SPECIAL
SECTION:
Clinical
Implications
BY RICHARD
I. SHADER,
Pharmacokinetic differences exist route ofelimination pharmacologically and other results clinical implications drug accumulation antianxiety therapy pharmacotherapy influence ofroute
Benzodiazepines
of Benzodiazepine M.D.,
AND
DAVID
J. GREENBLATF,
research has shown that clear among benzodiazepines in rate and and in the presence or absence of active metabolites. These findings ofpharmacokinetic research have in terms ofdosage schedules, during long-term therapy, in the elderly, drug interactions, in specific disease states, and the ofadministration on drug action.
IN TODAY’S CLIMATE of high social, economic, and personal stress, the use of antianxiety agents continues to grow. Benzodiazepines are by far the most common class of antianxiety agents prescribed in the United States (1). Quarterly data on 1974 refill prescriptions (1), for example, show steady increments for most benzodiazepines. For diazepam (DZ), the most popular benzodiazepine, 9, 191 ,000 refills were prescribed in the first quarter of 1974; this increased to 9,642,000 in the third quarter of the year. The newest benzodiazepine in the United States, clorazepate (CZP), had first and third quarter figures of 382,000 and 564,000 refill prescriptions, respectively. Clinical teaching about antianxiety agents usually stresses between-class drug differences and within-class
Presented Association,
at the 129th annual meeting Miami Beach, Fla. , May
of the American 10-14, 1976.
Psychiatric
Dr. Shader is Director, Psychopharmacology Research Laboratory, Massachusetts Mental Health Center, Harvard Medical School, Boston, Mass. Dr. Greenblatt is Acting Chief, Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Mass. Address reprint requests to Dr. Shader at the Massachusetts Mental Health Center, 74 Fenwood Rd. , Boston, Mass. 02115. This
work was supported Health Administration tute of Mental Health. tal
in part by Alcohol, grant MH-l2279
The authors are grateful for the assistance old S. Harmatz, Ann Ogletree, Hedy-Ann Dr. Jan Koch-Weser, Linda Robertson, 652
Am
J Psychiatry
134:6,
Drug Abuse, and from the National
and collaboration Tammerk, Kate and Ann Werner.
June
1977
Pharmacokinetics
MenInsti-
of JerFranke,
M.D.
drug similarities. Not surprisingly, most clinicians consider benzodiazepines as having few within-class differences. Controlled clinical trials demonstrate that each of the marketed benzodiazepine antianxiety agents, when given in adequate doses, is consistently more effective than placebo in anxious nonpsychotic patients (2). We have focused considerable attention on this class of compounds in recent years (2-5). Our most current studies involve investigation of their plasma levels and pharmacokinetic properties. These studies and the work of others indicate that clinically meaningful within-class differences do exist (6). The present report reviews some of these findings as well as other data from pharmacokinetic research. Such considerations make possible a more rational approach to the treatment of anxiety states. Table 1 presents the most commonly prescribed benzodiazepine antianxiety agents in the United States, Canada, and Great Britam.
PRINCIPLES
Comparison
OF
ofRoutes
PHARMACOKINETICS
of Administration
Pharmacokinetics is a clinical and mathematical discipline devoted to quantitative description of the absorption, distribution, metabolism, and elimination of drugs by the living organism (7-9). It involves study of drug concentrations in biological fluids and the changes in these levels that occur over time. The left portion of figure 1 illustrates a pharmacokinetic study of blood levels of chlordiazepoxide (CDX) following oral and intramuscular administration of 50 mg of chlordiazepoxide hydrochloride to a healthy male volunteer in a crossover study. Intramuscular administration results in delayed and possibly incomplete absorption of the parent drug as well as delayed appearance of its active metabolite, desmethyichiordiazepoxide (DMCDX). This phenomenon has been consistently observed in a large series of healthy volunteers (1 1, 12), and we are currently studying absorp-
RICHARD
TABLE
I.
SHADER
AND
DAVID
J.
GREENBLATT
1
Commonly Prescribed
Generic
Benzodiazepine
Name
Antianxiety
Trade
Agents
5-30
Chlordiazepoxide
Librium and many others
Diazepam Oxazepam Clorazepate** Lorazepam
Valium
20-50
Sera.x Tranxene
5-20 30-fif**
Ativan Nobrium
10-15
Medazepam
Quantitatively Major Active Metabolites
Elimination Half-life (hours)*
Name
Desmethylchlordiazepoxide Demoxepam Desmethyldiazepam Desmethyldiazepam None (Desmethyldiazepam)**
None Desmethylmedazepam
***
Desmethyldiazepam Diazepam Approximate **Hydrolyd
range. to desmethyldiazepam data are insufficient.
FIGURE 1* Pharmacokinetic Diazepam**
I
2.0
Studies
before absorption.
of Blood
Levels
of Chlordiazepoxide
:=
Chiordiazepoxide Diazepam
.
Desmethylchiordiazepoxide
24
36
0
HOURS
*The right portion Therapeutics
(10)
ofthis with
.
tract is nearly complete (12, 13). Intramuscular injection of CDX in high doses every 3 to 6 hours clearly does not constitute rational therapy of alcohol withdrawal ; the cumulative effect of multiple doses that are slowly absorbed could lead to excessive sedation of delayed onset, a situation not infrequently encountered by clinicians treating delirium tremens. There is a need for a benzodiazepine derivative that is rapidly and reliably absorbed following intramuscular injection. Neither CDX nor DZ appears to meet this need, and parenteral preparations of CZP and oxazepam (OXZ) are not available. Preliminary results in healthy volunteers given intramuscular lorazepam (LRZ), a 3-hydroxy benzodiazepine derivative similar in structure to OXZ, indicate that absorption of this drug from the injection site may be quite rapid and reliable, leading to more prompt onset of sedation. However, in this study, as in the work of others (14), anterograde amnesia occurs in some subjects. This property may be desirable in certain clinical conditions (e.g. preanesthesia, cardioversion).
E,T’E:
!
4812
and
figure
AFTER
is reprinted
0.5 DOSE
from ClinicaiPharmacology
and
permission.
**The left portion shows whole blood concentrations ofchlordiazepoxide and desmethylchlordiazepoxide (its active metabolic) for 36 hours following intramuscular and oral administration of 50 mg of chlordiazepoxide hydrochloride to a healthy male subject. The right portion shows the plasma 1evels of diazepam for 4 hours following intramuscular and oral administration of 20 mg of diazepam. Each point represents the mean of 6 subjects.
tion of intramuscular CDX in patients with acute and chronic alcoholism. Studies of intramuscular versus oral administration ofdiazepam have yielded similar results (10) (see right portion of figure 1). The findings have considerable clinical relevance for the treatment of alcohol withdrawal and acute episodes of anxiety, for preoperative sedation, or for other situations in which sedative effects of rapid onset are desired. Contrary to usual dinical teaching that intramuscular injection requires less medication and leads to more rapid clinical response, oral administration of CDX or DZ is more likely to produce rapid, reliable clinical effects than intramuscular injection of the same dose. Comparison of intravenous and oral administration of these two drugs also suggests that absorption from the gastrointestinal
,
Factors
Influencing
Gastrointestinal
Absorption
Clorazepate is hydrolized in the stomach to an adtive metabolite, desmethyldiazepam (DMDZ). Desmethyldiazepam is also the first major active metabolite of DZ, following its demethylation by the liver. Thus CZP and DZ, given orally, are both initially metabolized to DMDZ. This would suggest some similarity in clinical action for these two drugs. However, the rate and extent of hydrolysis of CZP to DMDZ probably depend on gastric acidity. The extent of hydrolysis, in turn, may influence the completeness of absorption, since CZP is too polar to be extensively absorbed as such. We calculated the half-lives for hydrolysis of CZP to DMDZ at 37#{176} C in relation to pH (see figure 2) from data published by Raihle and Papendick (15). As pH approaches 7, the hydrolysis half-life becomes very long, suggesting that gastric emptying may occur before a substantial degree of hydrolysis can occur. Am
J Psychiatry
134:6,
June
1977
653
CLINICAL
IMPLICATIONS
FIGURE 2 Rate of Hydrolysis Relation to Ph*
of Clorazepate
to Desmethyldiazepam
at 37#{176} C in
100
75
pH 6 )97.9
minutes)
50
N.J >. -J
0
pH 5(10.1
0 >-
minutes)
I
z 0
z
actions. One such study investigated the effects of 100 ml of a magnesium and aluminum hydroxide preparation (Maalox) on the absorption and elimination of single oral doses of 25 mg of CDX in young adult volunteers (18). For the majority of subjects and for the mean effect on the group as a whole, the antacid significantly delayed CDX absorption, although the total amount absorbed under the two conditions over 24 hours did not differ. We also observed that certain subjective drug effects were attenuated or eliminated in the antacid condition, suggesting that the perception of some drug effects may depend on the rate of drug absorption. These findings probably apply only to p.r.n. dosing situations and may not relate to chronic administration. Another important question is whether the lipophilic nature of DZ would lead to malabsorption of DZ in the presence of mineral oil. Coprescribing of these two substances is a common practice for elderly patients in nursing homes and other institutional settings.
25
w
0
Metabolism
cx LJ
12.5
.-
.1 0
10
20
.1..
I
-
30
40
50
60
70
MINUTES
Ba.SCd
on data presented
theses
indicate
hydrolysis
by Raihie
and Papendick
(15);
the times in paren-
half-life.
Patients with achiorhydria or those taking clinically effective doses of antacids may not produce and absorb clinically useful amounts of DMDZ following CZP dosage. In vitro studies ofantacid titration against gastric acid secretion suggest that effective doses of antacids given every 2 hours will keep the pH of gastric juice in the 4 to 6 range (16). Furthermore, gastric pH may become as high as 7.2 within 20 minutes of initial antacid dosing (16). Clinical studies are needed to evaluate the possible effect of gastric acidity on CZP absorption. As these observations suggest, antacids or anticholinergic agents can substantially influence the rate and/ or completeness of drug absorption when coadministered with particular drugs. This may occur because of alterations in pH or by delay in gastric emptying (17). Delayed gastric emptying may permit gastric acid to alter the structure of a susceptible drug or alter the amount ofdrug absorbed. Since many anxious patients with peptic ulcer disease take concomitant antacid or anticholinergic agents along with benzodiazepines, we have initiated studies on these potential drug inter654
Am
J Psychiatry’
134:6,
June
1977
With the exception of the hydrolysis of CZP to DMDZ in the stomach, the major site of biotransformation of benzodiazepines studied to date is the liver (2). Demethylation and/or hydroxylation are important steps in the biotransformation of CDX and DZ. Age, other drugs, and liver disease can influence demethylation and hydroxylation of a variety of drugs (19, 20). We have studied apparent rates of CDX absorption and elimination following a single 25mg oral dose to 8 healthy volunteers over 65 years of age, in comparison with 10 healthy subjects aged 30 years or less. The results are based on computer analysis of concentrations of CDX and DMCDX determined in multiple blood samples drawn over 24 hours after each dose in each subject. The apparent half-life of CDX absorption was significantly longer in the elderly group as a whole (see table 2); this is consistent with slower drug absorption in these individuals, but the size of the difference (approximately 7 minutes) was small and unlikely to be of clinical significance. The effect of age on the apparent elimination halflife, however, has more potential clinical importance (see table 2). The CDX elimination half-life in the elderly group as a whole was more than 60% longer than in the young volunteers. As expected, DMCDX appeared later and in reduced amounts in the older subjects. Our estimates of the total apparent volumes of distribution of CDX in these two age groups also suggest that these volumes are similar. Since the total metabolic clearance of a drug depends on both its apparent elimination half-life and its total volume of distribution (7-9), these findings indicate that older people may have reduced clearance of CDX. Dosage schedules that do not take account of this alteration in clearance could result in drug accumulation and an increased likelihood of unwanted effects in the elderly (e.g. excessive sedation and motor incoordination). Although studies of intravenous CDX are needed to ,
RICHARD
TABLE 2 Comparison
of Chiordiazepoxide
Pharmacokinetics
I.
SHADER
AND
Absorption*
Young
M volunteers
(N
=
10)
Elderlyvolunteers(N=8) t=2.53,
t3.78,
p
SECTION:
Clinical
Implications
BY RICHARD
I. SHADER,
Pharmacokinetic differences exist route ofelimination pharmacologically and other results clinical implications drug accumulation antianxiety therapy pharmacotherapy influence ofroute
Benzodiazepines
of Benzodiazepine M.D.,
AND
DAVID
J. GREENBLATF,
research has shown that clear among benzodiazepines in rate and and in the presence or absence of active metabolites. These findings ofpharmacokinetic research have in terms ofdosage schedules, during long-term therapy, in the elderly, drug interactions, in specific disease states, and the ofadministration on drug action.
IN TODAY’S CLIMATE of high social, economic, and personal stress, the use of antianxiety agents continues to grow. Benzodiazepines are by far the most common class of antianxiety agents prescribed in the United States (1). Quarterly data on 1974 refill prescriptions (1), for example, show steady increments for most benzodiazepines. For diazepam (DZ), the most popular benzodiazepine, 9, 191 ,000 refills were prescribed in the first quarter of 1974; this increased to 9,642,000 in the third quarter of the year. The newest benzodiazepine in the United States, clorazepate (CZP), had first and third quarter figures of 382,000 and 564,000 refill prescriptions, respectively. Clinical teaching about antianxiety agents usually stresses between-class drug differences and within-class
Presented Association,
at the 129th annual meeting Miami Beach, Fla. , May
of the American 10-14, 1976.
Psychiatric
Dr. Shader is Director, Psychopharmacology Research Laboratory, Massachusetts Mental Health Center, Harvard Medical School, Boston, Mass. Dr. Greenblatt is Acting Chief, Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Mass. Address reprint requests to Dr. Shader at the Massachusetts Mental Health Center, 74 Fenwood Rd. , Boston, Mass. 02115. This
work was supported Health Administration tute of Mental Health. tal
in part by Alcohol, grant MH-l2279
The authors are grateful for the assistance old S. Harmatz, Ann Ogletree, Hedy-Ann Dr. Jan Koch-Weser, Linda Robertson, 652
Am
J Psychiatry
134:6,
Drug Abuse, and from the National
and collaboration Tammerk, Kate and Ann Werner.
June
1977
Pharmacokinetics
MenInsti-
of JerFranke,
M.D.
drug similarities. Not surprisingly, most clinicians consider benzodiazepines as having few within-class differences. Controlled clinical trials demonstrate that each of the marketed benzodiazepine antianxiety agents, when given in adequate doses, is consistently more effective than placebo in anxious nonpsychotic patients (2). We have focused considerable attention on this class of compounds in recent years (2-5). Our most current studies involve investigation of their plasma levels and pharmacokinetic properties. These studies and the work of others indicate that clinically meaningful within-class differences do exist (6). The present report reviews some of these findings as well as other data from pharmacokinetic research. Such considerations make possible a more rational approach to the treatment of anxiety states. Table 1 presents the most commonly prescribed benzodiazepine antianxiety agents in the United States, Canada, and Great Britam.
PRINCIPLES
Comparison
OF
ofRoutes
PHARMACOKINETICS
of Administration
Pharmacokinetics is a clinical and mathematical discipline devoted to quantitative description of the absorption, distribution, metabolism, and elimination of drugs by the living organism (7-9). It involves study of drug concentrations in biological fluids and the changes in these levels that occur over time. The left portion of figure 1 illustrates a pharmacokinetic study of blood levels of chlordiazepoxide (CDX) following oral and intramuscular administration of 50 mg of chlordiazepoxide hydrochloride to a healthy male volunteer in a crossover study. Intramuscular administration results in delayed and possibly incomplete absorption of the parent drug as well as delayed appearance of its active metabolite, desmethyichiordiazepoxide (DMCDX). This phenomenon has been consistently observed in a large series of healthy volunteers (1 1, 12), and we are currently studying absorp-
RICHARD
TABLE
I.
SHADER
AND
DAVID
J.
GREENBLATT
1
Commonly Prescribed
Generic
Benzodiazepine
Name
Antianxiety
Trade
Agents
5-30
Chlordiazepoxide
Librium and many others
Diazepam Oxazepam Clorazepate** Lorazepam
Valium
20-50
Sera.x Tranxene
5-20 30-fif**
Ativan Nobrium
10-15
Medazepam
Quantitatively Major Active Metabolites
Elimination Half-life (hours)*
Name
Desmethylchlordiazepoxide Demoxepam Desmethyldiazepam Desmethyldiazepam None (Desmethyldiazepam)**
None Desmethylmedazepam
***
Desmethyldiazepam Diazepam Approximate **Hydrolyd
range. to desmethyldiazepam data are insufficient.
FIGURE 1* Pharmacokinetic Diazepam**
I
2.0
Studies
before absorption.
of Blood
Levels
of Chlordiazepoxide
:=
Chiordiazepoxide Diazepam
.
Desmethylchiordiazepoxide
24
36
0
HOURS
*The right portion Therapeutics
(10)
ofthis with
.
tract is nearly complete (12, 13). Intramuscular injection of CDX in high doses every 3 to 6 hours clearly does not constitute rational therapy of alcohol withdrawal ; the cumulative effect of multiple doses that are slowly absorbed could lead to excessive sedation of delayed onset, a situation not infrequently encountered by clinicians treating delirium tremens. There is a need for a benzodiazepine derivative that is rapidly and reliably absorbed following intramuscular injection. Neither CDX nor DZ appears to meet this need, and parenteral preparations of CZP and oxazepam (OXZ) are not available. Preliminary results in healthy volunteers given intramuscular lorazepam (LRZ), a 3-hydroxy benzodiazepine derivative similar in structure to OXZ, indicate that absorption of this drug from the injection site may be quite rapid and reliable, leading to more prompt onset of sedation. However, in this study, as in the work of others (14), anterograde amnesia occurs in some subjects. This property may be desirable in certain clinical conditions (e.g. preanesthesia, cardioversion).
E,T’E:
!
4812
and
figure
AFTER
is reprinted
0.5 DOSE
from ClinicaiPharmacology
and
permission.
**The left portion shows whole blood concentrations ofchlordiazepoxide and desmethylchlordiazepoxide (its active metabolic) for 36 hours following intramuscular and oral administration of 50 mg of chlordiazepoxide hydrochloride to a healthy male subject. The right portion shows the plasma 1evels of diazepam for 4 hours following intramuscular and oral administration of 20 mg of diazepam. Each point represents the mean of 6 subjects.
tion of intramuscular CDX in patients with acute and chronic alcoholism. Studies of intramuscular versus oral administration ofdiazepam have yielded similar results (10) (see right portion of figure 1). The findings have considerable clinical relevance for the treatment of alcohol withdrawal and acute episodes of anxiety, for preoperative sedation, or for other situations in which sedative effects of rapid onset are desired. Contrary to usual dinical teaching that intramuscular injection requires less medication and leads to more rapid clinical response, oral administration of CDX or DZ is more likely to produce rapid, reliable clinical effects than intramuscular injection of the same dose. Comparison of intravenous and oral administration of these two drugs also suggests that absorption from the gastrointestinal
,
Factors
Influencing
Gastrointestinal
Absorption
Clorazepate is hydrolized in the stomach to an adtive metabolite, desmethyldiazepam (DMDZ). Desmethyldiazepam is also the first major active metabolite of DZ, following its demethylation by the liver. Thus CZP and DZ, given orally, are both initially metabolized to DMDZ. This would suggest some similarity in clinical action for these two drugs. However, the rate and extent of hydrolysis of CZP to DMDZ probably depend on gastric acidity. The extent of hydrolysis, in turn, may influence the completeness of absorption, since CZP is too polar to be extensively absorbed as such. We calculated the half-lives for hydrolysis of CZP to DMDZ at 37#{176} C in relation to pH (see figure 2) from data published by Raihle and Papendick (15). As pH approaches 7, the hydrolysis half-life becomes very long, suggesting that gastric emptying may occur before a substantial degree of hydrolysis can occur. Am
J Psychiatry
134:6,
June
1977
653
CLINICAL
IMPLICATIONS
FIGURE 2 Rate of Hydrolysis Relation to Ph*
of Clorazepate
to Desmethyldiazepam
at 37#{176} C in
100
75
pH 6 )97.9
minutes)
50
N.J >. -J
0
pH 5(10.1
0 >-
minutes)
I
z 0
z
actions. One such study investigated the effects of 100 ml of a magnesium and aluminum hydroxide preparation (Maalox) on the absorption and elimination of single oral doses of 25 mg of CDX in young adult volunteers (18). For the majority of subjects and for the mean effect on the group as a whole, the antacid significantly delayed CDX absorption, although the total amount absorbed under the two conditions over 24 hours did not differ. We also observed that certain subjective drug effects were attenuated or eliminated in the antacid condition, suggesting that the perception of some drug effects may depend on the rate of drug absorption. These findings probably apply only to p.r.n. dosing situations and may not relate to chronic administration. Another important question is whether the lipophilic nature of DZ would lead to malabsorption of DZ in the presence of mineral oil. Coprescribing of these two substances is a common practice for elderly patients in nursing homes and other institutional settings.
25
w
0
Metabolism
cx LJ
12.5
.-
.1 0
10
20
.1..
I
-
30
40
50
60
70
MINUTES
Ba.SCd
on data presented
theses
indicate
hydrolysis
by Raihie
and Papendick
(15);
the times in paren-
half-life.
Patients with achiorhydria or those taking clinically effective doses of antacids may not produce and absorb clinically useful amounts of DMDZ following CZP dosage. In vitro studies ofantacid titration against gastric acid secretion suggest that effective doses of antacids given every 2 hours will keep the pH of gastric juice in the 4 to 6 range (16). Furthermore, gastric pH may become as high as 7.2 within 20 minutes of initial antacid dosing (16). Clinical studies are needed to evaluate the possible effect of gastric acidity on CZP absorption. As these observations suggest, antacids or anticholinergic agents can substantially influence the rate and/ or completeness of drug absorption when coadministered with particular drugs. This may occur because of alterations in pH or by delay in gastric emptying (17). Delayed gastric emptying may permit gastric acid to alter the structure of a susceptible drug or alter the amount ofdrug absorbed. Since many anxious patients with peptic ulcer disease take concomitant antacid or anticholinergic agents along with benzodiazepines, we have initiated studies on these potential drug inter654
Am
J Psychiatry’
134:6,
June
1977
With the exception of the hydrolysis of CZP to DMDZ in the stomach, the major site of biotransformation of benzodiazepines studied to date is the liver (2). Demethylation and/or hydroxylation are important steps in the biotransformation of CDX and DZ. Age, other drugs, and liver disease can influence demethylation and hydroxylation of a variety of drugs (19, 20). We have studied apparent rates of CDX absorption and elimination following a single 25mg oral dose to 8 healthy volunteers over 65 years of age, in comparison with 10 healthy subjects aged 30 years or less. The results are based on computer analysis of concentrations of CDX and DMCDX determined in multiple blood samples drawn over 24 hours after each dose in each subject. The apparent half-life of CDX absorption was significantly longer in the elderly group as a whole (see table 2); this is consistent with slower drug absorption in these individuals, but the size of the difference (approximately 7 minutes) was small and unlikely to be of clinical significance. The effect of age on the apparent elimination halflife, however, has more potential clinical importance (see table 2). The CDX elimination half-life in the elderly group as a whole was more than 60% longer than in the young volunteers. As expected, DMCDX appeared later and in reduced amounts in the older subjects. Our estimates of the total apparent volumes of distribution of CDX in these two age groups also suggest that these volumes are similar. Since the total metabolic clearance of a drug depends on both its apparent elimination half-life and its total volume of distribution (7-9), these findings indicate that older people may have reduced clearance of CDX. Dosage schedules that do not take account of this alteration in clearance could result in drug accumulation and an increased likelihood of unwanted effects in the elderly (e.g. excessive sedation and motor incoordination). Although studies of intravenous CDX are needed to ,
RICHARD
TABLE 2 Comparison
of Chiordiazepoxide
Pharmacokinetics
I.
SHADER
AND
Absorption*
Young
M volunteers
(N
=
10)
Elderlyvolunteers(N=8) t=2.53,
t3.78,
p
