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German Journal of Psychiatry

ISSN 1433-1055

Propranolol in Alcoholic Patients

 

Seppo Kähkönen


Bio Mag Laboratory and Department of Psychiatry

 Helsinki University Central Hospital, Tukholmankatu 8 F, 00290 Helsinki, Finland


 

Abstract

The present data characterises the pharmacokinetics and concentration-effect relationship of a single 80 mg oral dose of propranolol in eight detoxified alcoholic patients. Plasma concentrations and effects of propranolol on haemodynamics as quantified by changes in heart rate were measured for ten hours after the ingestion of propranolol. The t1/2 of propranolol did not differ from those reported for non-alcoholic subjects. Maximum haemodynamic effects preceded peak plasma propranolol concentrations, causing a clockwise hysteresis in concentration versus effect loops. It was suggested that acute tolerance to propranolol developed in alcoholic patients. An alternative explanation for the observed clockwise hysteresis may be the alterations in baseline heart rate linked to changes in circadian rhythms in alcoholic patients (German J Psychiatry, 1999, 2:12-18)

 

Key words: Alcohol dependence, propranolol, heart rate, pharmacokinetics


 

Introduction

Alcohol dependence is known to affect various neurotransmitter systems including monoamines in CNS and peripheral tissues. In particular, during withdrawal states marked changes in noradrenaline metabolism have been observed (Linnoila et al., 1987). Alterations in sensitivity of adrenoreceptors persist into remission (Glue et al., 1989). Propranolol is a nonselective beta-adrenoreceptor antagonist, which acts both at CNS and peripheral levels. It is shown to be efficacious in controlling arrhythmias and lowering blood pressure, pulse, and tremor during alcohol withdrawal (Zilm et al.,1980; Worner, 1994). Its pharmacokinetics and pharmacodynamics have been studied in detail in healthy subjects and in several clinical conditions. Ethanol is known to interact with various drugs by inhibiting or inducing drug metabolism or/and by interacting with drugs at tissue-receptor level, altering their pharmacological actions (Mattila, 1990; Shown and Linnoila, 1991). Acquired tolerance to several drugs may develop in alcoholic patients beyond the periods of alcohol abuse (Lieber, 1990). In this study the bradycardiac responses/pharmacokinetic relationship of propranolol was investigated in recently detoxified alcoholic patients.

 

Materials and methods

Patients and design. This was an open, single dose study with the beta-adrenoreceptor antagonist propranolol given to alcoholic patients. All the patients fulfilled the DSM-III-R criteria for alcohol dependence (American Psychiatric Association, 1987), they were admitted for the treatment of withdrawal symptoms. The patients underwent a routine clinical and psychiatric examination. Informed written consent and institutional approval were obtained. The characteristics of patients are presented in Table 1.

 

 

Table 1. Summary of clinical characteristics of patients

 

Subject

Age (yrs)

Duration of abuse (yrs)

Duration of withdrawal (yrs)

Maximal daily alcohol consumption (ml)

Duration of last abuse (days)

1

28

8

5

300

14

2

28

10

6

340

15

3

41

17

13

400

6

4

47

25

5

270

10

5

38

20

13

400

30

6

25

9

4

270

7

7

37

16

6

270

6

8

38

20

18

280

6

Mean ± SEM

35 (2.7)

15.6 (2.2)

8.8 (1.8)

316 (20.1)

11.8 (2.9)

 

 

The study was conducted on the 8th-12th day after admission. Withdrawal symptoms were treated with diazepam up to 30 mg/day. At the time of study, patients had been drug-free for at least five days. Relevant laboratory tests used to evaluate liver and kidney functions (ASAT, ALAT and plasma creatinine), a blood and urine examination, and an ECG were included. Propranolol 80 mg (PropralR 40 mg tablet, Orion Pharmaceutical Company Ltd, Espoo, Finland) was given orally with 100 ml of water to 8 male alcoholic patients at 9 a.m. The patients were not allowed to eat until two hours after taking the drug. The patients were resting supine during the study.

 

Blood sampling and drug assay. Blood (10 ml) was drawn from the left ulnar vein into a vacuum tube (VenojectR, Belgium) before the administration and after 0.5, 1, 1.5, 2, 3, 6 and 10 hr. Plasma was separated within 30 min and stored at -20oC until propranolol was determined by HPLC (Hänninen 1987). The sensitivity of the method was 2 ng/ml and the coefficient of variation (CV%) was less than 7% at a range of 10-70 ng/ml.

 

Haemodynamic measurement. The heart rate (HR, beat/min) was obtained from the ECG before the administration and after 0.5, 1, 1.5, 2, 3, 6, and 10 hr. The degree of beta-blockade (%R) was obtained from the equation:

 

%R = [ (HRo-HRx)/HRo/Hro] x 100

 

where HRo and HRx are initial HR and HR measured after drug administration, respectively.

 

Pharmacokinetic analysis. The pharmacokinetics of propranolol were characterised by the area under the drug plasma-time curve (AUC) calculated using the trapezoidal rule; with peak concentrations (Cmax); with peak concentration times (tmax); and with elimination half-lives (t1/2). The pharmacokinetic analysis was carried out with the MK model (Biosoft, Cambridge, UK).

 

Statistics. Results were expressed as the mean±SEM values. Correlation coefficients were calculated using the Spearman rank test.

 

Results

The calculated pharmacokinetic parameters are shown in Table 2. The mean t1/2 value was 3.5 h and varied from 2.4 to 4.8 h. No correlation was observed between t1/2, AUC and characteristics of patients.

 

Table 2. Summary of pharmacokinetic parameters resulting from a single 80 mg oral dose of propranolol in alcoholic patients

 

Subject

Cmax (ng/ml)

Tmax (h)

AUC(0-10h) (ng×ml-1×h)

t1/2 (h)

Subject

1

32.8

2

196

3.5

1

2

125.3

1.5

699

2.8

2

3

51.7

1.5

403

4.8

3

4

25.5

1.5

165

4.0

4

5

58

3

395

3.9

5

6

53.3

3

328

3.2

6

7

158.2

3

942

3.3

7

8

98.4

1

443

2.4

8

Mean± SEM

75.4 (16.6)

2.1 (0.3)

417 (98)

3.5 (0.3)

Mean± SEM

 

Symbols: Cmax = peak concentration; Tmax = peak concentration time; AUC(0-10h) = area under the drug plasma-time curve; t1/2 = elimination half-life; SEM=standard error of the mean

         

Figure 1 shows the dependence of bradycardiac effect on plasma propranolol concentration in the group of patients studied. When the measured changes in HR value were plotted against the respective value for concentration, less effect was seen at the same concentration at later points.

 

 

Figure.1 Dependence of bradycardiac effect on propranolol plasma concentration in alcoholic patients. The direction of rotation of the hysteresis loop is indicated by the arrow. The x-axis refers to the concentration of propranolol (ng/ml) and the y-axis refers to the degree of beta-blockade effect of propranolol (%).

 

 

Discussion

In the present study the mean half-life of propranolol was 3.5 h, which is approximately the same as that reported earlier in non-alcoholic subjects (Dollery, 1991). P450 isoenzymes CYP2D6 and 2C19 are known to partly metabolise propranolol (Ward et al., 1989). Ethanol is able to induce several P450 enzymes, in particular CYP2E1 (Lieber, 1994). As the t1/2 of propranolol in this study did not differ from those reported for non-alcoholic subjects, this may indicate that no induction of CYP2D6 and 2C19 occurred.

 

When the changes of beta-blockade were plotted against the propranolol plasma concentration, the time sequence of point followed a clockwise hysteresis loop for bradycardia. As far as is known, this clockwise hysteresis has not previously been described for propranolol in humans. This is in contrast to data of Takahashi et al. (1993) who found anti-clockwise hysteresis in time courses of the concentration-bradycardiac response curves after propranolol treatment in rabbits and in the isolated guinea-pig atrium.

 

The most common explanation for the observed clockwise hysteresis is the development of acute tolerance (Ellinwood et al., 1987). Acute tolerance can be produced by several mechanisms (Ellinwood et al., 1987). Propranolol is eliminated mainly by metabolism and over 20 different metabolites have been identified. One of these, 4-hydroxypropranolol has beta-adrenergic blocking properties. It is equipotent with propranolol, but does not appear to contribute much to pharmacodynamic effect, as it has a shorter half-life and is mainly present in the plasma as inactive conjugates (Dollery, 1991). One mechanism resulting in acute tolerance could be formation of an antagonistic metabolite once propranolol is broken down. There is no evidence of the formation of metabolites with antagonistic properties (Dollery, 1991). One more explanation for the observed clockwise hysteresis may be a disequilibrium between the plasma concentration of propranolol and that at the effector site.

 

The tolerance to propranolol may be based on the alteration of sensitivity or affinity of beta-receptors to propranolol in alcoholic patients in CNS and peripheral tissues. Alcoholic rats have a reduced density of beta-adrenoreceptors in cardiac (Banerjee et al., 1978; Hoffman et al., 1987) and brain tissues (Hoffman et al. 1987), although other studies have reported no difference in cardiac beta-adrenoreceptor levels between ethanol-fed and control rats (Segal and Mason, 1982) and in man (Bylund et al., 1984).

 

Circadian changes have been recognised in many biologic phenomena, including activities of the autonomic nervous system. HR is highest at 1 p.m. and then falls progressively to reach a low point at 4 a.m. (McCraight et al., 1978; Quyyumi, 1990). It is possible that the baseline HR may have modulated the bradycardiac response to propranolol in the present study. However, no data exists as far is known about circadian variation in HR in alcoholic patients. The dysregulation of autonomic function documented in many studies (Maitikainen et al., 1986; Malpas et al., 1991; Yokoyama et al., 1991) may lead to alterations of circadian rhythm in alcoholic patients. Further controlled studies are needed to detect the nature of the drug response-concentration relationship of propranolol in alcoholic patients.

 

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