Nadolol

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Abstract
Synopsis: Nadolol1 is a nonselective β-adrenoceptor blocking drug without intrinsic sympathomimetic or membrane stabilising activity. Its inherently long duration of activity makes it suitable for once daily administration in both hypertension and angina pectoris, and in these conditions it has been as effective as propranolol given in a traditional regimen 4 times daily. However, other β-blocking drugs can also be given with reduced frequency, especially in hypertension; and some, such as atenolol (a longer acting ‘cardioselective’ agent) or long-acting preparations of other β-blockers, have also been given once daily in angina prophylaxis. Nevertheless, nadolol is one of a few β-blocking drugs which have clearly been shown to be effective in both hypertension and angina with once daily administration. Other specific properties of nadolol, such as its excretion entirely in unmetabolised form, may offer advantages over other existing β-blocking drugs in specific patients, while some properties (such as lack of ‘cardioselectivity’ may be disadvantageous in others. The choice of a β-blocking drug should thus be based on a knowledge of the pharmacodynamic and pharmacokinetic properties of the different β-blocking drugs, and a careful consideration of how such properties can best be applied to benefit the individual patient. Pharmacodynamic Studies: In various studies using standard animal models, nadolol has been shown to be a nonselective β-adrenoceptor blocking drug without intrinsic sympathomimetic (partial agonist) or membrane stabilising (local anaesthetic) properties. In pharmacodynamic studies in animals and in man the relative β-blocking potency of nadolol was usually about 2 to 9 times that of propranolol (weight for weight), but the oral dose ratios employed in therapeutic studies using dosage titration in individual patients suggest that the relative potency of the 2 drugs is similar under these conditions. As with other β-blocking drugs, nadolol usually lowers both resting and exercise heart rates. Usual doses have little negative inotropic effect, although a moderate decrease in cardiac output has occurred in some patients, possibly related to the effect on heart rate. Other cardiovascular effects also resemble those seen with most of the β-blocking drugs, including increased systemic vascular resistance on acute administration, reduced myocardial oxygen consumption, and antiarrhythmic activity. Unlike other β-blockers, nadolol has been shown to increase renal blood flow, but its relative effect on renal function under conditions of clinical usage, compared with other β-blockers, needs further clarification. In common with other β-blocking drugs, nadolol appears to decrease plasma renin activity in most patients. Whether such an effect (or patients’ pretreatment renin profiles) can be correlated with subsequent blood pressure lowering response to therapy with β-blocking drugs needs further clarification. As would be expected, nadolol appears to resemble propranolol in its effects on airway function, and should not be used in patients with bronchospastic disease. In pharmacodynamic studies investigating the duration of action, effects following a single dose of nadolol were long lasting, the ‘pharmacological half-life’ in some studies being about 40 hours. Pharmacokinetic Studies: The oral bioavailability of nadolol is about 30%, and appears to be unaltered in man by the presence of food in the gut. Peak plasma concentrations occur about 1 to 4 hours after oral administration. Steady state mean minimum plasma concentrations of about 25 to 30, 63 to 73, 111 and 173ng/ml were observed with daily doses of 80, 160, 240 and 320mg, respectively. Nadolol is about 20 to 30% bound to plasma proteins. In common with other β-blocking drugs, it has a relatively large distribution volume (about 2L/kg). Nadolol appears in breast milk of lactating mothers in concentrations exceeding (up to 5 times) serum concentrations. The absorbed portion of nadolol is eliminated entirely in unchanged form, primarily by the kidneys (about 75%), but also to a lesser extent by nonrenal routes (probably biliary excretion). The elimination half-life with usual therapeutic doses is approximately 14 to 24 hours. As would be expected, elimination is prolonged in the presence of renal dysfunction, the half-life being about 45 hours in very severe renal impairment. Nadolol is readily removed from the circulation during haemodialysis. Although the interindividual variation in drug plasma concentrations with a given dose of nadolol may be less than that with metabolised drugs such as propranolol, as with other β-blocking drugs the correlation between plasma concentrations and clinical effects is tenuous, and dosage must thus be titrated in individual patients based on clinical response. Therapeutic Trials: In hypertension, most studies with nadolol have been well designed, although several were non-blinded in nature. In patients with essential hypertension, individually titrated doses of nadolol (usually given once daily) were clearly superior to a placebo and equally effective as titrated doses of propranolol given 4 times daily, or hydrochlorothiazide (25 to 100mg/day, given twice daily). Combining nadolol with hydrochlorothiazide resulted in a greater reduction in blood pressure than occurred with moderate doses of the diuretic alone. Nadolol was more effective than usual doses of methyldopa given alone, and was better tolerated. About 60 to 90% of patients were ‘fully’ controlled (i.e. supine diastolic pressure < 90mm Hg in most studies) with nadolol alone. In patients with angina pectoris all studies have been well designed. Individually titrated single daily doses of nadolol (up to 240mg daily) were more effective than a placebo and at least as effective as propranolol given 4 times daily using evaluation parameters such as reduced frequency of anginal attacks, improved exercise performance, reduced need for glyceryl trinitrate (nitroglycerin), and ECG evaluation on exercise. Most studies with nadolol have been short term, only a relatively small number of patients having been treated for extended periods. There have been no comparative trials with single daily doses of other β-blocking drugs, particularly with other longer acting drugs such as atenolol (a cardioselective drug) or sustained release preparations of drugs such as metoprolol, Oxprenolol or propranolol. Side Effects: Nadolol has been generally well tolerated. Side effects reported are typical of those associated with β-blockade, bradycardia occurring most frequently (about 3%), with general effects such as fatigue, dizziness and cold extremities being occasionally reported. Other reactions such as diarrhoea, nausea, dry mouth, sweating, paraesthesia, bronchospasm, congestive heart failure, cardiac conduction disturbances, etc. have occurred infrequently. Dosage: The dosage of nadolol is titrated in the individual patient according to clinical response. In hypertension, the initial starting dose is usually 40 to 80mg once daily, increased in 40 to 80mg increments at 3 to 7 day intervals. The usual maintenance dose is 80 to 320mg once daily (occasionally up to 640mg, but usually 160mg or less). In angina pectoris, the dosage titration is undertaken as in hypertension, the usual maintenance dose range being 80 to 240mg once daily (usually 160mg or less). In moderate to severe renal dysfunction the dosage interval should be extended according to the creatinine clearance, to 24 to 36, 24 to 48 and 40 to 60 hours for patients with a creatinine clearance of 31 to 50, 10 to 30 and less than 10ml/min/1.73m2, respectively.