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Principles of antihypertensive drug treatment
Principles
of Antihypertensive
Drug Treatment
Karl Heinz Rahn, MD
The main objectives of chronic drug treatment in essential hypertension are to decrease Mood pressure, improve prognosis, reduce the number and severity of adverse effects to a minimum, and use simple treatment schedufes. Simple treatment schedutes may be easily maintained with monotherapy (i.e., @blockers, diuretics, calcium antagonists and angiotensin-converting enzyme inhtbitors). if monotberapy is insufMentty effective, antihyperten&e drugs can be combined. Combination therapy makes use of the synergicitic effects of most antfhypertensive drugs. Further considerationrr of combiriation therapy of antihypertenstve agents are the inhibition of compensatory mechanisms working against blood pressure reduction and the decrease of the freqwmcy and severity of adverse effects. Combinations of 2 antihypertensive agents usually contain a diuretic or a calcium antagonist. (Am J Cardioi 1990;65:82G-84G)
Frotn the Department of Medicine D, University of Muenster, Federal Republic of Germany. Address for reprints: Karl Heinz Rahn, MD, Medizinische Klinik und Poliklinik, Abteilung fiir Innere Medizin D, Westfiilische Wilhelms-Universitlt Miinster, Albert-Schweitzer-Strasse 33, D-4400 Miinster, Federal Republic of Germany.
826
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
A
ntihypertensive agents are now widely used for the treatment of various forms of hypertension. Principles of chronic drug treatment in patients with essential hypertension are discussed. The final goal of antihypertensive agents, which are administered in order to decrease elevated blood pressure, is to improve the long-term prognosis of essential hypertension. Improvement in prognosis has only been demonstrated with a limited number of antihypertensive drugs. However, it seems justified to assume that numerous hypotensive agents have a similar effect, A further objective of chronic drug treatment in essential hypertension is to select antihypertensive agents to reduce the frequency and the severity of adverse effects to a minimum. Patients with essential hypertension generally require drug treatment during periods of years, often more than 10 years. Therefore, the use of simple treatment schedules is mandatory in order to maintain compliance. Antihypertensive agents in the form of monotherapy make simple treatment schedules possible; only a limited number of hypotensive drugs can be used in this way. These drugs are /3 blockers, diuretics, calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors (Table I). All other antihypertensive drugs cause sodium and water retention during chronic application. Thus, their blood pressure-lowering action decreases or even totally disappears. Beta blockers now have an established place in the monotherapy of essential hypertension. This is particularly true for the card&elective /3 blockers such as atenolol. To reduce the frequency and severity of adverse effects, cardioselective drugs are now given in lower daily doses than previously. In the case of atenolol, the daily doses range from 50 to 100 mg. The most serious adverse effects of /3 blockers are heart failure, bradycardic arrhythmias and bronchial constriction.’ These unwanted actions are now very rare because contraindications are carefully observed. The most frequent adverse effects of /3-adrenergic blocking agents are muscular fatigue and cold extremities. Diuretics, in particular thiazides, are frequently used in the chronic treatment of essential hypertension, and in lower doses than formally administered. In the case of hydrochlorothiazide, the daily doses range from 12.5 to 50 mg. The main adverse effects of thiazides are hypokalemia, hyperglycemia and hyperuricemia.’ When B blockers and diuretics were given to patients with essential hypertension for some weeks or months, relatively few and minor unwanted effects were observed. However, the picture is essentially different when these drugs are given for several years. The Medical Research Council Working Party study2 demonstrated that long-
TABLE
I Antihypertensive
Drugs
Used for Monotherapy
@Blockers
IV Useful Combination
of Three
B Blocker, diuretic and vasodilator (hydralazine. ACE inhibitor, postsynaptic al blocker) ACE inhibitor, diuretic and calcium antagonist
Diuretics Calcium antagonists ACE inhibitors ACE: Angwtensin-converting
TABLE Drugs
enzyme.
ACE = Angiotensinsonverting
Antihypertensive calcium
antagonist,
emyyme.
therapy of hypertension. The most frequent serious adverse effect of ACE inhibitors is hypotension. This usualClonidine: sedation: withdrawal syndrome ly is a consequence of an inadequately high initial dose of Guanfacine: orthostasis the drug. Renal function disturbances may result from Labetalol: orthostasis Methyldopa: sedation, orthostasis ACE inhibitor-induced hypotension. Rash, pruritus and Minoxidil: hypertrichosis taste disturbances are reversible adverse effects. A nonPrazosin: orthostasis productive cough caused by chronic application of ACE Reserpine: sedation, depression of mood inhibitors sometimes is misinterpreted as a symptom of Urapidil: orthostasis chronic bronchitis or of bronchial carcinoma. A rare but potentially life-threatening adverse effect of ACE inhibitors is angioneurotic edema. Neutropenia and proteinuria seldom occur with the relatively low doses of ACE inhibiTABLE Ill Useful Combinations of Two Antihypertensive Drugs tors currently used5 In marked contrast with the rare but sometimes seriB Blocker and diuretic ous side effects mentioned, ACE inhibitors in general are ACE inhibitor and diuretic Calcium antagonist and diuretic subjectively well tolerated by patients. These drugs have B blocker and calcium antagonist been shown to improve the index of general well-beinge6 ACE inhibitor and calcium antagonist In the same study, methyldopa decreased this parameter. ACE = Angiotensin-xmverttng enzyme. A number of antihypertensive agents may now no longer be considered as drugs of first choice for the treatment of hypertension. This is due to the fact that these term treatment with p blockers and diuretics often had to drugs cause more frequent or more serious side effects be discontinued because of adverse effects, many of than /3 blockers, diuretics, calcium antagonists and ACE inhibitors (Table II). All the drugs mentioned in Table II which were subjective. Calcium antagonists are often given to patients with cause salt and water retention during chronic application. hypertension. Verapamil is used in doses ranging from 80 Therefore, they ought to be combined with a diuretic and mg/day twice daily to 120 mg/day 3 times daily. The not be used as monotherapy. These drugs should mainly duration of blood pressure-lowering action of this drug is be considered as an alternative if /3 blockers, calcium 8 to 12 hours. Verapamil rarely causes bradycardic ar- antagonists or ACE inhibitors are contraindicated or rhythmias. The drug may cause headache and flush. The poorly tolerated. There are several reasons why antihypertensive agents most disturbing adverse effect during chronic application should be combined when monotherapy is not sufficiently of verapamil is constipation. The predominant adverse effect of nifedipine and oth- effective in reducing blood pressure. The main considerer dihydropyridine calcium antagonists is headache. ation is that most antihypertensive drugs have a synergisThese drugs rarely, if ever, cause bradycardic arrhythtic effect on blood pressure when given concomitantly. Furthermore, the addition of one antihypertensive drug mias and constipation represents no problem. As mentioned earlier, one of the most frequent un- to another may influence compensatory mechanisms wanted effects of /3 blockers is muscular fatigue. Mooy et working against blood pressure reduction. Thus, arterioal3 showed that verapamil has no influence on exercise lar-vasodilating drugs like hydralazine and minoxidil intolerance during submaximal work in patients with essen- crease cardiac output by reflex activation of the sympatial hypertension. Similarly, Lange-Andersen et al4 re- thetic nervous system. This reflex elevation of cardiac ported that 4 week of treatment with nifedipine did not output antagonizes the blood pressure-lowering effect of alter perceived subjective exertion during bicycle ergom- these agents. The antihypertensive action of the vasodilators mentioned can be enhanced by combining them with etry in patients with mild to moderate hypertension. Thus, treatment with calcium antagonists is an alterna- a drug which inhibits sympathetic function. These considtive for physically active hypertensive patients who com- erations are the basis of combinations consisting of an plain of muscular fatigue during treatment with @-recep arteriolar vasodilator with drugs like p blockers, resertor blocking agents. pine, clonidine and methyldopa. Finally, antihypertensive The first ACE inhibitors used for the treatment of agents may be combined in order to decrease the frequenhypertension were captopril and enalapril. Meanwhile, cy of adverse effects. The various groups of antihypertenfurther ACE-inhibiting drugs have been added to the sive drugs differ in their pattern of adverse effects. BeTABLE
II Side Effects
of Antihypertensive
Drugs
THE AMERICAN
JOURNAL
OF CARDIOLOGY
APRIL 3. 1990
836
A SYMPOSIUM:
ARTERIAL
RYPERYENSION
-
CARDlAC
HYPERTROPRY
cause of the synergistic effect on blood pressure, smaller doses of the individual drug can be used during combination therapy than during monotherapy for hypertension. The frequency and severity of side effects of many antihypertensive agents are dose dependent. By using smaller doses in the combination therapy, the severity and the frequency of side effects may be diminished. On the basis of these considerations, the maximal doses of hypotensive drugs used in the form of monotherapy are now considerably lower than in the past. Combination therapy rather than relatively high doses is now preferred if monotherapy proves insufficiently effective. Tables III and IV list useful combinations of 2 or 3 antihypertensive drugs, respectively.
846
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
AND
FAILURE
REFERENCES 1. Rahn KH. Frequency
and significance of side effects of antihypertensive drugs. Cardiouasc Rev Rep 198.?;2:517-521. 2. Medical Research Council Working Party on Mild to Moderate Hypertension. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lnncet 1981;2:539-543. 3. Mooy J, van Baak M, BBhm R, Does R, Petri H, van Kemenade .I, Rahn KH. The effects of verapamil and propranolol on exercise tolerance in hypertensive patients. Clin Pharmncol Ther 1987:41:490-495. 4. Lange-Anderson K, Piatkowski W, Green KA, Ottman W. Working ability and exercise tolerance during treatment of a mild hypertension. 1. Comparison between a fl-adrenoceptor blocking drug and a calcium antagonist. Int Arch Occup Environ Health 1985:56:41-47. 5. Rahn KH. Wirkungen der ACE-Hemmer bei Hypertonic. Z Kardiol 1988;77:suppl 3:69-71. 6. Croog SH, Levine S, Testa MA, Brown B, Bulpitt CJ, Jenkins D, Klerman GL, Williams GH. The effects of antihypertensive therapy on the quality of life. N Engl J Med 1986;314:1657-1664.
of Antihypertensive
Drug Treatment
Karl Heinz Rahn, MD
The main objectives of chronic drug treatment in essential hypertension are to decrease Mood pressure, improve prognosis, reduce the number and severity of adverse effects to a minimum, and use simple treatment schedufes. Simple treatment schedutes may be easily maintained with monotherapy (i.e., @blockers, diuretics, calcium antagonists and angiotensin-converting enzyme inhtbitors). if monotberapy is insufMentty effective, antihyperten&e drugs can be combined. Combination therapy makes use of the synergicitic effects of most antfhypertensive drugs. Further considerationrr of combiriation therapy of antihypertenstve agents are the inhibition of compensatory mechanisms working against blood pressure reduction and the decrease of the freqwmcy and severity of adverse effects. Combinations of 2 antihypertensive agents usually contain a diuretic or a calcium antagonist. (Am J Cardioi 1990;65:82G-84G)
Frotn the Department of Medicine D, University of Muenster, Federal Republic of Germany. Address for reprints: Karl Heinz Rahn, MD, Medizinische Klinik und Poliklinik, Abteilung fiir Innere Medizin D, Westfiilische Wilhelms-Universitlt Miinster, Albert-Schweitzer-Strasse 33, D-4400 Miinster, Federal Republic of Germany.
826
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
A
ntihypertensive agents are now widely used for the treatment of various forms of hypertension. Principles of chronic drug treatment in patients with essential hypertension are discussed. The final goal of antihypertensive agents, which are administered in order to decrease elevated blood pressure, is to improve the long-term prognosis of essential hypertension. Improvement in prognosis has only been demonstrated with a limited number of antihypertensive drugs. However, it seems justified to assume that numerous hypotensive agents have a similar effect, A further objective of chronic drug treatment in essential hypertension is to select antihypertensive agents to reduce the frequency and the severity of adverse effects to a minimum. Patients with essential hypertension generally require drug treatment during periods of years, often more than 10 years. Therefore, the use of simple treatment schedules is mandatory in order to maintain compliance. Antihypertensive agents in the form of monotherapy make simple treatment schedules possible; only a limited number of hypotensive drugs can be used in this way. These drugs are /3 blockers, diuretics, calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors (Table I). All other antihypertensive drugs cause sodium and water retention during chronic application. Thus, their blood pressure-lowering action decreases or even totally disappears. Beta blockers now have an established place in the monotherapy of essential hypertension. This is particularly true for the card&elective /3 blockers such as atenolol. To reduce the frequency and severity of adverse effects, cardioselective drugs are now given in lower daily doses than previously. In the case of atenolol, the daily doses range from 50 to 100 mg. The most serious adverse effects of /3 blockers are heart failure, bradycardic arrhythmias and bronchial constriction.’ These unwanted actions are now very rare because contraindications are carefully observed. The most frequent adverse effects of /3-adrenergic blocking agents are muscular fatigue and cold extremities. Diuretics, in particular thiazides, are frequently used in the chronic treatment of essential hypertension, and in lower doses than formally administered. In the case of hydrochlorothiazide, the daily doses range from 12.5 to 50 mg. The main adverse effects of thiazides are hypokalemia, hyperglycemia and hyperuricemia.’ When B blockers and diuretics were given to patients with essential hypertension for some weeks or months, relatively few and minor unwanted effects were observed. However, the picture is essentially different when these drugs are given for several years. The Medical Research Council Working Party study2 demonstrated that long-
TABLE
I Antihypertensive
Drugs
Used for Monotherapy
@Blockers
IV Useful Combination
of Three
B Blocker, diuretic and vasodilator (hydralazine. ACE inhibitor, postsynaptic al blocker) ACE inhibitor, diuretic and calcium antagonist
Diuretics Calcium antagonists ACE inhibitors ACE: Angwtensin-converting
TABLE Drugs
enzyme.
ACE = Angiotensinsonverting
Antihypertensive calcium
antagonist,
emyyme.
therapy of hypertension. The most frequent serious adverse effect of ACE inhibitors is hypotension. This usualClonidine: sedation: withdrawal syndrome ly is a consequence of an inadequately high initial dose of Guanfacine: orthostasis the drug. Renal function disturbances may result from Labetalol: orthostasis Methyldopa: sedation, orthostasis ACE inhibitor-induced hypotension. Rash, pruritus and Minoxidil: hypertrichosis taste disturbances are reversible adverse effects. A nonPrazosin: orthostasis productive cough caused by chronic application of ACE Reserpine: sedation, depression of mood inhibitors sometimes is misinterpreted as a symptom of Urapidil: orthostasis chronic bronchitis or of bronchial carcinoma. A rare but potentially life-threatening adverse effect of ACE inhibitors is angioneurotic edema. Neutropenia and proteinuria seldom occur with the relatively low doses of ACE inhibiTABLE Ill Useful Combinations of Two Antihypertensive Drugs tors currently used5 In marked contrast with the rare but sometimes seriB Blocker and diuretic ous side effects mentioned, ACE inhibitors in general are ACE inhibitor and diuretic Calcium antagonist and diuretic subjectively well tolerated by patients. These drugs have B blocker and calcium antagonist been shown to improve the index of general well-beinge6 ACE inhibitor and calcium antagonist In the same study, methyldopa decreased this parameter. ACE = Angiotensin-xmverttng enzyme. A number of antihypertensive agents may now no longer be considered as drugs of first choice for the treatment of hypertension. This is due to the fact that these term treatment with p blockers and diuretics often had to drugs cause more frequent or more serious side effects be discontinued because of adverse effects, many of than /3 blockers, diuretics, calcium antagonists and ACE inhibitors (Table II). All the drugs mentioned in Table II which were subjective. Calcium antagonists are often given to patients with cause salt and water retention during chronic application. hypertension. Verapamil is used in doses ranging from 80 Therefore, they ought to be combined with a diuretic and mg/day twice daily to 120 mg/day 3 times daily. The not be used as monotherapy. These drugs should mainly duration of blood pressure-lowering action of this drug is be considered as an alternative if /3 blockers, calcium 8 to 12 hours. Verapamil rarely causes bradycardic ar- antagonists or ACE inhibitors are contraindicated or rhythmias. The drug may cause headache and flush. The poorly tolerated. There are several reasons why antihypertensive agents most disturbing adverse effect during chronic application should be combined when monotherapy is not sufficiently of verapamil is constipation. The predominant adverse effect of nifedipine and oth- effective in reducing blood pressure. The main considerer dihydropyridine calcium antagonists is headache. ation is that most antihypertensive drugs have a synergisThese drugs rarely, if ever, cause bradycardic arrhythtic effect on blood pressure when given concomitantly. Furthermore, the addition of one antihypertensive drug mias and constipation represents no problem. As mentioned earlier, one of the most frequent un- to another may influence compensatory mechanisms wanted effects of /3 blockers is muscular fatigue. Mooy et working against blood pressure reduction. Thus, arterioal3 showed that verapamil has no influence on exercise lar-vasodilating drugs like hydralazine and minoxidil intolerance during submaximal work in patients with essen- crease cardiac output by reflex activation of the sympatial hypertension. Similarly, Lange-Andersen et al4 re- thetic nervous system. This reflex elevation of cardiac ported that 4 week of treatment with nifedipine did not output antagonizes the blood pressure-lowering effect of alter perceived subjective exertion during bicycle ergom- these agents. The antihypertensive action of the vasodilators mentioned can be enhanced by combining them with etry in patients with mild to moderate hypertension. Thus, treatment with calcium antagonists is an alterna- a drug which inhibits sympathetic function. These considtive for physically active hypertensive patients who com- erations are the basis of combinations consisting of an plain of muscular fatigue during treatment with @-recep arteriolar vasodilator with drugs like p blockers, resertor blocking agents. pine, clonidine and methyldopa. Finally, antihypertensive The first ACE inhibitors used for the treatment of agents may be combined in order to decrease the frequenhypertension were captopril and enalapril. Meanwhile, cy of adverse effects. The various groups of antihypertenfurther ACE-inhibiting drugs have been added to the sive drugs differ in their pattern of adverse effects. BeTABLE
II Side Effects
of Antihypertensive
Drugs
THE AMERICAN
JOURNAL
OF CARDIOLOGY
APRIL 3. 1990
836
A SYMPOSIUM:
ARTERIAL
RYPERYENSION
-
CARDlAC
HYPERTROPRY
cause of the synergistic effect on blood pressure, smaller doses of the individual drug can be used during combination therapy than during monotherapy for hypertension. The frequency and severity of side effects of many antihypertensive agents are dose dependent. By using smaller doses in the combination therapy, the severity and the frequency of side effects may be diminished. On the basis of these considerations, the maximal doses of hypotensive drugs used in the form of monotherapy are now considerably lower than in the past. Combination therapy rather than relatively high doses is now preferred if monotherapy proves insufficiently effective. Tables III and IV list useful combinations of 2 or 3 antihypertensive drugs, respectively.
846
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
AND
FAILURE
REFERENCES 1. Rahn KH. Frequency
and significance of side effects of antihypertensive drugs. Cardiouasc Rev Rep 198.?;2:517-521. 2. Medical Research Council Working Party on Mild to Moderate Hypertension. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lnncet 1981;2:539-543. 3. Mooy J, van Baak M, BBhm R, Does R, Petri H, van Kemenade .I, Rahn KH. The effects of verapamil and propranolol on exercise tolerance in hypertensive patients. Clin Pharmncol Ther 1987:41:490-495. 4. Lange-Anderson K, Piatkowski W, Green KA, Ottman W. Working ability and exercise tolerance during treatment of a mild hypertension. 1. Comparison between a fl-adrenoceptor blocking drug and a calcium antagonist. Int Arch Occup Environ Health 1985:56:41-47. 5. Rahn KH. Wirkungen der ACE-Hemmer bei Hypertonic. Z Kardiol 1988;77:suppl 3:69-71. 6. Croog SH, Levine S, Testa MA, Brown B, Bulpitt CJ, Jenkins D, Klerman GL, Williams GH. The effects of antihypertensive therapy on the quality of life. N Engl J Med 1986;314:1657-1664.