Aps 2005 Forensic Science International

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Review: The physiology of saliva andtransfer of drugs into saliva

Johan K.M. Aps *, Luc C. Martens

UZG-P8- Department of Paediatric Dentistry and Centre for Special Care, PaeCaMed Research Unit,

Ghent University, De Pintelaan 185, 9000 Gent, Belgium

Received 21 September 2004; received in revised form 10 October 2004; accepted 10 October 2004

Available online 5 April 2005

Abstract

Although saliva or oral fluid lacks the drama of blood, the sincerity of sweat and the emotional appeal of tears, quoting

Mandel in 1990 [I.D. Mandel, The diagnostic uses of saliva, J. Oral Pathol. Med. 19 (1990) 119125], it is now meeting the

demand for inexpensive, non-invasive and easy-to-use diagnostic aids for oral and systemic diseases, drug monitoring and

detection of illicit use of drugs of abuse, including alcohol. As the salivary secretion is a reflex response controlled by both

parasympathetic and sympathetic secretomotor nerves, it can be influenced by several stimuli. Moreover, patients taking

medication which influences either the central nervous system or the peripheral nervous system, or medication which mimic the

latter as a side effect, will have an altered salivary composition and salivary volume. Patients suffering from certain systemic

diseases may present the same salivary alterations. The circadian rhythm determines both the volume of saliva that will and can

be secreted and the salivary electrolyte concentrations. Dietary influences and the patients age also have an impact on

composition and volume of saliva. The latter implies a wide variation in composition both inter- and intra-individually. Samplingmust therefore be performed under standardized conditions. The greatest advantage, when compared to blood sample collection,

is that saliva is readily accessible and collectible. Consequently, it can be used in clinically difficult situations, such as in

children, handicapped and anxious patients, where blood sampling could be a difficult act to perform.

# 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Physiology of saliva; Oral fluid; Drugs; Electrolytes; Proteins; Circadian rhythm

1. Introduction

The majority of theoral fluid originates from three pairs of

major salivary glands (gl. parotis, gl. submandibularis and gl.sublingualis). Other sources, responsible for the composition

of the oral fluid, are the gingival crevicular sulci (area between

tooth andmarginalfreegingiva), an estimated numberof 450

750 minor accessory salivary glands, situated on the tongue,

the buccal mucosae and the palate, and oro-naso-pharyngeal

secretions. The oral fluid also contains bacteria and their

metabolites,epithelialcells,erythrocytes, leukocytes and food

debris. These cellular constituents are regularly reported as

potential indicatorsof riskin dentistry [25]. Duringinfection,epithelial cells are being released and degraded while the

blood capillaries permeability is increased, which results in

release of serum components, such as albumin. While in oral

healthy individuals, the chance of detecting serum compo-

nents, released from the blood vessels through the mucosae

andgingival crevicular sulci, is rather little. Further research is

being performed at several research centers to identify sali-

vary indicators in patients at risk for dental, gingival and

mucosal diseases [57].

www.elsevier.com/locate/forsciint

Forensic Science International 150 (2005) 119131

* Corresponding author. Tel.: +32 9 240 51 02;

fax: +32 9 240 38 51.

E-mail address: [email protected] (Johan K.M. Aps).

0379-0738/$ see front matter # 2005 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/j.forsciint.2004.10.026


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The major constituent of the oral fluid, however, is water.

Although the ionic concentrations in the oral fluid are not

constant, due to the circadian rhythm, the oral fluid is

hypotonic compared to serum. Salivation can either be

stimulated or reduced by several factors. The electrolyte

concentrations and the volume of saliva which is being

produced are not only influenced by the moment of the

day, but also by the type of the salivation stimulus. Taste and

olfactory stimuli, mechanical stimulation (chewing), pain,

pregnancy related hormonal changes, aggression and sym-

pathicomimetic and parasympathicomimetic drugs will

increase the salivary flow. In contrast to the latter, meno-

pause related hormonal changes, stress, anti-adrenergic and

anticholinergic drugs will decrease the salivary flow rate.

Under healthy conditions, adults will approximately

produce 5001500 ml saliva per day or between 0 and

6 ml/min. The latter figures should be interpreted with care,

as the circadian rhythm of salivation and other factors are not

taken into account.The volume and the composition of the oral fluid can vary

during the day and within time within every individual. As a

consequence, when salivary constituents from whatever

origin need to be identified, it should be emphasized that

the result will depend upon the subjects cooperation, psy-

chological status (e.g. angry or afraid), the host (hereditary

influences and oral hygiene), medication use, the method of

sampling (including the duration and the type of stimulation)

and the time of the day. As a consequence, it is obvious that

its composition varies continuously, both quantitative as well

as qualitative. This is the major difference between oral fluid

and serum, in which the concentrations of the variouscomponents can only vary between narrow border values.

It is clear that salivary research is not easy. Moreover,

both dental and medical researchers have been investigating

saliva for many years, though they appear to have been

working in parallel, instead of joining forces. The latter is

probably due to the different goals and different questions

from both groups of investigators.

The aim of this article is to focus on the physiology of

saliva and the transfer of drugs into the oral fluid. For this

purpose, a systematically approached search of published

literature was carried out, involving several types of pub-

lications;

A www browser was used to elicit web-based information

provided by academic centers and companies involved in

salivary research and drug detection in oral fluid.

A literature search on Medline, using PubMed was carried

out. Several keywords filtering for oral fluid, saliva(tion),

medication and drugs were used in this search. The period

covered was 19902004.

Hand-searching was used to identify reports, abstracts

published in congress books of both National and Inter-

national conferences, PhD theses and handbooks (one in

Dutch written handbook, by Professor Dr. A. Van Nieuw

Amerongen in particular, was used as reference guide and

as provider of critical information). Professor Dr. Van

Nieuw Amerongen gave the authors the permission to use

tables and figures from his work for this article. Both

English and non-English articles were considered valu-

able in this search. If certain reports were considered

valuable for this paper, the time period for this search was

not limited between 1990 and 2004.

2. Salivary glands

The three pairs of major glands have distinct orifices; the

ductus parotideus is also called the Ductus of Stenson, while

the ductus submandibularis and ductus sublingualis are

called ductus van Wharton and Bartholin, respectively

(Fig. 1). The other salivary glands, high in number, do

not have a collective orifice [810].The salivary glands are composed of acini, in which the

initial or primary saliva, isotonic compared to plasma, is

produced. The several acini are connected by intercalated

ducts and the secreted saliva is drained to the oral cavity

through striated and excretory ducts. During this passage,

the concentrations of several electrolytes change due to

active ionic transport (Fig. 2), which renders the oral fluid

its hypotonic character, when compared to plasma (Table 1).

The number of acini as well as the protein biosynthesis

activity, in general, decrease during ageing, although this can

be very different between individuals.

Every type of salivary gland produces a typical secrete.The glandula parotis produces a serous fluid, the glandula

Submandibularis a sero-mucous secrete, while the glandula

Sublingualis secretes only mucous saliva. The minor glands,

situated on the buccal mucosa of the lips and on the palate,

produce a viscous secrete [1113].

3. Physiology of salivation

Saliva is stored in secretion granules in the acini of the

salivary glands. These granules are filled with water, in

which electrolytes and proteins are dissolved. Even not

stimulated, salivary glands secrete a fluid, which is producedvia vesicles and not by exocytosis. For this process, the

saturation of the glands with blood, is of outmost importance

[1416]. It is an energy demanding process for which

adenosinetriphosphate (ATP) is needed, which is generated

by metabolizing intracellular glycogen [17]. Besides this

exocytotic process, there is also a paracellular source of

fluid, coming from the interstitium, which is especially the

case when salivation is stimulated. The latter obviously

depends upon the water household of the body. In case of

fever or diarrhea, for instance, less water will be available,

which results in a low volume of saliva and the patient

complains of a dry mouth.

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J.K.M. Aps, L.C. Martens / Forensic Science International 150 (2005) 119131 121

Fig. 2. Schematicrepresentationof thesecretion and resorption processes of electrolytes in a secretory unit, starting as a isotonic and resulting in

a hypotonic fluid, when compared to plasma. The concentration of the electrolytes at theglands orificedepends on the speed with which the fluid

passes through the duct: a high speed means less ion exchange, while a low speed the opposite.

Fig. 1. The anatomical positioning of the three pairs of large salivary glands; the glandula parotis (1), the glandula submandibularis (2) and the

glandula sublingualis (3). (Figure from A. Van Nieuw Amerongen, 2004.)


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The most abundant salivary electrolytes are sodium,potassium, chloride and bicarbonate. Calcium, magnesium

and phosphate are present in lesser concentrations (Table 1).

They all originate from serum, from which they are actively

transported into the acini and striated ducts.

The organic salivary components, proteins and glyco-

proteins, are synthesized by the secretory cells. Covalent

coupling with sugars, phosphates and/or sulphates, within

the cells can take place. Some proteins, such as lysozyme,

lactoferrine, lactoperoxidasis, cystatins and histatins, play an

important role as antibacterial and antifungal agents in the

oral fluid. Mucins also play an antiviral role, while alpha-

amylase, lipase, proteinase, DNase and RNase are importantin the digestive process.

These secretion proteins and electrolytes are conse-

quently collected into condensed vacuoles which are then

guided towards the apical part of the cell in secretion

granules. Secretion will take place when the salivation is

stimulated [12,18].

4. Salivation stimuli

The autonomic nervous system plays an important role in

salivation. The effects of the various nervous stimuli on the

volume, viscosity, protein and mucin concentration of thesecreted saliva is summarized in Table 2. The salivation

pathway of nervous stimulation is explained and illustrated

in Fig. 3. From this figure it can be observed that both

sympathic and parasympathic stimulation can cause saliva-

tion, although the respective secretion will be different in

constitution and volume.

The secretion cells of both serous and sero-mucous

glands are sympathically as well parasympathically inner-

vated. The secretion rate increases synergistically when both

innervations are simultaneously stimulated [1921]. There-

fore, cholinergic as well as a- or b-adrenergic stimulation of

the salivary glands is possible. An a-adrenergic stimulation

causes a calcium influx in the secretory cells, which results

in a protein rich secrete. Due to the low mucin concentration,

the clinical aspect is not foamy and viscous. This type of

stimulation also results in a low volume. A b-adrenergic

stimulation does not result in a flux of electrolytes, but

enables a high protein output from the acini and as a

consequence, b-adrenergic stimulation causes a viscous,

protein and mucin rich, secrete. This type of saliva willhave a foamy appearance, while the volume produced is

rather low [22].

Mucous glands, on the other hand, are only to be stimu-

lated cholinergically. This kind of stimulation causes ion

fluxes of both Na+/K+ and Ca2+ over the cell membranes and

eventually results in a watery substance, rich with electro-

lytes and high in volume [23,24].

5. Salivary flow rate and pH

The secretion rate depends upon the time of the day, theso-called circadian rhythm and the type of stimulation, as

described above. The secretion rate can vary from virtually

0 ml/min (e.g. during sleep) to 6 ml/min (e.g. chewing and

an acidic stimulus on the tongue). The contribution of the

different salivary glands to the total salivary production also

depends on the circadian rhythm and the type of stimulation.

From Table 3 it is clear that both glandulae Parotis and

Submandibularis contribute most to the total salivary

volume, except during sleep. During sleep, the production

of the glandula parotis can be ignored.

The speed with which the saliva passes through the

salivary ducts, will determine the electrolyte concentrations.

The higher the speed, the less time for the electrolyteexchange processes to take place. Due to a higher bicarbonate


Table 1

Electrolyte and total protein concentrations in whole human oral

fluid and plasma

Plasma Whole human

resting oral fluid

Whole human

stimulated oral

fluid

Na+

(mmol/l) 145 5 2080

K+ (mmol/l) 4 22 20

Ca2+

(mmol/l) 2.2 14 14

Cl

(mmol/l) 120 15 30100

HCO3 (mmol/l) 25 5 1580

Phosphate (mmol/l) 1.2 6 4

Mg2+ (mmol/l) 1.2 0.2 0.2

SCN

(mmol/l)


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concentration than under resting conditions, this results in ahigher buffering capacity of the oral fluid when salivation is

stimulated (Fig. 2). Initially the total protein and mucin

concentrations per millilitre decrease dramatically, when

the salivation rate is speeding up, to eventually reach a

constant volume. The total protein and mucin concentrations

secreted per minute, however, increase proportionally with

the secretion rate [18].

The proportion of bicarbonate as a salivary buffering

component during resting conditions is approximately 50%.

During these conditions, the parotid gland will produce

almost no saliva, while both other major glands will be

responsible for the production of saliva. The latter results in a

high viscous and protein rich secretion, which will stabilizethe oral fluids pH at around 7.0. The volume of secreted

fluid will, however, be low.

Under stimulated conditions, the role of bicarbonate as amajor buffering component will increase, as it will be

available in high concentrations, as described above. These

buffering capacities are important to protect the teeth against

demineralisation (dental decay) and to lubricate the soft oral

tissues [25,26].

6. Systemic diseases affecting the oral fluids

composition

6.1. Cystic fibrosis (CF)

Besides the increased visco-elasticity of the cystic fibro-sis patients saliva, there are several electrolyte and protein

concentration differences compared with healthy (not CF-


Fig. 3. Schematic overview of the salivation regulating processes in the glandula parotis and the site of interaction of certain drugs or products

(Scheme according to Vissink et al., 1997modified by Aps and Martens).

Table 3

Mean contribution (expressed as a % of the total) of the different salivary glands to the total salivary production according to a certain type of

stimulation

Sleep No stimulation Mechanical stimulation Citric acid stimulation

Gl. parotis 0 21 58 45

Gl. submandibularis 72 70 33 45

Gl. Sublingualis 14 2 2 2

Minor salivary glands 14 7 7 8


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heterozygotes) individuals. The RNase-activity is four times

higher in CF homozygotes than in control subjects. Due to

the increased calcium and total protein salivary concentra-

tions, insoluble calcium-protein complexes are formed. The

salivary concentrations of sodium and phosphate are also

significantly increased and are believed to play an important

role in the protection against dental decay [1,2731].

6.2. Multiple sclerosis

Very little changes are observed in whole saliva of

multiple sclerosis patients. There is, however, a significant

reduction in IgA production during rest, while in stimulated

saliva, the absence of a protein band of 140 kDa seems to be

very significant for the disease. It should however be

emphasized that these findings should not be considered

conclusive to diagnose the disease [32,33].

6.3. Graft-versus-host disease

Graft-versus-host disease is characterized by a destruc-

tion of the tissues of the salivary glands, clinically resulting

in a decreased salivary flow rate. This can either be acute,

shortly after a transplantation, or chronically, about 100 days

after the surgical procedure. It should be stressed that the

observed decreased salivation can be induced, in the first

place, by the accompanying irradiation or chemotherapy.

However, when the hyposalivation increases 100 days after

the transplantation, it may be indicative for a graft-versus-

host disease. Salivary sodium and lysozyme concentrations

are increased, while phosphates and s-IgAs are decreasedunder these circumstances [1,3436].

6.4. Diabetes mellitus

Insulin is able to stimulate salivation, therefore it is

obvious that the salivary flow rate in diabetes mellitus

patients is decreased. In this situation salivation is easy to

stimulate. It should be emphasized that typical medication

used in these patients can also be responsible for the

decreased salivary flow rate. Albumin and IgG concentra-

tions of non stimulated saliva are lower than in healthy

control subjects [1,33,37].

6.5. Alcoholic liver cirrhosis

The glandula parotis is enlarged in 50% of the patients,

resulting in a 50% reduction of the salivary flow rate and a

reduction of salivary sodium, bicarbonate and chlorine

concentrations as well as the total salivary protein concen-

tration [1,33].

6.6. Acquired human immunodeficiency syndrome

HIV antibodies and HIV inhibiting/inactivating factors

are also detectable in the oral fluid. It is suggested that

among several components the salivary mucins are co-

responsible for this aspect, as they aggregate the HIV

particles, which inhibits them to infiltrate epithelial cells.

The HIV patient has a lower salivary flow rate and therefore

the output of several antibacterial, antifungal and antiviral

factors is also lower, consequently resulting in an increased

vulnerability to infections. Once the disease is active, the

total salivary protein concentration will be increased, due to

leakage of serum proteins through the epithelia [33,3841].

6.7. Epilepsy

In patients with epilepsy, taking phenytoin, gingival

hypertrophy can be observed, due to an increased collagen

synthesis and accumulation of proteoglycans. The gingival

hypertrophy demands an impeccable oral hygiene. Another

side effect of phenytoin, is a selective IgA deficiency,

resulting in a decreased immunological defence. Similar

effects cannot be observed when cyclosporin A and nifedi-pine are used [1,33,42].

6.8. Burning mouth syndrome

This syndrome is relatively most prominent in post-

menopausal women. The male:female ratio is 1:7. Patients

complain of oral pain and dry mouth. The latter can also be

induced by the use of antidepressants, prescribed to these

people for several reasons. However, their salivation can be

easily stimulated mechanically and chemically. The total

salivary protein concentration of stimulated saliva is lower

than in control subjects, while the total mucin concentrationis higher. Salivary potassium, chloride and phosphate con-

centrations are also increased in these patients [33,43,44].

6.9. Kidney dysfunction

Half of all hemodialysis patients complain of hyposali-

vation, ammonium smelling breath, changes in taste and oral

mucosal pain [45,46]. The total salivary protein, sodium and

potassium concentrations mimic the plasmas. The salivary

pH of these patients is significantly higher than in healthy

controls, due to the significantly increased salivary urea

concentration [47,48].

7. Medication use and salivation

As the neuronal regulation of salivation is both directed

by the sympathetic as well as by the parasympathetic

autonomous nervous systems, all drugs which interfere on

the central and peripheral nervous systems, regardless of

their purpose, will have an influence on the production of

saliva. Some drugs may interfere with the nerve stimulation,

while others will either destruct or change the functions of

the glandular acini or ducts. These effects can either be

hypersalivation or hyposalivation. Both phenomena are



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sources of discomfort. The pathway of interaction sites of

several nervous blocking drugs is indicated in Fig. 3. It can

be observed that several sites of interaction are possible, but

the overall result is hyposalivation.

Hypertrophy or hyperplasia of the glandular tissue is also

possible, which consequently results in an altered salivary

composition. Pain, changes in taste experience and halitosis

also belong to the reported side effects of certain types ofmedication. It should be kept in mind that some patients will

not report any of the side effects, while others will have

serious complaints [49].

7.1. Reduction of salivary flow rate

Drugs blocking the nervous system (Fig. 3), will always

have salivary flow rate reduction as a side effect. As

described above, the type of innervation will determine

the volume and the composition of the secrete [5053].

Table 4 contains a list of therapeutic drugs which cause a

reduction of the salivary flow rate. In order to avoid oro-dental diseases and discomfort, special attention should be

paid to oral hygiene measures in patients taking this kind of

medication. Table 5 summarizes specific drugs with either a

direct anticholinergic or anticholinergic side effect. Both the

latter, as well as antipsychotics cause a substantial reduction

in salivary flow rate. In Table 6 therapeutic drugs with an

anti-a- or b-adrenergic effect are listed. The latter also

results in a reduction of salivary flow rate.

It should be clear that not only from a oro-dental health

point of view, attention should be drawn to this aspect when

prescribing these drugs and patients should be instructed to

have the correct oral hygiene measures, in order to avoid oral

mucosal infections and dental decay. These instructions are

generally either not known or are forgotten by prescribers.

7.2. Increase of salivary flow rate

In order to increase the salivary flow rate, it is necessary

to increase the amount of the neurotransmitters acetylcho-

line and noradrenaline. These neurotransmitters aredegraded very fast by the body and cause the secretion of

a high volume of saliva. This secretion will have a high water

and a low protein content. In Table 7 a list of direct and

indirect working parasympathetic substances is shown

[54,55]. This medication can be used, after serious consid-

eration of all the other possibilities to help patients com-

plaining of dry mouth.

As described above and shown in Table 2, stimulation of

the sympathetic nervous system also results in salivation,

although the volume will be low and the protein content of

J.K.M. Aps, L.C. Martens/ Forensic Science International 150 (2005) 119131 125

Table 4

An overview of therapeutic drugs which cause reduction of salivary

secretion flow rate

Analgesics Antihypertensives Cytotoxics

Antiarrhythmics Anti nausea agents Decongestives

Anticonvulsants Anti-Parkinson agents Diuretics

Antidepressives Anti pruretics ExpectorantsAntiemetics Antipsychotics Mono-amine-oxidase

inhibitors

Antihistamines Anti spasmodics Tranquilizers

Table 5

Therapeutic drugs with an anticholinergic (parasympathimimetic)

effect; reduction of the salivary flow rate (hyposalivation)

Anticholinergic

effect

Anticholinergic side

effect

Antipsychotica

Muscarine blockers Antidepressives Chlorpromazine

Atropine Amitriptyline Butyrophenone

Scopolamine Desipramine Lithium salts

Clidinium Imipramine

Ipratropium Lophepramine

Oxybutynine Maprotiline

Pirenzepine Nortriptyline

Propantheline Oxaprotiline

Scopolamine

Anti Parkinson drugs Antihistamines

Benzatropine Cyclizinef

Biperiden Diphenhydramine

Orphenadrine Promethazine

Trihexyphenidyl Tripelenamine

Procyclidine Antiarrhythmics Disopyramidine

Table 6Drugs with an anti-adrenergic effect; a-adrenergic stimulated salivation would normally result in a low volume, but a secretion rich of proteins,

while a b-adrenergic stimulation would result in a high volume and a secrete rich of proteins and a foamy viscous appearance

b a

b1 b1 + b2 b2 a1 a1 + a2 a2

Acebutolol Alprenolol Butoxamine Corynanthine Dibenamine Idazoxan

Atenolol Carteolol Doxazosine Dihydroergotamine Rauwolscine

Metoprolol Oxprenolol Prazosin Phenoxybenzamine Tolazoline

Paphenolol Pindolol Phentolamine Yohimbine

Practolol Propranolol

Sotalol

Tetratolol

Timolol


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the secrete high. The only difference between a b-adrenergic

and an a-adrenergic stimulation is that the first one men-

tioned will also have a secrete with a high viscosity, caused

by a high mucin concentration. Table 8 contains a list oftherapeutic medication, which either act on the b-adrenergic

or the a-adrenergic system. It should be emphasized that it is

reported that stimulation of the a2-receptor results in a

reduction of salivary flow [56].

7.3. Salivary gland morphological changes

Table 9 comprises a listing of therapeutic drugs which are

able to cause salivary gland hypertrophy. Drugs, such as

dobutamine and prenalterol, cause salivary gland hyperpla-

sia, due to b1-receptor stimulation. Metoprolol, a b1-antago-

nist, on the other hand, will decrease the glands weight[49,57].

7.4. Pain from the salivary glands

Why certain medication causes pain in the salivary

glands is still unknown. However, in several cases, a sec-

ondary infection is also present, which may explain the

sensation of pain. Patients taking guanethidine or ismeline

may only report pain when salivation is stimulated, which is

assumed to be caused by the passage of saliva through the

clung walls of the secretory ducts. The pain occurring in

patients taking a-methyldopa and bretylium is assumed to be

caused by a hyperperfusion of the glandula parotis, when

vasodilatation is engaged by sympathetic neurons. Betani-

dine, chlormethiazole, clonidine, cytarabine and nicardipine

are also known to cause pain in the salivary glands [49].

7.5. Taste and halitosis

Several drugs (Table 10) are responsible for bad taste,

varying from a change in taste sensation (e.g. no or very littledifference between salt and citric acid), a metal taste (e.g.

metronidazol) to bitter. Other drugs, especially those con-

taining sulphur, cause halitosis; dimethylsulphoxide, N-acet-

ylcysteine, and isosorbide dinitrate [49,5862].

8. Saliva as a diagnostic specimen to detect drugs or

hormones

The measurement of drugs in saliva is of interest both for

purposes of therapeutic drug monitoring and for the detec-

tion of illicit drug use. Moreover, detection of drugs in salivamay indicate recent drug use. Most drugs are bound to serum

proteins to a various degree. Only unbound or free drug is

pharmacologically active. Usually total drug concentration

is measured for therapeutic monitoring, because there is

equilibrium between bound and free drugs. The concentra-

tion of free drug can be predicted from total drug concen-

tration. However, under certain conditions, the equilibrium

may be disturbed and as a consequence the measured free

drug concentration may be significantly higher than

expected from the total drug concentrations. The latter is

especially the case for strongly protein-bound drugs and

clinically results in drug toxicity in the patient, even if the

total drug concentration was within the therapeutic range.


Table 7

Parasympathomimetic drugs causing an increase of the salivary flow

rate and the secrete will have a low viscosity

Directly working Indirectly working

Arecoline Cisapride

Bethanechol Neostigmine

Carbamylcholine (carbachol) Nizatidine

Cevimeline Physostigmine

Methacholine

Muscarine

Oxotremorine

Pilocarpine

Under strict controlled conditions, these drugs can be used to avoid

dry mouth.

Table 8

Sympathomimetics cause an increase of salivary flow rate

b a

b1 b1 + b2 b2 a1 + a2 a2

Dihydro-alprenolol Isoproterenol Metaproterenol Methoxamine Clonidine

Dobutamine Procaterol Phenylephrine Moxonidine

Prenalterol Salbutamol Oxymetazoline

Soterenol a-Methyldopa

Terbutaline a-Methyl-noradrenaline

The viscosity of the secrete (depends on the mucin concentration) will determine whether the stimulation is either b- or a-adrenergic.

Table 9

Drugs responsible for salivary gland hypertrophy

Cyclocitidine Methotrexate

Dobutamine Nitrophurantoine

Phenylbutazon Niphedipine

Insulin Oxyphenbutazon

Isoproterenol PrenalterolIodide Thiocyanate

Potassiumchlorine Thiouracil

a-Methyldopa Salbutamol (albuterol)


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Drugs which are not ionizable or are un-ionized within thesalivary pH range (e.g. phenytoin, carbamazepine and theo-

phylline) are candidates for salivary therapeutic drug mon-

itoring [63,64]. Before any drug circulating in plasma can be

discharged into the salivary duct it must pass through the

capillary wall, the basement membrane and the membrane of

the glandular epithelial cells. The rate-determining step for

this transportation is the passage of the drug through the

lipophilic layer of the epithelial membrane. Physicochem-

ical principles dictate that for such a passage to occur, the

drug must show a degree of lipophilicity. Several mechan-

isms can be involved in the passage of therapeutic substances

through the epithelial membranes; a passive diffusion pro-

cess (for highly lipid-soluble molecules), an active processagainst a concentration gradient (e.g. for electrolytes, IgA)

and ultrafiltration through pores in the membrane (small

polar molecules only, i.e. molecular weight less than

300 Da) [6567]. Pinocytosis seems to play a lesser role

than previously assumed [6870].

Most drugs appear to enter saliva by simple passive

diffusion, which is characterized by the transfer of drug

molecules down a concentration gradient with no expendi-

ture of energy. The rate of diffusion of a drug is a function of

the concentration gradient, the surface area over which the

transfer occurs, the thickness of the membrane, and a

diffusion constant that depends on the physico-chemical

J.K.M. Aps, L.C. Martens/ Forensic Science International 150 (2005) 119131 127

Table 10

Drugs which cause a change in taste sensation

(Bitter) metal taste Disturbed smell sensation Disturbed taste sensation Loss of taste

Azelastine Doxycycline Lincomycine Carbamizol

Procainbenzyl penicillin Scopolamine Sulphasalazine Propylthiouracil

Metronidazol Tegretol Penicillamine

Tetracycline Levo-dopa Bleomycin

Bignamidine Chlorhexidine Cis-platinum

Hexetidine Captopril

Lithium carbonate

Amphotericine

Griseophulvine

Captopril

Sodium dodecyl sulphate

Table 11

Different types of drugs and their detection reliability in oral fluid

Reliable detection in oral fluid Not reliable detectionin oral fluid

Literaturereferences

Steroids (mimic the serums free and active concentration) progesterone

(menstrual cycle) oestrogen oestradiol (>2.1 ng/ml correlates with

a 90% chance of having a premature birth)

Protein hormones

(too large for diffusion)

[7584]

Suldentafil (detectable 30 min after intake and remains so till 5.5 h) [85]

Cortisol (in cases where more than normal cortisol production is expected;

cushing syndrome and Adissons disease)

[86,87]

Melatonin (concentrations may be as low as 9 pg/ml and monitoring concentrations

may be difficult in elderly and patients complaining of dry mouth)

[88,89]

Lamotrigine (CAVE: wide interpatient variability in saliva/serum ratio) topiramate [90,91]

Moxifloxacin (per os) clarithromycin (per os) ofloxacin [92,93]

Fluconazole [94]

Nevirapine [95]Methotrexate [96]

Ethanol (the salivary concentration is about 9% higher than the plasmas) [9799]

Amphetamine (detectable within 10 min after intake and remains so for 72 h)

methamphetamine (detectable till 510 min after inhalation, smoking or ingestion)

[98,100,101]

cocaine (24 h detectable) benzoylecgonine (24 h detectable) ecgonine methyl ester

(all are detectable within 10 min after intake)

[98]

Morphine codeine (detectable within 1 h after intake, respecting a cut-off

level of 40 ng/ml) heroin methadone benzodiazepines

Low dose benzodiazepines

(flunitrazepam)

(insufficient sensitivity)

[98,102105]

Tetrahydrocannabinol (detectable very shortly after use and remains so for 14 h) [97,98,106]

Phencyclidine (angel dust) (concentrations may vary from 2 to 600 ng/ml) [107]


10/13

properties of each drug [71]. The variables which influence

this type of transport are pH and pKa, lipid solubility,

charge, molecular weight and spatial configuration, non

protein-bound plasma level, dose and clearance of the

drug, salivary flow rate and pH, salivary binding proteins

and salivary enzymes, capable of metabolizing the drug

[68,72,73]. It should be emphasized that one should

always take into account the intra-individual variability

of the saliva/plasma ratio of several drugs. Finally, salivary

drug concentrations generally reflect the free fraction of

the drug in blood [74]. Table 11 illustrates clearly that

several drugs can be monitored in oral fluid, either for

therapeutic purposes or for the search for the illicit use of

certain drugs.

9. Conclusion

Although saliva or oral fluid lacks the drama of blood,the sincerity of sweat and the emotional appeal of tears,

quoting Mandel in 1990 [1], it is now meeting the demand

for inexpensive, non-invasive and easy-to-use diagnostic

aids for oral and systemic diseases, drug monitoring and

detection of illicit use of drugs of abuse, including alcohol.

As the salivary secretion is a reflex response controlled by

both parasympathetic and sympathetic secretomotor nerves,

it can be influenced by several stimuli.

Patients taking medication, that either affects the central

nervous or the peripheral nervous systems, or taking med-

ication with the latter as a side effect, will have an altered

salivary composition and salivary volume. Certain systemicdiseases may include the same salivary alterations. The

circadian rhythm determines both the volume of saliva that

will and can be secreted and the salivary electrolyte con-

centrations. This implies a wide variation in composition

both inter- and intra-individually. Sampling must therefore

be performed under standardized conditions. However, it

should not be forgotten that the greatest advantage, when

compared to blood sample collection, is the readily acces-

sibility and collectability of the oral fluid. Consequently, it

can also be used in clinically difficult situations, such as in

children, handicapped and anxious patients, where blood

sampling is difficult.

Acknowledgement

The authors wish to thank Professor Dr. Van Nieuw

Amerongen for authorizing us to use figures and data from

his work.

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