Cardiac Pharmacology Adv. Cardio!., vo!' 26, pp. 38-43 (Karger, Basel 1979)
Propranolol and Newer Antihypertensive Drugs in the Management of Hypertension MARVIN MOSER
New York Medical College, Valhalla, N.Y., and Senior Medical Consultant at the National High Blood Pressure Education Program, National Institutes of Health, Betheseda, Md.
Introduction
Numerous antihypertensive drugs are presently available for the management of essential hypertension. They can be classified into three major categories according to their mode of action: (1) diuretics; (2) sympathetic inhibiting drugs, and (3) vasodilators. Another group of experimental drugs that act at various stages of the renin angiotensin system as competitive inhibitors of angiotensin II or inhibitors of converting enzyme may also prove to be of importance in the future.
Drugs
Propranolol is presently the only ~-adrenoreceptor blocking agent available for general use in the United States (metropropollhoppressor®). However, there are numerous ~-blockers that are presently under investigation. ~-Blockers act primarily by competitively inhibiting the effects of catecholamines at ~-receptor sites. Two subgroups of ~-receptors have been identified [3]: (1) the cardiac ~-adrenoreceptors (~-I receptors); and (2) receptors of the peripheral vasculature and bronchial smooth muscle (~-II receptors). Certain investigational ~-adrenergic blockers are 'cardioselective', specifically inhibiting cardiac ~-receptor activity and not affecting peripheral sympathetic activity. These agents might have some advantage in treating the patient with hypertension who also has bronchial or primary pulmonary disease, or peripheral vascular disease. However, current evidence suggests that the relative differences in potency, cardioselective activity, or intrinsic sympathomimetic
Downloaded by: University of Cambridge 131.111.164.128 - 1/31/2019 7:13:15 PM
~- Blocking
39
activity are probably of little significance in determining the antihypertensive effectiveness of various ~-blocking drugs [2]. Methods of Action of Propranolol. The long-term antihypertensive action of propranolol is probably related to the adaptation of peripheral resistance to a long-term reduction in flow as a result of a chronic reduction in cardiac output. A central effect on vasomotor centers probably also plays a role in blood pressure lowering [4]. Certain ~-blockers, such as practilol, which does not pass the blood-brain barrier, are also effective antihypertensive agents, suggesting that the central action is not the predominent one. Other ~-blockers reduce blood pressure without reducing cardiac output. Blood Pressure Effect of Renin Blockade. While it is well established that renin release can be inhibited and plasma renin levels lowered by propranolol, most data suggest that the reduction in plasma renin activity and the lowering of arterial pressure are not causally related. Relatively low doses of propranolol will suppress plasma renin activity, whereas substantially larger doses are usually required to lower blood pressure. Drugs such as pindolol, when given acutely, will cause considerable reduction in blood pressure with no or little obvious effect on the level of renin activity [8]. Duration of Action. Although most of the ~-blockers have a relatively short plasma half-life, with blood levels peaking at about 1-3 h, the duration of antihypertensive effect is relatively long-lasting and may persist for 24 h or more [1]. A correlation between the plasma level and therapeutic effect has been demonstrated, but the difference between the time course of the antihypertensive effect and the plasma level means that for most ~-blockers a twice-a-day or once-a-day dosage regimen can be used. While with most ~-blockers there may be a ceiling dose above which increasing the dose level does not lead to a greater antihypertensive response, propranolol may be an exception. Propranolol is subject to 'first pass' hepatic metabolism, and there is a great variation in the extent of this phenomenon between individuals. Very high doses of over 2 g/day may be needed in some cases to obtain a response. Although the drug is readily absorbed on oral administration, the amount available after hepatic metabolism is extremely variable. In the presence of liver disease, the 'first pass' may not affect propranolol as much, and lesser dosages can be used. Results of Treatment with Propranolol. When used by itself in dosages of between 40 and 480 mg/day, propranolol has been shown in a recent Veterans Administration Study to be 52% effective in lowering blood pressure to a goal of normotensive levels in patients with mild to moderately
Downloaded by: University of Cambridge 131.111.164.128 - 1/31/2019 7:13:15 PM
Propranolol and Newer Drugs in the Management of Hypertension
MOSER
40
severe disease [11]. In most cases, propranolol should be used as a step 2 drug if thiazides alone have failed to lower blood pressure adequately. Other step 2 drugs are reserpine and
Propranolol and Newer Antihypertensive Drugs in the Management of Hypertension MARVIN MOSER
New York Medical College, Valhalla, N.Y., and Senior Medical Consultant at the National High Blood Pressure Education Program, National Institutes of Health, Betheseda, Md.
Introduction
Numerous antihypertensive drugs are presently available for the management of essential hypertension. They can be classified into three major categories according to their mode of action: (1) diuretics; (2) sympathetic inhibiting drugs, and (3) vasodilators. Another group of experimental drugs that act at various stages of the renin angiotensin system as competitive inhibitors of angiotensin II or inhibitors of converting enzyme may also prove to be of importance in the future.
Drugs
Propranolol is presently the only ~-adrenoreceptor blocking agent available for general use in the United States (metropropollhoppressor®). However, there are numerous ~-blockers that are presently under investigation. ~-Blockers act primarily by competitively inhibiting the effects of catecholamines at ~-receptor sites. Two subgroups of ~-receptors have been identified [3]: (1) the cardiac ~-adrenoreceptors (~-I receptors); and (2) receptors of the peripheral vasculature and bronchial smooth muscle (~-II receptors). Certain investigational ~-adrenergic blockers are 'cardioselective', specifically inhibiting cardiac ~-receptor activity and not affecting peripheral sympathetic activity. These agents might have some advantage in treating the patient with hypertension who also has bronchial or primary pulmonary disease, or peripheral vascular disease. However, current evidence suggests that the relative differences in potency, cardioselective activity, or intrinsic sympathomimetic
Downloaded by: University of Cambridge 131.111.164.128 - 1/31/2019 7:13:15 PM
~- Blocking
39
activity are probably of little significance in determining the antihypertensive effectiveness of various ~-blocking drugs [2]. Methods of Action of Propranolol. The long-term antihypertensive action of propranolol is probably related to the adaptation of peripheral resistance to a long-term reduction in flow as a result of a chronic reduction in cardiac output. A central effect on vasomotor centers probably also plays a role in blood pressure lowering [4]. Certain ~-blockers, such as practilol, which does not pass the blood-brain barrier, are also effective antihypertensive agents, suggesting that the central action is not the predominent one. Other ~-blockers reduce blood pressure without reducing cardiac output. Blood Pressure Effect of Renin Blockade. While it is well established that renin release can be inhibited and plasma renin levels lowered by propranolol, most data suggest that the reduction in plasma renin activity and the lowering of arterial pressure are not causally related. Relatively low doses of propranolol will suppress plasma renin activity, whereas substantially larger doses are usually required to lower blood pressure. Drugs such as pindolol, when given acutely, will cause considerable reduction in blood pressure with no or little obvious effect on the level of renin activity [8]. Duration of Action. Although most of the ~-blockers have a relatively short plasma half-life, with blood levels peaking at about 1-3 h, the duration of antihypertensive effect is relatively long-lasting and may persist for 24 h or more [1]. A correlation between the plasma level and therapeutic effect has been demonstrated, but the difference between the time course of the antihypertensive effect and the plasma level means that for most ~-blockers a twice-a-day or once-a-day dosage regimen can be used. While with most ~-blockers there may be a ceiling dose above which increasing the dose level does not lead to a greater antihypertensive response, propranolol may be an exception. Propranolol is subject to 'first pass' hepatic metabolism, and there is a great variation in the extent of this phenomenon between individuals. Very high doses of over 2 g/day may be needed in some cases to obtain a response. Although the drug is readily absorbed on oral administration, the amount available after hepatic metabolism is extremely variable. In the presence of liver disease, the 'first pass' may not affect propranolol as much, and lesser dosages can be used. Results of Treatment with Propranolol. When used by itself in dosages of between 40 and 480 mg/day, propranolol has been shown in a recent Veterans Administration Study to be 52% effective in lowering blood pressure to a goal of normotensive levels in patients with mild to moderately
Downloaded by: University of Cambridge 131.111.164.128 - 1/31/2019 7:13:15 PM
Propranolol and Newer Drugs in the Management of Hypertension
MOSER
40
severe disease [11]. In most cases, propranolol should be used as a step 2 drug if thiazides alone have failed to lower blood pressure adequately. Other step 2 drugs are reserpine and
