LETTERS TO THE EDITOR, Acta
pharmacol. et toxicol. 1976, 39,573.
From the Pharmaceutical Plant Leiras, Turku, and the Department of Pharmacology, Turku University, Turku, Finland
Pharmacological Effect of Propranolol after a Single Oral Dose BY J. Kanto, T. Kleimola, R. Miintyla and E. Syvalahti (Received February 23, 1976; Accepted April 30, 1976)
Key-words: Propranolol - human volunteers
- pharmacological
effects.
The plasma half-life of propranolol is 2-3 hours (SHANDet al. 1970; GFDRGEet al. 1972). However, it has been reported that the blood pressure can be adequately controlled on a twice-daily regimen (BERGLUNDet al. 1973). Thus, the pharmacological half-life of propranolol may be much longer than its plasma half-life (CARRUTHERS et al. 1973). When comparing the absorption of two brands of 160 mg propranolol tablets we measured the heart rate and blood pressure of healthy volunteers during 24 hours to determine how long a single large oral dose would affect these parameters. The participants were 9 volunteers, 5 females and 4 males, age 24-42 years and weighing 53-99 kg. All the subjects were without any known disease and had no medication. After a night’s fasting the volunteers took randomly one reducer@ tablet (160 mg propranolol, Leiras) or one inderale tablet (160 mg propranolol, ICI) at one week’s interval. The blood samples were taken from the antecubital vein at 0 time and then at 1, 2, 3, 4, 6 and 24 hours after the drug administration. The heart rate and blood pressure of the volunteers were measured in the sitting position after 5 minutes rest at each time when the blood samples were drawn. Plasma concentrations of propranolol were measured fluorometrically according to SHANDet al. (1970). To determine the accuracy and reproducibility of the method a plasma sample with a known concentration of propranolol was analyzed. The mean (k S. E. M.) of 10 determinations of the sample containing 200 ng/ml of propranolol was 198k6.0 ng/ml and that of a
LE?TERS TO THE EDITOR, Acta
pharmacol. et toxicol. 1976,39,574.
sample containing 20 ng/ml of propranolol was 21.4 k 1.8 ng/ml. The lower limit of the method is 5 ng/ml plasma and it measures unmetabolized propranolol only. The plasma concentrations of propranolol after a single 160 mg oral dose are shown in fig. 1. There were no significant differences in these concentrations after reducer@ tablet and inderal@ tablet (Student’s t-test). The highest mean propranolol concentration in the plasma was measured at 2 hours (after reducer@ 160 mg tablet 163 f 34 ng/ml and after inderal@ 160 mg tablets 166 +- 37 ng/ml, mean f S. E. M.). In different subjects about 10 to 20-fold differences in the plasma concentrations of propranolol was found. At 2 hours they varied between 38-408 ng/ml. The plasma halflife of propranolol was 3.5 hoars. In comparison with inderal@ 160 mg tablet, the bioavailability calculated by the total area under the plasma drug concentration time curves from time 0 to 24 hours (AUCer)for reducorm 160 mg tablet was 99 %. The maximal decrease in the blood pressure and heart rate was observed at 3 hours (fig. 1). At that time the mean heart rate@was 22 ,% lower than the control value after reducer@ tablet (P< 0.0025, Student’s t-test) and
E
-REDUCOR
......INDERAL
W
c 4
KbO
0
3
5
Y
OBSERVATION TIME, HOURS
Fig. 1. Plasma concentrations of propranolol and their effect on blood pressure and heart rate after a single 160 mg oral dose in healthy volunteers.
LETTERS TO THE EDITOR,
ACta pharmacol. et to.tkOl. 1976, 39,575.
26 % lower after inderale tablet (P < 0.0005). There was no significant difference between the two tablets. As compared to the control values the systolic blood pressure was decreased 12 % (P < 0.0025) at 3 hours after reducer@ tablet and 9 % (P < 0.01) after inderal tablet. The same changes in diastolic blood pressure were 12 % (P < 0.0025) and 14 % (P < O.OOOS), respectively. Again, no significant differences between the two brands were found. Both after reducors tablet and inderal@ tablet there was a significant decrease in the heart rate from 1 to 24 hours, in the systolic blood pressure from 1 to 6 hours (at 24 hours P < 0.10), and in the diastolic blood pressure from 2 to 24 hours. In this respect, no significant differences between the two tablets were found. There was no correlation between the plasma concentration of proprano101 and the decrease in the heart rate (r-values -0.20 and -0.42, liner regression analysis), in the systolic blood pressure (r-values -0.27 and -0.03) and in the diastolic blood pressure (r-values -0.03 and -0.08). However, a positive correlation between the logarithm of the plasma Concentration and the per cent reduction of heart rate was observed (3-6 hours: r = 0.54, P < 0.01; at 6 hours: r = 0.73, P < 0.005). The plasma half-life of propranolol in our investigation was 3.5 hours. However, its effect on the heart rate and blood pressure of healthy volunteers lasted until up to 24 hours. This prolonged effect could be caused by metabolites with a longer plasma half-life than propranolol or by saturation et al. of the tissues with propranolol or its active metabolites (BERGLUND 1973), or by an effect on the central nervous system or on the plasma renin activity (NIES & SHAND1975). The main reason may be due to a biophase located in a “deep” compartment from which propranolol only slowly equilibrates with its plasma concentrations. The large volume of distribution of propranolol (320 f 82 liters, CHIDSEYet al. 1975) could explain the existence of such a “deep” compartment. On the other hand, the duration of drug action is determined by the dose as well as by the drug half-life. High doses have a long duration of action (NIES& SHAND 1975). As in earlier studies (SHAND1974), about 20-fold interindividual variation in the plasma concentrations of propranolol after the same oral dose was also found in this study. This is due to individual differences in the ability of the liver to extract propranold from the blood (“first-pass” effect, SHAND1974) or to the large volume of distribution (CHIDSEY et al. 1975). Even during chronic oral therapy this hepatic extraction is so high that only 20-509‘0 of the dose reaches the systemic circulation and this is the main reason for the wide range in oral dosage requirement (NIES& SHAND 1975). Plasma propranolol levels of about 100 ng/ml have been observed to
LETTERS TO THE EDITOR, Acta
pharmacol. et toxicol. 1976,39,576.
lower plasma renin activity and to cause a very high degree of blockade of cardiac receptors (NIB & SHAND 1975). The main determinants in llowering the heart rate and blood pressure after a single 160 mg oral dose seem to be the negative chrono- and inotropic effects in the heart. According to our results in the treatment of hypertension, propranolol can be given twice daily. A study with a oncedaily dolse regimen is warrant ed. REFERENCES Berglund, G., 0. Andersson, L. Hansson & R. Olander: Propranolol given twice daily in hypertension. Acta med. scand. 1973, 194, 513-515. Carruthers, S. G., J. G. Kelly, D. G. McDevitt, R. G. Shanks & M. J. Walsh: Duration of action of beta-blocking drugs. Brit. Med. J . 1973, 2, 177-179. Chidsey, C. A,, P. Morselli, G. Bianchetti, A. Morganti, G. Leonetti & Zanchetti: Studies of the absorption and removal of propranolol in hypertensive patients during therapy. Circulation 1975, 52, 313-318. George, C. F., T. Fenyvesi, M. E. Conolly & C. T. Dollery: Pharmacokinetics of dextro, laevo and racernic propranolol in man. Eur. J . Clin. Pharrnacol. 1972, 4, 74-78. Nies, A. S. & D. G. Shand: Clinical pharmacology of propranolol. Circulation 1975, 52, 6-16. Shand, D. G.: Individualization of propranolol therapy. Med. Clin. North. A m . 1974, 58, 1063-1069. Shand, D. G., E. M. Nucholls & J. A. Oates: Plasma propranolol levels in adults and children. Clin. Pharmacol. Therap. 1970, 11, 112-120.
pharmacol. et toxicol. 1976, 39,573.
From the Pharmaceutical Plant Leiras, Turku, and the Department of Pharmacology, Turku University, Turku, Finland
Pharmacological Effect of Propranolol after a Single Oral Dose BY J. Kanto, T. Kleimola, R. Miintyla and E. Syvalahti (Received February 23, 1976; Accepted April 30, 1976)
Key-words: Propranolol - human volunteers
- pharmacological
effects.
The plasma half-life of propranolol is 2-3 hours (SHANDet al. 1970; GFDRGEet al. 1972). However, it has been reported that the blood pressure can be adequately controlled on a twice-daily regimen (BERGLUNDet al. 1973). Thus, the pharmacological half-life of propranolol may be much longer than its plasma half-life (CARRUTHERS et al. 1973). When comparing the absorption of two brands of 160 mg propranolol tablets we measured the heart rate and blood pressure of healthy volunteers during 24 hours to determine how long a single large oral dose would affect these parameters. The participants were 9 volunteers, 5 females and 4 males, age 24-42 years and weighing 53-99 kg. All the subjects were without any known disease and had no medication. After a night’s fasting the volunteers took randomly one reducer@ tablet (160 mg propranolol, Leiras) or one inderale tablet (160 mg propranolol, ICI) at one week’s interval. The blood samples were taken from the antecubital vein at 0 time and then at 1, 2, 3, 4, 6 and 24 hours after the drug administration. The heart rate and blood pressure of the volunteers were measured in the sitting position after 5 minutes rest at each time when the blood samples were drawn. Plasma concentrations of propranolol were measured fluorometrically according to SHANDet al. (1970). To determine the accuracy and reproducibility of the method a plasma sample with a known concentration of propranolol was analyzed. The mean (k S. E. M.) of 10 determinations of the sample containing 200 ng/ml of propranolol was 198k6.0 ng/ml and that of a
LE?TERS TO THE EDITOR, Acta
pharmacol. et toxicol. 1976,39,574.
sample containing 20 ng/ml of propranolol was 21.4 k 1.8 ng/ml. The lower limit of the method is 5 ng/ml plasma and it measures unmetabolized propranolol only. The plasma concentrations of propranolol after a single 160 mg oral dose are shown in fig. 1. There were no significant differences in these concentrations after reducer@ tablet and inderal@ tablet (Student’s t-test). The highest mean propranolol concentration in the plasma was measured at 2 hours (after reducer@ 160 mg tablet 163 f 34 ng/ml and after inderal@ 160 mg tablets 166 +- 37 ng/ml, mean f S. E. M.). In different subjects about 10 to 20-fold differences in the plasma concentrations of propranolol was found. At 2 hours they varied between 38-408 ng/ml. The plasma halflife of propranolol was 3.5 hoars. In comparison with inderal@ 160 mg tablet, the bioavailability calculated by the total area under the plasma drug concentration time curves from time 0 to 24 hours (AUCer)for reducorm 160 mg tablet was 99 %. The maximal decrease in the blood pressure and heart rate was observed at 3 hours (fig. 1). At that time the mean heart rate@was 22 ,% lower than the control value after reducer@ tablet (P< 0.0025, Student’s t-test) and
E
-REDUCOR
......INDERAL
W
c 4
KbO
0
3
5
Y
OBSERVATION TIME, HOURS
Fig. 1. Plasma concentrations of propranolol and their effect on blood pressure and heart rate after a single 160 mg oral dose in healthy volunteers.
LETTERS TO THE EDITOR,
ACta pharmacol. et to.tkOl. 1976, 39,575.
26 % lower after inderale tablet (P < 0.0005). There was no significant difference between the two tablets. As compared to the control values the systolic blood pressure was decreased 12 % (P < 0.0025) at 3 hours after reducer@ tablet and 9 % (P < 0.01) after inderal tablet. The same changes in diastolic blood pressure were 12 % (P < 0.0025) and 14 % (P < O.OOOS), respectively. Again, no significant differences between the two brands were found. Both after reducors tablet and inderal@ tablet there was a significant decrease in the heart rate from 1 to 24 hours, in the systolic blood pressure from 1 to 6 hours (at 24 hours P < 0.10), and in the diastolic blood pressure from 2 to 24 hours. In this respect, no significant differences between the two tablets were found. There was no correlation between the plasma concentration of proprano101 and the decrease in the heart rate (r-values -0.20 and -0.42, liner regression analysis), in the systolic blood pressure (r-values -0.27 and -0.03) and in the diastolic blood pressure (r-values -0.03 and -0.08). However, a positive correlation between the logarithm of the plasma Concentration and the per cent reduction of heart rate was observed (3-6 hours: r = 0.54, P < 0.01; at 6 hours: r = 0.73, P < 0.005). The plasma half-life of propranolol in our investigation was 3.5 hours. However, its effect on the heart rate and blood pressure of healthy volunteers lasted until up to 24 hours. This prolonged effect could be caused by metabolites with a longer plasma half-life than propranolol or by saturation et al. of the tissues with propranolol or its active metabolites (BERGLUND 1973), or by an effect on the central nervous system or on the plasma renin activity (NIES & SHAND1975). The main reason may be due to a biophase located in a “deep” compartment from which propranolol only slowly equilibrates with its plasma concentrations. The large volume of distribution of propranolol (320 f 82 liters, CHIDSEYet al. 1975) could explain the existence of such a “deep” compartment. On the other hand, the duration of drug action is determined by the dose as well as by the drug half-life. High doses have a long duration of action (NIES& SHAND 1975). As in earlier studies (SHAND1974), about 20-fold interindividual variation in the plasma concentrations of propranolol after the same oral dose was also found in this study. This is due to individual differences in the ability of the liver to extract propranold from the blood (“first-pass” effect, SHAND1974) or to the large volume of distribution (CHIDSEY et al. 1975). Even during chronic oral therapy this hepatic extraction is so high that only 20-509‘0 of the dose reaches the systemic circulation and this is the main reason for the wide range in oral dosage requirement (NIES& SHAND 1975). Plasma propranolol levels of about 100 ng/ml have been observed to
LETTERS TO THE EDITOR, Acta
pharmacol. et toxicol. 1976,39,576.
lower plasma renin activity and to cause a very high degree of blockade of cardiac receptors (NIB & SHAND 1975). The main determinants in llowering the heart rate and blood pressure after a single 160 mg oral dose seem to be the negative chrono- and inotropic effects in the heart. According to our results in the treatment of hypertension, propranolol can be given twice daily. A study with a oncedaily dolse regimen is warrant ed. REFERENCES Berglund, G., 0. Andersson, L. Hansson & R. Olander: Propranolol given twice daily in hypertension. Acta med. scand. 1973, 194, 513-515. Carruthers, S. G., J. G. Kelly, D. G. McDevitt, R. G. Shanks & M. J. Walsh: Duration of action of beta-blocking drugs. Brit. Med. J . 1973, 2, 177-179. Chidsey, C. A,, P. Morselli, G. Bianchetti, A. Morganti, G. Leonetti & Zanchetti: Studies of the absorption and removal of propranolol in hypertensive patients during therapy. Circulation 1975, 52, 313-318. George, C. F., T. Fenyvesi, M. E. Conolly & C. T. Dollery: Pharmacokinetics of dextro, laevo and racernic propranolol in man. Eur. J . Clin. Pharrnacol. 1972, 4, 74-78. Nies, A. S. & D. G. Shand: Clinical pharmacology of propranolol. Circulation 1975, 52, 6-16. Shand, D. G.: Individualization of propranolol therapy. Med. Clin. North. A m . 1974, 58, 1063-1069. Shand, D. G., E. M. Nucholls & J. A. Oates: Plasma propranolol levels in adults and children. Clin. Pharmacol. Therap. 1970, 11, 112-120.
