Antianginal – Antihypertensive Agent
Action And Clinical Pharmacology: Nadolol is a noncardioselective beta-adrenergic blocking agent. It does not possess membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities.
The exact mechanism by which the drug exercises its anti-anginal effect is not certain. An important factor may be the reduction of myocardial oxygen requirements by blocking catecholamine-induced increases in heart rate, systolic blood pressure and the velocity and extent of myocardial contraction. However, oxygen requirements may be increased by such actions as increases in left ventricular fiber length, end diastolic pressure and the systolic ejection period. When the net physiological effect is advantageous in anginal patients, it manifests itself during exercise or stress by delaying the onset of pain and reducing the incidence and severity of anginal attacks. Nadolol can therefore increase the capacity for work and exercise in such patients.
The mechanism of nadolol’s antihypertensive effect has not yet been established. Among the factors that may be involved are: (a) competitive ability to antagonize catecholamine-induced tachycardia at the beta-receptor sites in the heart, thus decreasing cardiac output; (b) inhibition of renin release by the kidneys; (c) inhibition of vasomotor centers.
In humans, approximately 37% of orally administered nadolol is slowly absorbed. Approximately 30% of the nadolol present in serum is reversibly bound to plasma proteins and the drug is extensively distributed to extravascular tissues. Maximum serum concentrations are reached 2 to 4 hours after oral administration, while steady state serum concentrations are reached after 6 to 9 days. The serum half-life is 20 to 24 hours at therapeutic dose levels.
Nadolol is not detectably metabolized by man. Urinary and fecal excretion of nadolol after oral administration to humans averaged approximately 20% and 70% respectively. The latter fraction would include both unabsorbed drug and that fraction of the absorbed drug which is excreted by the liver. Nadolol elimination was found to be proportional to creatinine clearance in patients with renal impairment.
Indications And Clinical Uses: Prophylaxis of angina pectoris.
In mild or moderate hypertension. Nadolol is usually used in combination with other drugs, particularly a thiazide diuretic. However, it may be tried alone as an initial agent in those patients in whom, in the judgment of the physician, treatment should be started with a beta-blocker rather than a diuretic.
The combination of nadolol with a diuretic has been found to be compatible and generally more effective than nadolol alone. In a few cases where peripheral vasodilators were used with nadolol, no evidence of incompatibility was seen.
Not recommended for the emergency treatment of hypertensive crises.
Contra-Indications: Allergic rhinitis, bronchospasm (including bronchial asthma), or severe chronic obstructive pulmonary disease (see Precautions); sinus bradycardia; second and third degree AV block; right ventricular failure secondary to pulmonary hypertension; congestive heart failure (see Warnings); cardiogenic shock; anesthesia with agents that produce myocardial depression, e.g., ether.
Manufacturers’ Warnings In Clinical States: Cardiac Failure: Special caution should be exercised when administering nadolol to patients with a history of heart failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and inhibition with beta-blockade always carries a potential hazard of further depressing myocardial contractility and precipitating cardiac failure. In patients without a history of cardiac failure, continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of impending cardiac failure during nadolol therapy, patients should be fully digitalized, and/or given a diuretic, and the response observed closely.
Nadolol acts selectively without blocking the inotropic action of digitalis on the heart muscle. However, the positive inotropic action of digitalis may be reduced by nadolol’s negative inotropic effect when the two drugs are used concomitantly. The effects of beta-blockers and digitalis are additive in depressing AV conduction. If cardiac failure continues, despite adequate digitalization and diuretic therapy, discontinue nadolol (see Warning below).
Abrupt Cessation of Therapy: Patients with angina should be warned against abrupt discontinuation of nadolol. There have been reports of severe exacerbation of angina, and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of beta-blocker therapy. The last 2 complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of nadolol is planned in patients with angina pectoris, reduce the dosage gradually over a period of about 2 weeks and observe the patient carefully. Maintain the same frequency of administration. In situations of greater urgency, discontinue nadolol therapy stepwise and under conditions of closer observance. If angina markedly worsens or acute coronary insufficiency develops, reinstitute nadolol treatment promptly, at least temporarily.
Oculomucocutaneous Syndrome: Various skin rashes and conjunctival xerosis have been reported with beta-blockers, including nadolol. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis and sclerosing serositis has occurred with the chronic use of one beta-adrenergic blocking agent (practolol). This syndrome has not been observed with nadolol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.
Sinus Bradycardia: Severe sinus bradycardia due to unopposed vagal activity occurs in approximately 3% of patients following nadolol administration. In such cases, reduce dosage or consider the use of i.v. atropine; if no improvement is seen, consider i.v. isoproterenol.
Thyrotoxicosis: In patients with thyrotoxicosis, nadolol may give a false impression of improvement by diminishing peripheral manifestations of hyperthyroidism without improving thyroid function; therefore, abrupt withdrawal may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.
Precautions: Nadolol should be administered with caution to patients prone to nonallergic bronchospasm (e.g., chronic bronchitis, emphysema) since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta receptors.
Epinephrine and Beta-blockers: There may be increased difficulty in treating an allergic type reaction in patients on beta-blockers. In these patients, the reaction may be more severe due to pharmacologic effects of the beta-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other hand, these doses can be associated with excessive alpha adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of beta agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.
Administer nadolol with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blockers may mask the premonitory signs and symptoms of acute hypoglycemia. As beta-blockade also reduces insulin release in response to hyperglycemia, it may be necessary to adjust the dosage of antidiabetic drugs.
Nadolol dosage should be individually adjusted when used concomitantly with other antihypertensive agents (see Dosage).
Patients receiving catecholamine depleting drugs, such as reserpine or guanethidine, should be closely monitored if nadolol is administered concomitantly. The added catecholamine blocking action of nadolol may produce an excessive reduction of the resting sympathetic nervous activity.
Suitable laboratory tests should be carried out at appropriate intervals and caution should be observed in patients with impaired renal or hepatic function. Since nadolol is excreted mainly by the kidneys, dosage reduction may be necessary when renal insufficiency is present.
Patients Undergoing Surgery: The management of patients being treated with beta-blockers and undergoing elective or emergency surgery is controversial. Although beta-adrenergic receptor blockade impairs the heart’s ability to respond to beta-adrenergically mediated reflex stimuli, abrupt discontinuation of nadolol therapy may be followed by severe complications (see Warnings). Some patients receiving beta-adrenergic blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported.
For these reasons, in patients with angina undergoing elective surgery, withdraw nadolol gradually following the recommendation given under Abrupt cessation of therapy (see Warnings). Available evidence suggests that the clinical and physiologic effects of beta-blockade induced by nadolol are essentially absent 5 days after cessation of therapy.
In emergency surgery, since nadolol is a competitive inhibitor of beta-adrenergic receptor agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol or norepinephrine.
Pregnancy: Nadolol has been shown to produce embryo/fetal toxicity in rabbits, but not in rats or hamsters, at doses of 100 to 300 mg/kg. No teratogenic potential was observed in any of these species. Nadolol, when given to pregnant rats, readily crossed the placental barrier.
There is no adequate information on the use of nadolol in pregnant women. Nadolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates whose mothers were receiving nadolol at parturition have exhibited bradycardia, hypoglycemia and associated symptoms.
Lactation: Nadolol is excreted in human milk. Therefore, use of this drug in lactating women is not recommended.
Children: There is no experience with nadolol in the treatment of pediatric age groups.
Adverse Reactions: The most serious adverse reactions encountered are congestive heart failure, AV block and bronchospasm.
The most common adverse reactions reported in clinical trials are severe bradycardia (3%), dizziness (3%), fatigue (2%), hypotension (1%), congestive heart failure (1%) and cold sensations (1%).
Adverse reactions, grouped by system, are as follows:
Cardiovascular: congestive heart failure, pulmonary edema, cardiac enlargement; rhythm or conduction disturbances including AV block, bigeminy and Adams-Stokes syndrome; chest pain; severe bradycardia; hypotension, orthostatic hypotension, syncope; peripheral vascular insufficiency including intermittent claudication and cold extremities; edema.
Respiratory: bronchospasm, dyspnea, cough.
CNS: dizziness; depression, anxiety, nervousness, irritability, hallucinations; lethargy, fatigue; sleep disturbances including insomnia and nightmares; paresthesia; headache; tinnitus; slurred speech.
Gastrointestinal: abdominal pain or pressure; nausea, vomiting, diarrhea, constipation, flatulence; gastritis; anorexia.
Dermatological (see Warnings): rash, pruritus, dry skin.
Ophthalmologic: conjunctivitis, blurred vision, dry eyes.
Miscellaneous: impotence, decreased libido; enlarged thyroid; nasal stuffiness, dry mouth, sweating; weight gain.
Clinical Laboratory: The following parameters have most frequently been found to be outside the normal range: serum triglycerides, blood glucose, serum potassium, AST, ALT, LDH, BUN.
Symptoms And Treatment Of Overdose: Symptoms: The most common signs to be expected with overdosage of a beta-adrenergic blocking agent are bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia.
Treatment: If overdosage occurs, in all cases, discontinue nadolol therapy and observe the patient closely. In addition, if required, the following therapeutic measures are suggested: 1. Bradycardia: Atropine or another anticholinergic drug. 2. Heart block (second or third degree): Isoproterenol or transvenous cardiac pacemaker. 3. Congestive heart failure: Conventional therapy. 4. Hypotension (depending on associated factors): Epinephrine rather than isoproterenol or levarterenol may be useful in addition to atropine and digitalis (see Precautions). 5. Bronchospasm: Aminophylline or isoproterenol. 6. Hypoglycemia: I.V. glucose.
It should be remembered that nadolol is a competitive antagonist of isoproterenol and hence, large doses of isoproterenol can be expected to reverse many of the effects of excessive doses of nadolol. However, the complications of excess isoproterenol should not be overlooked.
Dosage And Administration: Nadolol should be administered as a single daily dose without regard to meals since the presence of food in the gastrointestinal tract does not affect the rate or extent of nadolol’s absorption.
Adjust the dosage to the patient’s individual needs in accordance with the following guidelines:
Angina Pectoris: Initially, 80 mg daily. If an adequate response is not observed after 1 week, dosage may be increased by 80 mg increments at weekly intervals, until a satisfactory response is achieved. The maximum recommended daily dose is 240 mg. Patients stabilized on 80 mg daily might be tried on 40 mg daily as this dose has been found to be effective in some cases.
The value and safety of doses above 240 mg daily in angina pectoris have not been established.
Hypertension: Initially, 80 mg daily. If an adequate response is not observed after 1 week, dosage may be increased by 80 mg increments at weekly intervals, until a satisfactory response is achieved. The maximum recommended daily dose is 320 mg, although most patients respond to 240 mg or less.
The value and safety of doses above 320 mg daily have not been established.
Availability And Storage: 40 mg: Each off-white round, biconvex tablet, scored on one side and engraved “CORGARD 40” on the other contains: nadolol 40 mg. Nonmedicinal ingredients: citric acid, cornstarch, magnesium stearate, microcrystalline cellulose and povidone. Bottles of 100 and 500.
80 mg: Each off-white, round, biconvex tablet, engraved with “SQUIBB” and a partial bisect bar on one side and “CORGARD 80” on the other contains: nadolol 80 mg. Nonmedicinal ingredients: citric acid, cornstarch, magnesium stearate, microcrystalline cellulose and povidone. Bottles of 100.
160 mg: Each blue, flat, capsule-shaped tablet, scored on both sides with a partial bisect bar and engraved “SQUIBB” on one side and “Corgard 160” on the other contains: nadolol 160 mg. Nonmedicinal ingredients: citric acid, cornstarch, FD&C No. 2 and blue No. 2 aluminum lake, magnesium stearate, microcrystalline cellulose and povidone. Bottles of 100 and 1 000.
Store in tightly closed containers at room temperature (15 to 30°C). Protect from heat, light and moisture. (Shown in Product Recognition Section)
CORGARD® Squibb Nadolol Antianginal – Antihypertensive Agent