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R EVIEW ARTICLE

Pharmacokinetics and Pharmacodynamics in Clinical Use of Scopolamine

Ulf D. Renner, Reinhard Oertel, and Wilhelm Kirch

Abstract: The alkaloid L-( 2 )-scopolamine [ L -( 2 )-hyoscine] com- petitively inhibits muscarinic receptors for acetylcholine and acts as

a nonselective muscarinic antagonist, producing both peripheral anti-

muscarinic properties and central sedative, antiemetic, and amnestic effects. The parasympatholytic scopolamine, structurally very similar

to atropine (racemate of hyoscyamine), is used in conditions requiring

decreased parasympathetic activity, primarily for its effect on the eye, gastrointestinal tract, heart, and salivary and bronchial secretion glands,

and in special circumstances for a CNS action. Therefore, scopolamine

is most suitable for premedication before anesthesia and for antie-

metic effects. This alkaloid is the most effective single agent to prevent

motion sickness. Scopolamine was the first drug to be made commer- cially available in a transdermal therapeutic system (TTS-patch) de- livering alkaloid. Recently, pharmacokinetic data on scopolamine in different biozlogic matrices were obtained most efficiently using liq- uid chromatographic–tandem mass spectrometric (LC-MS/MS) or gas chromatography online coupled to mass spectrometry. Pharmacokinetic parameters are dependent on the dosage form (oral dose, tablets; parenteral application; IV infusion; SC and IM in- jection). Scopolamine has a limited bioavailability if orally admin- istered. The maximum drug concentration occurs approximately 0.5 hours after oral administration. Because only 2.6% of nonmet- abolized L-( 2)-scopolamine is excreted in urine, a first-pass metab- olism is suggested to occur after oral administration of scopolamine. Because of its short half-life in plasma and dose-dependent adverse effects (in particular hallucinations and the less serious reactions, eg, vertigo, dry mouth, drowsiness), the clinical use of scopolamine administered orally or parenterally is limited. To minimize the relatively high incidence of side effects, the transdermal dosage form has been developed. The commercially available TTS-patch contains a 1.5-mg drug reservoir and a priming dose (140 mg) to reach the steady-state concentration of scopolamine quickly. The patch releases 0.5 mg alkaloid over a period of 3 days (releasing rate 5 mg/h). Following the transdermal application of scopolamine, the plasma concentrations of the drug indicate major interindividual variations. Peak plasma concentrations (C max ) of approximately 100 pg/mL (range 11–240 pg/ mL) of the alkaloid are reached after about 8 hours and achieve steady state. During a period of 72 hours the plaster releases scopolamine, so constantly high plasma levels (concentration range 56–245 pg/mL) are obtained, followed by a plateau of urinary scopolamine excretion.

Received for publication November 1, 2004; accepted March 1, 2005. From the Institute of Clinical Pharmacology, Medical Faculty Carl Gustav Carus, Technical University of Dresden, Dresden, Germany. Reprints: Dr. Reinhard Oertel, Institute of Clinical Pharmacology, Medical Faculty Carl Gustav Carus, Technical University of Dresden, Fiedlerstrasse 27, D-01307 Dresden, Germany (e-mail: reioer@rcs.urz.tu-dresden.de). Copyright 2005 by Lippincott Williams & Wilkins

Ther Drug Monit Volume 27, Number 5, October 2005

Although scopolamine has been used in clinical practice for many years, data concerning its metabolism and the renal excretion in man are limited. After incubation with b-glucuronidase and sulfatase, the recovery of scopolamine in human urine increased from 3% to approximately 30% of the drug dose (intravenously administered). According to these results from enzymatic hydrolysis of scopolamine metabolites, the glucuronide conjugation of scopolamine could be the relevant pathway in healthy volunteers. However, scopolamine metabolism in man has not been verified stringently. An elucidation of the chemical structures of the metabolites extracted from human urine is still lacking. Scopolamine has been shown to undergo an oxidative demethylation during incubation with CYP3A (cytochrome P-450 subfamily). To inhibit the CYP3A located in the intestinal mucosa, components of grapefruit juice are very suitable. When scopolamine was administered together with 150 mL grapefruit juice, the alkaloid concentrations con- tinued to increase, resulting in an evident prolongation of t max (59.5 6 25.0 minutes; P , 0.001). The AUC 024h values of scopolamine were higher during the grapefruit juice period. They reached approximately 142% of the values associated with the control group (P , 0.005). Consequently, the related absolute bioavailabilities (range 6% to 37%) were significantly higher than the corresponding values of the drug orally administered together with water (range 3% to 27%). The effect of the alkaloid on quantitative electroencephalogram (qEEG) and cognitive performance correlated with pharmacokinetics was shown in studies with healthy volunteers. From pharmacokinetic– pharmacodynamic modeling techniques, a direct correlation between serum concentrations of scopolamine and changes in total power in a-frequency band (EEG) in healthy volunteers was provided. The alkaloid readily crosses the placenta. Therefore, scopolamine should be administered to pregnant women only under observation. The drug is compatible with nursing and is considered to be nonteratogenic. In conclusion, scopolamine is used for premedication in anesthesia and for the prevention of nausea and vomiting associated with motion sickness. Pharmacokinetics and pharmacodynamics of scopolamine depend on the dosage form. Effects on different cognitive functions have been extensively documented.

Key Words: scopolamine, pharmacokinetics, pharmacodynamics

( Ther Drug Monit 2005;27:655–665)

CHEMISTRY AND DOSAGE FORMS OF SCOPOLAMINE

T he parasympathicolytic drugs constitute a large class of anticholinergic agents and can be divided into 2 sub-

classes: (1) natural parasympathicolytics (eg, scopolamine, atropine) and (2) (semi)synthetic parasympathicolytic agents.

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The latter subclass consists of quaternary ammonium com- pounds with ganglioplegic effects (eg, N-butyl-scopolamine) and substances with additional myogenous spasmolytic properties (eg, denaverine). The quaternary ammonium moiety

in synthetic parasympatholytic drugs minimize the side effects on the central nervous system (CNS) because the polar structures decrease their lipid solubility and prevent crossing the blood–cerebrospinal fluid barrier. L -(2 )-Scopolamine (synonym: L-( 2)-hyoscine) is found in various Solanaceae, eg, Scopola carniolica, Hyoscyamus niger, and Datura stramonium . The structure of the tertiary amine L -(2 )-scopolamine (tropic acid ester with scopine; MW = 303.4; Fig. 1) is very similar to that of atropine [(6)-hyoscyamine = racemate of hyoscyamine]. The structures of both substances have 1 asymmetric carbon atom (chiral center) localized in the tropic acid com- ponent [S-( 2 )-tropate]. Derived from the tropine substructure

in the atropine compound, the scopine moiety differs only in an

epoxy function, bridged over the C-C bond (position C-6b and C-7b ) of the 1 a H,5 a H-tropan-3 a -ol (tropine). Scopolamine has a weak basic character (pK a = 7.6) and

a good lipid solubility expressed by a partition coefficient of

1.2 (n-octanol:buffer pH 7.4). The drug reacts as a nonselective muscarinic antagonist with both peripheral antimuscarinic properties and central sedative, antiemetic, and amnestic effects. 1 The atropine-like drugs are used in conditions requiring decreased parasympathetic activity, primarily for their effect on the eye, gastrointestinal tract, heart, secretions, and in special circumstances for a CNS action. Scopolamine is more potent than atropine on the eye, salivary and bronchial secre- tion glands, and on CNS. Therefore, this drug is most suitable for use for preoperative sedation as an injection and for its antiemetic effect as subcutaneous dosage. Scopolamine was the first drug to be made commercially available as a transdermal therapeutic system (TTS) delivering drug (‘‘Scopoderm’’ TTS patches, Novartis). 2 Because the postauricular area is the most permeable skin site, a trans- dermal scopolamine patch is placed on a hairless area behind the ear for motion sickness and prevention of postoperative nausea and vomiting. For refraction, ophthalmic scopolamine (1 or 2 drops) is applied topically to the eye 1 hour before refraction; for uveitis, 1 or 2 drops are applied up to 4 times daily.

Scopolamine is available in infusion solutions with 0.3, 0.5, or 1.0 mg/mL scopolamine hydrobromide 3H 2 O in a transdermal patch containing a reservoir of 1.5 mg scopol- amine (mean release 1.0 mg/72 hours) and in eye drops with 2.1 mg scopolamine borate dissolved in 1 g solution. A nasal administration of scopolamine was tested using an aerosol spray releasing 0.1% or 0.2% scopolamine hydrobromide. 3,4

ANALYTIC METHODS

First data 1,59 about pharmacokinetics (PK) of scopol- amine were obtained using a stereospecific enzyme immuno- assay [sensitivity to L -(2 )-hyoscine, 20 ng/L] or a radio- receptor assay (RRA) for the hyoscine racemate based on the competition between the alkaloid and a radiolabeled ligand for binding to a certain receptor. To remove compounds interfering with scopolamine detection by a radioreceptor assay, high-performance liquid chromatography (HPLC) was used to separate the analyte. 3 Several HPLC methods were developed for the analysis of scopolamine in biologic matrices (eg, plasma, urine, plants). 1012 Capillary zone electrophoresis (CZE) coupled to UV detection and interfaced with electrospray ionization (ESI) mass spectrometry is described for the analysis of scopolamine in plants. 13 In recent years both liquid chromatography–tandem mass spectrometry (LC-MS/MS) 10,14 and gas chromatography online coupled to mass spectrometry (GC-MS) have been used to determine concentrations of scopolamine in different bio- logic matrices (eg, plasma, serum). 1520 For GC-MS/MS methods for generating pharmacoki- netic data on scopolamine in 1 mL serum 19 or 4 mL plasma, 16 respectively, extensive sample preparation consisted of a liquid–liquid extraction, and a precolumn derivatization is necessary to achieve a sensitivity of 50 ng/L. The liquid chromatography–tandem mass spectrometry (LC-MS/MS) with an automated solid-phase extraction (SPE) sample preparation is the most qualified method to determine scopolamine in serum samples of patients, requiring smaller serum volumes and enabling a lower limit of quantification. The chromatographic separation is performed on a RP18e column with a mobile phase gradient. High sensitivity is provided by detecting both mass transitions between m/z 304 and m/z 138 and between m/z 304 and m/z 156 in the tandem

m/z 138 and between m/z 304 and m/z 156 in the tandem FIGURE 1. Structure of

FIGURE 1. Structure of L-(2)-scopolamine (L-(2)-hyoscine), atropine (hyoscyamine), and N-butyl-L-(2)-scopolamine; * = chiral center.

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mass spectrometer. The limit of quantification of scopolamine,

ie, a coefficient of variation , 20% for 6 repeated measure-

ments, is 20 ng/L. 10

PHARMACOKINETICS Administration and Plasma Concentrations

The pharmacokinetic parameters depend on the dosage form (Table 1). The oral dose (tablets), parenteral injection (intravenous, subcutaneous, or intramuscular), and the trans- dermal form are different administration modes well established

for scopolamine.

Following oral administration the bioavailability of scopolamine is limited. The pharmacokinetic profile com-

prises levels returning close to baseline 5 to 6 hours after dose. The pharmacokinetics of 0.5 mg scopolamine orally admin- istered together with 150 mL water to female and male healthy volunteers were (geometric mean 6 geometric SD) t max = 23.5 6 8.2 minutes, C max = 0.54 6 0.10 ng/mL, t ½ = 63.7 6 1.3 minutes, AUC 024h = 50.77 6 1.76 ng min/mL, and F = 13 6 1% (F = AUC oral /AUC IV ; absolute bioavailability). 15 The pharmacokinetic parameters of scopolamine (after

IV

infusion of 0.5 mg over period of 15 minutes) were shown

to

be as follows (geometric mean 6 geometric SD): CL =

81.2 6 1.55 L/h, V d = 141.3 6 1.6 l, t ½ = 68.7 6 1.0 minutes,

C max = 5.00 6 0.43 ng/mL, and AUC 024h = 369.4 6 2.2 ng min/mL (Fig. 2). The C max value in the male subjects was

significantly higher compared with the value in the female subjects (6.61 6 0.63 ng/mL vs 3.93 6 0.04 ng/mL; P = 0.007). Relating to the other parameters, there were no dif- ferences in sex. The pharmacokinetic parameters obtained after oral and intravenous administration were calculated according to a noncompartment model. 15 After subcutaneous administration of 0.4, 0.6, or 0.8 mg scopolamine to male healthy volunteers, C max increased from

3.27 ng/mL to 18.81 ng/mL, and AUC 08h from 158.2 to 455.6

ng min/mL, dependent on dose. In contrast, t max ranged between 11.4 and 17.8 minutes, t ½ between 3.3 and 3.8 hours, and CL between 0.14 and 0.17 L/h independent of the alkaloid dose. A large interindividual variation of the serum concen-

trations of scopolamine was found. 17 Scopolamine is rapidly absorbed from muscle, eg, deltoid muscle. Following intramuscular injection of scopol- amine (0.5 mg), the corresponding pharmacokinetic values

amine (0.5 mg), the corresponding pharmacokinetic values FIGURE 2. Area under scopolamine concentration in serum–

FIGURE 2. Area under scopolamine concentration in serum– versus–time (AUC) curve following intravenous infusion of 0.5 mg scopolamine in 7 healthy male ( ) and 7 healthy female volunteers (s). The solid bar represents infusion dura- tion. From Ebert et al 15 with permission.

were C max = 0.96 6 0.17 ng/mL (mean of 10 individual maximum drug concentrations 6 SD), t max = 18.5 6 4.7 minutes (mean 6 SD), AUC 06h = 81.27 6 11.21 ng min/mL (mean 6 SD), t lag = 3.4 6 1.40 minutes (lag time after IM injection; mean 6 SD), and t ½ b = 69.1 6 8.00 minutes (mean 6 SD). 20 Because of its short half-life in plasma and dose- dependent adverse effects (in particular hallucinations and the less serious reactions, eg, vertigo, dry mouth, drowsiness), the clinical use of scopolamine administered orally or parenterally (bolus therapy) is limited. An intravenous infusion study established the relationship between adverse effects of the drug and the increasing urinary excretion of scopolamine. 21,22 To minimize the relatively high incidence of side effects, the transdermal dosage form was developed. The transdermal delivery system for scopolamine was introduced in 1981. The commercially available small round TTS-patch (4 layers; thickness 0.2 mm; size 2.5 cm 2 ) contains a 1.5-mg drug reservoir and a priming dose (140 mg) to bring plasma con- centrations of scopolamine to steady state. The patch releases 0.5 mg alkaloid over a period of 3 days (releasing rate 5 mg/h). Relative to the release and skin permeation of scopol- amine in vitro, the urinary drug excretion in vivo approaches a 0.1-fold rate of the alkaloid release in vitro approximately 4 hours after application of the TTS patch, assuming a recovery of only 10% unchanged drug in urine. Thus, scopolamine is constantly excreted in urine over a period of many hours. 23,24

TABLE 1. The Most Important Pharmaco Kinetic Data

Application

IV

Oral

SC

IM

IN

Dose (mg) C max (ng/mL) t max (min) AUC (ng * min/mL) t 1/2 (min) F (%)

0.5

0.5

0.4

0.5

0.4

5.00 6 0.43

0.54 6 0.10 23.5 6 8.2

3.27

0.96 6 0.17 18.5 6 4.7

1.68 6 0.23 2.2 6 3

5.0

14.6

369.4 6 2.2 68.7 6 1.0

50.8 6 1.76 63.7 6 1.3 13 6 1

158.2

81.3 6 11.2 69.1 6 8.0 ND

167 6 20 ND 83 6 10

213

100

ND

ND, no data.

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Following the transdermal application of a scopolamine via TTS-patch, the plasma scopolamine concentrations com- bined with the urinary excretion of the drug were analyzed in patients and children. 2540 The plasma concentrations of the drug indicated major interindividual variations. Peak plasma concentrations (C max ) of approximately 100 pg/mL (range 11– 240 pg/mL) of the alkaloid were achieved after about 8 hours

and reached steady state. Over a period of 72 hours the plaster was releasing scopolamine, constant high plasma levels (range of the peak values: 56–245 pg/mL) were obtained, followed by a plateau of urinary scopolamine excretion. For comparison to the oral and IV administration, the bioavailability of scopolamine intranasally (IN) administered was analyzed in healthy nonsmoking male volunteers. 3 The subjects received a 0.4-mg dose of scopolamine hydrobromide intranasally on 3 occasions, with at least 2 weeks separating the doses. The absorption after IN drug application was rapid, and the pharmacokinetic parameters (mean 6 SD) were C max = 1.68 6 0.23 ng/mL, t max = 22.2 6 3 minutes, AUC 024h =

166.8 6 19.8 ng min/mL, and F IN = 83 6 10%. The absolute

bioavailability F IN was found to significantly greater than that of F PO (P , 0.05). Time to reach maximum effect was 1.05 hours after IN dosage. 3 After ocular administration, scopolamine is rapidly,

efficiently, and systemically absorbed. The systemic absorp- tion of the alkaloid eye drops (40 mL 0.25% scopolamine hydrobromide ophthalmic solution) given unilaterally to the lower cul-de-sac of the operated or affected eye was quantified in 8 patients. 5 The 2 groups, scopolamine and control placebo group, did not differ with respect to sex distribution, age,

weight, or height. The plasma concentration (mean 6 SD) of scopolamine was 400 6 50 pg/mL after 3 minutes and was decreased to 120 6 20 pg/mL at 90 minutes. C max (mean 6 SD) was 550 6 60 pg/mL and was reached within 15 minutes (t max ) in all but 2 patients. In these 2 subjects the peak plasma concentration of scopolamine was at 60 minutes with a value of 340 pg/mL, and at 30 minutes with a peak concentration of 280 pg/mL, respectively. Compared with the placebo group, ocular scopolamine did not affect the blood pressure in patients. Before administration the salivary secretion was

0.319 6 0.05 g in the scopolamine and 0.416 6 0.147 g in the

placebo group. Thirty minutes after eye drop application, the secretion was reduced by 0.012 6 0.040 g in the scopolamine

and increased by 0.074 6 0.048 g ( P = 0.19) in the placebo group from the pretreatment value.

Protein Binding

The plasma protein binding of drugs has been shown to have significant effects on numerous aspects of clinical pharmacokinetics (PK) and pharmacodynamics (PD). Hitherto existing measurements of the protein binding of scopolamine are in rats and showed a low value of 30 6 10%. 41

Metabolism and Excretion

Although the drug scopolamine has been used in clinical practice for many years, little data concerning its metabolism and renal excretion in healthy volunteers and patients have been published up to now.

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Scopolamine is a relatively nonpolar, tertiary amino compound and should be well absorbed from the gastroin- testinal tract. However, one of the pharmacological effects of this drug is the suppression of int estinal motility and gastric secretion. Both effects may influence the absorption after oral administration and limit oral b ioavailability of scopol- amine. 42 Only 2.6% of the drug is excreted in urine in a pharmacologically active form. 43 Based on this fact, a first- pass metabolism is suggested to occur after oral administra- tion of scopolamine. Concerning the limited data about metabolism of scopolamine in man and, on the other hand, the potential variety of scopolamine metabolites, the metabolic pathways of scopolamine analyzed in animal studies are to be described more in detail. In studies with scopolamine administered subcutane- ously and intraperitoneally, respectively, different metabolites were identified chemically in the urine of several mam- mals. 44,45 Total unchanged scopolamine and the metabolites excreted in 24-hour urine of mammals varies in diverse animal species both qualitatively and quantitatively (range 29% to .80% of the administered dose). Various metabolic pathways are shown in Figure 5. Following the administration and metabolism of L -(2 )-[9- 14 C]scopolamine, the radioactivity of the N-methyl group of the scopine component was expired as 14 CO 2 by mammals. The same result was obtained after injection of L -(2 )-[9- 14 C]scopolamine-9 #-glucuronide into these mammalian species. With expiring 14 CO 2 , this

mammalian species. With expiring 1 4 CO 2 , this FIGURE 3. Changes in subjective alertness

FIGURE 3. Changes in subjective alertness after scopolamine (SC). From Ebert et al 17 with permission.

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Scopolamine Pharmacokinetics

scopolamine conjugate was also metabolized to its corre- sponding nor-compound. 44 The different apo compounds of the scopolamine, L-( 2)-aposcopolamine and L -(2 )-aponorscopolamine, were shown not to be artifacts derived during the extraction of the drug and its conjugates from the biologic matrix. L-( 2)- Aposcopolamine, a gem-substituted styrene derivative, was proved to be generated (dehydratation reaction) via the scopolamine-O-sulfate ester, which was produced by an en- zymatic (sulfotransferase) reaction. 46 Without any structure elucidation of the educts of the following enzymatic reaction, a mixture of enzymes, b -glucuronidase and b -glucuronide sulfatase (eg, glusulase TM ), was used in vitro for hydrolysis of the conjugated scopolamine metabolites in mammalian urine. 45 Accordingly, it is just pos- sible that the sulfate conjugation might have a role in the metabolism of the alkaloid. However, the fact that saccharo-1,4- lactone, an inhibitor of b -glucuronidase, completely inhibited hydrolysis of the conjugates with b -glucuronidase/sulfatase preparation indicated no or minimal excretion of sulfate con- jugates as in vivo metabolites of scopolamine in mammals. 45 In addition, there was no racemization of the scopol- amine itself or any optically active metabolites in any animal species during passage through the organism. This result was obtained indirectly using the stereospecific (2 )-hyoscyamine acylhydrolase enzyme for the analysis of the optical activity of scopolamine and its metabolites. Under the catalysis of this enzyme, an ester cleavage in the L -(2 )-scopolamine structure takes place, resulting in scopine and L -(2 )-tropic acid. The (2 )-hyoscyamine acylhydrolase is contained in organ homogenates and body fluids of several mammals, especially in rabbit serum, but in matrices of humans the enzyme is hardly traceable. 44 The amounts of metabolites excreted in mammals are highly species specific, and their relationship is largely inde- pendent of the administered dose. The pharmacological ac- tivities of the identified metabolites have not been analyzed so far. Little data about the metabolism in healthy volunteers has been published, indicating the glucuronide or sulfate conjugation as the significant metabolic pathway of L -(2 )-scopolamine. Following an incubation with b -glucuronidase/sulfatase, the amount of scopolamine in human urine increased from 3% up to approximately 30% of the drug dose (intravenously administered). 15,47 However, an analysis stringently verifying the metabolism in man is still lacking. Compared with the metabolism in mammals, it is also not evident so far how many different glucuronide conjugates of scopolamine and its derivatives (apo- and nor-compounds) are produced in man. Therefore, following a complete chromatographic analysis, the chemical structures of the metabolites isolated from human urine still have to be elucidated. Scopolamine metabolites excreted in urine of mammals or man are summarized in Figure 5. Another possible route to eliminate metabolites is excre- tion into feces. Verifying the excretion of the drug via the intestine, there are only few data. In studies describing scopo- lamine metabolism in mice, small amounts of the unchanged L-(2 )-scopolamine and the scopolamine-9#-glucuronide were

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found in feces combined with intestinal contents. 44 However, neither the drug itself nor any of its metabolites were detected in feces of rats. 45 Results of analogous investigations in man have not been published.

Factors Affecting Scopolamine Pharmacokinetics

In vitro studies on the interaction of scopolamine with microsomal cytochrome P-450 (CYP) have shown an oxidative demethylation of the drug during incubation with CYP. 48 The demethylation is related to the CYP3A sub- family. 49 This result is confirmed by the in vivo investigations using L -(2)-[9- 14 C]scopolamine (see above). To inhibit the CYP3A enzymes efficiently, components of grapefruit juice are very suitable. 50,51 Here, the predominant in vivo mechanism was suggested to be located primarily in the mucosa of the small intestine 52 because grapefruit juice has no essential effect on drug metabolism in the liver. 53 The CYP3A activity in hepatic and intestinal micro- somes has been demonstrated to be greater in women than in men. 54,55 In a clinical study the influence of grapefruit juice on scopolamine pharmacokinetics in healthy male and female volunteers was shown. 15 When scopolamine was administered together with 150 mL grapefruit juice scopolamine concen- trations continued to increase for a longer period, resulting in an evident prolongation of t max (59.5 6 25.0 minutes; P , 0.001). The AUC 024h values of scopolamine were higher during the grapefruit juice period. They reached approximately 142% of the values associated with the control group (water period; P . 0.005). Consequently, the corresponding absolute bioavailabilities of scopolamine (range 6% to 37%) were significantly higher than the values after oral administration together with water (range 3% to 27%). C max of scopolamine administered intravenously and determined in male subjects was significantly higher compared with the corresponding C max in female subjects. But after oral administration of scopolamine together with grapefruit juice or water, no differences in the pharmacokinetic parameters of the drug were found between male and female subjects. Appro- ximately 30% of the dose administered was excreted in urine as unchanged drug or as glucuronide conjugate independent of the sex and of the route of administration (infusion, per os administration with water or with grapefruit juice). The elimination was not significantly affected. 15 With regard to transdermal delivery of scopolamine, the skin temperature of the patients is not decisive. However, permeation across human skin in vitro is significantly intensified by increasing the scopolamine concentration or raising the pH of the diffusing drug solution. 23,56 In the same manner the nasal absorption of scopolamine in human subjects is influenced by pH value and dosage. The average AUC value was found to be significantly higher for pH 9.0 formulation as compared with those of pH 4.0 and pH 7.0, respectively. Both the C max and AUC values were almost doubled with doubling the dose. The average t max values decreased linearly with a decrease in formulation pH at both doses. 14 Pharmacokinetics of scopolamine is able to be influenced by oral contraceptives. Depending on the dose administered,

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et al Ther Drug Monit Volume 27, Number 5, October 2005 FIGURE 4. Representative example of

FIGURE 4. Representative example of the concentration–EEG effect relationship (a power) in occipital electrode positions after intravenous infusion of 0.5 mg scopolamine hydro- bromide in a healthy volunteer. Solid line represents the optimal fit of the actual data points. C (t) = predicted serum concentration of scopolamine at time t. From Ebert et al 20 with permission.

p

the contraceptives may inhibit the metabolism of scopolamine, decrease plasma albumin concentrations by 3% to 12%, and may change the clearance. 5759

PHARMACODYNAMICS AND ADVERSE EFFECTS OF SCOPOLAMINE

After IV infusion, scopolamine significantly decreased subjective alertness in both male and female subjects compared with baseline ( P , 0.05) without any differences by sex. 15,6062 Time-dependent disturbances occurred maxi- mally 0.5–2 hours after starting IV infusion of scopolamine in both male and female volunteers. In addition a slight decrease in subject alertness was

observed after oral administration of scopolamine with water

or grapefruit juice compared with baseline ( P , 0.05) in both male and female subjects without any differences by sex. 15

and female subjects without any differences by sex. 1 5 FIGURE 5. Metabolic pathways of L

FIGURE 5. Metabolic pathways of L-(2)-scopolamine.

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Scopolamine Pharmacokinetics

Twenty-four hours after drug administration, the sub- jective state was not significantly different from baseline value in either male or female subjects. 15 Scopolamine orally administered shows an effectiveness in preventing motion sickness within 0.5 hours for a period of 6 hours. The transdermal administration of the same drug is effective over a period of 72 hours. However, by this route the effect is not achieved until 6 to 8 hours postapplication. 9 On the other hand, simultaneously with the stimulation or inhibition, respectively, of other neurotransmitters (eg, serotonergic neu- rotransmission 63 and the dopaminergic system 64 ), the cholin- ergic system is involved in the storage and retrieval of information during new learning. The blockade of central muscarinic receptors induces a memory deficit in young sub-

jects that is similar to that occurring in elderly subjects. 60,62,65 Age-related changes in the central cholinergic system are reflected in a decreased functional activity of cholinoreceptive neurons. In addition, studies in patients with Alzheimer dis- ease have shown a severe loss of neurons in the nucleus basalis of Meynert. 66 The decrease in cortical choline acetyltransfer- ase found in Alzheimer patients is suggested to reflect a specific loss of cholinergic input to the cortex 65 because the nucleus basalis of Meynert is believed to provide the primary cholinergic input to the cortical mantle. 67 It is postulated that postsynaptic muscarinic receptors are permanently destroyed or inactivated in dementia of the Alzheimer type. 68 In stud- ies of electroencephalogram (EEG) changes and drug effects on different cognitive functions, scopolamine is commonly used as a pharmacological model substance based on the ‘‘cholinergic hypothesis’’ of memory loss in senile dementia of the Alzheimer type. However, the ‘‘scopolamine model’’ is insufficient to indicate the full range of memory deficits found in patients with Alzheimer disease. 69 The effects of intravenously, 20 intramuscularly, 20,61 and subcutaneously 17 administered scopolamine on quantitative EEG (qEEG) and cognitive performance related to pharma- cokinetic parameters were demonstrated in studies with healthy volunteers. Scopolamine produced a dose- and time- dependent impairment of memory and attention. After admin- istration of scopolamine (0.4–0.8 mg SC), the drug generated

a time-dependent increase in d power (1.25–4.50 Hz) and a

decrease in fast a power (9.75–12.50 Hz) on qEEG for more than 8 hours. The temporary changes in cognitive behavior

evaluated by qEEG and psychometric tests (eg, changes in choice reaction time) are shown in Figure 3. Pharmacodynamic measurements after intravenous and intramuscular scopolamine administration (0.5 mg scopol-

amine hydrobromide over a period of 15 minutes, and 0.5 mg in the upper right arm, respectively) indicated no interday variability of the baseline values of EEG. The absolute power in a band (7.50–11.25 Hz) decreased after scopolamine administration. This effect returned gradually to baseline. Fifteen minutes after beginning scopolamine infusion,

a significant decrease in absolute a power occurred at frontal,

central, and occipital brain areas compared with placebo. This effect was persistent up to 180 minutes after drug adminis- tration ( P , 0.05). 20

Figure 4 shows the relationship between scopolamine serum concentrations and EEG effects ( a power in occipital

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electrode positions) derived for an individual healthy subject after IV scopolamine administration (PK-PD modeling). No time delay between serum concentrations and EEG effect was observed, and the corresponding values were directly corre-

lated to each other by a sigmoid E max model (E max is the maximal drug effect). 20 Scopolamine administered in pharmacologically effec- tive doses generates fatigue, dreamless sleep (reduction in rapid eye movement, REM), amnesia, vertigo, vestibular de- pression. In contrast, in patients receiving higher scopolamine doses, the drug can produce a stimulation of the CNS with symptoms, eg, excitement, hallucinations, irritability. 70 The mechanism of action of the anticholinergic (antimuscarinic) drug scopolamine is the competitive antag- onism of acetylcholine at the muscarinic receptors. 71 For a better understanding of the pharmacodynamics and the di- versity of adverse effects caused by scopolamine, the local distribution of muscarinic receptors (a family of 5 subtypes,

M 1 –M 5 , is expressed in man) has to be considered. Each of the

human muscarinic receptor proteins (M 1 –M 5 ) is encoded by a unique gene, and its corresponding amino acid sequence has been described. 72,73 As found with PCR, receptor subtype mRNAs of M 1 to M 5 are expressed in the human brainstem, cerebellum, and cortex. In contrast, the vestibular ganglia and

the vestibular end organs in humans express only M 1 , M 2 , and

M 5 . 74 In consequence of these results and previous electro-

physiological and immunohistochemical analyses, the efferent cholinergic axosomatic and axodentritic synapses are sug- gested to have muscarinic components having an effect on motion sickness. 75,76 Based on pharmacological studies with experimental drugs, eg, pirenzepine, AFDX-116, or methocramine (each a selective antagonist), 3 subtypes (M 1 , M 2 , and M 3 ) of muscari- nic receptors can be defined. 72,77 The receptors have been found to regulate a broad range of physiological and biochemical activities throughout the CNS via the activation of guanidine nucleotide binding (G) proteins. Nevertheless the physiological function of these receptor subtypes is still poorly defined, but the anatomic location of the subtypes suggests that the neuronal tissues have

a preponderance of M 1 receptors. The subtype M 2 is situated predominantly in the heart, and M 3 is the glandular sub- type. 72,73 Similar to atropine, L -(2 )-scopolamine is a nonselective muscarinic antagonist. 78 The sensitivity of the subtypes seems to vary in such a way that the inhibition of salivation (M 3 receptors) can be produced with low doses, whereas much higher doses are needed for heart effects (M 2 receptors). 79,80 As a result of the mechanism of action described above, the measured plasma levels of scopolamine do not necessarily correlate with the pharmacodynamic effects of the drug. The effects of scopolamine on the cardiovascular system are complex and dose dependent. 40 Low doses of the alkaloid give rise to a slowing of heart rate, whereas higher doses produce an increase in heart rate dose-dependently. Follow- ing the inhibition of the vagal transmission of the sinoatrial node, tachycardia is produced. Such a biphasic dose–response curve is prominent with scopolamine. Intravenously admin- istered doses up to 2.8 mg/kg body weight (bw) produce only

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bradycardia. After a dose of more than 8.4 mg/kg bw, a tran- sient tachycardia is observed, is reversed within 30 minutes, and is followed by a long-lasting bradycardia. 81 Scopolamine produces mydriasis and cycloplegia. Here, the sphincter muscle of the iris and the ciliary muscle of the lens are paralyzed. 40 Eye functions may be impaired up to 7– 12 days when scopolamine is administered locally. After orally or parenterally administered scopolamine, visual problems are both slow to develop and slow to reverse. 82 In addition, only a small effect on eye pressure is described after oral or parenteral scopolamine. This is in contrast to the local administration. However, in patients with narrow-angle glaucoma, the systemic application of L-(2)scopolamine may induce a dangerous increase in eye pressure. 40 Scopolamine gives a rise to an inhibition of gastric salivation and secretion. The drug produces dryness of the mouth and decreases the tone of the smooth muscle in the gastrointestinal and urinary tract, leading to a decreased motility. 79 Additionally, the motility of stomach and esophagus is decreased. Adverse effects of scopolamine in the respiratory tract are dryness of the mucous membranes of the nasopharynx, mouth, bronchi, and bronchioli. Following a relaxation of the smooth muscles after scopolamine administration, the airway resistance in the respiratory tract is reduced. Scopolamine (IV) reduces the sweat gland activity and, hence, the galvanic skin response. 83 The tonus and the amplitude of urethra and bladder contractions may be decreased after scopolamine application. Therefore, there is a contraindication to the use of the drug in patients with obstructive uropathy. 40

TOXICITY

Because of the limited information on species differ- ences in the acute toxicity of scopolamine, it is not clear which

metabolites contribute to the toxicity of the drug. For instance, in toxicity studies of atropine, the metabolite apoatropine, a styrene derivative, has been demonstrated to possess more potent acute toxicity than atropine itself. 45,84

If the same relation between aposcopolamine and sco-

polamine obtains, the contribution of the dehydrated metab- olite to the occurrence of scopolamine toxicity may be most significant in guinea pig because these mammals have the highest dehydrating capacity among the species examined. The alkaloid readily crosses the placenta. Therefore, the administration of scopolamine in pregnant women should occur only under clinical observation. 85,86 The drug is com- patible with nursing and is not considered to be teratogenic. 87 Scopolamine toxicity has been described in a newborn with symptoms such as tachycardia, fever, and lethargy. The signs and symptoms of an anticholinergic intoxi- cation include somnolence, coma, confusion, agitation, hallu- cinations, convulsion, visual disturbance, dry flushed skin, dry mouth, urinary retention, decreased bowel sounds, hyperten- sion, and supraventricular arrythmias.

A case of Frey syndrome is reported characterized by

gustatory sweating and erythema of the face on mastication

662

after injury to the parotid gland. 88 LD 50 was determined in rats administered 3800 mg/kg bw subcutaneously. 89 Although many epoxides have been observed to show a highly muta- genic activity, the parasympatholytic drug scopolamine does not posses such an activity. 90

DOSAGE REGIMEN

Scopolamine is used mainly in the prevention of motion sickness, in various gastrointestinal disorders, and as premed- ication before anesthesia. Commercially available patches applied to the postaur- icular area contain a scopolamine reservoir of 1.5 mg and

deliver 0.5 mg of the drug over a time period of 3 days. Therefore, after a priming dose of 140 mg delivered in the first few hours, the drug is released with a constant rate of 5 mg/h over the following 3 days. The recommended dose applied to

an

adult is a single TTS-patch placed on the postauricular area

at

least 46 hours before an antiemetic effect is required. If

a

shorter period is required to prevent motion sickness,

a

combination of a TTS patch and a 0.3 mg tablet is intended

for administration 1 hour before travel. If there is an insuf- ficient clinical response, a higher dose (0.6-mg scopolamine

tablet) has to be used. The combination of transdermal and oral scopolamine is extremely efficient in achieving a fast and prolonged prophylactic protection against motion sickness. 9 TTS-patch is not recommended for administration in children and should be used with special caution in patients with pyloric obstruction, intestinal obstruction, impaired liver and kidney function, and urinary bladder neck obstruction. The scopolamine patch is contraindicated in patients with plaster allergy, in patients with glaucoma, and in pregnant women. The clinical effects of scopolamine in patients un- dergoing cesarean section under general anesthesia were determined in a clinical study. Using scopolamine instead of the routine atropine medication, 3 groups of parturients were administered the alkaloid intravenously, intramuscularly, or oropharyngeally (intubated patients). The patients of group 1 (IV injection) were slightly se dated only, without amnesia, and the dryness of the mouth subjectively was reported to be only moderate. In contrast, in group 2 (IM injection) and group 3 (oropharyngeal application), all patients were markedly sedated and had complete amnesia up to 1.5–2 hours after the end of the anesthesia. All of them reported a strong dryness of the mouth. According to these measured pharmacodynamics

a single intravenous dose of 5 m g scopolamine per kg bw is

clinically useful without prominent residual effects, but both the 10 mg/kg intramuscular and 35 m g/kg oropharyngeal doses caused too strong adverse effects. 91 Male patients scheduled for minor surgery under spinal anesthesia were studied. Patients received scopolamine (6 mg/kg bw) plus morphine (200 mg/kg bw) injected in either deltoid or gluteal muscle. The sedative effect of the drug combination was prominent and long lasting in both groups. 6

CONCLUSION

Scopolamine is a nonselective muscarinic antagonist. The mechanism of action of the anticholinergic drug

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Scopolamine Pharmacokinetics

scopolamine is the competitive antagonism of acetylcholine at the muscarinic receptors. As a result of the nonpolar structure of the native parasympatholytic drug, its good lipid solubility permits almost complete and rapid gastrointestinal absorption and crossing of the blood–cerebrospinal fluid barrier. Scopol- amine shows profound sedative, amnesic, and antiemetic ac- tions. Because of the large number of adverse effects and the short duration of action following oral, intravenous, or intramuscular administration, the clinical use is limited. Nevertheless, scopolamine is the most effective single agent to prevent motion sickness. To minimize the relatively high incidence of adverse effects and to extend the duration of action, the TTS-patch was developed. In several studies TTS- patches have been shown to reach protective levels after 6–8 hours, achieving a steady state. The optimal efficacy is maintained over a period of 72 hours. In contrast, scopolamine administered orally or intravenously shows an effectiveness in preventing motion sickness within 0.5 hours for a period of only 6 hours. However, its bioavailability is limited after oral administration. The glucuronide conjugation of scopolamine could be the relevant pathway in a healthy human. This will be suggested by the results of the enzymatic hydrolysis of con- jugated metabolites with b -glucuronidase and sulfatase. How- ever, scopolamine metabolism in humans is not completely known, and a complete chromatographic analysis followed by elucidation of the exact chemical structures of the metabolites extracted from human urine is still lacking. Inhibiting the CYP3A enzyme with components of grapefruit juice influences the pharmacokinetics of scopolamine to produce evident prolongation of t max , and the AUC 024h values and consequently the bioavailabilities of scopolamine were significantly higher.

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