Antihypertensive – Antianginal
Action And Clinical Pharmacology: Pindolol is a beta-adrenergic-receptor-blocking agent which possesses partial agonist activity (intrinsic sympathomimetic activity – I.S.A.).
Hypertension: The mechanism of the antihypertensive effect of pindolol has not been established. Among the factors that may be involved are: competitive ability to antagonize catecholamine-induced tachycardia at the beta-receptor sites in the heart, thus decreasing cardiac output; a reduction in total peripheral resistance; inhibition of the vasomotor centres; inhibition of renin release by the kidneys.
Angina Pectoris: The mechanism of the antianginal effect of pindolol has not been established. Pindolol may reduce the oxygen requirement of the heart at any level of effort by blocking catecholamine-induced increases in the 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 fibre length, end diastolic pressure and the systolic ejection period. When the net effect is beneficial 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.
In humans, orally-administered pindolol is rapidly and almost completely absorbed (³95%). Because of negligible hepatic first pass effect, the bioavailability of oral pindolol is high and approaches 90% of the oral dose. Maximum plasma concentrations are reached 1 to 2 hours after oral administration and the plasma half-life is approximately 3.5 hours. The elimination rate of pindolol is not dose dependent. Forty percent of pindolol is bound to plasma proteins. Pindolol has a volume of distribution of 2 to 3L/kg and a total clearance of 500 mL/min.
Pindolol is patially metabolized with approximately 40% of an oral dose being excreted unchanged in the urine. The remaining 60% is excreted in the urine and feces as inactive metabolites. The principle metabolites of pindolol consist of the conjugated glucuronide, and phenolic derivatives of pindolol conjugated with sulfuric or glucuronic acid.
Approximately 80% of an oral dose is accounted for in the urine within 24 hours.
Indications And Clinical Uses: a) Mild to moderate hypertension. Pindolol is usually used in combination with other drugs, particularly a thiazide diuretic. However, it may be used 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 pindolol with a diuretic and/or peripheral vasodilator has been found to be compatible and generally more effective than pindolol alone. Limited experience with other antihypertensive agents, including methyldopa, has not shown evidence of incompatibility with pindolol.
Not recommended for the emergency treatment of hypertensive crises.
b) The prophylaxis of angina pectoris.
Contra-Indications: 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; bronchospasm, including bronchial asthma or severe chronic obstructive pulmonary disease (see Precautions).
Manufacturers’ Warnings In Clinical States: Cardiac Failure: Special caution should be exercised when administering pindolol 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 the potential hazard of further depressing myocardial contractility and precipitating cardiac failure. Pindolol may reduce but does not abolish the inotropic action of digitalis on the heart muscle. However, the positive inotropic action of digitalis may be reduced by pindolol’s negative inotropic effect when the 2 drugs are used concomitantly. The effects of beta-blockers and digitalis are additive in depressing AV conduction. 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, patients should be fully digitalized and/or given a diuretic and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, pindolol should be immediately withdrawn.
Abrupt Cessation of Therapy: Warn patients with angina against abrupt discontinuation of pindolol. 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 pindolol is planned in patients with angina pectoris, the dosage should be gradually reduced over a period of about 2 weeks and the patient should be observed carefully. The same frequency of administration should be maintained. In situations of greater urgency, discontinue pindolol therapy stepwise and under conditions of very close observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with pindolol be reinstituted promptly, at least temporarily.
Various skin rashes and conjunctival xerosis have been reported with beta-blockers, including pindolol. A severe oculo-muco-cutaneous 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 pindolol. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.
Sinus bradycardia may occur with the use of pindolol due to unopposed vagal activity remaining after blockade of beta1-adrenergic receptors. Due to its intrinsic sympathomimetic activity, pindolol causes less bradycardia at rest than some other beta-adrenergic-blocking agents. If excessive bradycardia occurs, reduce the dosage.
In patients with thyrotoxicosis, possible deleterious effects from long-term use of pindolol have not been adequately appraised. Beta-blockade may mask the clinical signs of continuing hyperthyroidism or complications, and give a false impression of improvement. Therefore, abrupt withdrawal of pindolol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.
Precautions: Caution should be exercised in patients prone to nonallergic bronchospasm (e.g., chronic bronchitis, emphysema) since pindolol may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta receptors.
Pindolol should be administered with caution to patients with allergic rhinitis prone to bronchospasm.
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.
Pindolol should be administered 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 (tachycardia, tremor) of acute hypoglycemia.
Pindolol dosage should be individually adjusted when used concomitantly with other antihypertensive agents (see Dosage).
Patients receiving catecholamine depleting drugs, such as reserpine of guanethidine, should be closely monitored because the added beta-adrenergic-blocking action of pindolol may produce an excessive reduction of sympathetic activity. Do not combine pindolol with other beta-blockers.
Appropriate laboratory tests should be performed at regular intervals during long-term treatment.
Patients Undergoing Elective or Emergency 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 ability of the heart to respond to beta-adrenergically-mediated reflex stimuli, abrupt discontinuation of pindolol 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 pindolol gradually following the recommendation given under “Abrupt cessation of therapy” (see Warnings). According to available evidence, all clinical and physiological effects of beta-blockade are no longer present 48 hours after cessation of medication.
In emergency surgery, since pindolol is a competitive inhibitor of beta-adrenergic-receptor agoinsts, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol or levarterenol.
Impaired Renal or Hepatic Function: b-blocking agents should be used with caution in patients with impaired hepatic or renal function. Poor renal function has only minor effects on pindolol clearance, but poor hepatic function may cause blood levels of pindolol to increase substantially.
Pregnancy: Since pindolol has not been studied in human pregnancy, it should not be given to pregnant women. The use of any drug in patients of child-bearing potential requires that the anticipated benefit be weighed against possible hazards. Pindolol crosses the placental barrier.
Lactation: Pindolol passes in small quantities into breast milk.
Children: There is no experience with pindolol in the treatment of pediatric age groups.
Occupational Hazards: Because dizziness or fatigue may occur during initiation of treatment with b-adrenoreceptor blocking drugs, patients driving vehicles or operating machinery should exercise caution until they have determined their individual response to treatment.
Adverse Reactions: Cardiovascular: Congestive heart failure, severe bradycardia (see Warnings) may occur. Syncope, lightheadedness and postural hypotension. Lengthening of PR interval, second degree AV block, palpitation, chest pains, cold extremities, Raynaud’s phenomenon, claudication, hot flushes. Very rarely: arrhythmia, coronary insufficiency.
CNS: insomnia, nightmares, vivid dreams, fatigue, drowsiness, weakness, dizziness, vertigo, tinnitus, headache, mental depression, nervousness. Rarely have the following adverse reactions been reported: aggressiveness, motor disorders, confusion.
Gastrointestinal: diarrhea, constipation, flatulence, heartburn, nausea and vomiting, abdominal pain and dry mouth.
Respiratory: shortness of breath and/or dyspnea, wheezing, bronchospasm.
Allergic, Dermatological (see Warnings): exanthema, sweating, pruritus, psoriasiform rash.
Eyes: itching, burning, grittiness, dryness.
Miscellaneous: muscle cramps, appetite stimulation, weight gain, urinary frequency.
Clinical Laboratory: The following parameters have been rarely elevated: transaminases, alkaline phosphatase, LDH, serum uric acid. Rarely reduction in bilirubin.
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, or hypoglycemia.
Treatment: If overdosage occurs, in all cases therapy with pindolol should be discontinued and the patient observed 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 norepinephrine may be useful in addition to atropine and digitalis (see Precautions concerning the use of epinephrine).
5. Bronchospasm: Aminophylline or isoproterenol.
6. Hypoglycemia: I.V. glucose.
It should be remembered that pindolol 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 pindolol. However, the complications of excess isoproterenol should not be overlooked.
Dosage And Administration: Hypertension: Pindolol is usually used in conjunction with other antihypertensive agents, particularly a thiazide diuretic but may be used alone (see Indications). Pindolol should be taken with meals.
The dosage of pindolol must always be adjusted to the individual requirements of the patients in accordance with the following guidelines: therapy should be initiated with doses of 5 mg in the morning with breakfast and 5 mg with the evening meal. If an adequate response is not achieved after 1 to 2 weeks, the dose should be increased to 10 mg twice daily.
If after 1 to 2 additional weeks an adequate response is not observed, dosage may be increased to 30 mg daily with 15 mg given in the morning with breakfast and 15 mg with the evening meal.
Doses greater than 30 mg daily must be given on a t.i.d. schedule.
Patients who show a satisfactory response to pindolol at daily doses of 10 to 20 mg may be maintained by giving the required total dose once daily in the morning with breakfast.
The usual maintenance dose is within the range of 15 to 45 mg daily which should not be exceeded. However, during long-term therapy, some patients may be maintained on smaller doses.
Angina Pectoris: The dosage must always be adjusted to the individual requirements of the patient.
In angina, pindolol should be administered on a 3 or 4 times per day dosing regimen. Therapy should be initiated with doses of 5 mg 3 times a day with meals. If after 1 to 2 weeks an adequate response is not observed dosage may be increased. The usual maintenance dose is 15 mg up to the maximum of 40 mg/day.
Availability And Storage: 5 mg: Each whitish, compressed tablet, 7 mm diameter, slope faced, bisected with “LB” embossed on one side and flat faced, beveled edge with “VISKEN 5” embossed on reverse side, contains: pindolol 5 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide and starch. Bottles of 100.
10 mg: Each whitish, compressed tablet, 8 mm diameter, slope faced, bisected on one side and flat-faced, beveled edge with “VISKEN 10” embossed on reverse side, contains: pindolol 10 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide and starch. Bottles of 100.
15 mg: Each whitish, compressed tablet, 9 mm diameter, slope faced, bisected with “JU” embossed on one side and flat faced, beveled edge with “VISKEN 15” embossed on reverse side, contains: pindolol 15 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide and starch. Bottles of 100.
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VISKEN® Novartis Pharmaceuticals Pindolol Antihypertensive – Antianginal