Antihypertensive – Antianginal Agent
Action And Clinical Pharmacology: Timolol is a beta-adrenergic receptor blocking agent. The mechanism of the antihypertensive effect of beta- adrenergic receptor blocking agents has not yet 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; inhibition of renin release by the kidneys; inhibition of the vasomotor centres.
The exact mechanism by which timolol exercises its anti-anginal effect is not certain but it may reduce the oxygen requirements of the heart 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 fibre 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. Timolol can therefore increase the capacity for work and exercise in such patients. In a multi-clinic study, two-thirds of the patients treated with timolol maleate benefitted to some degree.
Timolol has been found effective in prophylactic use for secondary prevention in patients with ischemic heart disease who have survived the acute phase of a myocardial infarction. At the present time, the mechanism of this protective effect of timolol is unknown.
Indications And Clinical Uses: For patients with mild or moderate hypertension. Timolol is usually used in combination with other drugs, particularly a thiazide diuretic. However, timolol 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 timolol maleate with a diuretic or peripheral vasodilator has been found to be compatible and generally more effective than timolol alone. Limited experience with other antihypertensive agents has not shown evidence of incompatibility with timolol.
Timolol is not indicated in the treatment of hypertensive emergencies.
Angina pectoris due to ischemic heart disease.
Patients who have survived the acute phase of a myocardial infarction, and are clinically stable, to reduce cardiovascular mortality and the risk of re-infarction. In the study which showed these benefits, treatment with timolol was begun 7 to 28 days after the acute phase. Data are not available as to whether benefit would ensue if the treatment is initiated later.
Prophylactic treatment of migraine. Timolol is not indicated in the management of acute migraine attacks.
Contra-Indications: Congestive heart failure (see Warnings); right ventricular failure secondary to pulmonary hypertension; significant cardiomegaly; sinus bradycardia; AV block; cardiogenic shock; allergic rhinitis, bronchospasm (including asthma), or a history of bronchospasm or severe chronic obstructive pulmonary disease (including severe chronic bronchitis and emphysema) (see Warnings); anesthesia with agents that produce myocardial depression, e.g., ether; hypersensitivity to any component of this product.
Manufacturers’ Warnings In Clinical States: Cardiac Failure: Special caution should be exercised when administering timolol 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. In rare instances this has been observed during therapy with timolol.
Therefore, at the first sign or symptom of impending cardiac failure occurring during drug therapy, patients should be fully digitalized and/or given a diuretic, and the response observed closely. Timolol acts selectively without blocking the inotropic action of digitalis on the heart muscle. However, the positive inotropic action of digitalis may be reduced by the negative inotropic effect of timolol when the 2 drugs are used concomitantly. The effects of timolol and digitalis are additive in depressing AV conduction. If cardiac failure persists, therapy with timolol should be discontinued (see below).
Abrupt Cessation of Therapy: Patients with ischemic heart disease should be warned against stopping timolol abruptly. Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy. Myocardial infarction, ventricular arrhythmias, or sudden death has been reported in such patients following abrupt discontinuation of therapy with beta-adrenergic receptor blocking agents, with or without preceding exacerbation of angina pectoris. Therefore, in angina and postmyocardial infarction, the dosage of timolol should be gradually reduced over about 2 weeks (maintaining the same frequency of administration) and the patient should be carefully observed. In patients with angina pectoris, if the angina still markedly worsens, or in any patient if acute coronary insufficiency develops, it is recommended that timolol be reinstated, 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.
Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild to moderate severity should in general not receive beta-blockers, particularly the nonselective beta-blockers such as timolol (see Contraindications). If timolol must be given to such patients, it should be given with caution and under careful medical supervision since it may block bronchodilation produced by endogenous catecholamine stimulation of beta receptors (see Precautions).
Various skin rashes and conjunctival xerosis have been reported with beta-blockers including timolol. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis and sclerosing serositis have occurred with the chronic use of one beta-adrenergic blocking agent. This syndrome has not been observed with timolol. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.
Severe sinus bradycardia due to unopposed vagal activity may result from the administration of timolol; in such cases, consider the use of i.v. atropine, and, if no improvement is seen, i.v. isoproterenol.
In patients with thyrotoxicosis, timolol 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 timolol to aggravate congestive heart failure. Timolol 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.
Precautions: 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-blocker 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, these doses can be associated with excessive alpha-adrenergic stimulation with consequent hypertension, reflex bradycardia, 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.
Timolol 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 of acute hypoglycemia.
Timolol dosage should be individually adjusted when used concomitantly with other antihypertensive agents (see Dosage).
Suitable laboratory tests should be carried out at appropriate intervals and caution should be observed in patients with impaired renal or hepatic function. Since timolol is partially metabolized in the liver and excreted mainly by the kidneys, dosage reduction may be necessary when hepatic or renal insufficiency is present. Marked hypotension has been observed in patients with severe renal insufficiency undergoing renal hemodialysis following oral administration of 20 mg of timolol.
Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenic symptoms.
Because of potential effects of beta-adrenergic blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow are observed, consideration should be given to discontinuing these agents.
Patients Undergoing Elective or Emergency Surgery: The management of patients with angina, being treated with beta-blockers and undergoing elective or emergency surgery, is controversial because beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli, but abrupt discontinuation of 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, timolol should be withdrawn gradually following the recommendation given under Abrupt Cessation of Therapy (see Warnings). According to available evidence, all clinical and physiologic effects of beta blockade are no longer present 48 hours after cessation of medication.
In emergency surgery, since timolol is a competitive inhibitor of beta-adrenergic receptor agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol, levarterenol, dopamine or dobutamine.
Pregnancy: Since timolol has not been studied in human pregnancy, the drug should not be given to pregnant women. The use of any drug in patients of childbearing potential requires that the anticipated benefit be weighed against possible hazards.
Lactation: Timolol is detectable in human milk. Because of the potential for serious adverse reactions from timolol in infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Children: Safety and effectiveness in children have not been established.
Risk of Anaphylactic Reaction: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.
Drug Interactions: Close observation of the patient is recommended when timolol is administered to patients receiving catecholamine-depleting drugs such as reserpine or guanethidine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Attenuation of the antihypertensive effect of beta-adrenoceptor blocking agents by NSAIDs has been reported. When using these agents concomitantly, patients should be observed carefully to confirm that the desired therapeutic effect has been obtained.
The potential exists for hypotension, AV conduction disturbances and left ventricular failure to occur in patients receiving a beta-blocking agent and an oral calcium entry blocker concurrently. The nature of any cardiovascular adverse effect tends to depend on the type of calcium entry blocker used. The dihydropyridine derivatives such as nifedipine are more likely to lead to hypotension whereas verapamil and diltiazem have a greater propensity to lead to AV conduction disturbances or left ventricular failure when used with a beta-blocker. Oral calcium antagonists may be used with caution in combination with beta-adrenergic blocking agents when cardiac function is normal, but should be avoided in patients with impaired cardiac function. However in exceptional cases, when in the opinion of the physician, concomitant use is considered essential in patients with impaired cardiac function, such use should be instituted gradually, in a hospital setting, under careful supervision.
I.V. calcium entry blockers should not be used in patients receiving beta-adrenoceptor blocking agents.
The concomitant use of beta-adrenergic blocking agents and digitalis with either diltiazem or verapamil may have additive effects in prolonging cardiac AV conduction time.
Adverse Reactions: Adverse Reactions Reported During Clinical Trials: Cardiovascular: Congestive heart failure in 3 to 4% of patients (see Warnings). Secondary effects of decreased cardiac output, about 4%, which could include: syncope, vertigo, lightheadedness, postural hypotension; decreased renal perfusion. Severe bradycardia in about 1% of patients, lengthening of the PR interval, 2nd- and 3rd-degree A-V block, sinus arrest (if SA node previously diseased), cold extremities, Raynaud’s phenomenon, claudication or paresthesia, hypotension.
Respiratory: dyspnea has occurred in about 10% of patients, bronchospasm in about 1% of patients, laryngospasm occurs rarely.
CNS: most frequently reported: headache, tinnitus. Less frequently: drowsiness, anxiety, vertigo, dizziness, weakness, insomnia, sedation, mental depression. Rarely: vivid dreams.
Integumentary (see Warnings): occasionally rashes, including one case of psoriasiform rash reported to date, and pruritus. Rarely: exfoliative dermatitis (one case).
Gastrointestinal: vomiting in about 4% of patients, diarrhea in about 5% of patients, constipation, epigastric distress, nausea.
Special Senses: dry eyes.
Adverse Reactions Reported Since the Drug was Marketed: Cardiovascular: cardiac arrest, cerebral vascular accident, palpitation, arrhythmia, edema, pulmonary edema, worsening of arterial insufficiency, worsening of angina pectoris, vasodilatation.
Hematologic: nonthrombocytopenic purpura.
Respiratory: rales, cough.
CNS: Rarely: nightmares, nervousness, diminished concentration, hallucinations, increased dreaming, decreased libido.
Integumentary (see Warnings): skin irritation, increased pigmentation, sweating.
Gastrointestinal: dyspepsia, hepatomegaly.
Special Senses: visual disturbances, diplopia, ptosis, eye irritation.
Urogenital: impotence, micturition difficulties.
Body as a Whole: asthenia, fatigue, chest pain, extremity pain, decreased exercise tolerance, weight loss.
Endocrine: hypoglycemia, hyperglycemia.
Clinical Laboratory: Slight increases in blood urea nitrogen, serum potassium, serum uric acid and triglycerides, and slight decreases in hemoglobin, hematocrit, and HDL-cholesterol have occurred, but were not progressive or associated with clinical manifestations. Slight increases in ALT have also occurred.
Symptoms And Treatment Of Overdose: Symptoms: The most common signs expected are bradycardia, hypotension, bronchospasm, or acute cardiac failure.
If overdosage occurs, in all cases therapy with timolol should be discontinued and the patient observed closely. In addition, the following therapeutic measures are suggested:Treatment: Gastric lavage.
Bradycardia: Use atropine sulfate i.v. 0.25 mg to 2 mg to induce vagal blockade. If bradycardia persists, i.v. isoproterenol HCl should be administered cautiously. In refractory cases the use of a cardiac pacemaker may be considered.
Heart Block (second degree or complete): isoproterenol HCl or a cardiac pacemaker.
Acute Cardiac Failure: Conventional therapy with digitalis, diuretics, and oxygen should be instituted immediately. In refractory cases the use of i.v. aminophylline is suggested. This may be followed, if necessary, by glucagon HCl which has been reported to be useful.
Hypotension: Use sympathomimetic pressor drug therapy, such as levarterenol, epinephrine, dopamine or dobutamine. The response to epinephrine in such patients may be altered (see Precautions). In refractory cases the use of glucagon HCl has been reported to be useful.
Bronchospasm: Use isoproterenol HCl. Additional therapy with aminophylline may be considered.
Hypoglycemia: I.V. glucose and/or i.m. glucagon.
An in vitro hemodialysis study, using C4timolol added to human plasma or whole blood, showed that timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not dialyze readily.
It should be remembered that timolol 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 timolol. However, the complications of excess isoproterenol, such as tachycardia, headache, flushing of the skin, arrhythmias, nausea, weakness, tremor and sweating, should not be overlooked.
Dosage And Administration: Hypertension: Timolol is usually used in conjunction with other antihypertensive agents, particularly a thiazide diuretic, but may be used alone (see Indications).
The dose must always be adjusted to the individual requirements of the patient, in accordance with the following guidelines.
When timolol is given to patients already receiving other antihypertensive agents, the initial dose should be 5 to 10 mg twice a day. If after 1 to 2 weeks an adequate response is not observed, dosage may be increased by increments of 5 mg twice daily, at intervals of 2 weeks. A 60 mg daily dose should not be exceeded.
When timolol is used alone the initial dose should be 10 mg twice a day and dosage increased if required, following the regimen described above.
In those patients who are found to be adequately controlled on daily doses of 20 mg or less, the administration of the total dose in the morning should be tried, as studies show adequate response to this dose regimen.
Angina: The recommended dosage range is 15 to 45 mg/day. The majority of patients respond to a daily dosage of 35 to 45 mg. Therapy should be initiated with 5 mg 2 or 3 times a day. Depending on response, increases in dosage may be necessary. The first increase should not exceed 10 mg/day in divided doses. Subsequent increases should not exceed 15 mg/day in divided doses. A total daily dose of 45 mg should not be exceeded. There should be an interval of at least 3 days between increases in dosage.
After the titration period, some patients may be maintained on a twice-daily schedule.
Preventive Use in Ischemic Heart Disease: For long-term preventive use in patients who have survived the acute phase of myocardial infarction, the maintenance dose is 10 mg twice daily. Therapy should be initiated with 5 mg twice daily and the patient observed carefully. If no adverse reaction occurs, the dosage should then be increased after 2 days to 10 mg twice daily. In the studies evaluating timolol following myocardial infarction, treatment was begun 7 to 28 days after the acute phase.
Migraine: Dosage must be individualized. The recommended dosage for prevention of migraine headache is 10 mg twice daily. The dosage range is 10 to 30 mg/day. If a satisfactory response is not obtained after 6 to 8 weeks of the maximum suggested dosage, therapy with timolol should be discontinued.
Availability And Storage: Each light-blue, flat, beveled-edged tablet, scored on one side, marked Frosst on other, contains: timolol maleate 10 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose and pregelatinized starch. Gluten-, lactose- and tartrazine-free. Bottles of 100. Keep container tightly closed. Store between 15 and 30°C. Protect from light.
BLOCADREN® Frosst Timolol Maleate Antihypertensive – Antianginal Agent