Cardiology 64 (Suppl. 1): 96 -104 (1979)
Clinical Pharmacology of Adrenergic-Blocking Drugs' W.J. Louis, M.J. Rand, J.J. McNeil,2 0. Drummer and B. Jarrott Clinical Pharmacology and Therapeutics Unit and Pharmacology Department, University o f Melbourne, Heidelberg, Vic.
Introduction
The use of the terms a- and /3-adrenoreceptors for describing cardiovascular receptors is now generally accepted. /3-adrenoreceptors occur in a variety of sites, including blood vessels, heart, brain and kidneys, and drugs which act on these receptors can modify not only cardiovascular disorders such as angina, high blood pressure and the cardiac arrhythmias, but also diseases such as asthma, thyrotoxicosis and migraine. There are at least two types of /3-adrenoreceptors, ¡3, and /32, and tissues vary in their receptor complement. For clinical purposes it is reasonable to use the classification in table I. However, tissues such as heart which contain predomi nantly /3i-receptors also contain some /}2-receptors and consequently selectivity is usually not absolute (Carlsson et al., 1972).
Table I.
Classification of tissue ^-adrenoreceptors
Tissue
Type of receptor
Heart Lung Peripheral blood vessel Central nervous system Metabolic receptors
0. 03 0 ..0 3 usually 0r but many arc unclassified
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1 This work was supported by the Life Insurance Medical Research Fund o f Australia and New Zealand. 2 National Heart Foundation Postgraduate Research Scholar.
Clinical Pharmacology of Adrenergic-Blocking Drugs
97
Structurally tire (3-blocking drugs are all modifications of tire /3-adreno receptor stimulant, isoprénaline. They consist of an isoprenaline-like side chain with a different aromatic nucleus. When isoprénaline attaches to the (3-receptor on the membrane surface there are a number of specific linkages involved. Each linkage is actually a weak bond; these bonds are formed rapidly, but are also easily broken. The highly specific way in which isoprénaline attaches itself to the receptor results in maximum activation of the receptor which is believed to be linked to adenylate cyclase (Robison and Sutherland, 1970). The attachment of the blocking drug to the receptor resembles that of isoprénaline but there are important differences. The attachment to the receptor results in less or no activation of adenylate cyclase and prolonged occupation of the receptor results in blockade. The mechanism of the occupation is uncertain but it is known that these compounds compete with isoprénaline and other (3-agonists for the receptor.
Classification
(3-Receptor-blocking drugs differ in three clinically important respects: in trinsic sympathomimetic activity, cardiac selectivity and bioavailability. The membrane-stabilising properties of these compounds usually occur at doses greater than those used in clinical practice (Mylecharane and Raper, 1971). These drugs can be classified in two ways, in terms of their selectivity and their intrinsic sympathomimetic activity. The commonly used non-selective com pounds include drugs without intrinsic sympathomimetic activity such as pro pranolol, timolol and labetalol. Labetalol can also block a-adrenoreceptors. Oxprenolol, alprenolol and pindolol are non-selective drugs which possess in trinsic sympathomimetic activity. Cardiac selective drugs without intrinsic sympathomimetic activity include metoprolol. atenolol and bevantolol. Practolol is cardiac selective and has in trinsic sympathomimetic activity.
Comparative Clinical Trials in Hypertension
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Non-Selective (3-Blocking Drugs In 1974 we reported a cross-over study in which the antihypertensive efficacy of two non-selective drugs without intrinsic sympathomimetic activity, propran-
98
Louis/ Rand/McNeil/Drummer/Jarrott Table II.
Trial plan Week
Group 1 Group 2
0 -3
4 -1 3
14 23
24-25
placebo placebo
propranolol pindolol
propranolol placebo pindolol placebo
26-35
36 -4 5
alprenolol timolol
alprenolol timolol
olol and timolol, were compared with pindolol and alprenolol, two non-selective compounds with intrinsic sympathomimetic activity (.Morgan et al., 1974). 20 patients who had previously responded to |3-blocking drugs entered into this double-blind trial designed initially to compare the efficacy o f pindolol with propranolol, and subsequently of alprenolol with timolol. During the trial the doses of other antihypertensive drugs and the intake of sodium were not varied. All patients were taking a thiazide diuretic and 4 were receiving methyldopa as well. The format of the trial is indicated in table 11. Pindolol, 5 mg; propranolol, 40 mg; alprenolol, 100 mg; timolol, 5 mg, and placebo were placed in identical capsules. All previously used /3-adrenergic-blocking drugs were stopped for 2 weeks and the blood pressure at the end of this time was taken as the control value. The placebo was then given for 4 weeks, the blood pressure being recorded 2 and 4 weeks after its commencement. Tire means of these values are recorded in the results. A capsule containing either pindolol or propranolol was then given three times daily and increased to two capsules three times daily if control was not adequate at 2 weeks. The means of the blood pressures taken 6 and 10 weeks after commencing the active agent were recorded in the results. At the end of this time, the patients were crossed over to the capsule containing the other drug, and the dose again commenced with one capsule three times a day and adjusted as before. After a further 10 weeks, treatment with a placebo was resubstituted, and 2 weeks later a second cross-over trial of alprenolol and timolol was commenced using the technique described above. The blood pressure was recorded standing and recumbent on each occasion, after a 10-min rest period. Since these pressures were similar, the mean of the recumbent and standing pressure was presented. At each visit the patients were asked specifi cally if they had any of the symptoms in a check-list and also whether they had any other symptoms.
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There were 10 patients in each group.
Clinical Pharmacology of Adrenergic-Blocking Drugs
99
The effects of treatment on blood pressure and pulse rate are shown in figure 1. The systolic and diastolic blood pressure and pulse rate on all four drugs were significantly below placebo values. The fall in blood pressure and pulse rate occurred promptly and was present in all cases after 2 weeks, although increased doses then produced a further fall. Similar falls in systolic and diastolic blood pressures were achieved with all 0-adrenergic-blocking drugs. The mean doses used were: for pindolol, 23 ± 8 (SEM)mg; propranolol, 176 ± 6 0 mg; alprenolol, 460 ± 156 mg, and timolol, 24 ± 7 mg. The side effects of this group of patients are indicated in table III. The incidence of dreams, frequently of a bizarre or nightmarish nature, was high when the patients were specifically questioned. These appeared to be most frequent and severe in patients taking pindolol. However, they also occurred during treatment with the other 0-adrenergic-blocking drugs, although they were least frequent on timolol. 3 patients developed bronchospasm while on pro-
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Fig. 1. Pulse rate and systolic and diastolic blood pressure (± SEM) in patients during various treatment phases of the double-blind crossover study which compared the anti hypertensive action o f pindolol, propranolol, alprenolol and MK-950 (timolol).
Louis/Rand/McNeil/Drummer/Jarrott Table III.
Side effects elicited by direct questioning during double-blind cross-over study
Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14
100
Placebo
Pindolol
headaches angina headaches
D* tingling D** cramp D** tingling [)***
headaches D*
Propranolol Placebo
headaches
D**
D*
D** D*
D***
D*
D*** D* D*
D*
angina
D** D* D*
insomnia
depressed
D** tingling D** D»*
unwell cramps D**
cramps D*
angina
D**
B* VBI D* VBI B*
unwell
Timolol B*
B** D*
tingling D**
Alprenolol
B*
B* D*
The patients not listed had no side effects. D* = Frequent dreams; D** = frequent bizarre dreams; D*** = nightmares; B* = bronchospasm; B** = severe bronchospasms; VB1 = symptoms of vertebro-basilar insufficiency.
Cardiac Selectivity and a-Blockade We have recently completed a similar cross-over study comparing pindolol, metoprolol, atenolol and labetalol. Trial design is summarised in table IV. 26 outpatients (10 males and 16 females, mean age 51 years) known to respond to /3-blocking drugs were randomised and entered the study. 3 patients were withdrawn late in the study because of severe bradycardia (pulse rate less than
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pranolol and timolol. The incidence of tingling, cold extremities, and cramps was low. 2 patients taking propranolol developed symptoms suggestive of vertebro basilar insufficiency unrelated to hypotension. These symptoms were not present with the other antihypertensive drugs when the blood pressure was at the same or lower levels. Table III also indicates certain positive features. Headaches and angina disappeared when /3-adrenergic-blocking drugs were started and reappeared when a placebo was substituted.
101
Clinical Pharmacology o f Adrenergic-Blocking Drugs Table IV .
Flow chart of trial comparing non-seleetive and selective 0-blocking drugs Weeks 0
Consultation Chest X-ray Laboratory tests Therapy
1 3
7
11
12 14 18 22
23 25 29 33
34 36 40 44
X X X X X X X X X X X X X X X XX X X X X X X PL PL C PL A PL D B
__x_
A = Metoprolol; B = pindolol; C = atenolol; D = labetalol; PL = placebo.
Fig. 2. Pulse rate and supine levels of systolic and diastolic blood pressure in patients during various treatm ent phases o f the study which compared the antihypertensive action o f metoprolol, pindolol, atenolol and labetalol. The mean dose o f pindolol employed was 24 ± 2 mg/day. Corresponding values were 234 ± 22 mg/day for metoprolol, 138 ± 13 mg/day for atenolol and 308 ± 34 mg/day for labetalol.
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50 beats/min), 2 were taking atenolol and 1 metoprolol. These patients were included in the analysis. Mean supine levels (± SEM) of systolic and diastolic blood pressure and pulse are summarised in figure 2 together with the average dose of 0-blocking drugs used following tire stabilisation period. Similar falls in blood pressure were produced by all the drugs studied. However, as in the previous study, two of the
Louis/Rand/McNcil/Drummcr/Jarrott
102
Table V. Incidence of bradycardia in 26 patients on various (3-blockers at doses required for control of blood pressure
Pindolol
Metoprolol
Atenolol
1
2
Labetalol
Pulse rate < 5 0 treatment ceased Pulse rate < 55 inadequate control Pulse rate < 55 but adequate control
1
3
6
-
Total
1
5
8
-
1
Bioavailability The third way in which 0-receptor-blocking drugs differ clinically is in their bioavailability. When a drug is taken orally as a tablet the following events must occur before it can act. Firstly, the tablet disintegrates in the stomach, and as it does, the drug goes into solution. The drug molecules are then absorbed through the mucous membrane of the gut and enter the blood that flows into the portal venous system and must pass through the liver before they reach the systemic circulation where they are carried to their sites of action. The percentage of the dose of an orally administered drug that reaches the systemic circulation pro vides the index of bioavailability.
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drugs without intrinsic sympathomimetic activity (metoprolol and atenolol) produced appreciably slower pulse rates than pindolol (a non-selective 0-blocking drug with intrinsic sympathomimetic activity). The incidence of bradycardia during the study is further shown in table V and it is apparent that 5 patients during metoprolol treatment and 8 patients during atenolol treatment had pulse rates less than 55 beats/min. However this degree of bradycardia was not seen with labetalol. It is not certain whether the lack of bradycardia with labetalol. a drug which lacks intrinsic sympathomimetic activity reflects its associated a-blocking properties or perhaps more importantly its weaker pA2 for the 0-adrenoreceptor. For equal antihypertensive effect labetalol produced a smaller reduction in exercise-induced tachycardia than the other three 0-blocking drugs. Its antihypertensive effectiveness indicates a possible useful role for weaker 0-blocking drugs, whether or not they in addition have a-blocking properties, in the treatment of mild hypertensives.
Clinical Pharmacology o f Adrenergic-Blocking Drugs
Absorption of characteristics of some /3-blockers
Drug
Absorption rate
Extcnt of absorption % of dose
Extent of bioavail ability % of dose
Dosedependent bioavailability
Plasma protein binding
Alprenolol Propranolol Oxprenolol Pindolol Practolol Metoprolol Atenolol
rapid rapid rapid rapid rapid rapid rapid
complète complété complété complété complété complété complète
MO MO MO MO MOO MO 40-60%
yes yes no no no no no
85 93 80 50 60 1 10 10
Good bioavailability depends on (a) rapid disintegration of the tablet and dissolution of the drug; (b) a high degree of absorption from the gut, and (c) not too great a loss by metabolism on its first passage through the liver. /3-Receptor-blocking drugs are generally well absorbed from the gut and rapid disintegration of the tablet and dissolution of the drug is generally not a problem. But there are considerable differences between the drugs in the extent of their metabolism in the liver. It is apparent from table VI that there are substantial differences in bioavailability - alprenolol is 10% bioavailable. In other words, about 90% of it is metabolised in its first passage through the liver. Propranolol is 30%, timolol 75%, pindolol 80% and oxprenolol approximately 60% bioavailable. Drugs like propranolol and alprenolol which have relatively poor bioavail ability, require larger doses to produce the same effects. More importantly, when bioavailability is poor, there is usually a much larger variation in the dose needed to produce the same fall in blood pressure in different patients. This is because individual patients vary considerably in their rate of drug metabolism in the liver. For example, in the comparative study with alprenolol, timolol, propran olol and pindolol, the range of effective antihypertensive dose was much wider for propranolol and alprenolol than it was for pindolol and timolol. Differences in bioavailability, however, are not the only reason for dif ferences in clinical potency between various /3-receptor-blocking drugs, plasma protein binding and the affinity of the blocking drugs for the receptors is also important. Clinical potency therefore, is proportional to bioavailability and affinity for receptors, and inversely proportional to protein binding.
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Table V I.
103
Louis/Rand/McNeil/Drummer/Jarrott
104
Conclusion
The development of drugs that block (3-adrenoreceptors have provided an important group of agents for the treatment of common cardiovascular dis orders, hypertension, angina pectoris and cardiac arrhythmias and for the management of patients with thyrotoxicosis. For clinical purposes these drugs can be divided into two groups: (1) those without intrinsic sympathomimetic activity (a) non-selective propranolol, (b) non-selective with a-blockade - labetalol, (c) cardiac selective - metoprolol, atenolol, and (2) those with intrinsic sympathomimetic activity (a) non-selective —pindolol, oxprenolol and alprenolol, (b) cardiac selective —practolol. These drugs resemble isoprenaline in chemical structure, but interact with the (3-adrenoreceptors in such a way that there is no response, or only a slight response in the case of drugs with intrinsic sympathomimetic activity. By occupying the receptors, they block excitation by noradrenaline released from the sympathetic nerves and by adrenaline from the adrenal medulla. Drugs with intrinsic sympathomimetic activity appear to have a lower risk of excessive depression of cardiac activity and less interference with bronchodilator drive. (3-Blocking drugs differ considerably in their bioavailability because of differences in the rate and extent of metabolism in the first passage through the liver after absorption from the gut. The therapeutic dose range is wide for those with low bioavailability. The dosage is more predictable with those having high bioavailability. These drugs also differ in their ability to bind to plasma protein and in their receptor affinity. References
W.J. Louis, MD, Professor of Clinical Pharmacology and Therapeutics, Austin Hospital, Heidelberg, Vic. 3084 (Australia)
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Carlsson, E.: Ablad. B.; Bradstrom, A., and Carlsson, B.: Differentiated blockade on the chronotropic effects of various adrenergic stimuli in the cat heart. Life Sci. 2: (part 1) 9 5 3 -9 5 8 (1972). Morgan, T.O.; Sabto, J.; Anavekar, S.N., and Louis, W.J.: A comparison o f beta adrenergic blocking drugs in the treatment o f hypertension. Post-grad. med. J. 50: 253-259 (1974). Mylecharane, E.J. and Raper, C.: Beta-receptor blocking and cardiodepressant actions of 2-nitrilophenoxypropanolamines. Eur. J. Pharmacol. 16: 1 4 -2 0 (1971). Robison, A. and Sutherland, E.W.: Sympathin E, Sympathin 1, and the intracellular level of cyclic AMP. Circulation Res. 26 2 7: suppl. 1, pp. 147-161 (1970).
Clinical Pharmacology of Adrenergic-Blocking Drugs' W.J. Louis, M.J. Rand, J.J. McNeil,2 0. Drummer and B. Jarrott Clinical Pharmacology and Therapeutics Unit and Pharmacology Department, University o f Melbourne, Heidelberg, Vic.
Introduction
The use of the terms a- and /3-adrenoreceptors for describing cardiovascular receptors is now generally accepted. /3-adrenoreceptors occur in a variety of sites, including blood vessels, heart, brain and kidneys, and drugs which act on these receptors can modify not only cardiovascular disorders such as angina, high blood pressure and the cardiac arrhythmias, but also diseases such as asthma, thyrotoxicosis and migraine. There are at least two types of /3-adrenoreceptors, ¡3, and /32, and tissues vary in their receptor complement. For clinical purposes it is reasonable to use the classification in table I. However, tissues such as heart which contain predomi nantly /3i-receptors also contain some /}2-receptors and consequently selectivity is usually not absolute (Carlsson et al., 1972).
Table I.
Classification of tissue ^-adrenoreceptors
Tissue
Type of receptor
Heart Lung Peripheral blood vessel Central nervous system Metabolic receptors
0. 03 0 ..0 3 usually 0r but many arc unclassified
Downloaded by: University of Connecticut 132.174.250.220 - 3/22/2018 5:42:41 AM
1 This work was supported by the Life Insurance Medical Research Fund o f Australia and New Zealand. 2 National Heart Foundation Postgraduate Research Scholar.
Clinical Pharmacology of Adrenergic-Blocking Drugs
97
Structurally tire (3-blocking drugs are all modifications of tire /3-adreno receptor stimulant, isoprénaline. They consist of an isoprenaline-like side chain with a different aromatic nucleus. When isoprénaline attaches to the (3-receptor on the membrane surface there are a number of specific linkages involved. Each linkage is actually a weak bond; these bonds are formed rapidly, but are also easily broken. The highly specific way in which isoprénaline attaches itself to the receptor results in maximum activation of the receptor which is believed to be linked to adenylate cyclase (Robison and Sutherland, 1970). The attachment of the blocking drug to the receptor resembles that of isoprénaline but there are important differences. The attachment to the receptor results in less or no activation of adenylate cyclase and prolonged occupation of the receptor results in blockade. The mechanism of the occupation is uncertain but it is known that these compounds compete with isoprénaline and other (3-agonists for the receptor.
Classification
(3-Receptor-blocking drugs differ in three clinically important respects: in trinsic sympathomimetic activity, cardiac selectivity and bioavailability. The membrane-stabilising properties of these compounds usually occur at doses greater than those used in clinical practice (Mylecharane and Raper, 1971). These drugs can be classified in two ways, in terms of their selectivity and their intrinsic sympathomimetic activity. The commonly used non-selective com pounds include drugs without intrinsic sympathomimetic activity such as pro pranolol, timolol and labetalol. Labetalol can also block a-adrenoreceptors. Oxprenolol, alprenolol and pindolol are non-selective drugs which possess in trinsic sympathomimetic activity. Cardiac selective drugs without intrinsic sympathomimetic activity include metoprolol. atenolol and bevantolol. Practolol is cardiac selective and has in trinsic sympathomimetic activity.
Comparative Clinical Trials in Hypertension
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Non-Selective (3-Blocking Drugs In 1974 we reported a cross-over study in which the antihypertensive efficacy of two non-selective drugs without intrinsic sympathomimetic activity, propran-
98
Louis/ Rand/McNeil/Drummer/Jarrott Table II.
Trial plan Week
Group 1 Group 2
0 -3
4 -1 3
14 23
24-25
placebo placebo
propranolol pindolol
propranolol placebo pindolol placebo
26-35
36 -4 5
alprenolol timolol
alprenolol timolol
olol and timolol, were compared with pindolol and alprenolol, two non-selective compounds with intrinsic sympathomimetic activity (.Morgan et al., 1974). 20 patients who had previously responded to |3-blocking drugs entered into this double-blind trial designed initially to compare the efficacy o f pindolol with propranolol, and subsequently of alprenolol with timolol. During the trial the doses of other antihypertensive drugs and the intake of sodium were not varied. All patients were taking a thiazide diuretic and 4 were receiving methyldopa as well. The format of the trial is indicated in table 11. Pindolol, 5 mg; propranolol, 40 mg; alprenolol, 100 mg; timolol, 5 mg, and placebo were placed in identical capsules. All previously used /3-adrenergic-blocking drugs were stopped for 2 weeks and the blood pressure at the end of this time was taken as the control value. The placebo was then given for 4 weeks, the blood pressure being recorded 2 and 4 weeks after its commencement. Tire means of these values are recorded in the results. A capsule containing either pindolol or propranolol was then given three times daily and increased to two capsules three times daily if control was not adequate at 2 weeks. The means of the blood pressures taken 6 and 10 weeks after commencing the active agent were recorded in the results. At the end of this time, the patients were crossed over to the capsule containing the other drug, and the dose again commenced with one capsule three times a day and adjusted as before. After a further 10 weeks, treatment with a placebo was resubstituted, and 2 weeks later a second cross-over trial of alprenolol and timolol was commenced using the technique described above. The blood pressure was recorded standing and recumbent on each occasion, after a 10-min rest period. Since these pressures were similar, the mean of the recumbent and standing pressure was presented. At each visit the patients were asked specifi cally if they had any of the symptoms in a check-list and also whether they had any other symptoms.
Downloaded by: University of Connecticut 132.174.250.220 - 3/22/2018 5:42:41 AM
There were 10 patients in each group.
Clinical Pharmacology of Adrenergic-Blocking Drugs
99
The effects of treatment on blood pressure and pulse rate are shown in figure 1. The systolic and diastolic blood pressure and pulse rate on all four drugs were significantly below placebo values. The fall in blood pressure and pulse rate occurred promptly and was present in all cases after 2 weeks, although increased doses then produced a further fall. Similar falls in systolic and diastolic blood pressures were achieved with all 0-adrenergic-blocking drugs. The mean doses used were: for pindolol, 23 ± 8 (SEM)mg; propranolol, 176 ± 6 0 mg; alprenolol, 460 ± 156 mg, and timolol, 24 ± 7 mg. The side effects of this group of patients are indicated in table III. The incidence of dreams, frequently of a bizarre or nightmarish nature, was high when the patients were specifically questioned. These appeared to be most frequent and severe in patients taking pindolol. However, they also occurred during treatment with the other 0-adrenergic-blocking drugs, although they were least frequent on timolol. 3 patients developed bronchospasm while on pro-
Downloaded by: University of Connecticut 132.174.250.220 - 3/22/2018 5:42:41 AM
Fig. 1. Pulse rate and systolic and diastolic blood pressure (± SEM) in patients during various treatment phases of the double-blind crossover study which compared the anti hypertensive action o f pindolol, propranolol, alprenolol and MK-950 (timolol).
Louis/Rand/McNeil/Drummer/Jarrott Table III.
Side effects elicited by direct questioning during double-blind cross-over study
Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14
100
Placebo
Pindolol
headaches angina headaches
D* tingling D** cramp D** tingling [)***
headaches D*
Propranolol Placebo
headaches
D**
D*
D** D*
D***
D*
D*** D* D*
D*
angina
D** D* D*
insomnia
depressed
D** tingling D** D»*
unwell cramps D**
cramps D*
angina
D**
B* VBI D* VBI B*
unwell
Timolol B*
B** D*
tingling D**
Alprenolol
B*
B* D*
The patients not listed had no side effects. D* = Frequent dreams; D** = frequent bizarre dreams; D*** = nightmares; B* = bronchospasm; B** = severe bronchospasms; VB1 = symptoms of vertebro-basilar insufficiency.
Cardiac Selectivity and a-Blockade We have recently completed a similar cross-over study comparing pindolol, metoprolol, atenolol and labetalol. Trial design is summarised in table IV. 26 outpatients (10 males and 16 females, mean age 51 years) known to respond to /3-blocking drugs were randomised and entered the study. 3 patients were withdrawn late in the study because of severe bradycardia (pulse rate less than
Downloaded by: University of Connecticut 132.174.250.220 - 3/22/2018 5:42:41 AM
pranolol and timolol. The incidence of tingling, cold extremities, and cramps was low. 2 patients taking propranolol developed symptoms suggestive of vertebro basilar insufficiency unrelated to hypotension. These symptoms were not present with the other antihypertensive drugs when the blood pressure was at the same or lower levels. Table III also indicates certain positive features. Headaches and angina disappeared when /3-adrenergic-blocking drugs were started and reappeared when a placebo was substituted.
101
Clinical Pharmacology o f Adrenergic-Blocking Drugs Table IV .
Flow chart of trial comparing non-seleetive and selective 0-blocking drugs Weeks 0
Consultation Chest X-ray Laboratory tests Therapy
1 3
7
11
12 14 18 22
23 25 29 33
34 36 40 44
X X X X X X X X X X X X X X X XX X X X X X X PL PL C PL A PL D B
__x_
A = Metoprolol; B = pindolol; C = atenolol; D = labetalol; PL = placebo.
Fig. 2. Pulse rate and supine levels of systolic and diastolic blood pressure in patients during various treatm ent phases o f the study which compared the antihypertensive action o f metoprolol, pindolol, atenolol and labetalol. The mean dose o f pindolol employed was 24 ± 2 mg/day. Corresponding values were 234 ± 22 mg/day for metoprolol, 138 ± 13 mg/day for atenolol and 308 ± 34 mg/day for labetalol.
Downloaded by: University of Connecticut 132.174.250.220 - 3/22/2018 5:42:41 AM
50 beats/min), 2 were taking atenolol and 1 metoprolol. These patients were included in the analysis. Mean supine levels (± SEM) of systolic and diastolic blood pressure and pulse are summarised in figure 2 together with the average dose of 0-blocking drugs used following tire stabilisation period. Similar falls in blood pressure were produced by all the drugs studied. However, as in the previous study, two of the
Louis/Rand/McNcil/Drummcr/Jarrott
102
Table V. Incidence of bradycardia in 26 patients on various (3-blockers at doses required for control of blood pressure
Pindolol
Metoprolol
Atenolol
1
2
Labetalol
Pulse rate < 5 0 treatment ceased Pulse rate < 55 inadequate control Pulse rate < 55 but adequate control
1
3
6
-
Total
1
5
8
-
1
Bioavailability The third way in which 0-receptor-blocking drugs differ clinically is in their bioavailability. When a drug is taken orally as a tablet the following events must occur before it can act. Firstly, the tablet disintegrates in the stomach, and as it does, the drug goes into solution. The drug molecules are then absorbed through the mucous membrane of the gut and enter the blood that flows into the portal venous system and must pass through the liver before they reach the systemic circulation where they are carried to their sites of action. The percentage of the dose of an orally administered drug that reaches the systemic circulation pro vides the index of bioavailability.
Downloaded by: University of Connecticut 132.174.250.220 - 3/22/2018 5:42:41 AM
drugs without intrinsic sympathomimetic activity (metoprolol and atenolol) produced appreciably slower pulse rates than pindolol (a non-selective 0-blocking drug with intrinsic sympathomimetic activity). The incidence of bradycardia during the study is further shown in table V and it is apparent that 5 patients during metoprolol treatment and 8 patients during atenolol treatment had pulse rates less than 55 beats/min. However this degree of bradycardia was not seen with labetalol. It is not certain whether the lack of bradycardia with labetalol. a drug which lacks intrinsic sympathomimetic activity reflects its associated a-blocking properties or perhaps more importantly its weaker pA2 for the 0-adrenoreceptor. For equal antihypertensive effect labetalol produced a smaller reduction in exercise-induced tachycardia than the other three 0-blocking drugs. Its antihypertensive effectiveness indicates a possible useful role for weaker 0-blocking drugs, whether or not they in addition have a-blocking properties, in the treatment of mild hypertensives.
Clinical Pharmacology o f Adrenergic-Blocking Drugs
Absorption of characteristics of some /3-blockers
Drug
Absorption rate
Extcnt of absorption % of dose
Extent of bioavail ability % of dose
Dosedependent bioavailability
Plasma protein binding
Alprenolol Propranolol Oxprenolol Pindolol Practolol Metoprolol Atenolol
rapid rapid rapid rapid rapid rapid rapid
complète complété complété complété complété complété complète
MO MO MO MO MOO MO 40-60%
yes yes no no no no no
85 93 80 50 60 1 10 10
Good bioavailability depends on (a) rapid disintegration of the tablet and dissolution of the drug; (b) a high degree of absorption from the gut, and (c) not too great a loss by metabolism on its first passage through the liver. /3-Receptor-blocking drugs are generally well absorbed from the gut and rapid disintegration of the tablet and dissolution of the drug is generally not a problem. But there are considerable differences between the drugs in the extent of their metabolism in the liver. It is apparent from table VI that there are substantial differences in bioavailability - alprenolol is 10% bioavailable. In other words, about 90% of it is metabolised in its first passage through the liver. Propranolol is 30%, timolol 75%, pindolol 80% and oxprenolol approximately 60% bioavailable. Drugs like propranolol and alprenolol which have relatively poor bioavail ability, require larger doses to produce the same effects. More importantly, when bioavailability is poor, there is usually a much larger variation in the dose needed to produce the same fall in blood pressure in different patients. This is because individual patients vary considerably in their rate of drug metabolism in the liver. For example, in the comparative study with alprenolol, timolol, propran olol and pindolol, the range of effective antihypertensive dose was much wider for propranolol and alprenolol than it was for pindolol and timolol. Differences in bioavailability, however, are not the only reason for dif ferences in clinical potency between various /3-receptor-blocking drugs, plasma protein binding and the affinity of the blocking drugs for the receptors is also important. Clinical potency therefore, is proportional to bioavailability and affinity for receptors, and inversely proportional to protein binding.
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Table V I.
103
Louis/Rand/McNeil/Drummer/Jarrott
104
Conclusion
The development of drugs that block (3-adrenoreceptors have provided an important group of agents for the treatment of common cardiovascular dis orders, hypertension, angina pectoris and cardiac arrhythmias and for the management of patients with thyrotoxicosis. For clinical purposes these drugs can be divided into two groups: (1) those without intrinsic sympathomimetic activity (a) non-selective propranolol, (b) non-selective with a-blockade - labetalol, (c) cardiac selective - metoprolol, atenolol, and (2) those with intrinsic sympathomimetic activity (a) non-selective —pindolol, oxprenolol and alprenolol, (b) cardiac selective —practolol. These drugs resemble isoprenaline in chemical structure, but interact with the (3-adrenoreceptors in such a way that there is no response, or only a slight response in the case of drugs with intrinsic sympathomimetic activity. By occupying the receptors, they block excitation by noradrenaline released from the sympathetic nerves and by adrenaline from the adrenal medulla. Drugs with intrinsic sympathomimetic activity appear to have a lower risk of excessive depression of cardiac activity and less interference with bronchodilator drive. (3-Blocking drugs differ considerably in their bioavailability because of differences in the rate and extent of metabolism in the first passage through the liver after absorption from the gut. The therapeutic dose range is wide for those with low bioavailability. The dosage is more predictable with those having high bioavailability. These drugs also differ in their ability to bind to plasma protein and in their receptor affinity. References
W.J. Louis, MD, Professor of Clinical Pharmacology and Therapeutics, Austin Hospital, Heidelberg, Vic. 3084 (Australia)
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Carlsson, E.: Ablad. B.; Bradstrom, A., and Carlsson, B.: Differentiated blockade on the chronotropic effects of various adrenergic stimuli in the cat heart. Life Sci. 2: (part 1) 9 5 3 -9 5 8 (1972). Morgan, T.O.; Sabto, J.; Anavekar, S.N., and Louis, W.J.: A comparison o f beta adrenergic blocking drugs in the treatment o f hypertension. Post-grad. med. J. 50: 253-259 (1974). Mylecharane, E.J. and Raper, C.: Beta-receptor blocking and cardiodepressant actions of 2-nitrilophenoxypropanolamines. Eur. J. Pharmacol. 16: 1 4 -2 0 (1971). Robison, A. and Sutherland, E.W.: Sympathin E, Sympathin 1, and the intracellular level of cyclic AMP. Circulation Res. 26 2 7: suppl. 1, pp. 147-161 (1970).
