Professional Information
Beta-adrenergic Blocking Agents (Systemic)
1) Acebutolol
2) Atenolol
3) Betaxolol †
4) Bisoprolol †
5) Carteolol †
6) Labetalol
7) Metoprolol
8) Nadolol
9) Oxprenolol *
10) Penbutolol †
11) Pindolol
12) Propranolol
13) Sotalol
14) Timolol
VA CLASSIFICATION
Acebutolol
Primary: CV100
Secondary: CV250; CV300; CV409; CV900; CN900
Atenolol
Primary: CV100
Secondary: CV250; CV300; CV409 ; CV900; CN105; CN900
Betaxolol
Primary: CV100
Secondary: CV409
Bisoprolol
Primary: CV100
Secondary: CV409
Carteolol
Primary: CV100
Secondary: CV409
Labetalol
Primary: CV100
Secondary: CV250; CV409
Metoprolol
Primary: CV100
Secondary: CV250; CV300; CV409; CV900; CN105 ; CN900
Nadolol
Primary: CV100
Secondary: CV250; CV300; CV409 ; CV900; CN105; CN900
Oxprenolol
Primary: CV100
Secondary: CV250; CV300; CV409; CV900; CN900
Penbutolol
Primary: CV100
Secondary: CV409
Pindolol
Primary: CV100
Secondary: CV250; CV409; CN900
Propranolol
Primary: CV100
Secondary: CV250; CV300; CV409; CV900; CN105 ; CN900
Sotalol
Primary: CV100
Secondary: CV250; CV300; CV409 ; CV900; CN900
Timolol
Primary: CV100
Secondary: CV250; CV300; CV409 ; CV900; CN105; CN900; OP111
Commonly used brand name(s): Apo-Atenolol2; Apo-Metoprolol7; Apo-Metoprolol (Type L)7; Apo-Propranolol12; Apo-Timol14; Betaloc7; Betaloc Durules7; Betapace13; Blocadren14; Cartrol5; Corgard8; Detensol12; Inderal12; Inderal LA12; Kerlone3; Levatol10; Lopresor7; Lopresor SR7; Lopressor7; Monitan1; Normodyne6; Novo-Atenol2; Novo-Pindol11; Novo-Timol14; Novometoprol7; Novopranol12; Nu-Metop7; Sectral1; Slow-Trasicor9; Sotacor13; Syn-Nadolol8; Syn-Pindolol11; Tenormin2; Toprol-XL7; Trandate6; Trasicor9; Visken11; Zebeta4; pms Propranolol12.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
*Not commercially available in the U.S.
†Not commercially available in Canada.
Category:
Note: All of the beta-adrenergic blocking agents have similar pharmacologic actions; however, clinical uses among specific agents may vary because of pharmacologic or pharmacokinetic differences, availability of specific testing, and/or availability of clinical-use data.
Antiadrenergic—Acebutolol; Atenolol; Betaxolol; Carteolol; Labetalol; Metoprolol; Nadolol; Oxprenolol; Penbutolol; Pindolol; Propranolol; Sotalol; Timolol;
Antianginal—Acebutolol; Atenolol; Carteolol; Labetalol; Metoprolol; Nadolol; Oxprenolol; Penbutolol; Pindolol; Propranolol; Sotalol; Timolol;
Antiarrhythmic—Acebutolol; Atenolol; Metoprolol; Nadolol; Oxprenolol; Propranolol; Sotalol; Timolol;
Antihypertensive—Acebutolol; Atenolol; Betaxolol; Bisoprolol; Carteolol; Labetalol; Metoprolol; Nadolol; Oxprenolol; Penbutolol; Pindolol; Propranolol; Sotalol; Timolol;
Hypertrophic cardiomyopathy therapy adjunct—Acebutolol; Atenolol; Metoprolol; Nadolol; Oxprenolol; Pindolol; Propranolol; Sotalol; Timolol;
Myocardial infarction prophylactic and therapy—Acebutolol; Atenolol; Metoprolol; Nadolol; Oxprenolol; Propranolol; Sotalol; Timolol;
Neuroleptic–induced akathisia therapy—Betaxolol; Metoprolol; Nadolol; Propranolol;
Pheochromocytoma therapy adjunct—Acebutolol; Atenolol; Labetalol; Metoprolol; Nadolol; Oxprenolol; Propranolol; Sotalol; Timolol;
Vascular headache prophylactic—Atenolol; Metoprolol; Nadolol; Propranolol; Timolol;
Antitremor agent—Acebutolol; Atenolol; Metoprolol; Nadolol; Oxprenolol; Pindolol; Propranolol; Sotalol; Timolol;
Antianxiety therapy adjunct—Acebutolol; Metoprolol; Oxprenolol; Propranolol; Sotalol; Timolol;
Thyrotoxicosis therapy adjunct—Acebutolol; Atenolol; Metoprolol; Nadolol; Oxprenolol; Propranolol; Sotalol; Timolol;
Antiglaucoma agent—Timolol;
Indications
Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.
Accepted
Angina pectoris, chronic (treatment)—[ Acebutolol], atenolol, [carteolol] , [labetalol]1 , metoprolol, nadolol, oxprenolol1 , [ penbutolol] , [pindolol] , propranolol, [sotalol] , and [timolol] are indicated in the treatment of classic angina pectoris, also referred to as ``effort-associated angina."" {42} {44} {47} {49}
Arrhythmias, cardiac (prophylaxis and treatment) {55} {56} {57} {58} {66} {173}—Propranolol is indicated in the control and correction of supraventricular arrhythmias, ventricular tachycardias, digitalis-induced tachyarrhythmias, and catecholamine-induced tachyarrhythmias during anesthesia (with extreme caution because of possible additive myocardial depression with general anesthesia). Propranolol by intravenous injection is recommended only in the treatment of cardiac arrhythmias that occur while the patient is unable to receive oral medication, or when a rapid and observable effect is desired. [Acebutolol]1 , [atenolol]1 , [ metoprolol]1 , [ nadolol]1 , oxprenolol1 , sotalol1 , and [ timolol]1 are also used for their antiarrhythmic effects, especially in supraventricular arrhythmias and ventricular tachycardias. Acebutolol1 is indicated in the control and correction of premature ventricular contractions.
Hypertension (treatment)—Acebutolol, atenolol, betaxolol, bisoprolol, carteolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, [sotalol] , and timolol are indicated in the treatment of hypertension when used alone or in combination with other antihypertensive medication. {32} {33} {35} {38} {40} {41} {42} {43} {44} {45} {46} {47} {48} {50}
—Parenteral labetalol is indicated for treatment of severe hypertension. {45} Intravenous metoprolol and propranolol are not recommended for the management of hypertensive emergencies. However, intravenous propranolol has proven useful in controlling hypertension during anesthesia and surgery.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.
Cardiomyopathy, hypertrophic (treatment)—[ Acebutolol]1, [ atenolol]1 , [metoprolol ]1 , [nadolol]1 , oxprenolol1 , [ pindolol]1 , propranolol, [ sotalol]1 , and [ timolol]1 are indicated in the management of angina, palpitations, and syncope associated with hypertrophic subaortic stenosis.
Myocardial infarction (treatment and prophylaxis)—[Acebutolol]1, atenolol1 , metoprolol, [ nadolol]1 , oxprenolol1 , propranolol, [sotalol]1 , and timolol are indicated in clinically stable patients recovering from an initial definite or suspected acute myocardial infarction in order to reduce cardiovascular mortality and to decrease the risk of reinfarction. {51} {52} {53} {54} {121} {159} {174}
Pheochromocytoma (treatment adjunct)—Propranolol is indicated in the management of symptoms of tachycardia due to excessive beta-receptor stimulation in pheochromocytoma. However, it should be used only after primary treatment with an alpha-adrenergic blocking agent (since use without concomitant alpha-blockade could lead to serious blood pressure elevation {01}). [Acebutolol ]1 , [atenolol]1 , [labetalol (with caution)]1 , [metoprolol]1 , [nadolol]1 , oxprenolol1 , [sotalol]1 , and [timolol]1 also may be used.
Headache, vascular (prophylaxis)—Propranolol {172} and timolol {157} {221} are indicated for reducing frequency and severity of migraine headaches but are not recommended for treatment of acute attacks. [ Atenolol]1 {176}, [ metoprolol]1 {176} {214}, and [nadolol]1 {176} {222} are also useful for prophylaxis of migraine. A beta-adrenergic blocking agent is the drug of choice for vascular headache prophylaxis. {02} {59} {60} {176}
Tremors (treatment) {61} {62} {63}—Propranolol is indicated in the treatment of essential, familial, and senile tremors. Propranolol also has been used to reduce the agitation and tremors of alcohol withdrawal. [ Acebutolol]1 , [ atenolol]1 , [metoprolol ]1 , [nadolol]1 , oxprenolol1 , [ pindolol]1 , [sotalol ]1 , and [timolol ]1 also may be used to treat tremors. Propranolol is the drug of choice for treatment of essential tremor {02}.
Anxiety (treatment adjunct)—[ Propranolol]1 is used to control the physical manifestations of anxiety such as tachycardia and tremor. {171} It is not particularly useful for chronic anxiety or panic attacks but is most useful for reducing anxiety and improving performance in specific stressful situations. [Acebutolol]1 , [metoprolol]1 , oxprenolol1 , [ sotalol]1 , and [ timolol]1 also have been used for this purpose.
Thyrotoxicosis (treatment adjunct)—[ Propranolol]1 has been effective in the short-term preoperative management of thyrotoxic crises (until thioamide therapy is effective) by reducing symptoms such as fever, tachycardia, and hyperkinesia. There is no effect on the hormone production of the thyroid. Abrupt withdrawal of beta-blocker treatment may provoke ``thyroid storm."" [Acebutolol ]1 , [atenolol]1 , [metoprolol]1 , [nadolol]1 , oxprenolol1 , [sotalol]1 , and [timolol]1 are also used for thyrotoxicosis.
Mitral valve prolapse syndrome (treatment)—[ Acebutolol]1, [ atenolol]1 , [metoprolol ]1 , [nadolol]1 , oxprenolol1 , [ pindolol]1 , [propranolol ]1 , [sotalol]1 , and [timolol]1 are used in the treatment of mitral valve prolapse syndrome {02}.
[Hypotension, controlled (induction and maintenance)]1—Parenteral labetalol is used to produce controlled hypotension during surgery to reduce bleeding into the surgical field.
[Glaucoma, open-angle (treatment) ]1—Timolol is used to lower intraocular pressure in the treatment of open-angle glaucoma {02}.
[Neuroleptic-induced akathisia (treatment) ]1—Propranolol may be used to relieve the somatic and subjective symptoms associated with neuroleptic-induced akathisia (NIA). {223} {224} {225} {226} {227} {228} {229} Betaxolol, metoprolol, and nadolol have also been used for NIA. {230} {231} {232} {233} {234} {235} {236}
1 Not included in Canadian product labeling.
Pharmacology/Pharmacokinetics
Table 1. Pharmacology/Pharmacokinetics {252}
| Drug |
Site of Effect |
Oral Absorption (%) |
Protein Binding |
Biotransformation |
Half-life (hr) |
Time to Peak Effect— Single dose (hr) |
Elimination (% un- changed) |
Removable by Hemodialysis |
|---|---|---|---|---|---|---|---|---|
| Acebutolol |
Beta-1 * |
70 † |
Low (26%) |
Hepatic ‡ |
3–4 ‡ |
2.5 ‡ |
30–40% Renal; 50–60% Biliary/fecal |
Yes |
| Atenolol |
Beta-1 * |
50–60 |
Very low to low (6–16%) |
Hepatic (minimal) |
6–7 § |
2–4 |
85–100% Renal |
Yes ** |
| Betaxolol |
Beta-1 * |
80–89 † |
Moderate (50–55%) |
Hepatic |
14–22 § |
3–4 |
>80% (15) Renal |
No |
| Bisoprolol |
Beta-1 |
80–90 |
Low (26–33%) |
Hepatic |
9–12 |
Renal (50) <2% Fecal |
No |
|
| Carteolol |
Beta-1; Beta-2 |
85 |
Low (23–30%) |
Hepatic (minimal) |
6 § |
1–3 |
Renal (50–70) |
? |
| Labetalol |
Beta-1; Beta-2 |
100 † |
Moderate (50%) |
Hepatic |
6–8 (oral); ~5.5 (IV) |
2–4 (oral); 5 min (IV) |
55–60% (<5) Renal; Biliary/fecal |
No |
| Metoprolol |
Beta-1 * |
95 † |
Low (12%) |
Hepatic |
3–7 § |
1–2 (oral— regular); 6–12 (oral— long-acting); 20 min (IV) |
Renal (3–10) |
No |
| Nadolol |
Beta-1; Beta-2 |
30 |
Very low to low (4 to 30%) |
None |
20–24 § |
4 |
Renal (70) |
Yes |
| Oxprenolol |
Beta-1; Beta-2 |
90 † |
High (80%) |
Hepatic |
1.3–1.5 |
? |
Renal (<5) |
? |
| Penbutolol |
Beta-1; Beta-2 |
100 |
High to very high (80–98%) |
Hepatic |
5 § |
1.5–3 |
90% (0) Renal |
No |
| Pindolol |
Beta-1; Beta-2 |
90–100 |
Moderate (40%) |
Hepatic |
3–4 § |
1–2 |
Renal (40) |
? |
| Propranolol |
Beta-1; Beta-2 |
90 † |
Very high (93%) |
Hepatic |
3–5 |
1–1.5 |
Renal (<1) |
No |
| Sotalol |
Beta-1; Beta-2 |
> 80 |
None |
Hepatic |
7–18 § |
2–3 |
Renal (75) |
Yes |
| Timolol |
Beta-1; Beta-2 |
90 † |
Very low (<10%) |
Hepatic |
4 |
1–2 |
Renal (20); Fecal |
No |
† First-pass metabolism results in a decrease (usually significant) in bioavailability.
Acebutolol—The effect is not reduced because of the active metabolite. Bioavailability of acebutolol may be increased 2-fold in the elderly because of reduced first-pass metabolism and renal function.
Betaxolol—First-pass effect is small {40}.
‡ Acebutolol—Major metabolite (diacetolol) is pharmacologically active and even more cardioselective than acebutolol; time to peak effect is 3.5 hours {19}; the half-life of diacetolol is 8 to 13 hours.
§ Atenolol—Increased to 16–27 hours or more in patients with renal function impairment (up to 144 hours when severe {02}).
Betaxolol—Increased by approximately 33% in hepatic function impairment, but clearance unchanged {40}.
—Approximately doubled in renal function impairment; dosage reduction necessary {40}.
Carteolol—Prolonged in renal failure {38} {70}.
Metoprolol—No change in renal failure.
Nadolol—Increased in renal failure.
Penbutolol—Increased in renal failure {36}.
Pindolol—Varies from 2.5 to more than 30 hours in patients with hepatic function impairment.
—Increased to 3 to 11.5 hours in patients with renal function impairment.
—Increased to an average of 7 hours (and as high as 15 hours) in the elderly.
Sotalol—Increased in renal failure. {35}
** Atenolol—Patients should receive 50 mg of atenolol after each dialysis and remain under supervision since marked hypotension may occur.
Physicochemical characteristics:
Molecular weight—
Acebutolol: 336.43
Atenolol: 266.34
Betaxolol hydrochloride: 343.89
Bisoprolol fumarate: 766.97 {237}
Carteolol hydrochloride: 328.84
Labetalol hydrochloride: 364.87
Metoprolol succinate: 652.83 {237}
Metoprolol tartrate: 684.82
Nadolol: 309.40
Oxprenolol hydrochloride: 301.81
Penbutolol sulfate: 680.94
Pindolol: 248.32
Propranolol hydrochloride: 295.81
Sotalol hydrochloride: 308.82
Timolol maleate: 432.49
pKa—
Acebutolol: 9.20 {07}
Carteolol: 9.74 {23}
Labetalol: 9.45 {07}
Metoprolol: 9.68
Nadolol: 9.67
Penbutolol: 9.3 {24}
Timolol: Approximately 9 in water at 25 °C
Lipid solubility
Acebutolol: Low
Atenolol: Very {02} low (log partition coefficient for octanol/water=0.23)
Bisoprolol: Moderate (equally hydrophilic and lipophilic) {41}
Carteolol: Low {23}
Labetalol: Low
Metoprolol: Moderate
Nadolol: Low
Oxprenolol: Moderate
Penbutolol: Moderate {27}
Pindolol: Moderate
Propranolol: High
Sotalol: Low {14}
Timolol: Moderate
Mechanism of action/Effect:
Beta-adrenergic blocking agents block the agonistic effect of the sympathetic neurotransmitters by competing for receptor binding sites. When they predominantly block the beta-1 receptors in cardiac tissue, they are said to be cardioselective. When they block both beta-1 receptors and beta-2 receptors (primarily located in tissues other than cardiac), they are said to be nonselective. In general, so-called cardioselective beta-adrenergic blocking agents are relatively cardioselective—at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases.
Some beta-adrenergic blocking agents also have intrinsic sympathomimetic activity (ISA or partial agonist activity), which is the ability to cause weak stimulation of beta-adrenergic receptors while simultaneously blocking the effect of endogenous catecholamines; {175} however, the significance of this property has not been established. {175} Possession of ISA theoretically may result in fewer adverse effects related to unopposed beta blockade (e.g., bradycardia, heart block, bronchoconstriction, peripheral vascular constriction), but studies have not proven clinical benefit. Pindolol exhibits the most ISA of the beta-adrenergic blocking agents currently available; carteolol {26} {29}, oxprenolol, and penbutolol {26} {29} have moderate ISA; acebutolol has mild to moderate ISA; and the other members of the group have little, if any, such activity {40}.
Propranolol possesses moderate membrane-stabilizing (quinidine-like) activity; acebutolol, betaxolol {40}, metoprolol, and oxprenolol have slight activity. The other beta-adrenergic blocking agents of this group show little, if any, such activity {22}. At one time membrane-stabilizing activity was thought to be related to the antiarrhythmic effect, but it is no longer considered to be significant because it occurs only at very high (much greater than therapeutic) doses. {175}
Antianginal:
Reduction in myocardial oxygen demand through negative chronotropic and inotropic effects. {175}
Antiarrhythmic:
May involve beta-blockade–induced reduction in the rate of spontaneous firing of sinus and ectopic pacemakers and slowing of atrioventricular (AV) nodal conduction. {175} In the Vaughan Williams classification of antiarrhythmics, beta-adrenergic blocking agents are considered to be class II agents {01} {175}.
Antihypertensive:
The precise mechanism of antihypertensive effect is not known. {175} Possible mechanisms include reduced cardiac output, decreased sympathetic outflow to peripheral vasculature, and inhibition of renin release by the kidneys {01} {02} {175}; with labetalol, may also be related to reduced peripheral vascular resistance as a result of alpha-adrenergic blockade.
Hypertrophic cardiomyopathy therapy adjunct:
Reduction of elevated outflow pressure gradient, which is exacerbated by beta-receptor stimulation.
Myocardial infarction therapy and prophylactic:
Possible reduction in severity of myocardial ischemia by decrease of myocardial oxygen requirements; postinfarction mortality may also be reduced through an antiarrhythmic action.
Vascular headache prophylactic:
Involves several mechanisms, including prevention of arterial dilation through beta-blockade, blockade of catecholamine-induced platelet aggregation and lipolysis, reduction of platelet adhesiveness, prevention of coagulation factor elevation during epinephrine release, promotion of oxygen release to tissues, and inhibition of renin secretion. {176}
Antitremor agent:
Precise mechanism not known, but antitremor effect may be mediated predominantly by peripheral beta-2 receptor mechanisms. {61} {62}
Antianxiety therapy adjunct:
Precise mechanism unknown; however, thought to involve improvement of somatic symptoms secondary to beta-blockade. {171}
Thyrotoxicosis therapy adjunct:
Unknown, but probably related to reduction of symptoms such as tremor, tachycardia, and elevated blood pressure {02} caused by increased sensitivity to catecholamines {08}.
Other actions/effects:
Labetalol also has selective alpha-1-adrenergic blocking effects, which lead to vasodilation, reduced peripheral vascular resistance, and postural hypotension.
Precautions to Consider
Note: In general, because of the similarity of effect and because the cardioselectivity of beta-1 blockers is relative, the same precautions, especially drug interactions and medical problems, apply to all beta-adrenergic blocking agents.
Carcinogenicity/Tumorigenicity
Acebutolol—Studies in rats and mice given up to 300 mg per kg of body weight (mg/kg) per day (equivalent to 15 times the maximum recommended human dose) found no evidence of carcinogenicity. Diacetolol, the major metabolite, also did not produce evidence of carcinogenicity in rats given up to 1800 mg/kg per day {01} {39} {158}.
Atenolol—Two 18- to 24-month studies in rats and one study for up to 18 months in mice given up to 150 times the maximum recommended human antihypertensive dose found no evidence of carcinogenicity. {48} However, a 24-month study in rats given up to 750 times the maximum recommended human antihypertensive dose revealed increased incidences of benign adrenal medullary tumors in males and females, mammary fibroadenomas in females, and anterior pituitary adenomas and thyroid parafollicular cell carcinomas in males. {48}
Betaxolol—Studies in mice given up to 60 mg/kg per day orally (up to 90 times the maximum recommended human dose based on 60-kg body weight) and in rats given up to 48 mg/kg per day orally (up to 72 times the maximum recommended human dose) found no evidence of carcinogenicity {40} {50}.
Bisoprolol—Studies in mice and rats given 625 and 312 times, respectively, the maximum recommended human dose by weight found no evidence of carcinogenicity. {41}
Carteolol—A 2-year study in rats and mice given 280 times the maximum recommended human dose (10 mg per 70 kg of body weight per day) found no evidence of carcinogenicity {38} {109}.
Labetalol—Studies for 18 months in mice and 2 years in rats found no evidence of carcinogenicity. {46}
Metoprolol—A 1-year study in dogs given up to 105 mg/kg per day orally, a 2-year study in rats given up to 800 mg/kg per day orally, and a 21-month study in mice given up to 750 mg/kg per day orally found no evidence of carcinogenicity, although the incidence of small benign adenomas of the lung was higher in the treated female mice. {159} A repeat of the 21-month study in mice found no increased incidence of any type of tumor. {159}
Nadolol—A 2-year study in rats and mice found no evidence of carcinogenicity. {42}
Oxprenolol—Long-term studies in mice and rats found no evidence of carcinogenicity.
Penbutolol—A 21-month study in mice and a 2-year study in rats at doses up to 500 times the maximum recommended human dose found no evidence of carcinogenicity {36}.
Pindolol—Two-year studies in rats and mice found no evidence of carcinogenicity at doses as high as 50 and 100 times, respectively, the maximum recommended human dose. {120}
Propranolol—Eighteen-month studies in rats and mice given up to 150 mg/kg per day found no evidence of carcinogenicity. {47}
Timolol—A 2-year study found an increased incidence of adrenal pheochromocytomas in male rats given 300 times (but not 25 or 80 times) the maximum recommended human dose. {157} Another study found an increased incidence of benign and malignant pulmonary tumors and benign uterine polyps in female mice given 500 (but not 5 or 50) mg/kg per day and an increase in mammary adenocarcinomas associated with elevations in serum prolactin at 500 mg/kg per day. {157}
Mutagenicity
Acebutolol—Ames mutagenicity studies with acebutolol and diacetolol were negative. {158}
Atenolol—Mutagenicity studies were negative. {48}
Betaxolol—Betaxolol was not found to be mutagenic in a variety of in vitro and in vivo bacterial and mammalian cell assays {40} {50}.
Bisoprolol—Bisoprolol was not found to be mutagenic in a variety of in vitro and in vivo assays. {41}
Carteolol—Carteolol was not found to be mutagenic in the Ames test, recombinant (rec)-assay, in vivo cytogenetics tests, and dominant lethal assay {38} {109}.
Labetalol—Labetalol was not found to be mutagenic in dominant lethal assays in rats and mice or in modified Ames tests. {46}
Metoprolol—Metoprolol was not found to be mutagenic in several tests, including a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella /mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei. {159}
Penbutolol—Penbutolol was not found to be mutagenic in the Salmonella mutagenicity test (Ames test), the point mutation induction test (Saccharomyces ), or the micronucleus test. {36}
Timolol—In vivo (mouse) and in vitro mutagenicity studies were negative; {157} in Ames tests, some changes were seen, but not enough to make the test positive. {157}
Pregnancy/Reproduction
Fertility—
Acebutolol: No adverse effect on fertility was observed in male or female rats given up to 240 mg/kg per day of acebutolol and 1000 mg/kg per day of diacetolol. {158}
Atenolol: No adverse effect on fertility was observed in male or female rats given 100 times the maximum recommended human dose. {44}
Betaxolol: No adverse effect on fertility or mating performance was observed in male or female rats given 380 times the maximum recommended human dose. {50}
Bisoprolol: No adverse effect on fertility was observed in rats given 375 times the maximum recommended human dose by weight. {41}
Carteolol: No adverse effect on fertility was observed in male or female rats and mice given 1052 times the maximum recommended human dose. {109}
Metoprolol: No adverse effect on fertility was observed in rats given up to 55.5 times the maximum human daily dose of 450 mg. {159}
Nadolol: No adverse effect on fertility was observed in rats given nadolol. {42}
Pindolol: Mortality and decreased weight gain were observed in male rats given 100 mg/kg per day. Decreased mating was associated with atrophy and/or decreased spermatogenesis at 30 mg/kg per day. Mating behavior decreased and offspring mortality increased in females given 100 mg/kg per day and 30 mg/kg per day. {120} In addition, there was an increase in prenatal mortality at a dose of 10 mg/kg per day, although there was not a clear dose-response relationship. {120} In females necropsied on the 15th day of gestation, an increased resorption rate was observed at a dose of 100 mg/kg per day. {120}
Propranolol: No adverse effect on fertility was observed in animal studies. {47}
Timolol: No adverse effect on fertility was observed in male or female rats at doses up to 125 times the maximum recommended human dose. {157}
Pregnancy—
Beta-adrenergic blocking agents cross the placenta. {74} The safety of these agents in pregnancy is not fully established. {74} {93} Fetal and neonatal bradycardia, hypotension, hypoglycemia, and respiratory depression have been reported with administration of a cardioselective or a noncardioselective beta-adrenergic blocking agent to pregnant women. {32} {34} {46} {82} {83} {84} {85} {86} {88} {89} {92} {158} In addition, intrauterine growth retardation has been reported rarely with atenolol and nadolol. {86} {87} {110} {253} However, other reports seem to indicate successful treatment of maternal hypertension during pregnancy with no apparent effects on the fetus or neonate {75} {76} {77} {78} {79} {80} {81} {91} {94}.
Acebutolol
Acebutolol was not teratogenic in rats or rabbits given up to 31.5 and 6.8 times, respectively, the maximum recommended therapeutic dose in a 60-kg human. {158} However, slight fetal growth retardation occurred in rabbits given 135 mg/kg per day. {158} An elevation in postimplantation loss was seen in rabbit dams given 450 mg/kg per day of diacetolol. {158}
FDA Pregnancy Category B. {158}
Atenolol
Dose-related increases in embryo/fetal resorptions were observed in rats given atenolol in doses greater than or equal to 25 times the maximum recommended human antihypertensive dose. {44} This effect was not seen in rabbits given 12.5 times the maximum recommended human antihypertensive dose. {44}
FDA Pregnancy Category D. {253}
Betaxolol
Administration of betaxolol to pregnant rats in doses up to 600 times the maximum recommended human dose was associated with increased postimplantation loss, reduced litter size and weight, and increased incidence of skeletal and visceral abnormalities, which may or may not have resulted from maternal drug toxicity. {50} In another study, betaxolol, given at doses of up to 300 times the maximum recommended human dose, was associated with an increase in resorptions, but no teratogenicity. {50} Administration of 380 times the maximum recommended human dose caused a marked increase in total litter loss within 4 days postpartum. {50} A marked increase in postimplantation loss, but no teratogenicity, was observed in pregnant rabbits given up to 54 times the maximum recommended human dose. {50}
FDA Pregnancy Category C. {50}
Bisoprolol
Bisoprolol was not teratogenic in rats or rabbits given 375 and 31 times, respectively, the maximum recommended human dose by weight. {41} However, there was an increase in late resorptions in rats given bisoprolol at doses 125 times the maximum recommended human dose by weight. {41}
FDA Pregnancy Category C. {41}
Carteolol
Increased resorptions and decreased fetal weights occurred in rabbits and rats given maternally toxic doses 1052 and 5264 times, respectively, the maximum recommended human dose. {109} A dose-related increase in fetal wavy ribs was seen in pregnant rats given 212 times the maximum recommended human dose. {109} However, this was not observed in mice given up to 1052 times the maximum recommended human dose. {109}
FDA Pregnancy Category C. {109}
Labetalol
Teratogenic effects were not seen in rats and rabbits given 6 and 4 times, respectively, the maximum recommended human dose. {46} Administration of labetalol to rats during late gestation through weaning at doses up to 2 to 4 times the maximum recommended human dose resulted in decreased neonatal survival. {46}
FDA Pregnancy Category C. {46}
Metoprolol
Increased postimplantation loss and decreased neonatal survival were observed in rats given up to 55.5 times the maximum human daily dose of 450 mg. {159} No evidence of teratogenicity was seen in animal studies. {159}
FDA Pregnancy Category C. {159}
Nadolol
Evidence of embryotoxicity and fetotoxicity was found in rabbits given up to 10 times the maximum indicated human dose. {42} However, these effects were not seen in rats or hamsters. {42} Teratogenic effects were not seen in any of these species. {42}
FDA Pregnancy Category C. {42}
Pindolol
No evidence of embryotoxicity or teratogenicity was found in rats and rabbits given doses exceeding 100 times the maximum recommended human dose. {120}
FDA Pregnancy Category B. {120}
Propranolol
Embryotoxicity occurred in animals given 10 times the maximum recommended human dose. {47}
FDA Pregnancy Category C. {47}
Timolol
No evidence of fetal malformations was observed in mice and rabbits given up to 50 times the maximum recommended human dose. {157} In rats, at similar doses, delayed fetal ossification was observed, but there were no adverse effects on postnatal development of offspring. {157} Increased fetal resorptions were seen in mice and rabbits given 1000 and 100 times, respectively, the maximum recommended human dose. {157}
FDA Pregnancy Category C. {157}
Breast-feeding
Acebutolol (and diacetolol) {96} {158}, atenolol {44} {97} {98} {99} {100}, betaxolol {50}, labetalol {46} {101}, metoprolol {98} {100} {102} {103} {159}, nadolol {42} {104}, oxprenolol {106} {107}, pindolol {120}, propranolol {47} {99} {105}, sotalol {108}, and timolol {106} are distributed into breast milk. It is not known whether bisoprolol {41}, carteolol {109}, and penbutolol are distributed into breast milk. Cyanosis and bradycardia resulted from maternal therapy with atenolol in one breast-fed neonate; {97} hypotension, bradycardia, and transient tachypnea resulted from maternal acebutolol therapy in another. {96} Adverse neonatal effects resulting from maternal ingestion of other beta-adrenergic blocking agents have not been reported. Although the risk appears to be small, breast-fed infants should be monitored for signs of beta-adrenergic blockade, especially bradycardia, hypotension, respiratory distress, and hypoglycemia {04} {108}.
Pediatrics
Use of beta-adrenergic blocking agents in a limited number of neonates, infants, and children has not demonstrated pediatrics-specific problems that would limit the usefulness of these medications in children. {111} {112} {113} {114} {115} {116} {117} {118} {119}
Geriatrics
Beta-adrenergic blocking agents have been used safely and efficaciously in elderly patients. {41} {121} {153} {155} {213} However, elderly patients may be more susceptible to some adverse effects of these agents. Beta-adrenergic blocking agents have been reported to cause or exacerbate mental impairment in the elderly. {151} However, other evidence suggests that these agents do not produce significant lethargy or impairment in mental performance. {154} It is possible that the likelihood of central nervous system (CNS) effects may be related to lipophilicity of the beta-adrenergic blocking agent. {156} However, this relationship has not been conclusively established. {151} {154}
Elderly patients are more likely to have age-related peripheral vascular disease, which may require caution in patients receiving beta-adrenergic blocking agents. In addition, the risk of beta-blocker–induced hypothermia may be increased in elderly patients.
Surgical
Recent evidence suggests that withdrawal of antihypertensive therapy prior to surgery may be undesirable. However, the anesthesiologist must be aware of such therapy. {247}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Information concerning interactions between beta-adrenergic blocking agents and other medications is still limited. Therefore, some of the following potential interactions are stated for cautionary reference until additional information is available.
» Allergen immunotherapy or
» Allergenic extracts for skin testing (use of these agents in patients taking beta-adrenergic blocking agents may increase the potential for serious systemic reaction or anaphylaxis; {181} {182} {183} {184} if possible, another medication should be substituted for a beta-adrenergic blocking agent in patients on allergen immunotherapy; {182} allergen immunotherapy for conditions that are not life-threatening should be avoided in patients who cannot discontinue beta-adrenergic blocking agent therapy {20})
Amiodarone (concurrent administration with beta-adrenergic blocking agents may result in additive depressant effects on conduction and negative inotropic effects, especially in patients with underlying sinus node dysfunction or atrioventricular node dysfunction {244} {245})
Anesthetics, hydrocarbon inhalation,{123} such as:
Chloroform
Cyclopropane
Enflurane
» Halothane
Isoflurane
Methoxyflurane
Trichloroethylene (concurrent use with beta-adrenergic blocking agents may increase the risk of myocardial depression and hypotension because beta-blockade reduces the ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli {122} {123}; if necessary to reverse the effects of beta-adrenergic blocking agents during surgery, agonists such as dobutamine, dopamine, isoproterenol, or norepinephrine may be used but should be administered with caution. In patients scheduled for major surgery, most practitioners believe the risk of precipitating myocardial infarction following abrupt cessation of beta-adrenergic blocking agent therapy prior to surgery outweighs the risks of continuing therapy while compensating for medication effects by anesthetic techniques {251})
(high concentrations of halothane [3% or above] or high concentrations of other halogenated hydrocarbon anesthetics should not be used when labetalol is used to produce controlled hypotension during anesthesia because of the risk of excessive hypotension, large reduction in cardiac output, and increase in central venous pressure)
» Antidiabetic agents, oral or
» Insulin (concurrent use with beta-adrenergic blocking agents may impair glycemic control; {124} {125} {126} there may be an increased risk of hyperglycemia secondary to a slight deterioration in carbohydrate metabolism and peripheral insulin resistance; {125} {126} beta-adrenergic blocking agents may impair recovery from hypoglycemia in diabetics because they block the effects of catecholamines, which promote glycogenolysis and mobilize glucose in response to hypoglycemia; {41} {124} {127} {169} beta-adrenergic blocking agents also may mask certain symptoms of developing hypoglycemia such as increases in pulse rate and blood pressure, {127} {148} thus complicating patient monitoring; labetalol and selective or relatively selective beta-adrenergic blocking agents, such as acebutolol, atenolol, betaxolol, bisoprolol, or metoprolol, may cause fewer problems with blood glucose levels, especially at lower dosages, although they may still mask the symptoms of hypoglycemia)
Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin{128}{129}{130} (NSAIDs may reduce the antihypertensive effects of beta-adrenergic blocking agents, possibly by inhibiting renal prostaglandin synthesis and/or causing sodium and fluid retention {32} {150})
Beta-adrenergic blocking agents, ophthalmic (if significant systemic absorption of the ophthalmic beta-adrenergic blocking agent occurs, concurrent use may result in an additive effect either on intraocular pressure or on systemic effects of beta-blockade)
» Calcium channel blocking agents or
» Clonidine or
Diazoxide or
» Guanabenz or{17}
Reserpine or
Hypotension-producing medications, other, (See Appendix II ) with the exception of monoamine oxidase (MAO) inhibitors (blood pressure control may be impaired when clonidine or guanabenz is used concurrently with a beta-adrenergic blocking agent; potentiation of antihypertensive effect should be anticipated when other hypotension-producing medications are used concurrently; although combinations of antihypertensive agents and/or diuretics are often used for therapeutic advantage, dosage adjustment may be needed when any hypotension-producing medication is added to or withdrawn from a regimen including a beta-adrenergic blocking agent)
(symptomatic bradycardia, with or without serious hemodynamic effects, has been reported during concurrent use of diltiazem or verapamil with systemic beta-adrenergic blocking agents; {131} {132} {134} {135} {136} although these effects may occur in the absence of overt pre-existing sinoatrial disease, {131} older patients and patients with left ventricular dysfunction or sinoatrial or atrioventricular conduction abnormalities may be at increased risk; {132} concurrent use of nifedipine with beta-adrenergic blocking agents, although usually well tolerated, may produce excessive hypotension and in rare cases may increase the possibility of congestive heart failure {137} {138} {139})
(calcium channel blocking agents may decrease the hepatic metabolism of propranolol, metoprolol, and possibly other beta-adrenergic blocking agents with substantial hepatic biotransformation; although the clinical significance of this effect appears to be minimal, caution is warranted given the potential for additive cardiodepressant effects during concurrent use {133} {140} {141} {142})
(concurrent use of diazoxide with beta-adrenergic blocking agents prevents the tachycardia produced by diazoxide but may also increase the hypotensive effects)
(concurrent use of reserpine with beta-adrenergic blocking agents may result in additive and possibly excessive beta-adrenergic blockade; close observation is recommended since bradycardia and hypotension may occur)
Cimetidine (cimetidine may reduce the clearance of hepatically metabolized beta-adrenergic blocking agents, resulting in elevations of plasma concentrations {143} {144} {160} {161})
» Cocaine{21} (cocaine may inhibit the therapeutic effects of beta-adrenergic blocking agents)
(although beta-adrenergic blocking agents are recommended to reduce tachycardia, myocardial ischemia, and/or arrhythmias induced by cocaine, concurrent use of a beta-adrenergic blocking agent with cocaine may increase the risk of hypertension, excessive bradycardia, and possibly heart block, because beta-adrenergic blockade may leave cocaine's alpha-adrenergic activity unopposed; {145} {146} the risk of these adverse effects may be decreased with labetalol because labetalol also has some alpha-adrenergic blocking activity, although its beta-adrenergic blocking activity predominates {146} {147})
Contrast media, iodinated (concurrent use of beta-adrenergic blocking agents with intravenous contrast media may increase the risk of moderate to severe anaphylaxis; {170} {180} an anaphylactic event may be refractory to treatment {170} {179} {180})
Estrogens (concurrent use may decrease the antihypertensive effect of beta-adrenergic blocking agents because estrogen-induced fluid retention may lead to increased blood pressure {03})
Fentanyl and derivatives (preoperative chronic use of systemic beta-adrenergic blocking agents may decrease the frequency and/or severity of hypertensive responses to surgery, especially during sternotomy and sternal spread in cardiac or coronary artery surgery; however, chronic preoperative use of systemic beta-adrenergic blocking agents may also increase the risk of initial bradycardia following induction doses of fentanyl or any of its derivatives {149})
Flecainide (although there have been no reports of adverse effects during concurrent administration of flecainide with the beta-adrenergic blocking agents, caution is recommended because of the potential for additive negative inotropic effects, especially in patients with compromised left ventricular function [ejection fraction < 30%] {246})
Lidocaine (concurrent use with beta-adrenergic blocking agents may reduce lidocaine elimination and increase the risk of lidocaine toxicity because of reduced hepatic blood flow; lidocaine dosage should be adjusted on the basis of serum lidocaine concentrations {02} {09} {36} {67})
Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline (significant hypertension theoretically may occur up to 14 days following discontinuation of the MAO inhibitor; although sufficient clinical reports are lacking, concurrent use with beta-adrenergic blocking agents is not recommended)
Neuromuscular blocking agents, nondepolarizing (beta-adrenergic blocking agents may potentiate and prolong the action of nondepolarizing neuromuscular blocking agents when used concurrently; careful postoperative monitoring of the patient may be necessary following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade)
Nicotine chewing gum or
Smoking deterrents, other or
Smoking, tobacco, cessation of (smoking cessation may increase therapeutic effects of propranolol by decreasing metabolism, thereby increasing serum concentrations; dosage adjustments may be necessary {163})
Nitroglycerin (labetalol reduces the reflex tachycardia caused by nitroglycerin and may increase the antihypertensive effect)
Phenothiazines{238}{239}{240} (concurrent use with beta-adrenergic blocking agents results in an increased plasma concentration of each medication)
Phenytoin (concurrent use of propranolol, and probably other beta-adrenergic blocking agents, with intravenous phenytoin may produce additive cardiac depressant effects)
Phenoxybenzamine or
Phentolamine (concurrent use with labetalol may result in additive alpha-adrenergic blocking effects)
Propafenone (concurrent use with metoprolol or propranolol may result in significant increases in plasma concentrations and half-life of propranolol and metoprolol, without affecting plasma propafenone concentrations; dosage reduction of the beta-adrenergic blocking agent may be necessary {241} {242})
» Sympathomimetics (concurrent use of beta-adrenergic blocking agents with sympathomimetic amines having beta-adrenergic stimulant activity may result in mutual inhibition of therapeutic effects; for sympathomimetic agents with beta-adrenergic effects, beta-blockade may antagonize beta-1-adrenergic cardiac effects [dobutamine, dopamine] or the beta-2-adrenergic bronchodilating effect [albuterol, ethylnorepinephrine, isoetharine, isoproterenol, metaproterenol, terbutaline] or both [isoproterenol]; use of a cardioselective beta-1-adrenergic blocker [atenolol, betaxolol, or metoprolol] or labetalol [because of its alpha-blocking activity] at low doses may prevent antagonism of the bronchodilating effect)
(sympathomimetic agents with both alpha- and beta-adrenergic effects [amphetamines, ephedrine, epinephrine, metaraminol, norepinephrine, phenylephrine, pseudoephedrine], beta-blockade may result in unopposed alpha-adrenergic activity with a risk of hypertension and excessive bradycardia and possible heart block; risk should be less with labetalol because of its alpha-blocking activity; beta-blockade also antagonizes the bronchodilating effect of ephedrine and epinephrine)
» Xanthines, especially aminophylline or theophylline{243} (concurrent use with beta-adrenergic blocking agents may result in mutual inhibition of therapeutic effects; in addition, concurrent use with the xanthines [except dyphylline] may decrease xanthine clearance, especially in patients with increased theophylline clearance induced by smoking; {164} concurrent use requires careful monitoring)
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With diagnostic test results
Amphetamine determinations, urinary (labetalol may produce false-positive results when commercially available assay methods [thin-layer chromatographic assay or radioenzymatic assay] are used; during labetalol therapy, positive results should be confirmed with more specific methods, such as a gas chromatographic-mass spectrometer technique {34} {45})
Catecholamine determinations (urinary concentrations of catecholamines and/or their metabolites [metanephrine, normetanephrine, vanillylmandelic acid] may be falsely increased by labetalol when measured by fluorimetric or photometric methods; a specific method, such as high performance liquid chromatography assay with solid phase extraction, should be used instead {34} {45})
Glaucoma screening test (may be interfered with by systemic beta-blockade, which reduces intraocular pressure {38})
Radionuclide ventriculography (beta-adrenergic blocking agents may blunt the exercise-induced changes in cardiac function in the evaluation of coronary artery disease by decreasing heart rate {02})
With physiology/laboratory test values
Alkaline phosphatase, serum and
Lactate dehydrogenase (LDH), serum and
Transaminases, serum{41} (may be increased by acebutolol, {32} labetalol, or metoprolol {49} {159}; it is recommended that labetalol be withdrawn if jaundice or laboratory signs of hepatic function impairment occur)
Antinuclear antibody (ANA) titers (may be increased by beta-adrenergic blocking agents {40}; dose-related)
Blood glucose concentrations (nonselective beta-adrenergic blocking agents impair glycogenolysis and the hyperglycemic response to endogenous epinephrine, leading to persistence of hypoglycemia and delayed recovery of blood glucose to normal levels, especially in diabetics; studies have shown no such effect in resting nondiabetics with therapeutic doses; beta-adrenergic blocking agents, especially nonselective agents, decrease the release of insulin in response to hyperglycemia; effects on blood glucose may be less likely with labetalol or cardioselective agents such as acebutolol, betaxolol, atenolol, and metoprolol, especially at lower doses)
Blood urea nitrogen (BUN) (usually in patients with severe heart disease) and
Potassium concentrations, serum and
Uric acid concentrations, serum (may be increased)
Lipoproteins, serum and
Triglycerides, serum (concentrations may be increased)
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Note: In general, because of the similarity of effect and because the cardioselectivity of beta-1 blockers is relative, the same precautions apply to all beta-adrenergic blocking agents.
Except under special circumstances, this medication should not be used when the following medical problems exist:
For all indications:
» Cardiac failure, overt or
» Cardiogenic shock or
» Heart block, 2nd- or 3rd-degree atrioventricular (AV) block or
» Sinus bradycardia (heart rate less than 45 beats per minute) (risk of further myocardial depression; risk may be less with carteolol, labetalol, oxprenolol, penbutolol, and pindolol {02}; beta-adrenergic blocking agents may be used with extreme caution in some patients with cardiac failure {15} {177} {178} [e.g., high output failure associated with thyrotoxicosis {17} {185} {186}])
For use in myocardial infarction:
» Hypotension (patients dependent on sympathetic stimulation to maintain adequate cardiac output and blood pressure, such as patients with hypotension in the setting of myocardial infarction, may not benefit from beta-adrenergic blockade; {43} {157} {159} studies of beta-adrenergic blockade in the treatment of myocardial infarction excluded patients with systolic pressures less than 100 mm Hg {43} {157})
Risk-benefit should be considered when the following medical problems exist
For all beta-adrenergic blocking agents:
» Allergy, history of or
» Asthma, bronchial or
» Emphysema or nonallergenic bronchitis (beta-adrenergic blocking agents may promote bronchospasm and block the bronchodilating effect of epinephrine; cardioselective agents such as acebutolol, atenolol, {48} betaxolol, {50} bisoprolol, {41} and metoprolol, {159} or agents with ISA such as carteolol, oxprenolol, penbutolol, or pindolol are theoretically less likely to cause such effects when used at lower doses; labetalol may also pose less risk of bronchoconstriction; however, caution is necessary with all beta-adrenergic blocking agents)
(severity and duration of anaphylactic reactions to allergens and allergen immunotherapy may be increased in some patients being treated with beta-adrenergic blocking agents; if possible, another medication should be substituted for a beta-adrenergic blocking agent in patients receiving allergen immunotherapy, or, for conditions that are not life-threatening, allergen immunotherapy should be avoided in patients who cannot discontinue beta-adrenergic blocking agent therapy; caution is also recommended during skin testing in patients on beta-adrenergic blocking agents {20})
» Congestive heart failure (risk of further depression of myocardial contractility; {41} {44} {46} {48} {50} {109} {120} {157} labetalol and agents with ISA such as carteolol, oxprenolol, penbutolol, pindolol, and possibly acebutolol may theoretically be associated with less risk and may be used with caution in patients who are well-compensated)
» Diabetes mellitus (beta-adrenergic blocking agents may mask tachycardia associated with hypoglycemia, but not dizziness and sweating; beta-adrenergic blocking agents may adversely affect recovery from hypoglycemia {124} {127} {169} and impair peripheral circulation; these effects may theoretically be more likely with the noncardioselective agents {169} and less likely with labetalol and cardioselective agents)
Hepatic function impairment (metabolism of beta-adrenergic blocking agents that undergo hepatic metabolism may be decreased; patients with impaired hepatic function may require lower doses of beta-adrenergic blocking agents [exceptions are atenolol, betaxolol, {50} carteolol, {109} metoprolol (except in severe impairment), and nadolol, which require no dosage adjustment]; such reduction in dosage frequently applies to geriatric patients, many of whom have reduced hepatic function)
» Hyperthyroidism (beta-adrenergic blocking agents may mask tachycardic symptoms; abrupt withdrawal may intensify symptoms)
» Mental depression, or history of (although the association between beta-adrenergic blocking agents and depression is not fully established, {187} {188} {189} {190} these medications should be used cautiously in these patients {190})
Myasthenia gravis (beta-adrenergic blocking agents may potentiate a myasthenic condition, including muscle weakness and double vision {191} {192})
Pheochromocytoma (although labetalol is used to lower blood pressure, higher-than-usual doses may be required; paradoxical hypertensive responses to labetalol have been reported in a few patients; with other beta-adrenergic blocking agents, there is a risk of hypertension if effective alpha-adrenergic blockade is not achieved first {45})
Psoriasis (may be exacerbated {11} {12} {13})
Renal function impairment (may impair beta-adrenergic blocking agent clearance {17}; risk of reduced renal blood flow {17}; patients with impaired renal function may require reduced doses of beta-adrenergic blocking agents {40} [exceptions are labetalol, metoprolol, oxprenolol, penbutolol {30}, pindolol (unless impairment is severe), propranolol, and timolol, which require no dosage adjustment]; such reduction in dosage frequently applies to geriatric patients, many of whom have reduced renal function; specific dosage recommendations, where available, are included in the Dosage Forms section for the particular agent)
Sensitivity to the beta-blocker prescribed{40}
For all beta-adrenergic blocking agents except labetalol:
Raynaud's syndrome and other peripheral vascular diseases (beta-adrenergic blocking agents may reduce peripheral circulation and worsen these conditions; {41} cardioselective agents such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, or agents with ISA such as acebutolol, carteolol, oxprenolol, penbutolol, or pindolol are theoretically less likely to produce adverse effect)
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Blood cell counts and
Blood glucose concentrations (for diabetic patients) and
» Cardiac function monitoring and
Hepatic function determinations and
» Pulse rate determinations and
Renal function determinations (may be required at periodic intervals)
» Blood pressure and
» Electrocardiogram (ECG) and
» Heart rate (should be carefully monitored during intravenous administration)
» Blood pressure determinations (recommended at periodic intervals to monitor efficacy and safety of therapy in patients being treated for hypertension; selected patients may be trained to perform blood pressure measurements at home and report the results at regular physician visits)
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent
Bradycardia, symptomatic (dizziness)
bronchospasm (difficulty breathing and/or wheezing)
congestive heart failure (swelling of ankles, feet, and/or lower legs; shortness of breath)
mental depression
reduced peripheral circulation (cold hands and feet)—except labetalol
Note: Risk of bronchospasm or reduced peripheral circulation is theoretically reduced with acebutolol, atenolol, betaxolol, bisoprolol, carteolol, metoprolol, oxprenolol, penbutolol, or pindolol.
Mental depression is usually reversible and mild, but may progress to catatonia.
Incidence rare
Allergic reaction (skin rash)
arrhythmias (irregular heartbeat)
back pain or joint pain
chest pain
confusion —especially in the elderly
hallucinations
hepatotoxicity (dark urine, yellow eyes or skin)—for acebutolol, bisoprolol, or labetalol
leukopenia (fever, sore throat)
orthostatic hypotension (dizziness or lightheadedness when getting up from a lying or sitting position)
psoriasiform eruption (red, scaling, or crusted skin)
thrombocytopenia (unusual bleeding and bruising)
Note: Hepatotoxicity is usually reversible; however, hepatic necrosis and death have been reported with labetalol. {34}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Decreased sexual ability
drowsiness —especially with higher doses
trouble in sleeping
unusual tiredness or weakness
Incidence less frequent
Anxiety and/or nervousness
constipation
diarrhea
nasal congestion (stuffy nose)
nausea or vomiting
stomach discomfort
Incidence rare
Changes in taste
dry, sore eyes
frequent urination —for acebutolol or carteolol
itching of skin
nightmares and vivid dreams
numbness and/or tingling of fingers, toes, or skin, especially the scalp —for labetolol
Those indicating the need for medical attention if they occur after medication is discontinued
Arrhythmias (fast or irregular heartbeat)
chest pain
general feeling of discomfort, illness, or weakness
headache
shortness of breath, sudden
sweating
trembling
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Bradycardia
dizziness, severe, or fainting
hypotension
irregular heartbeat
difficulty breathing
bluish-colored fingernails or palms of hands
or seizures
Treatment of overdose
Decreased absorption—Gastric lavage {196} {198} {200} {204} and administration of activated charcoal. {193} {197} {202} {206} {210}
Specific treatment:
Atropine: May be administered for severe bradycardia in the presence of hypotension. {193} {194} {195} {201} {203} {209} {210} {211}
Diazepam or lorazepam {17}: May be used intravenously to treat associated seizures. {195} {206} {211}
Dobutamine, dopamine, epinephrine, norepinephrine, or isoproterenol {194} {195} {196} {197} {199} {201} {203}: May be administered for chronotropic and inotropic support and treatment of severe hypotension. However, the effects of sympathomimetic agents may be inhibited by the presence of significant beta-blockade. {194} {197} {209} Therefore, hypotension and ensuing pump failure may be refractory to treatment with catecholamines. {195} {196} {201} {203} {204} {209}
Glucagon: Glucagon has been used effectively in the treatment of bradycardia and hypotension in beta-adrenergic blocking agent overdose. {194} {195} {196} {200} {201} {202} {203} {206} Glucagon demonstrates major inotropic and less dramatic chronotropic effects. {194} {208} These effects appear to be independent of the beta-adrenergic receptor. {194} {197} {208} Therefore, glucagon may be an advantageous alternative treatment to reverse the hemodynamic depression of beta-adrenergic blocking agent overdose. {197}
Transvenous pacing: May be necessary for heart block. {195} {212}
Other therapy: May include furosemide or digitalis glycoside {44} {109} {157} for pulmonary edema {195} or cardiac failure {44}; or a beta-2 agonist such as isoproterenol and/or a theophylline derivative for bronchospasm {44} {109} {157}.
There is limited evidence that calcium chloride may be effective in improving myocardial contractility and hemodynamic status. {201} {205} {210} It is speculated that hypocalcemia resulting from beta-adrenergic blocking agent overdose may contribute to a decline in myocardial contractility. {210}
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Beta-adrenergic Blocking Agents (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to the beta-blocker prescribed
Pregnancy—Beta-adrenergic blocking agents cross the placenta; risk of hypoglycemia, respiratory depression, bradycardia, and hypotension in the fetus and neonate
Breast-feeding—Beta-adrenergic blocking agents pass into breast milk; bradycardia, cyanosis, hypotension, and tachypnea have been reported in breast-fed infants whose mothers ingested atenolol or acebutolol
Use in the elderly—Older patients may be more susceptible to some side/adverse effects; increased risk of beta-blocker–induced hypothermia
Other medications, especially allergen immunotherapy and allergenic extracts used for skin testing, oral antidiabetic agents, insulin, calcium channel blocking agents, clonidine, guanabenz, cocaine, MAO inhibitors, sympathomimetics, or xanthines
Other medical problems, especially overt cardiac failure, cardiogenic shock, 2nd- or 3rd- degree AV block, sinus bradycardia, hypotension (when used in myocardial infarction), history of allergy, bronchial asthma, emphysema or nonallergenic bronchitis, congestive heart failure, diabetes mellitus, hyperthyroidism, or mental depression
Proper use of this medication
Proper administration of extended-release dosage forms: Swallowing whole without crushing, breaking (except with metoprolol succinate), or chewing
Proper use of concentrated oral propranolol solution
Measuring with calibrated dropper
Mixing with liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce, and puddings; making sure entire dose is taken
Not storing after mixing
Checking pulse, if directed to do so by physician, and notifying physician if pulse falls below the rate designated by physician {267}
Taking medication at the same time(s) each day to maintain the therapeutic effect
» Importance of not missing doses, especially with schedules of one dose per day
» Proper dosing
Missed dose: Taking as soon as possible; not taking at all if within 4 hours of next scheduled dose (8 hours for atenolol, betaxolol, carteolol, labetalol, nadolol, penbutolol, sotalol, or extended-release oxprenolol or propranolol); not doubling doses
» Proper storage
For use as an antihypertensive
Possible need for control of weight and diet, especially sodium intake
» Compliance with therapy; patient may not experience symptoms of hypertension; importance of taking medication only as directed and keeping appointments with physician, even if feeling well
» Does not cure, but helps control hypertension; possible need for lifelong therapy; checking with physician before discontinuing medication; serious consequences of untreated hypertension
Precautions while using this medication
Making regular visits to physician to check progress
» Checking with physician before discontinuing medication; gradual dosage reduction may be necessary
Having enough medication on hand to get through weekends, holidays, and vacations; possibly carrying second written prescription for emergency use
Carrying medical identification card during therapy
» Caution if any kind of surgery (including dental surgery) or emergency treatment is required
» Diabetics: May mask signs and symptoms of hypoglycemia or may cause increased blood glucose concentrations or prolong hypoglycemia
» Caution when driving or doing things requiring alertness, because of possible drowsiness, dizziness, or lightheadedness
Caution during exposure to cold weather because of possible increased sensitivity to cold
» Caution against overexertion in response to decreased chest pain
Caution if any laboratory tests required; possible interference with test results
Patients with allergies to foods, medications, or stinging insect venom: Possible increase in severity of allergic reactions; checking with physician immediately if severe allergic reaction occurs {20}
For use as an antihypertensive
» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician
For oral labetalol only
» Caution when getting up suddenly from a lying or sitting position, especially during initiation of therapy or when dosage is increased
» Caution in using alcohol, while standing for long periods or exercising, and during hot weather because of enhanced orthostatic hypotensive effects
For parenteral labetalol only
» Lying down during injection and for up to 3 hours after getting injection, then getting up gradually
Side/adverse effects
Signs of potential side effects, especially bradycardia, breathing difficulty and/or wheezing, congestive heart failure, mental depression, reduced peripheral circulation, allergic reaction, arrhythmias, back pain or joint pain, chest pain, confusion, hallucinations, hepatotoxicity, leukopenia, psoriasiform eruption, thrombocytopenia, and withdrawal reaction
For labetalol: Transient scalp tingling may occur, usually at beginning of treatment
General Dosing Information
Although plasma concentrations of beta-adrenergic blocking agents can be ascertained, there is not always a predictable relationship between plasma concentration and pharmacological effects. Pharmacological effects have been observed when plasma concentrations were not discernible. Therefore, titration of dosage with measurement of heart rate and blood pressure is used to guide therapy.
In some patients, once-daily dosing is effective.
When beta-adrenergic blocking agent therapy is discontinued in patients concurrently receiving clonidine or guanabenz, the beta-adrenergic blocking agent should be gradually discontinued several days before the clonidine or guanabenz is gradually discontinued in order to avoid clonidine- or guanabenz-withdrawal hypertensive crisis.
For oral dosage forms only
When a beta-adrenergic blocking agent must be withdrawn from established therapy (especially in patients with ischemic heart disease), it is recommended that the dosage be reduced gradually to minimize risk of exacerbation of angina or development of myocardial infarction. Dosage reduction should occur over a period of approximately 2 weeks {159} {218} {219}. During this time the patient should avoid vigorous physical activity in order to minimize the danger of infarction or arrhythmias. {159} {218} {219} If signs of withdrawal (e.g., angina) occur, beta-adrenergic blocking agent therapy should be reinstated temporarily and then carefully withdrawn after the patient has stabilized. {159} {218} {219}
It is recommended that beta-adrenergic blocking agent therapy be withdrawn if drug-induced mental depression occurs.
Diet/Nutrition
Oral beta-adrenergic blocking agents may be taken either with food or on an empty stomach. Studies indicate that bioavailability of labetalol, propranolol, and possibly metoprolol may be enhanced by administration with food, which may slow the hepatic metabolism of the medication. Bioavailability of acebutolol, atenolol, nadolol, oxprenolol, penbutolol, and pindolol are not affected by food intake {17} {18} {40}. Concurrent food intake may slow carteolol absorption, but does not affect bioavailability {38}. Sotalol does not undergo significant first-pass metabolism. {220} Food, especially milk and milk products, may reduce the bioavailability of sotalol. {220}
Summary of Differences
Pharmacology/pharmacokinetics:
Mechanism of action/Effect—Mild to moderate intrinsic sympathomimetic activity (ISA); relatively cardioselective; low lipid solubility.
Absorption—Bioavailability significantly reduced by first-pass metabolism but effect not reduced because of active metabolite.
Protein binding—Low.
Elimination—Removable by hemodialysis.
Precautions:
Medical considerations/contraindications—Dosage reduction necessary in hepatic function and renal function impairment.
Side/adverse effects:
Theoretical reduced risk of bronchospasm, hypoglycemia, and peripheral vasoconstriction because of cardioselectivity.
Oral Dosage Forms
ACEBUTOLOL HYDROCHLORIDE CAPSULES
Usual adult dose
Antiarrhythmic
Oral, 200 mg two times a day, the dosage being adjusted according to response, generally in the range of 600 to 1200 mg per day. {158}
Antihypertensive
Oral, initially 400 mg per day as a single dose or in two divided daily doses, the dosage being adjusted according to response, with maintenance doses usually in the range of 400 to 800 mg per day. {158}
Note: Geriatric patients may have increased or decreased sensitivity to the effects of the usual adult dose.
It is recommended that the dosage of acebutolol be reduced in patients with renal function impairment as follows:
| Creatinine clearance (mL/min/1.73m) |
% of normal dose to be given |
|---|---|
| <50 |
50 |
| <25 |
25 |
Usual geriatric prescribing limits
In geriatric patients, daily doses should not exceed a total of 800 mg.
Usual pediatric dose
Dosage has not been established.
Strength(s) usually available
U.S.—
200 mg (Rx) [Sectral][Generic]
400 mg (Rx) [Sectral][Generic]
Canada—
Not commercially available.
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.
Auxiliary labeling:
• Do not take other medicine without your doctor's advice.
Note: Check refill frequency to determine compliance in hypertensive patients.
ACEBUTOLOL HYDROCHLORIDE TABLETS
Usual adult dose
Antianginal
Oral, initially 200 mg two times a day, the dosage being adjusted according to response, generally in the range of 600 to 1200 mg per day. {217}
Antihypertensive
Oral, initially 100 mg two times a day, the dosage being adjusted weekly according to response, up to a maximum of 400 mg two times a day.
Antiarrhythmic1
Oral, 200 mg two times a day, the do