Drugs 17: 129-133 0012-6667/79/0200-129/$01.00/0 © ADIS Press Australasia Pty Ltd. All rights reserved.
~ -Blockers in Hypertension: How to Get the Best Results
Hendrika J. Waal-Manning Wellcome Medical Research Institute, Department of Medicine, University of Otago Medical School, Dunedin
~-Adrenoceptor blocking drugs (~-blockers) are the drugs of choice in the treatment of hypertension in all patients who are free from heart failure, asthma or catecholamine excess. Best therapeutic results are obtained by a knowledge of: I) The type of hypertension which responds to
teristics which have been shown to identify subjects who will respond to ~-blockers. The only form of hypertension that cannot be treated by ~-blockers is phaeochromocytoma and other catecholamine excess states like clonidine withdrawal or hypoglycaemia.
~-blockade
2) Whether ~-blockers should be given alone or in combination with other antihypertensive drugs 3) Comparative efficacy of the different ~-blockers in lowering blood pressure 4) The clinical relevance of pharmacological and pharmacokinetic differences between the different ~-blockers
5) How the choice of ~-blocker in the individual patient is modified by associated disease conditions. and concomitant drugs 6) The side effects of ~-blockers in general and of individual compounds.
1. Type of Hypertension Does Not Influence Response All forms of hypertension, renal or essential, mild, severe, even malignant are amenable to therapy with ~-blockers. The response rate is high 'especially if a diuretic is given concomitantly. There are no charac-
2.
~-Blockers
Alone or in Combination
In young mild hypertensives, ~-blockers can be used alone. Older patients are best established on a diuretic before a ~-blocker is started and in more severe unresponsive cases, ~-blockers are best used with a diuretic and a vasodilator such as prazosin or hydrallazine. ~-Blockers have an additive antihypertensive effect when used in combination with a diuretic and methyldopa or adrenergic neurone blockers, but not with clonidine which may antagonise or be antagonised by ~-blockers.
3. Comparative Effectiveness in Lowering Blood Pressure The antihypertensive action of the various ~ blockers is approximately equal at dosages propor-
~-Blockers
130
in Hypertension
Table I. Side effects with individual ~-blockers Propranolol Tiredness or depression
Pindolol High dose -
Substitute a ~-blocker with partial agonist activity (table II)
BP rise
Muscle cramps
Dreams
Practolol Oculomucocutaneous syndrome
Reduce dose or substitute a ~-blocker lacking partial agonist activity Reduce dose or substitute a ~-blocker lacking partial agonist activity Avoid an evening dose or give it early
Practolol should not be used
tional to their ~1-blocking potency. The cardioselective ~-blockers like atenolol and metoprolol are equally effective as antihypertensive drugs as the older non-selective ~-blockers like propranolol and oxprenolol. In patients resistant to full dosage of one ~-blocker drug, changing to another usually does not help in controlling the patient's blood pressure. However, when a dose limiting side effect occurs with one ~-blocker, then changing to another ~-blocker may be worthwhile. Side effects which occur with individual ~-blockers are given in table 1.
4. Clinical Relevance of Pharmacological and Pharmacokinetic D(f{erences ~-Blockers have different chemical structures which confer differences in potency of ~-blockade in non-specific pharmacological effects such as cardioselectivity and partial agonist activity (see table II) and in pharmacokinetics. There are differences in absorption, liver metabolism which also determines
bioavailability, and there are also differences in renal elimination. The practical consequences in clinical use are that the daily dose of different ~-blockers varies in amount and range. Because there are variations in duration of antihypertensive effect dosage schedules vary from once daily to tds regimens. The ~-blockers also differ in the accumulation that can be expected in liver disease or in renal failure (table II). 4.1 Cardioselectivity ~-Blockers which block ~1- and ~2-adrenoceptors are non-selective; those that block ~1-receptors, the cardiac ~~adrenoceptors only, are cardioselective. The cardioselective ~-blockers do not block ~2-receptors, the ~-adrenoceptors of blood vessels and bronchioles. Cardioselectivity lessens the risk of bronchospasm, drugs having this property (atenolol and metoprolol at low dosages) do not block the bronchodilator effect of ~2-adrenoceptor stimulation with agents such as salbutamol and terbutaline. There may be less tendency to impaired peripheral circulation, heart failure and hypertensive reactions in states of catecholamine excess such as hypoglycaemia. Cardioselectivity does not affect antihypertensive action.
4.2 Partial Agonist Activity
Propranolol, metoprolol and atenolol cause no observable effect when they interact with ~-adrenocep tors in the absence of a primary agonist such as adrenaline or isoprenaline. The others: oxprenolol, alprenolol, acebutolol but especially pindolol, cause a measurable agonist response indicating that they themselves have agonist activity. This agonist activity differs from that of adrenaline or isoprenaline in that the maximum response which can be obtained is less. Partial agonist activity lessens pulse slowing, A-V conduction impairment and reduction in cardiac output, and probably also lessens the effect on renin and incidence of mental depression. It may be associated with a decreased effectiveness in hyperthyroidism and a paradoxical decrease in antihypertensive effect with dose increase.
~-Blockers
131
in Hypertension
Table II. Differences in pharmacological properties and in effective dose (mean and range) of different ~-blockers
Receptor blockade
Drug
Partial agolJist activity
Potency ratio'
~,
~2
Acebutolol
+
±
+
Alprenolol
+
+
++
Atenolol
+
0
0
Metoprolol
+
0
0
Oxprenolol
+
+
Pindolol
+
Timolol Propranolol
1
Accumulation expected
Effective dose
liver disease
renal failure
mean
range
0.3
yes
yes
300
200-800
0.3
yes
yes
300
200-800
no
yes
100
25-200
yes
no
200
100-450
++
0.5-1
yes
no
200
80-480
+
+++
6
no
no
15
5-30
+
+
±
6
yes
no
15
5-40
+
+
0
yes
yes
160
60-480 (960)
Propranolol = 1.
4.3 Practical Regimens Except in severe hypertension it is best to start with a single drug and assess its effect. In the older hypertensive (45 to 55 years) start with a diuretic; in the young mild hypertensive a ~-blocker can be given alone. For conditions influencing the choice of ~ blocker see table III (associated disease) and table IV (other drug therapy). 4.3.1 Initial Dosage
Start with a low dosage given as a tds regimen for the shorter acting drugs such as propranolol, oxprenolol, acebutolol and alprenolol or as a bd regimen for medium acting drugs like metoprolol, pindolol, timolol and the long acting atenolol. These multiple doses/ day regimens at low daily dosages are especially indicated when there is associated disease such as arrhythmia and angina, the control of which is more directly dependent on an effective level of ~ blockade than that of hypertension. In patients with liver disease or renal failure it is imperative to use small doses of those ~-blockers (or their active meta-
bolites) that accumulate in these conditions (see table II) and often once daily dosage will suffice in these patients. 4.3.2 Dose Increments
About 75 % of the antihypertensive effect will be seen in 4 days and most of it in I to 2 weeks. Therefore dosage should be increased in stages at I to 2 week intervals. The dose finding period will be longer for ~-blockers which show a large variation between individuals in drug response as reflected in their large effective dose range (e.g. propranolol). It will be shorter for the drugs with less variation between individuals in drug response as reflected in a narrower effective dose range (e.g. atenolol, metoproloJ). As the daily dosage requirement increases, doses can be given less frequently or the larger dose slow release preparations can be used. As there is diurnal variation in blood pressure with a tendency for lower levels to prevail during sleep and higher levels during waking hours it is best on bd regimens to give two-thirds of the daily dose in the morning and one-third in the evening. Likewise,
~-Blockers
132
in Hypertension
Table III. Associated disease conditions which modify the choice of ~-blocker in hypertension Associated disease
Choice of ~-blocker
Angina
Cardioselective ones may have an advantage. Avoid sudden withdrawal of ~-blockade, especially in those with severe angina, which may precipitate myocardial infarction
once daily doses should be given in the morning. Any evening dose is best given early to minimise dreaming which can be a troublesome side effect of a number of ~-blockers.
4.3.3 Ceiling Dose
Most ~-blockers have a ceiling dose beyond which it is unlikely that further antihypertensive effect will occur (upper value of dosage shown in table 10. In the case of pindolol, some patients seem to show. after an initial partial antihypertensive effect, a paradoxical increase in blood pressure as pindolol dosage is increased. This has been ascribed to its relatively high partial agonist activity and can be avoided by limiting the daily dose to 30mg.
Asthma
All ~-blockers are contraindicated (see also under bronchitis)
A-V conduction defects Prolonged PR Other forms
generally contraindicated with partial agonist activity can be tried with caution ~-Blockers contraindicated
Bradycardia
~-Blockers with partial agonist activity have less pulse slowing effect and are to be preferred
Bronchitis with bronchospasm
Small doses of cardioselective ~-blockers (atenolol. metoproloI) can be used with caution with or without a ~2-stimulant, orally or by inhaler. Non-selective ~-blockers are contraindicated
Cold extremities Raynaud's phenomenon Intermittent claudication
Cardioselective ones and those with partial agonist activity may have an advantage. Keep ~-blocker dose low, add vasodilator or use labetalol
Depression
Avoid propranolol especially
Diabetes mellitus
Cardioselective ones probably preferable
Heart failure
Only after diuretics and digitalisation; cardioselective ones may have an advantage
Liver disease
See table II for compounds that tend to accumulate; use small doses of these
Migraine
Non-selective ones without partial agonist activity may be preferable
Muscle cramps
Avoid pindolol and possibly others with partial agonist activity
~-blocker
Phaeochromocytoma and other catecholamine excess states
Avoid all ~-blockers unless an a-blocker is also given
Insulin
Renal failure
Use reduced doses of those compounds that tend to accumulate in renal failure (table III and of those (propranolol. alprenolol) whose oral bioavailability is increased in urae- mia. Also, consider possible accumulation of active metabolites of alprenolol and propranolol
Thyrotoxicosis
~-Blockers ~-Blockers
All with control symptoms; those without partial agonist activity (table 11) are to be preferred
4.3.4 When to Add Other Drugs When the ceiling dose or the maximum effective dose has been reached and blood pressure levels are not satisfactory it is best to add another drug. Where the ~-blocker is being used alone a diuretic should be added. The next step is the addition of a vasodilator such as prazosin or hydrallazine. The ~-blocker counteracts the increase in heart rate caused by the vasodilators which in turn lessen the peripheral circulatory impairment often seen with ~-blockade. As a final step in patients not responding to the previous 3
Table IV. Other drug therapy which modifies the choice of in hypertension
Sulphonylurea compounds
Non-selective ~-blockers may intensify hypoglycaemia, mask its symptoms and cause a hypertensive response to it. Hypoglycaemia is less with cardioselective ~-blocker
Clonidine
Antagonism of antihypertensive effect. Avoid sotalol, probably others also (especially non-selective ones)
Antidepressants
No contraindication to use of ~-blockers but avoid propranolol
~-Blockers
133
in Hypertension
Table V. Side effects and toxic reactions of 1.
~-blockers
Asthma - this can occur unpredictably in susceptible patients, even with cardioselective drugs (atenolol. metoprolol), but patients on cardioselective drugs respond to ~2-stimulants orally or by inhaler.
2.
Heart failure - in patients with myocardial impairment. Avoid by giving digitalis and a diuretic before ~-blockade.
3.
Bradyarrhythmias and A-V conduction block - less for ~-blockers with partial agonist activity (e.g. pindolol).
4.
Impairment of peripheral circulation - most troublesome with non-selective ~-blockers without partial agonist activity (e.g. propranolol).
5.
eNS effects (dreams, nightmares, occasional depression) - avoid evening dose or give it early.
6.
Muscle cramps -
7.
Acute hypertensive responses in catecholamine excess states - less with cardioselective ~-blockers.
8.
Metabolic effects - hyperglycaemia, hypoglycaemia, increase in serum potassium, possible long term effect on atheroma. Significance uncertain.
9.
Deterioration in renal function -
especially with pindolol.
rare.
10.
Gastrointestinal symptoms -
1 1.
Haematological reactions -
12.
Skin rash -
13.
Immune reaction oculomucocutaneous syndrome, probably peculiar to practolol.
rare. rare.
rare.
drugs, methyldopa or an adrenergic neurone blocker can be added, but not clonidine. 4.3.5 Maintenance Dose Adjustment When blood pressure control has been attained by a stepwise increase in dose and addition of other drugs, it is imperative after a period of good control to establish for long term maintenance the minimum effective dosages of each drug by dose reduction of each in turn. Sudden withdrawal of ~-blockade, especially in patients with severe ischaemic heart disease must be avoided for fear of precipitation of myocardial infarction.
Table VI. Principles of practical regimens of ~-blockers in hypertension
1. Start with a single drug and assess its effect -
except in
severe hypertension
2. Start with a low dosage as a divided dose regimen 3. Increase dosage gradually every 1 to 2 weeks
4. As daily dosage requirement increases, doses can be given less frequently or slow release preparations used
5. For bd regimens give two-thirds daily dose in morning and one-third at night. Give once daily doses in the morning
6. When ceiling dose or maximum effective dose reached. add another agent if blood pressure not adequately controlled
7. Once control achieved, establish for long term maintenance minimum effective dosage of each drug
5. Choice of ~-Blocker in the Individual Patient The conditions which modify the choice of ~ blocker for hypertension in the individual patient are the associated disease states of the patient (listed alphabetically in table III); other drug therapy the patient may be taking (table IV); side effects with (table I) and cost of individual ~-blockers.
6. Side Effects and Toxic Reactions of ~-Blockade
The side effects of ~-blockers in general and of individual compounds are given in tables I and V.
Acknowledgement This work was supported by the Medical Research Council of New Zealand.
Author's address; Dr Hendrika J. Waal-Manning, Wellcome Medical Research Institute. Department of Medicine, Medical School, P.O. Box 9/3 (Dunedin).
~ -Blockers in Hypertension: How to Get the Best Results
Hendrika J. Waal-Manning Wellcome Medical Research Institute, Department of Medicine, University of Otago Medical School, Dunedin
~-Adrenoceptor blocking drugs (~-blockers) are the drugs of choice in the treatment of hypertension in all patients who are free from heart failure, asthma or catecholamine excess. Best therapeutic results are obtained by a knowledge of: I) The type of hypertension which responds to
teristics which have been shown to identify subjects who will respond to ~-blockers. The only form of hypertension that cannot be treated by ~-blockers is phaeochromocytoma and other catecholamine excess states like clonidine withdrawal or hypoglycaemia.
~-blockade
2) Whether ~-blockers should be given alone or in combination with other antihypertensive drugs 3) Comparative efficacy of the different ~-blockers in lowering blood pressure 4) The clinical relevance of pharmacological and pharmacokinetic differences between the different ~-blockers
5) How the choice of ~-blocker in the individual patient is modified by associated disease conditions. and concomitant drugs 6) The side effects of ~-blockers in general and of individual compounds.
1. Type of Hypertension Does Not Influence Response All forms of hypertension, renal or essential, mild, severe, even malignant are amenable to therapy with ~-blockers. The response rate is high 'especially if a diuretic is given concomitantly. There are no charac-
2.
~-Blockers
Alone or in Combination
In young mild hypertensives, ~-blockers can be used alone. Older patients are best established on a diuretic before a ~-blocker is started and in more severe unresponsive cases, ~-blockers are best used with a diuretic and a vasodilator such as prazosin or hydrallazine. ~-Blockers have an additive antihypertensive effect when used in combination with a diuretic and methyldopa or adrenergic neurone blockers, but not with clonidine which may antagonise or be antagonised by ~-blockers.
3. Comparative Effectiveness in Lowering Blood Pressure The antihypertensive action of the various ~ blockers is approximately equal at dosages propor-
~-Blockers
130
in Hypertension
Table I. Side effects with individual ~-blockers Propranolol Tiredness or depression
Pindolol High dose -
Substitute a ~-blocker with partial agonist activity (table II)
BP rise
Muscle cramps
Dreams
Practolol Oculomucocutaneous syndrome
Reduce dose or substitute a ~-blocker lacking partial agonist activity Reduce dose or substitute a ~-blocker lacking partial agonist activity Avoid an evening dose or give it early
Practolol should not be used
tional to their ~1-blocking potency. The cardioselective ~-blockers like atenolol and metoprolol are equally effective as antihypertensive drugs as the older non-selective ~-blockers like propranolol and oxprenolol. In patients resistant to full dosage of one ~-blocker drug, changing to another usually does not help in controlling the patient's blood pressure. However, when a dose limiting side effect occurs with one ~-blocker, then changing to another ~-blocker may be worthwhile. Side effects which occur with individual ~-blockers are given in table 1.
4. Clinical Relevance of Pharmacological and Pharmacokinetic D(f{erences ~-Blockers have different chemical structures which confer differences in potency of ~-blockade in non-specific pharmacological effects such as cardioselectivity and partial agonist activity (see table II) and in pharmacokinetics. There are differences in absorption, liver metabolism which also determines
bioavailability, and there are also differences in renal elimination. The practical consequences in clinical use are that the daily dose of different ~-blockers varies in amount and range. Because there are variations in duration of antihypertensive effect dosage schedules vary from once daily to tds regimens. The ~-blockers also differ in the accumulation that can be expected in liver disease or in renal failure (table II). 4.1 Cardioselectivity ~-Blockers which block ~1- and ~2-adrenoceptors are non-selective; those that block ~1-receptors, the cardiac ~~adrenoceptors only, are cardioselective. The cardioselective ~-blockers do not block ~2-receptors, the ~-adrenoceptors of blood vessels and bronchioles. Cardioselectivity lessens the risk of bronchospasm, drugs having this property (atenolol and metoprolol at low dosages) do not block the bronchodilator effect of ~2-adrenoceptor stimulation with agents such as salbutamol and terbutaline. There may be less tendency to impaired peripheral circulation, heart failure and hypertensive reactions in states of catecholamine excess such as hypoglycaemia. Cardioselectivity does not affect antihypertensive action.
4.2 Partial Agonist Activity
Propranolol, metoprolol and atenolol cause no observable effect when they interact with ~-adrenocep tors in the absence of a primary agonist such as adrenaline or isoprenaline. The others: oxprenolol, alprenolol, acebutolol but especially pindolol, cause a measurable agonist response indicating that they themselves have agonist activity. This agonist activity differs from that of adrenaline or isoprenaline in that the maximum response which can be obtained is less. Partial agonist activity lessens pulse slowing, A-V conduction impairment and reduction in cardiac output, and probably also lessens the effect on renin and incidence of mental depression. It may be associated with a decreased effectiveness in hyperthyroidism and a paradoxical decrease in antihypertensive effect with dose increase.
~-Blockers
131
in Hypertension
Table II. Differences in pharmacological properties and in effective dose (mean and range) of different ~-blockers
Receptor blockade
Drug
Partial agolJist activity
Potency ratio'
~,
~2
Acebutolol
+
±
+
Alprenolol
+
+
++
Atenolol
+
0
0
Metoprolol
+
0
0
Oxprenolol
+
+
Pindolol
+
Timolol Propranolol
1
Accumulation expected
Effective dose
liver disease
renal failure
mean
range
0.3
yes
yes
300
200-800
0.3
yes
yes
300
200-800
no
yes
100
25-200
yes
no
200
100-450
++
0.5-1
yes
no
200
80-480
+
+++
6
no
no
15
5-30
+
+
±
6
yes
no
15
5-40
+
+
0
yes
yes
160
60-480 (960)
Propranolol = 1.
4.3 Practical Regimens Except in severe hypertension it is best to start with a single drug and assess its effect. In the older hypertensive (45 to 55 years) start with a diuretic; in the young mild hypertensive a ~-blocker can be given alone. For conditions influencing the choice of ~ blocker see table III (associated disease) and table IV (other drug therapy). 4.3.1 Initial Dosage
Start with a low dosage given as a tds regimen for the shorter acting drugs such as propranolol, oxprenolol, acebutolol and alprenolol or as a bd regimen for medium acting drugs like metoprolol, pindolol, timolol and the long acting atenolol. These multiple doses/ day regimens at low daily dosages are especially indicated when there is associated disease such as arrhythmia and angina, the control of which is more directly dependent on an effective level of ~ blockade than that of hypertension. In patients with liver disease or renal failure it is imperative to use small doses of those ~-blockers (or their active meta-
bolites) that accumulate in these conditions (see table II) and often once daily dosage will suffice in these patients. 4.3.2 Dose Increments
About 75 % of the antihypertensive effect will be seen in 4 days and most of it in I to 2 weeks. Therefore dosage should be increased in stages at I to 2 week intervals. The dose finding period will be longer for ~-blockers which show a large variation between individuals in drug response as reflected in their large effective dose range (e.g. propranolol). It will be shorter for the drugs with less variation between individuals in drug response as reflected in a narrower effective dose range (e.g. atenolol, metoproloJ). As the daily dosage requirement increases, doses can be given less frequently or the larger dose slow release preparations can be used. As there is diurnal variation in blood pressure with a tendency for lower levels to prevail during sleep and higher levels during waking hours it is best on bd regimens to give two-thirds of the daily dose in the morning and one-third in the evening. Likewise,
~-Blockers
132
in Hypertension
Table III. Associated disease conditions which modify the choice of ~-blocker in hypertension Associated disease
Choice of ~-blocker
Angina
Cardioselective ones may have an advantage. Avoid sudden withdrawal of ~-blockade, especially in those with severe angina, which may precipitate myocardial infarction
once daily doses should be given in the morning. Any evening dose is best given early to minimise dreaming which can be a troublesome side effect of a number of ~-blockers.
4.3.3 Ceiling Dose
Most ~-blockers have a ceiling dose beyond which it is unlikely that further antihypertensive effect will occur (upper value of dosage shown in table 10. In the case of pindolol, some patients seem to show. after an initial partial antihypertensive effect, a paradoxical increase in blood pressure as pindolol dosage is increased. This has been ascribed to its relatively high partial agonist activity and can be avoided by limiting the daily dose to 30mg.
Asthma
All ~-blockers are contraindicated (see also under bronchitis)
A-V conduction defects Prolonged PR Other forms
generally contraindicated with partial agonist activity can be tried with caution ~-Blockers contraindicated
Bradycardia
~-Blockers with partial agonist activity have less pulse slowing effect and are to be preferred
Bronchitis with bronchospasm
Small doses of cardioselective ~-blockers (atenolol. metoproloI) can be used with caution with or without a ~2-stimulant, orally or by inhaler. Non-selective ~-blockers are contraindicated
Cold extremities Raynaud's phenomenon Intermittent claudication
Cardioselective ones and those with partial agonist activity may have an advantage. Keep ~-blocker dose low, add vasodilator or use labetalol
Depression
Avoid propranolol especially
Diabetes mellitus
Cardioselective ones probably preferable
Heart failure
Only after diuretics and digitalisation; cardioselective ones may have an advantage
Liver disease
See table II for compounds that tend to accumulate; use small doses of these
Migraine
Non-selective ones without partial agonist activity may be preferable
Muscle cramps
Avoid pindolol and possibly others with partial agonist activity
~-blocker
Phaeochromocytoma and other catecholamine excess states
Avoid all ~-blockers unless an a-blocker is also given
Insulin
Renal failure
Use reduced doses of those compounds that tend to accumulate in renal failure (table III and of those (propranolol. alprenolol) whose oral bioavailability is increased in urae- mia. Also, consider possible accumulation of active metabolites of alprenolol and propranolol
Thyrotoxicosis
~-Blockers ~-Blockers
All with control symptoms; those without partial agonist activity (table 11) are to be preferred
4.3.4 When to Add Other Drugs When the ceiling dose or the maximum effective dose has been reached and blood pressure levels are not satisfactory it is best to add another drug. Where the ~-blocker is being used alone a diuretic should be added. The next step is the addition of a vasodilator such as prazosin or hydrallazine. The ~-blocker counteracts the increase in heart rate caused by the vasodilators which in turn lessen the peripheral circulatory impairment often seen with ~-blockade. As a final step in patients not responding to the previous 3
Table IV. Other drug therapy which modifies the choice of in hypertension
Sulphonylurea compounds
Non-selective ~-blockers may intensify hypoglycaemia, mask its symptoms and cause a hypertensive response to it. Hypoglycaemia is less with cardioselective ~-blocker
Clonidine
Antagonism of antihypertensive effect. Avoid sotalol, probably others also (especially non-selective ones)
Antidepressants
No contraindication to use of ~-blockers but avoid propranolol
~-Blockers
133
in Hypertension
Table V. Side effects and toxic reactions of 1.
~-blockers
Asthma - this can occur unpredictably in susceptible patients, even with cardioselective drugs (atenolol. metoprolol), but patients on cardioselective drugs respond to ~2-stimulants orally or by inhaler.
2.
Heart failure - in patients with myocardial impairment. Avoid by giving digitalis and a diuretic before ~-blockade.
3.
Bradyarrhythmias and A-V conduction block - less for ~-blockers with partial agonist activity (e.g. pindolol).
4.
Impairment of peripheral circulation - most troublesome with non-selective ~-blockers without partial agonist activity (e.g. propranolol).
5.
eNS effects (dreams, nightmares, occasional depression) - avoid evening dose or give it early.
6.
Muscle cramps -
7.
Acute hypertensive responses in catecholamine excess states - less with cardioselective ~-blockers.
8.
Metabolic effects - hyperglycaemia, hypoglycaemia, increase in serum potassium, possible long term effect on atheroma. Significance uncertain.
9.
Deterioration in renal function -
especially with pindolol.
rare.
10.
Gastrointestinal symptoms -
1 1.
Haematological reactions -
12.
Skin rash -
13.
Immune reaction oculomucocutaneous syndrome, probably peculiar to practolol.
rare. rare.
rare.
drugs, methyldopa or an adrenergic neurone blocker can be added, but not clonidine. 4.3.5 Maintenance Dose Adjustment When blood pressure control has been attained by a stepwise increase in dose and addition of other drugs, it is imperative after a period of good control to establish for long term maintenance the minimum effective dosages of each drug by dose reduction of each in turn. Sudden withdrawal of ~-blockade, especially in patients with severe ischaemic heart disease must be avoided for fear of precipitation of myocardial infarction.
Table VI. Principles of practical regimens of ~-blockers in hypertension
1. Start with a single drug and assess its effect -
except in
severe hypertension
2. Start with a low dosage as a divided dose regimen 3. Increase dosage gradually every 1 to 2 weeks
4. As daily dosage requirement increases, doses can be given less frequently or slow release preparations used
5. For bd regimens give two-thirds daily dose in morning and one-third at night. Give once daily doses in the morning
6. When ceiling dose or maximum effective dose reached. add another agent if blood pressure not adequately controlled
7. Once control achieved, establish for long term maintenance minimum effective dosage of each drug
5. Choice of ~-Blocker in the Individual Patient The conditions which modify the choice of ~ blocker for hypertension in the individual patient are the associated disease states of the patient (listed alphabetically in table III); other drug therapy the patient may be taking (table IV); side effects with (table I) and cost of individual ~-blockers.
6. Side Effects and Toxic Reactions of ~-Blockade
The side effects of ~-blockers in general and of individual compounds are given in tables I and V.
Acknowledgement This work was supported by the Medical Research Council of New Zealand.
Author's address; Dr Hendrika J. Waal-Manning, Wellcome Medical Research Institute. Department of Medicine, Medical School, P.O. Box 9/3 (Dunedin).
