
even know they should take water.
A B S O R P T I O N
For effect in the gut Advantages are that the drug is
placed at the site of action (neomycin, anthelminthics), and with nonabsorbed drugs the local concentration can be higher than would be safe in the blood
Disadvantages are that drug distribution may be
uneven, and in some diseases of the gut the whole thickness of the wall is affected (severe bacillary dysentery, typhoid) and effective blood concentra-tions (as well as luminal concentraconcentra-tions) may be needed
Sublingual or buccal for systemic effect
Advantages are that quick effect is obtained, e.g.
with glyceryl trinitrate as an aerosol spray, or as sublingual tablets which can be chewed, giving greater surface area for solution Spitting out the tablet will terminate the effect
Disadvantages are the inconvenience if use has to
be frequent, irritation of the mucous membrane and excessive salivation which promotes swallowing,
so losing the advantages of bypassing presystemic elimination
Rectal administration For systemic effect (suppositories or solutions).
The rectal mucosa has a rich blood and lymph supply and, in general, dose requirements are either the same or slightly greater than those needed for oral use Drugs chiefly enter the portal system, but those that are subject to hepatic first-pass elimination may escape this if they are absorbed from the lower rectum which drains directly to the systemic circulation The degree of presystemic elimination thus depends on distribution within the rectum and this is somewhat unpredictable
Advantages are that a drug that is irritant to the
stomach can be given by suppository (aminophylline, indomethacin); the route is suitable in vomiting, motion sickness, migraine or when a patient cannot swallow, and when cooperation is lacking (sedation
in children)
Disadvantages are psychological in that the
patient may be embarrassed or may like the route too much; rectal inflammation may occur with repeated use and absorption can be unreliable, especially if the rectum is full of faeces
Trang 7For local effect, e.g in proctitis or colitis, an obvious
use
A survey in the UK showed that a substantial
proportion of patients did not remove the wrapper
before inserting the suppository
ADVANTAGES AND DISADVANTAGES
OF PARENTERAL ADMINISTRATION
(for systemic and local effect)
Intravenous (bolus or infusion)
An i.v bolus, i.e rapid injection, passes round the
circulation being progressively diluted each time; it
is delivered principally to the organs with high
blood flow (brain, liver, heart, lung, kidneys)
Advantages are that the i.v route gives swift,
effective and highly predictable blood concentration
and allows rapid modification of dose, i.e immediate
cessation of administration is possible if unwanted
effects occur during administration The route is
suitable for administration of drugs that are not
absorbed from the gut or are too irritant (anticancer
agents) to be given by other routes
Disadvantages are the hazard if a drug is given
too quickly, as plasma concentration may rise at
such a rate that normal mechanisms of distribution
and elimination are outpaced Some drugs will act
within one arm-to-tongue (brain) circulation time
which is 13 ± 3 seconds; with most drugs an
injection given over 4 or 5 circulation times seems
sufficient to avoid excessive plasma concentrations
Local venous thrombosis is liable to occur with
prolonged infusion and with bolus doses of irritant
formulations, e.g diazepam, or microparticulate
components of infusion fluids, especially if small
veins are used Infection of the intravenous catheter
and the small thrombi on its tip are also a risk
during prolonged infusions
Intramuscular injection
Blood flow is greater in the muscles of the upper
arm than in the gluteal mass and thigh, and also
increases with physical exercise (Usually these
influences are unimportant but one football-playing
patient who was given an intramuscular injection
of a sustained-release phenothiazine developed an
extrapyramidal disorder towards the end of the game, presumably due to too rapid absorption of the drug.)
Advantages are that the route is reliable, suitable
for irritant drugs, and depot preparations (neuroleptics, hormonal contraceptives) can be used at monthly
or longer intervals Absorption is more rapid than following subcutaneous injection (soluble prep-arations are absorbed within 10-30 min)
Disadvantages are that the route is not acceptable
for self-administration, it may be painful, and if any adverse effects occur to a depot formulation, it cannot be removed
Subcutaneous injection
Advantages are that the route is reliable and is
acceptable for self-administration
Disadvantages are poor absorption in peripheral
circulatory failure Repeated injections at one site can cause lipoatrophy, resulting in erratic absorption (see Insulin)
By inhalation
As a gas, e.g volatile anaesthetics
As an aerosol, e.g P2-adrenoceptor agonist bron-chodilators Aerosols are particles dispersed in a gas, the particles being small enough to remain in suspension for a long time instead of sedimenting rapidly under the influence of gravity; the particles may be liquid (fog) or solid (smoke)
As a powder, e.g sodium cromoglicate Particle
size and air flow velocity are important Most particles above 5 micrometres in diameter impact in the upper respiratory areas; particles of about 2 micrometres reach the terminal bronchioles; a large proportion of particles less than micrometer will be exhaled Air flow velocity diminishes considerably
as the bronchi progressively divide, promoting drug deposition peripherally
Advantages are that drugs as gases can be rapidly
taken up or eliminated, giving the close control that has marked the use of this route in general anaesthesia from its earliest days Self-administration
is practicable Aerosols and powders provide
Trang 8high local concentration for action on bronchi,
minimising systemic effects
Disadvantages are that special apparatus is
needed (some patients find pressurised aerosols
difficult to use to best effect) and a drug must be
nonirritant if the patient is conscious Obstructed
bronchi (mucus plugs in asthma) may cause therapy
to fail
Topical application
For local effect, e.g to skin, eye, lung, anal canal,
rectum, vagina
Advantage is the provision of high local
con-centration without systemic effect (usually12)
Disadvantage is that absorption can occur,
especially when there is tissue destruction so that
systemic effects result, e.g adrenal steroids and
neomycin to the skin, atropine to the eye Ocular
administration of a (3-adrenoceptor blocker may
cause systemic effects (any first-pass elimination is
bypassed) and such eye drops are contraindicated
for patients with asthma or chronic lung disease.13
There is extensive literature on this subject
charac-terised by expressions of astonishment that serious
effects, even death, can occur
For systemic effect Transdermal delivery systems
(TDS) release drug through a rate-controlling
membrane into the skin and so into the systemic
circulation Fluctuations in plasma concentration
associated with other routes of administration are
largely avoided, as is first-pass elimination in the
D I S T R I B U T I O N
liver Glyceryl trinitrate and postmenopausal hormone replacement therapy may be given this way, in the form of a sticking plaster attached to the skin14 or as an ointment (glyceryl trinitrate) A nasal spray containing sumatriptan may be used to treat migraine
Distribution
If a drug is required to act throughout the body or
to reach an organ inaccessible to topical admin-istration, it must be got into the blood and into other body compartments Most drugs distribute widely, in part dissolved in body water, in part bound to plasma proteins, in part to tissues Distribution is often uneven, for drugs may bind selectively to plasma or tissue proteins or be localised within particular organs Clearly, the site
of localisation of a drug is likely to influence its action, e.g whether it crosses the blood-brain barrier to enter the brain; the extent (amount) and strength (tenacity) of protein or tissue binding (stored drug) will affect the time it spends in the body and thereby its duration of action
Drug distribution, its quantification and its clinical implications are now discussed
DISTRIBUTION VOLUME
The pattern of distribution from plasma to other body fluids and tissues is a characteristic of each
12 A cautionary tale A 70-year-old man reported left breast
enlargement and underwent mastectomy; histological
examination revealed benign gynaecomastia Ten months
later the right breast enlarged Tests of endocrine function
were normal but the patient himself was struck by the fact
that his wife had been using a vaginal cream (containing
0.01% dienestrol) initially for atrophic vaginitis but latterly
the cream had been used to facilitate sexual intercourse
which took place two to three times a week On the
assumption that penile absorption of oestrogen was
responsible for the disorder, exposure to the cream was
terminated The gynaecomastia in the remaining breast then
resolved (Di Raimondo C V et al 1980 New England Journal
of Medicine 302:1089).
13 Two drops of 0.5% timolol solution, one to each eye, can
equate to 10 mg by mouth.
14 But TDS may have an unexpected outcome for, not only may the sticking plaster drop off unnoticed, it may find its way onto another person A hypertensive father rose one morning and noticed that his clonidine plaster was missing from his upper arm He could not find it and applied a new plaster His nine-month-old child, who had been taken into the paternal bed during the night because he needed comforting, spent an irritable and hypoactive day, refused food but drank and passed more urine than usual The missing clonidine patch was discovered on his back when he was being prepared for his bath No doubt this was accidental, but children also enjoy stick-on decoration and the possibility of poisoning from misused, discarded or new (e.g strong opioid, used in palliative care) drug plasters means that these should be kept and disposed of as carefully
as oral formulations (Reed M T et al 1986 New England Journal of Medicine 314: 1120).
Trang 9The distribution volume of a drug is the volume in which
it appears to distribute (or which it would require) if the
concentration throughout the body were equal to that in
plasma, i.e as if the body were a single compartment.
drug that enters the circulation and it varies between
drugs Precise information on the concentration of
drug attained in various tissues and fluids requires
biopsy samples and for understandable reasons this
is usually not available for humans (although
positive emission tomography offers a prospect of
obtaining similar information).15 What can be
sampled readily in humans is blood plasma, the
drug concentration in which, taking account of the
dose, is a measure of whether a drug tends to
remain in the circulation or to distribute from the
plasma into the tissues If a drug remains mostly in
the plasma, its distribution volume will be small; if
it is present mainly in other tissues the distribution
volume will be large
Such information is clinically useful Consider
drug overdose Removing a drug by haemodialysis
is likely to be a beneficial exercise only if a major
proportion of the total body load is in the plasma,
e.g with salicylate which has a small distribution
volume; but haemodialysis is an inappropriate
treatment for overdose with dothiepin which has a
large distribution volume These, however, are
generalisations and if the knowledge of distribution
volume is to be of practical value it must be
quantified more precisely
The principle for establishing the distribution
volume is essentially that of using a dye to find the
volume of a container filled with liquid The weight
of dye that is added divided by the concentration of
dye once mixing is complete gives the distribution
volume of the dye, which is the volume of the
container Similarly, the distribution volume of a
drug in the body may be determined after a single
15 With positron emission tomography (PET), a positron
emitting isotope, e.g 15 O, is substituted for a stable atom
without altering the chemical behaviour of the molecule.
The radiation dose is very low but can be imaged
tomographically using photomultiplier-scintillator detectors.
PET can be used to monitor effects of drugs on metabolism in
the brain, e.g 'on' and 'off phases in parkinsonism There
are many other applications.
intravenous bolus dose by dividing the dose given
by the concentration achieved in plasma.16 The result of this calculation, the distribution volume, in fact only rarely corresponds with a physiological body space such as extracellular water or total body water, for it is a measure of the volume a drug would apparently occupy knowing the dose given and the plasma concentration achieved and assuming the entire volume is at that concentration For this reason, it is often referred to
as the apparent distribution volume Indeed, for some
drugs that bind extensively to extravascular tissues, the apparent distribution volume, which is based
on the resulting low plasma concentration, is many times total body volume
Distribution volume is the volume of fluid in which the drug appears to distribute with a concentration equal to that in plasma.
The list in Table 7.2 illustrates a range of apparent distribution volumes The names of those substances that distribute within (and have been used to measure) physiological spaces are printed
in italics
Selective distribution within the body occurs because of special affinity between particular drugs and particular body constituents Many drugs bind to proteins in the plasma; phenothiazines and chloro-quine bind to melanin-containing tissues, including the retina, which may explain the occurrence of retinopathy Drugs may also concentrate selectively
in a particular tissue because of specialised transport mechanisms, e.g iodine in the thyroid
16 Clearly a problem arises in that the plasma concentration is not constant but falls after the bolus has been injected To get round this, use is made of the fact that the relation between the logarithm of plasma concentration and the time after a single intravenous dose is a straight line The log concentration-time line extended back to zero time gives the theoretical plasma concentration at the time the drug was given In effect, the assumption is made that drug distributes instantaneously and uniformly through a single
compartment, the distribution volume This mechanism, although seeming artificial, does usefully characterise drugs according to the extent to which they remain in or distribute out from the circulation.
Trang 10TABLE 7.2 Apparent distribution volume of some
drugs (Figures are in litres for a 70 kg person who
would displace about 70 I) 17
Drug
Evans blue
heparin
aspirin
inulin
gentamicin
frusemide
amoxycillin
antipyrine
Distribution
volume
3 (plasma volume)
5
II
15 (extracellular
water)
18
21
28
43 (total body
water)
Drug
atenolol diazepam pethidine digoxin nortriptyline nortriptyline dothiepin chloroquine
Distribution volume 77 140 280 420
1000 1000
4900 13000
PLASMA PROTEIN ANDTISSUE
BINDING
Many natural substances circulate around the body
partly free in plasma water and partly bound to
plasma proteins; these include cortisol, thyroxine,
iron, copper and, in hepatic or renal failure,
byproducts of physiological intermediary
metab-olism Drugs, too, circulate in the protein-bound and
free states, and the significance is that the free fraction
is pharmacologically active whereas the protein-bound
component is a reservoir of drug that is inactive
because of this binding Free and bound fractions
are in equilibrium and free drug removed from the
plasma by metabolism, dialysis or excretion is
replaced by drug released from the bound fraction
Albumin is the main binding protein for many
natural substances and drugs Its complex structure
has a net negative charge at blood pH and a high
capacity but low (weak) affinity for many basic
drugs, i.e a lot is bound but it is readily released
Two particular sites on the albumin molecule bind
acidic drugs with high affinity (strongly) but these
sites have low capacity Saturation of binding sites
on plasma proteins in general is unlikely in the
doses in which most drugs are used
Other binding proteins in the blood include
lipoprotein and o^-acid glycoprotein, both of which
carry basic drugs such as quinidine, chlorpromazine
and imipramine Such binding may have implications
17 Litres per kg are commonly used, but give a less vivid
image of the implication of the term 'apparent', e.g.
chloroquine.
D I S T R I B U T I O N
for therapeutic drug monitoring according to plasma concentration Thyroxine and sex hormones are bound in the plasma to specific globulins
Disease may modify protein binding of drugs to
an extent that is clinically relevant as Table 7.3 shows
In chronic renal failure, hypoalbuminaemia and
retention of products of metabolism that compete for binding sites on protein are both responsible for the decrease in protein binding of drugs Most affected are acidic drugs that are highly protein bound, e.g phenytoin, and special care is needed when initiating and modifying the dose of such drugs for patients with renal failure (see also Prescribing in renal disease, p 541)
Chronic liver disease also leads to
hypoalbumin-aemia and increase of endogenous substances such
as bilirubin that may compete for binding sites on protein Drugs that are normally extensively protein bound should be used with special caution, for increased free concentration of diazepam, tolbutamide and phenytoin have been demonstrated
in patients with this condition (see also Prescribing
in liver disease, p 652)
The free, unbound and therefore pharmacologically active percentages of some drugs are listed in Table 7.3 to illustrate the range and, in some cases, the changes caused by disease
Drugs may interact competitively at plasma protein
binding sites as is discussed on page 131
Tissue binding Some drugs distribute readily to regions of the body other than plasma, as a glance
TABLE 7.3 Examples of plasma protein binding of drugs and effects of disease
Drug warfarin diazepam frusemide (furosemide) tolbutamide
clofibrate amitriptyline phenytoin triamterene trimethoprim theophylline morphine digoxin amoxicillin ethosuximide
% unbound (free)
1
2 (6% in liver disease)
2 (6% in nephrotic syndrome) 2
4 ( 1 1 % in nephrotic syndrome) 5
9 (19% in renal disease)
1 9 (40% in renal disease) 30
35 (71% in liver disease) 65
75 (82% in renal disease) 82
100