Timolol (Systemic)
Drug class: Antineoplastic Agents
Usage of Timolol (Systemic)
Hypertension
Management of hypertension (alone or in combination with other classes of antihypertensive agents).
β-Blockers generally not preferred for first-line therapy of hypertension according to current evidence-based hypertension guidelines, but may be considered in patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics). Timolol is one of several β-blockers (including bisoprolol, carvedilol, metoprolol succinate, metoprolol tartrate, nadolol, and propranolol) recommended by a 2017 ACC/AHA multidisciplinary hypertension guideline as first-line therapy for hypertension in patients with stable ischemic heart disease/angina.
Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).
The 2017 ACC/AHA hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension. (See Table 1.)
Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.
Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).
Table 1. ACC/AHA BP Classification in Adults1200Category
SBP (mm Hg)
DBP (mm Hg)
Normal
<120
and
<80
Elevated
120–129
and
<80
Hypertension, Stage 1
130–139
or
80–89
Hypertension, Stage 2
≥140
or
≥90
The goal of hypertension management and prevention is to achieve and maintain optimal control of BP. However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.
The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk. In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg. These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.
Other hypertension guidelines generally have based target BP goals on age and comorbidities. Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients compared with those recommended by the 2017 ACC/AHA hypertension guideline.
Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.
Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.
For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors. ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.
ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).
For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.
Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg. Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.
In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP. Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.
Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to β-blockers. However, diminished response to β-blockers is largely eliminated when administered concomitantly with a thiazide diuretic.
MI
Secondary prevention following acute MI.
Administration within 7–28 days following MI associated with reductions in cardiovascular mortality and nonfatal reinfarction.
Experts recommend β-blocker therapy in all patients with left ventricular systolic dysfunction and prior MI; a β-blocker with proven mortality benefit (bisoprolol, carvedilol, or metoprolol succinate) is preferred. Although benefits of long-term β-blockade in patients with normal left ventricular function are less well established, experts recommend continuing β-blocker therapy for at least 3 years in such patients.
Vascular Headache
Prophylaxis of common or classic migraine headache.
Chronic Stable Angina
Has been used in the management of chronic stable angina pectoris† [off-label].
β-Blockers are recommended as first-line anti-ischemic drugs in most patients with chronic stable angina; despite differences in cardioselectivity, intrinsic sympathomimetic activity, and other clinical factors, all β-blockers appear to be equally effective for this use.
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How to use Timolol (Systemic)
General
BP Monitoring and Treatment Goals
Administration
Oral Administration
Administer orally, usually twice daily.
For management of hypertension, once-daily dosing may be possible in some patients.
In patients with chronic stable angina pectoris† [off-label], administer orally in 3 or 4 divided doses.
During maintenance therapy in patients with vascular headaches (migraine), may administer daily dosage as a single rather than divided dose.
Dosage
Available as timolol maleate; dosage expressed in terms of the salt.
Adults
Hypertension OralInitially, 10 mg twice daily, either alone or in combination with a diuretic.
Increase dosage gradually at weekly (or longer) intervals until optimum effect is obtained.
Usual maintenance dosage is 20–40 mg daily, given in 2 divided doses; once-daily dosing may be possible in some patients. Increases up to a maximum of 60 mg daily (given in 2 divided doses) may be necessary.
MI OralSecondary prevention after acute phase of MI: Usual dosage is 10 mg twice daily.
Optimal duration of therapy for secondary prevention remains to be established. Experts generally recommend long-term therapy in post-MI patients with left ventricular dysfunction, and at least 3 years of therapy in those with normal left ventricular function.
Chronic Stable Angina† [off-label] Oral15–45 mg daily, given in 3 or 4 divided doses. Adjust dosage according to clinical response and to maintain a resting heart rate of 55–60 bpm.
Vascular Headaches (Migraine) OralInitially, 10 mg twice daily. Adjust dosage according to clinical response and patient tolerance; do not exceed 30 mg daily, given in divided doses (e.g., 10 mg in the morning and 20 mg in the evening).
During maintenance therapy, can administer 20-mg daily dosage as a single rather than divided dose; some patients may respond adequately to 10 mg once daily.
If an adequate response is not achieved after 6–8 weeks at the maximum recommended dosage, discontinue therapy.
Prescribing Limits
Adults
Hypertension OralMaximum 60 mg daily.
Vascular Headaches (Migraine) OralMaximum 30 mg daily.
Special Populations
Hepatic Impairment
Must modify doses and/or frequency of administration in response to degree of hepatic impairment.
Renal Impairment
Must modify doses and/or frequency of administration in response to degree of renal impairment.
Geriatric Patients
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. Initiate at low end of dosing range.
Warnings
Contraindications
Warnings/Precautions
Warnings
Heart FailurePossible precipitation of heart failure.
Avoid use in patients with overt heart failure; may use cautiously in patients with inadequate myocardial function and, if necessary, in patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics).
Adequate treatment (e.g., with a cardiac glycoside and/or diuretic) and close observation recommended if signs or symptoms of impending heart failure occur; if heart failure continues, discontinue therapy, gradually if possible.
Abrupt Withdrawal of TherapyAbrupt withdrawal of therapy is not recommended as it may exacerbate angina symptoms or precipitate MI in patients with coronary artery disease.
Gradually decrease dosage over a period of 1–2 weeks and monitor patients carefully; advise patients to temporarily limit their physical activity during withdrawal of therapy.
If exacerbation of angina occurs or acute coronary insufficiency develops, reinstitute therapy promptly, at least temporarily, and initiate appropriate measures for management of unstable angina pectoris.
Bronchospastic DiseasePossible inhibition of bronchodilation produced by endogenous catecholamines.
Generally should not be used in patients with bronchospastic disease, but may use with caution in patients who do not respond to or cannot tolerate alternative treatment. Use with caution in patients with nonallergic bronchospasm (e.g., chronic bronchitis, emphysema) or a history of nonallergic bronchospasm. (See Contraindications under Cautions.)
Major SurgeryPossible increased risks associated with general anesthesia (e.g., severe hypotension, difficulty restarting or maintaining heart beat) due to decreased ability of the heart to respond to reflex β-adrenergic stimuli.
Some clinicians recommend gradual withdrawal before elective surgery. Manufacturers recommend administration of β-agonists (e.g., dopamine, dobutamine, isoproterenol) to reverse β-adrenergic blockade if necessary during surgery.
Diabetes and HypoglycemiaPossible decreased signs and symptoms of hypoglycemia (e.g., tachycardia, but not sweating or dizziness). Use with caution in patients with diabetes mellitus receiving hypoglycemic drugs.
ThyrotoxicosisMay mask signs of hyperthyroidism (e.g., tachycardia). Possible thyroid storm if therapy is abruptly withdrawn; carefully monitor patients having or suspected of developing thyrotoxicosis.
Sensitivity Reactions
Anaphylactic ReactionsPatients with a history of atopy or anaphylactic reactions to a variety of allergens may be more reactive to repeated, accidental, diagnostic, or therapeutic challenges with such allergens while taking β-blocking agents; such patients may be unresponsive to usual doses of epinephrine.
General Precautions
Muscle Weaknessβ-Adrenergic blockade reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, generalized weakness). Increased muscle weakness reported rarely in some patients with myasthenia gravis or myasthenic symptoms.
Cerebrovascular InsufficiencyPossible cardiovascular effects (e.g., hypotension, bradycardia) that can adversely affect cerebral blood flow. Use with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggestive of reduced cerebral blood flow occur, consider discontinuance.
Other PrecautionsShares the toxic potentials of β-blockers; observe usual precautions of these agents.
Specific Populations
PregnancyCategory C.
LactationDistributed into milk. Discontinue nursing or the drug.
Pediatric UseSafety and efficacy not established.
Geriatric UseInsufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.
Substantially eliminated by the kidneys; assess renal function periodically and adjust dosage since geriatric patients are more likely to have decreased renal function. (See Geriatric Patients under Dosage and Administration.)
Hepatic ImpairmentUse with caution; dosage adjustment may be necessary. (See Hepatic Impairment under Dosage and Administration.)
Renal ImpairmentUse with caution; dosage adjustment may be necessary. (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Fatigue, headache, bradycardia, arrhythmia, pruritus, dizziness, dyspnea, eye irritation.
What other drugs will affect Timolol (Systemic)
Appears to be metabolized partly by CYP2D6.
Drugs Affecting Hepatic Microsomal Enzymes
CYP2D6 inhibitors: Potential pharmacodynamic (increased β-adrenergic blockade) and pharmacokinetic interaction (increased plasma timolol concentrations).
Specific Drugs
Drug
Interaction
Comments
Calcium-channel blocking agents
Potential hypotension, AV conduction disturbances, and left ventricular failure
Avoid concomitant use in patients with impaired cardiac function
Clonidine
β-Adrenergic blockade may exacerbate rebound hypertension which may occur following clonidine discontinuance
Discontinue β-blockers several days before gradual withdrawal of clonidine
If clonidine therapy is to be replaced by a β-blocker, delay administration for several days after clonidine discontinuance
Digoxin
Possible additive effect in prolonging AV conduction time when used concomitantly with diltiazem or verapamil
Hypotensive agents (hydralazine, methyldopa)
Possible increased hypotensive effect
Careful dosage adjustment is recommended
NSAIAs
Potential blunting of hypotensive effects
Monitor patients carefully
Quinidine
Possible potentiation of β-adrenergic blockade (e.g., decreased heart rate)
Reserpine
Possible additive effects
Observe closely for evidence of marked bradycardia or hypotension (may be manifested as vertigo, presyncope or syncope, or orthostatic changes in BP without compensatory tachycardia)
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