Nadolol is a nonselective β-adrenergic blocking agent (β-blocker).
Nadolol is used for the management of hypertension135, 1200 and angina. Nadolol has been used for the management of supraventricular tachyarrhythmias (e.g., atrial flutter or fibrillation†) and for the prophylaxis of sinus headache†.100, 101, 148
The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance.154, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171 While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients,1235 evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited.160, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171 Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent. 162, 163, 164, 165, 168, 170, 171
In the management of hypertension or chronic stable angina, many clinicians prefer to use low dosages of a β1-selective adrenergic blocking agent (e.g., atenolol, metoprolol), rather than a nonselective agent like nadolol, in patients with chronic obstructive pulmonary disease (COPD) or insulin-dependent diabetes mellitus.168 However, selectivity of these agents is relative and dose dependent.172, 173 Some clinicians also will recommend using a β1-selective agent or pindolol (because of its intrinsic sympathomimetic activity), rather than a nonselective agent, for the management of hypertension or angina pectoris in patients with peripheral vascular disease, but there is no evidence that the choice of β-blocker substantially affects efficacy.172, 174, 175
Nadolol is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.1200
Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501, 502, 503, 504, 1200 Most guidelines no longer recommend β-blockers as first-line therapy for hypertension because of the lack of established superiority over other recommended drug classes and evidence from at least one study demonstrating that β-blockers may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, myocardial infarction (MI), or stroke.176, 501, 503, 504, 515, 1200 However, therapy with a β-blocker may still be considered in hypertensive patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes.501, 502, 503, 504, 523, 524, 527, 800, 1200 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension, in Atenolol 24:24 and in Metoprolol 24:24.) Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).501, 502, 503, 504, 515, 1200, 1201
A 2017 multidisciplinary hypertension guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a target blood pressure goal (i.e., blood pressure to achieve with drug therapy and/or nonpharmacologic intervention) of less than 130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200 In addition, a systolic blood pressure goal of less than 130 mm Hg generally is recommended for noninstitutionalized ambulatory patients 65 years of age or older with an average systolic blood pressure of at least 130 mm Hg.1200 These blood pressure goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200, 1202, 1210 Previous hypertension guidelines, such as those from an expert panel of the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8), generally have recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients501, 504, 536 compared with those recommended by the 2017 ACC/AHA hypertension guideline.1200 The blood pressure thresholds used to define hypertension, the optimum blood pressure threshold at which to initiate antihypertensive drug therapy, and the ideal target blood pressure values remain controversial.501, 503, 504, 505, 506, 507, 508, 515, 523, 526, 530, 1200, 1201, 1207, 1209, 1222, 1223, 1229
Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with β-blockers.154, 158, 159, 501, 504, 1200 Although β-blockers have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients; however, this population difference in response does not appear to occur during combined therapy with a β-blocker and a thiazide diuretic.500 (See Race under Hypertension: Other Special Considerations for Antihypertensive Drug Therapy, in Uses in Atenolol 24:24 and in Metoprolol 24:24.)
In contrast to many other antihypertensive agents, nadolol and other β-blockers lower blood pressure equally well in the upright or supine position. The drug appears to be safe and effective in the treatment of hypertension in patients with renal damage. Nadolol reduces blood pressure in patients with low, normal, or elevated plasma renin levels. Tolerance to the hypotensive effect of nadolol apparently does not occur during long-term treatment.
For additional information on the role of β-blockers in the management of hypertension, see Uses: Hypertension, in Atenolol 24:24 and in Metoprolol 24:24. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.
Nadolol is used for the long-term management of chronic stable angina pectoris. β-Blockers are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; despite differences in cardioselectivity, intrinsic sympathomimetic activity, and other clinical factors, all β-blockers appear to be equally effective for this use.1101 Long-term use of β-blockers in patients with chronic stable angina has been shown to reduce the frequency of anginal attacks, allow a decrease in nitroglycerin dosage, and increase exercise tolerance.
Combination therapy with a β-blocker and a nitrate appears to be more effective than either drug alone because β-blockers attenuate the increased sympathetic tone and reflex tachycardia associated with nitrate therapy while nitrate therapy (e.g., nitroglycerin) counteracts the potential increase in left-ventricular wall tension associated with a decrease in heart rate.1101 Combined therapy with a β-blocker and a dihydropyridine calcium-channel blocker also may be useful because the tendency to develop tachycardia with the calcium-channel blocker is counteracted by the β-blocker.1101 However, caution should be exercised in the concomitant use of β-blockers and the nondihydropyridine calcium-channel blockers verapamil or diltiazem because of the potential for excessive fatigue, bradycardia, or atrioventricular (AV) block.1101 (See Drug Interactions: Cardiovascular Drugs.)
Supraventricular Tachyarrhythmias
Nadolol has been used in patients with atrial flutter or fibrillation† for the management of frequent ventricular premature complexes, paroxysmal atrial tachycardia, and sinus tachycardia and to decrease heart rate.
Nadolol has been used for the prophylaxis of migraine headache†.100, 101, 148 The US Headache Consortium states that there is some evidence of efficacy for this indication from randomized clinical trials of the drug and that clinical experience suggests that nadolol produces clinically important improvement in most patients receiving the drug for migraine prophylaxis.148 For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.
Nadolol is administered orally once daily.
Since there is no consistent interpatient correlation between the dosage of nadolol and therapeutic response, dosage must be individualized according to the response of the patient. If long-term nadolol therapy is to be discontinued, dosage of the drug should be gradually reduced over a period of 1-2 weeks. (See Cautions: Precautions and Contraindications.)
For the management of hypertension, the initial adult dosage of nadolol is 20-40 mg daily, either alone or in combination with a diuretic. The manufacturers state that dosage may be gradually increased in increments of 40-80 mg daily until optimum blood pressure response is achieved. The usual adult maintenance dosage of nadolol recommended by the manufacturers is 40-80 mg daily, although dosages up to 240 or 320 mg daily may be needed. Some experts state the usual dosage range is 40-120 mg once daily;1200 it is usually preferable to add another antihypertensive agent to the regimen rather than to continue increasing nadolol dosage since the patient may not tolerate such continued increases.157
Nadolol/Bendroflumethiazide Combination Therapy
Although nadolol is available in fixed combination with bendroflumethiazide, preparations of bendroflumethiazide alone are no longer commercially available in the US. The manufacturer states that bendroflumethiazide alone usually was administered at a dosage of 5 mg daily, and the usual initial dosage of nadolol is 40 mg once daily, whether used alone or in combination with a diuretic.135 Therefore, the initial dosage of the fixed combination may be 40 mg of nadolol and 5 mg of bendroflumethiazide once daily.135 If needed, dosage may be increased to the fixed-combination preparation containing 80 mg of nadolol and 5 mg of bendroflumethiazide administered once daily.135 The manufacturer cautions that bendroflumethiazide in the fixed-combination preparation with nadolol is about 30% more bioavailable than the drug alone. If blood pressure is not adequately controlled with the fixed combination alone, another nondiuretic hypotensive agent can be added gradually, starting with 50% of the usual recommended starting dosage in order to avoid excessive reduction in blood pressure.135
The manufacturers state that commercially available preparations containing nadolol in fixed combination with bendroflumethiazide should not be used for initial antihypertensive therapy.601
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200, 1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with nadolol, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200, 1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505, 506, 507, 508, 515, 523, 530, 1201, 1207, 1209, 1222 While previous hypertension guidelines have based target blood pressure goals on age and comorbidities,501, 504, 536 the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) for all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200, 1220
For the management of angina pectoris, the initial adult dosage of nadolol is 40 mg daily. Dosage is gradually increased by 40-80 mg daily at 3- to 7-day intervals until optimum control of angina is obtained or there is pronounced slowing of the heart rate (i.e., to less than 55 beats/minute). The usual maintenance dosage of nadolol is 40 or 80 mg daily, but there is wide variation in individual requirements and dosage must be carefully titrated to achieve optimum results. Nadolol dosages up to 160 or 240 mg daily may be needed. The value and safety of dosage greater than 240 mg daily have not been established. During chronic therapy, the patient should be periodically reevaluated to determine the need for dosage alteration or continued therapy.
Supraventricular Tachyarrhythmias
In patients with various cardiac arrhythmias†, maintenance nadolol dosages of 60-160 mg daily in single or divided doses have been used.
The usual effective dosage for the prophylaxis of migraine headache† is 80-240 mg daily.148
In patients with renal impairment, the usual dose of nadolol alone or in fixed combination with bendroflumethiazide is given at the following intervals depending on the patient's creatinine clearance (see Table):
Most adverse effects of nadolol are mild and transient and occur more frequently at the onset of therapy than during prolonged treatment. The most common, serious adverse effects of nadolol are related to its β-adrenergic blocking activity. Severe reactions result from the inability of severely ill patients to withstand a decrease in normal β-adrenergic stimulation.
The most common adverse cardiovascular effects of nadolol are bradycardia (heart rate less than 60 beats/minute) and peripheral vascular insufficiency, usually of the Raynaud's type. Heart rates less than 40 beats/minute and/or symptomatic bradycardia, and peripheral vascular insufficiency have occurred in about 2% of patients. Severe bradycardia should be treated with IM or IV administration of atropine sulfate. If there is an inadequate response to atropine, IV isoproterenol may be administered with caution; large doses may be required. (See Drug Interactions: Sympathomimetic Agents.) Cardiac failure, postural hypotension, palpitation, and disturbances in cardiac rhythm and conduction have each occurred in about 1% of patients. In patients without a prior history of heart failure, prolonged depression of the myocardium by nadolol may result in heart failure in rare instances. First- and third-degree AV block have occurred and intensification of AV block which has occurred with other β-adrenergic blocking agents (β-blockers) may occur with nadolol.
During surgery, some patients who have received β-adrenergic blockers may experience severe, protracted hypotension, low cardiac output, or difficulty in restarting and maintaining heart beat. The untoward effects of nadolol may be reversed during surgery by IV administration of β-adrenergic agonists (e.g., isoproterenol, dopamine, or dobutamine).
The most common adverse CNS effects of nadolol are dizziness and fatigue, which occur in about 2% of patients. Paresthesia, sedation, malaise, and change in behavior have occurred less frequently. Insomnia and sleep disturbances have been reported, but a causal relationship to nadolol has not been established. Potential adverse CNS effects include reversible mental depression progressing to catatonia, visual disturbances, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, short-term memory loss, emotional lability with slightly clouded sensorium, and decreased performance on neuropsychometric tests.
GI symptoms such as nausea, diarrhea, abdominal discomfort, constipation, vomiting, indigestion, anorexia, bloating, and flatulence have occurred in about 0.1-0.5% of patients receiving nadolol.
Results of a large prospective cohort study of nondiabetic adults 45-64 years of age indicate that use of β-blockers in hypertensive patients is associated with increased risk (about 28%) of developing type 2 diabetes mellitus compared with hypertensive patients who were not receiving hypotensive therapy.137, 138 In this study, the number of new cases of diabetes per 1000 person-years was 33.6 or 26.3 in patients receiving a β-blocker or no drug therapy, respectively.137 The association between the risk of developing type 2 diabetes mellitus and use of β-blockers reportedly was not confounded by weight gain, hyperinsulinemia, or differences in heart rate.137, 138 It is not known if the risk of developing diabetes is affected by β-receptor selectivity.137 Further studies are needed to determine whether concomitant use of ACE inhibitors (which may improve insulin sensitivity) would abrogate β-blocker induced adverse effects related to glucose intolerance.138 Therefore, until results of such studies are available, the proven benefits of β-blockers in reducing cardiovascular events in hypertensive patients must be weighed carefully against the possible risks of developing type 2 diabetes mellitus.137
Hypoglycemia136 , which may result in loss of consciousness, also may occur in nondiabetic patients receiving β-blockers. Patients most at risk for the development of β-blocker-induced hypoglycemia are those undergoing dialysis, prolonged fasting, or severe exercise regimens.136
β-Blockers may mask signs and symptoms of hypoglycemia (e.g., palpitation, tachycardia, tremor) and potentiate insulin-induced hypoglycemia.136 Although it has been suggested that nonselective β-blockers are more likely to induce hypoglycemia than selective β-blockers, such an adverse effect also has been reported with selective β-blocking agents (e.g., atenolol).136 In addition, selective β-blockers are less likely to mask symptoms of hypoglycemia or delay recovery from insulin-induced hypoglycemia than nonselective β-blockers because of their vascular sparing effects; however, selective β-blockers can decrease insulin sensitivity by approximately 15-30%, which may result in increased insulin requirements.136
Bronchospasm has occurred in about 0.1% of patients receiving nadolol. Other adverse effects which have occurred infrequently in patients receiving the drug include rash; pruritus; headache; dry mouth, eyes, and skin; reversible alopecia; impotence or decreased libido; facial swelling; weight gain; slurred speech; cough; nasal stuffiness; sweating; tinnitus; blurred vision; weakness; and numbness.
Potential hematologic effects of β-blockers include agranulocytosis and thrombocytopenic or nonthrombocytopenic purpura. Potential adverse allergic effects include fever with aching and sore throat, laryngospasm, and respiratory distress. Other β-blockers have caused mesenteric arterial thrombosis, ischemic colitis, Peyronie's disease, and erythematous rash.
Precautions and Contraindications
Nadolol shares the toxic potentials of β-blockers, and the usual precautions of these agents should be observed. When nadolol is used as a fixed-combination preparation that includes bendroflumethiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with nadolol.
In patients with heart failure, sympathetic stimulation is vital for the support of circulatory function. Nadolol should be used with caution in patients with inadequate cardiac function, since heart failure may be precipitated by blockade of β-adrenergic stimulation when nadolol therapy is administered. In addition, in patients with latent cardiac insufficiency, prolonged β-adrenergic blockade may lead to cardiac failure. Although β-blockers should be avoided in patients with overt heart failure, nadolol may be administered cautiously, if necessary, to patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics). Patients receiving nadolol therapy should be instructed to consult their physician at the first sign or symptom of impending cardiac failure and should be adequately treated (e.g., with a cardiac glycoside and/or diuretic) and observed closely; if cardiac failure continues, nadolol should be discontinued, gradually if possible.
Sudden cessation of β-blocker therapy in patients with angina pectoris and/or coronary artery disease may lead to increased frequency, duration, and severity of angina episodes and, in some cases, myocardial infarction (MI) and ventricular arrhythmias. In patients without coronary artery disease, abrupt withdrawal of β-blocker therapy has also caused transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Therefore, patients receiving nadolol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their clinician. When discontinuance of long-term nadolol therapy is planned, particularly in patients with ischemic heart disease, dosage of the drug should be gradually reduced over a period of about 1-2 weeks and the patient should be carefully monitored. If exacerbation of angina occurs or acute coronary insufficiency develops after nadolol therapy is interrupted or discontinued, treatment with the drug should be reinstituted promptly, at least temporarily, and appropriate measures for the management of unstable angina pectoris should be initiated. Because coronary artery disease is common and may be unrecognized, the manufacturers caution that it may be prudent not to discontinue nadolol therapy abruptly, even in patients being treated only for hypertension.
Since β-blockers may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic disease. Nadolol should be used with caution in patients with nonallergic bronchospasm (e.g., chronic bronchitis, emphysema). Nadolol also may interfere with the bronchodilation produced by exogenous β2-adrenergic bronchodilators.
Signs of hyperthyroidism (e.g., tachycardia) may be masked by nadolol, and patients having or suspected of developing thyrotoxicosis should be monitored closely because abrupt withdrawal of β-adrenergic blockade might precipitate thyroid storm.
It is recommended that nadolol be used with caution in patients with diabetes mellitus (especially those with labile diabetes or those prone to hypoglycemia) since the drug also may mask the signs and symptoms associated with acute hypoglycemia (e.g., tachycardia and blood pressure changes but not sweating). In addition, β-blockers also may impair glucose tolerance; delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia; alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response; and possibly impair peripheral circulation. (See Cautions: Endocrine Effects.) If nadolol is used in diabetic patients receiving hypoglycemic agents, it may be necessary to adjust the dosage of the hypoglycemic agent. However, many clinicians state that patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers.134 (See Uses: Heart Failure, in Metoprolol 24:24.) In one study in nondiabetic patients, nadolol therapy did not produce changes in glucose tolerance.
Patients who have a history of anaphylactic reactions to a variety of allergens reportedly may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with such allergens while taking β-blocking agents and may be unresponsive to usual doses of epinephrine used to treat anaphylactic reactions.
Nadolol should be used with caution in patients undergoing major surgery involving general anesthesia. The necessity of withdrawing β-adrenergic blocking therapy prior to major surgery is controversial. The manufacturer states that chronically administered β-blocking therapy should not be routinely withdrawn prior to major surgery; however, the decreased ability of the heart to respond to reflex β-adrenergic stimuli may increase the risks associated with general anesthesia and surgical procedures.600 Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients who have received β-blockers. If nadolol is continued during surgery, the anesthesiologist should be informed that the patient is receiving the drug. (See Cautions: Cardiovascular Effects.)
Nadolol should be used with caution in patients with renal or hepatic impairment, and it may be necessary to reduce the dosage of the drug in those with renal impairment.
Nadolol is contraindicated in patients with bronchial asthma, sinus bradycardia and heart block greater than first degree, cardiogenic shock, or overt cardiac failure.
Safety and efficacy of nadolol in children have not been established. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
No evidence of nadolol-induced carcinogenicity was observed in mice and rats receiving the drug orally for 2 years.
Pregnancy, Fertility, and Lactation
Nadolol has been shown to be embryotoxic and fetotoxic in rabbits, but not in rats or hamsters, when given at dosages 5-10 times the maximum recommended human dosa no teratogenic potential was observed in any of these species. There are no adequate and well-controlled studies using nadolol in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Neonates whose mothers were receiving nadolol at parturition have exhibited bradycardia, hypoglycemia, and associated symptoms.
Reproduction studies in rats using nadolol have not revealed evidence of impaired fertility.
Nadolol is distributed into milk. Because of the potential for adverse reactions to nadolol in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Although some of the drug interactions that have occurred with propranolol have not been reported to date during nadolol therapy, it should be kept in mind that nadolol and propranolol have similar pharmacologic effects and probably have similar drug interactions.
The β-adrenergic stimulating effects of sympathomimetic agents are antagonized by nadolol. This interaction is especially pronounced with isoproterenol, and very large doses of isoproterenol may be needed to overcome the β-adrenergic blocking effects of nadolol. In patients receiving nadolol, epinephrine should be administered with caution since a decrease in pulse rate with first- and second-degree heart block and hypertension may occur.
Antimuscarinic agents, such as atropine, may counteract the bradycardia caused by nadolol by reestablishing the balance between sympathetic and parasympathetic actions on the heart.
When nadolol is administered with diuretics or other hypotensive drugs, the hypotensive effect of nadolol may be increased. This effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly. Phenothiazines and nadolol may have additive hypotensive activity, especially when phenothiazines are administered in large doses. In addition to its potentially additive hypotensive effect, reserpine theoretically may add to the β-adrenergic blocking activity of nadolol through its catecholamine-depleting activity, and patients receiving both drugs should be observed for hypotension and/or excessive bradycardia.
Concomitant use of β-adrenergic blocking agents (β-blockers) and certain other cardiovascular drugs (e.g., cardiac glycosides, nondihydropyridine calcium-channel blocking agents) can have additive negative effects on SA or AV nodal conduction.116, 117 Slowing or complete suppression of SA node activity with development of slow ventricular rates (e.g., 30-40 bpm), often misdiagnosed as complete AV block, has been reported in patients receiving the nondihydropyridine calcium-channel blocking agent mibefradil (no longer commercially available in the US), principally in geriatric patients and in association with concomitant β-blocker therapy.116, 117
High doses of nadolol may potentiate and prolong the effects of neuromuscular blocking agents such as tubocurarine chloride.
Limited information is available on nadolol overdosage. In general, overdosage of nadolol may be expected to produce effects that are mainly extensions of pharmacologic effects, including symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure.
If nadolol ingestion is recent, emesis should be induced or, if the patient is comatose, having seizures, or lacks the gag reflex, endotracheal intubation should be performed followed by gastric lavage with activated charcoal. Magnesium sulfate (250 mg/kg) may be given orally as a cathartic. Management of nadolol overdosage includes supportive therapy and continuous cardiac monitoring; because of nadolol's prolonged duration of action, therapy may be required for several days. For excessive bradycardia, IV atropine sulfate may be given; if bradycardia persists, IV isoproterenol hydrochloride may be administered cautiously. A vasopressor (e.g., dobutamine, dopamine, epinephrine, norepinephrine) may be given cautiously for hypotension, and a β2-adrenergic agonist and/or IV aminophylline may be given for bronchospasm. An IV cardiac glycoside and diuretic may be used for cardiac failure; IV glucagon also may be useful. Hemodialysis may be useful in severe nadolol overdosage.
Like propranolol, nadolol inhibits response to adrenergic stimuli by competitively blocking β1-adrenergic receptors within the myocardium and β2-adrenergic receptors within bronchial and vascular smooth muscle.
Through its myocardial β1-adrenergic blocking action, nadolol decreases resting heart rate, inhibits exercise-induced increases in heart rate, and decreases cardiac output at rest and during exercise. The drug also decreases conduction velocity through the atrioventricular (AV) node and decreases myocardial automaticity via β1-adrenergic blockade. Nadolol apparently has little direct myocardial depressant activity and no membrane-stabilizing effect on the heart nor does it exhibit intrinsic sympathomimetic activity.
β-Adrenergic blockade may also increase peripheral resistance initially, as a result of unopposed α-adrenergic vasoconstriction. Although studies have not been conducted to date, peripheral resistance probably tends to decrease toward normal after chronic administration of nadolol. In one study in patients with essential hypertension, IV administration of nadolol in doses of 0.3-10 mcg/kg increased renal blood flow; studies on the effects of chronic nadolol therapy on renal blood flow and glomerular filtration rate are not available.
The precise mechanism of nadolol's hypotensive action has not been established. It has been postulated that β-adrenergic blocking agents (β-blockers) reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release. Nadolol decreases blood pressure in both supine and standing positions.
In the management of angina pectoris, the mechanism of action of nadolol is thought to be blockade of catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure which result in a net decrease in myocardial oxygen consumption. However, nadolol may increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure.
Through its β-adrenergic blocking action, nadolol increases airway resistance (especially in asthmatic patients) and inhibits the release of free fatty acids and insulin by adrenergic stimulation.
Following oral administration of nadolol, absorption is variable and averages about 30-40% of a dose. The presence of food in the GI tract does not affect the rate or extent of absorption. After oral administration of 2 mg of nadolol (in a capsule), peak plasma concentrations usually occur in 2-4 hours. In one study in hypertensive adults who received 80 mg, 160 mg, or 320 mg of nadolol daily, mean steady-state plasma concentrations were 25.5-35.5 ng/mL, 51.7-74.1 ng/mL, and 154-191.4 ng/mL, respectively. With doses of 40-320 mg daily, the duration of nadolol's antihypertensive and antianginal effects is at least 24 hours.
Nadolol is widely distributed into body tissues. In dogs, minimal amounts of nadolol were detected in the brain and, in rats, the drug crosses the placenta. The drug is distributed into bile. Nadolol is distributed into milk.
About 30% of nadolol in serum is bound to plasma proteins.
In patients with normal renal function, the plasma half-life of nadolol is 10-24 hours and, with once-daily doses, steady-state is attained in 6-9 days. In patients with renal impairment, plasma half-life is increased.
Nadolol is not metabolized. Following oral administration of 2 mg of radiolabeled nadolol (in a capsule) in one study in patients with normal renal function, about 24.6% and 76.9% of the radioactivity was recovered in urine and feces, respectively, in 4 days. Nadolol is removed by hemodialysis.
Nadolol is a nonselective β-adrenergic blocking agent (β-blocker) that is structurally and pharmacologically similar to propranolol. Nadolol occurs as a white to off-white, practically odorless, crystalline powder and is freely soluble in alcohol, is soluble in water at pH 2, and is slightly soluble in water at pH 7-10. The drug has a pKa of 9.67.
Nadolol tablets should be stored in tight, light-resistant containers at room temperature.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 20 mg* | Corgard® (scored) | |
40 mg* | Corgard® (scored) | Pfizer | ||
Nadolol Tablets | ||||
80 mg* | Corgard® (scored) | Pfizer | ||
Nadolol Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 40 mg with Bendroflumethiazide 5 mg* | Corzide® (scored) | Pfizer |
Nadolol and Bendroflumethiazide Tablets | ||||
80 mg with Bendroflumethiazide 5 mg* | Corzide® (scored) | Pfizer | ||
Nadolol and Bendroflumethiazide Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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