Pindolol – Hydrochlorothiazide
Action And Clinical Pharmacology: Viskazide contains the antihypertensive activity of 2 agents: a beta-adrenergic receptor blocking agent (pindolol) and a diuretic (hydrochlorothiazide).
Pindolol is a nonselective beta-adrenergic receptor blocking agent which possesses partial agonist activity (intrinsic sympathomimetic activity-ISA).
The mechanism of the antihypertensive effect of beta-adrenergic receptor blocking agents has not 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) a reduction in total peripheral resistance; (c) inhibition of the vasomotor centres; (d) inhibition of renin release by the kidneys.
Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts, and may cause a simultaneous, usually minimal, loss of bicarbonate. Natriuresis is usually accompanied by some loss of potassium. The mechanism of the antihypertensive effect of thiazides may be related to the excretion and redistribution of body sodium. Hydrochlorothiazide usually does not decrease normal blood pressure.
The combination of pindolol with thiazide-like diuretics has been shown to be compatible and generally more effective than either of the drugs used alone in reducing elevated blood pressure.
In humans, orally administered pindolol is rapidly and completely absorbed. 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 within 2 hours after oral administration and the plasma half-life is approximately 3.5 hours. The elimination of pindolol is not dose dependent.
In man, pindolol is partially metabolized with approximately 40% of an oral dose being excreted unchanged in the urine. The principal 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.
The onset of the diuretic action of hydrochlorothiazide occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 to 12 hours. Hydrochlorothiazide is eliminated rapidly by the kidney.
Indications And Clinical Uses: This fixed combination is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. It is always better to adjust the dosage of each antihypertensive drug separately, but when the fixed combination corresponds to the optimum drug and dose requirements of the patient, its use may be more convenient in patient management. For further adjustment of dosage, however, it is best to use the individual drugs again. The treatment of hypertension is not static, but must be re-evaluated as conditions in each patient warrant.
Viskazide is indicated for the maintenance therapy of patients with hypertension who require pindolol and hydrochlorothiazide in the dosage and ratios present in Viskazide.
Contra-Indications: The presence of: congestive heart failure (see Warnings); right ventricular failure secondary to pulmonary hypertension; significant cardiomegaly; sinus bradycardia, second and third degree AV block; cardiogenic shock; bronchospasm (including bronchial asthma), or severe chronic obstructive pulmonary disease (see Precautions); anesthesia with agents that produce myocardial depression, e.g., ether; anuria; hypersensitivity to pindolol, hydrochlorothiazide, or to sulfonamide derived drugs.
Manufacturers’ Warnings In Clinical States: Cardiac Failure: Special caution should be exercised when administering Viskazide 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.
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 occurring during therapy, patients should be fully digitalized and/or given additional diuretic therapy, and the response observed closely.
Pindolol acts selectively without blocking the inotropic action of digitalis on heart muscle. However, the positive inotropic action of digitalis may be reduced by the negative inotropic effect of pindolol when the 2 drugs are used concomitantly. The effects of pindolol and digitalis are additive in depressing AV conduction. If cardiac failure persists, therapy with Viskazide should be discontinued (see below).
Abrupt Cessation of Therapy in Angina Pectoris: Patients with angina should be warned against abrupt discontinuation of Viskazide. 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 Viskazide is planned in patients with angina pectoris, the dosage should be reduced over a period of about 2 weeks and the patient should continue to be observed. The same frequency of administration should be maintained.
In situations of greater urgency, therapy should be discontinued stepwise and under conditions of closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment be reinstituted promptly, at least temporarily.
Since ischemic heart disease may be unrecognized, the above advice should be followed in patients considered to be at risk of having asymptomatic ischemic heart disease.
Various skin rashes and conjunctival xerosis have been reported with beta-blockers, including pindolol. A severe syndrome (oculo-mucocutaneous 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 (ISA), pindolol causes less bradycardia at rest than some other beta-adrenergic blocking agents. If excessive bradycardia occurs, the dosage should be reduced.
In patients with thyrotoxicosis, pindolol may give a false impression of improvement by diminishing peripheral manifestations of hyperthyroidism without improving thyroid function. Special considerations should be given to the potential of pindolol to aggravate congestive heart failure. Pindolol does not alter thyroid function tests. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might precipitate a thyroid storm. Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
In patients with renal disease, thiazides may precipitate azotemia, and cumulative effects may develop in the presence of impaired renal function. If progressive renal impairment becomes evident, Viskazide should be discontinued.
In patients with impaired hepatic function or progressive liver disease, even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Hepatic encephalopathy, manifested by tremors, confusion, and coma, has been reported in association with diuretic therapy including hydrochlorothiazide.
In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma.
The possible exacerbation or activation of systemic lupus erythematosus has been reported with thiazides.
Precautions: Viskazide should be administered with caution to patients prone to non allergic bronchospasm (e.g., chronic bronchitis, emphysema) since beta-blockade may block bronchodilatation produced by endogenous and exogenous catecholamine stimulation of beta receptors.
Elective or Emergency Surgery: Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. Some patients receiving beta-adrenergic receptor 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 pectoris undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents (see recommendations given under Warnings – Abrupt Cessation of Therapy).
In emergency surgery, since pindolol 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 levarterenol.
Viskazide should be administered with caution to patients with allergic rhinitis prone to bronchospasm.
Beta-adrenergic receptor blocking agents may mask the premonitory signs and symptoms of acute hypoglycemia. Therefore, Viskazide should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especialy those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Insulin requirements in diabetic patients may be increased, decreased, or unchanged by thiazides. Diabetes mellitus which has been latent may become manifest during administration of thiazide diuretics.
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.
Patients receiving catecholamine depleting drugs, such as reserpine or guanethidine, should be closely monitored because the added beta-adrenergic blocking action of Viskazide may produce an excessive reduction of sympathetic activity. Viskazide should not be combined with other beta-blockers.
Patients receiving thiazides should be carefully observed for clinical signs of fluid and electrolyte imbalance (hyponatremia, hypochloremic alkalosis and hypokalemia). Periodic determination of serum electrolytes should be performed at appropriate intervals. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or during concomitant use of corticosteroids or ACTH. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium supplements, potassium sparing agents or foods with a high potassium content.
Any chloride deficit during thiazide therapy is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances, when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Because calcium excretion is decreased by thiazides, Viskazide should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy; however, the common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen.
The antihypertensive effects of thiazides may be enhanced in the postsympathectomy patient.
Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazide therapy.
The combination of Viskazide with an antihypertensive peripheral vasodilator produces a greater fall in blood pressure than either drug alone. The same degree of blood pressure control can be achieved by lower than usual doses of each drug. Therefore, when using such combined therapy, careful monitoring of the dosages is required until the patient is stabilized.
Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude the therapeutic effectiveness of the pressor agent in therapy.
Thiazides may increase the responsiveness to tubocurarine.
Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such preparations with Viskazide.
Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates or narcotics.
Pregnancy: Thiazides cross the placental barrier and appear in cord blood. The use of Viskazide in pregnancy or in women of child bearing potential requires that the anticipated benefit be weighed against possible risk to mother and/or fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly, other adverse reactions which have occurred in the adult.
Lactation: Thiazides appear in human milk. If use of Viskazide is deemed essential, the patient should stop nursing.
Children: The safety for use of pindolol in children has not been established; therefore, Viskazide is not recommended in the pediatric age group.
Adverse Reactions: Cardiovascular: congestive heart failure (see Warnings), severe bradycardia (see Warnings) may occur as may 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. Orthostatic hypotension may be potentiated by alcohol, barbiturates or narcotics.
CNS: insomnia, nightmares, vivid dreams, fatigue, drowsiness, weakness, paresthesias, dizziness, vertigo, tinnitus, headache, mental depression, nervousness. Rarely have the following adverse reactions been reported: aggressiveness, motor disorders, confusion, xanthopsia.
Gastrointestinal: anorexia, gastric irritation, cramping, diarrhea, constipation, flatulence, heartburn, nausea and vomiting, abdominal pain, dry mouth, jaundice (intrahepatic, cholestatic), pancreatitis, sialadenitis.
Respiratory: shortness of breath and/or dyspnea, wheezing, bronchospasm (see Contraindications and Precautions).
Hematologic: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia.
Hypersensitivity: exanthema, sweating, pruritus, purpura, photosensitivity, urticaria, exfoliative dermatitis, psoriasiform rash, necrotizing angiitis vasculitis, cutaneous vasculitis, fever, respiratory distress, including pneumonitis, anaphylactic reactions.
Special Senses: visual disturbances, including xanthopsia and transient blurred vision, dry eyes, conjunctivitis, itching and/or burning eyes, tinnitus, vestibular disorder.
Other: hyperglycemia, glycosuria, hyperuricemia, muscle cramps, weakness, restlessness, weight gain or loss, urinary frequency, appetite stimulation.
Clinical Laboratory Test Findings: On rare occasions, changes in the following parameters were noted: elevations in transaminases, alkaline phosphate, LDH, serum uric acid; a reduction in bilirubin. The most common changes associated with the thiazide component are increases in uric acid and decreases in serum potassium and chloride.
Symptoms And Treatment Of Overdose: Symptoms: The pindolol component may cause bradycardia, hypotension, bronchospasm, hypoglycemia or acute cardiac failure.
The hydrochlorothiazide component may cause excessive diuresis with electrolyte depletion and dehydration. Signs are dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, gastrointestinal disturbances, mental confusion, delirium, convulsions, shock and coma.
If digitalis has also been administered, hypokalemia may accentuate myocardial abnormalities (e.g., cardiac arrhythmias).
Hydrochlorothiazide may precipitate hepatic coma in cirrhotics, potentiate other antihypertensive agents and decrease responsiveness to norepinephrine.
Treatment: Discontinue Viskazide. There is no specific antidote. If ingestion is, or may have been, recent, gastric lavage or emesis may reduce absorption; when ingestion has been earlier, infusions may be helpful to promote urinary excretion.
If required the following therapeutic measures are suggested: Bradycardia: Atropine or another anticholinergic drug. Heart block: (second or third degree) Isoproterenol or transvenous cardiac pacemaker. Congestive heart failure: Conventional therapy. Hypotension: (depending on associated factors) Epinephrine rather than isoproterenol or norepinephrine may be useful in addition to atropine and digitalis. Bronchospasm: Aminophylline or isoproterenol. Hypoglycemia: I.V. glucose. Stupor or Coma: Supportive therapy as clinically warranted. Gastrointestinal Effects: Though usually of short duration, these may require symptomatic treatment.
Abnormalities in BUN and/or Serum Electrolytes: Monitor serum electrolyte levels and renal function; institute supportive measures as required individually to maintain hydration, electrolyte balance, respiration and cardiovascular-renal function.
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 Viskazide. However, the complications of excess isoproterenol should not be overlooked.
Dosage And Administration: Dosage must be determined for individual patients by titration of each component separately. Where the fixed combination in Viskazide supplies the dosage so determined, the combination product may be used for maintenance therapy. 1 or 2 Viskazide tablets once daily in the morning can be used to administer up to 20 mg pindolol and 100 mg hydrochlorothiazide.
If higher doses of either ingredient are needed, the individual components should be used.
When necessary, another antihypertensive agent may be added gradually, beginning with 50% of the usual recommended starting dose to avoid excessive reduction in blood pressure.
If dosage adjustment is necessary during maintenance therapy, it is advisable to use the individual drugs.
Availability And Storage: Viskazide 10/25: Each peach, round, compressed tablet, 9 mm diameter, one side slope-faced and bisected with “10/25” embossed on each side of the bisect, reverse side flat-faced with beveled edge and embossed with “VISKAZIDE” around the circumference and ”
“centered, contains: pindolol 10 mg and hydrochlorothiazide 25 mg. Nonmedicinal ingredients: FD&C Yellow #6 Lake, magnesium stearate, microcrystalline cellulose, pregelatinized starch and silicon dioxide. Calendar packs of 35.
Viskazide 10/50: Each orange, round, compressed tablet, 9 mm diameter, one side slope-faced and bisected with “10/50” embossed on each side of the bisect, reverse side flat-faced with beveled edge and embossed with “VISKAZIDE” around the circumference and ”
“centered, contains: pindolol 10 mg and hydrochlorothiazide 50 mg. Nonmedicinal ingredients: FD&C Yellow #6 Lake, magnesium stearate, microcrystalline cellulose, pregelatinized starch and silicon dioxide. Calendar packs of 35. (Shown in Product Recognition Section)
VISKAZIDE® Novartis Pharmaceuticals Pindolol – Hydrochlorothiazide Antihypertensive