indication

In its oral form it is used to treat high blood pressure and prevent heart attacks, and occasionally to prevent migraine headaches. In its opthalmic form it is used to treat open-angle and occasionally secondary glaucoma.

pharmacology

Similar to propranolol and nadolol, timolol is a non-selective, beta-adrenergic receptor antagonist. Timolol does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity, but does possess a relatively high degree of lipid solubility. Timolol, when applied topically to the eye, has the action of reducing elevated, as well as normal, intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss and optic nerve damage.

mechanism of action

Like propranolol and nadolol, timolol competes with adrenergic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart and vascular smooth muscle and beta(2)-receptors in the bronchial and vascular smooth muscle. Beta(1)-receptor blockade results in a decrease in resting and exercise heart rate and cardiac output, a decrease in both systolic and diastolic blood pressure, and, possibly, a reduction in reflex orthostatic hypotension. Beta(2)-blockade results in an increase in peripheral vascular resistance. The exact mechanism whereby timolol reduces ocular pressure is still not known. The most likely action is by decreasing the secretion of aqueous humor.

toxicity

LD₅₀=1190 mg/kg (oral, mice), LD₅₀=900 mg/kg (oral, rat). Symptoms of overdose include drowsiness, vertigo, headache, and atriventricular block.

biotransformation

Primarily hepatic (80%) via the cytochrome P450 2D6 isoenzyme.

absorption

Bioavailability is about 60%

half life

2.5-5 hours

route of elimination

Timolol and its metabolites are primarily excreted in the urine.

drug interactions

Acetohexamide: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Aminophylline: Antagonism of action and increased effect of theophylline

Celecoxib: The NSAID, Celecoxib, may antagonize the antihypertensive effect of Timolol.

Chlorpropamide: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Cimetidine: Cimetidine may increase the serum concentration of timolol by decreasing its metabolism.

Clonidine: Increased hypertension when clonidine stopped

Diclofenac: The NSAID, Diclofenac, may antagonize the antihypertensive effect of Timolol.

Diflunisal: The NSAID, Diflunisal, may antagonize the antihypertensive effect of Timolol.

Dihydroergotamine: Ischemia with risk of gangrene

Dihydroergotoxine: Ischemia with risk of gangrene

Diltiazem: Additive effects of decreased heart rate and contractility may occur. Increased risk of heart block.

Disopyramide: The beta-blocker, timolol, may increase the toxicity of disopyramide.

Dyphylline: Antagonism of action and increased effect of theophylline

Epinephrine: Hypertension, then bradycardia

Ergonovine: Ischemia with risk of gangrene

Ergotamine: Ischemia with risk of gangrene

Etodolac: The NSAID, Etodolac, may antagonize the antihypertensive effect of Timolol.

Fenoprofen: The NSAID, Fenoprofen, may antagonize the antihypertensive effect of Timolol.

Fenoterol: Antagonism

Flurbiprofen: The NSAID, Flurbiprofen, may antagonize the antihypertensive effect of Timolol.

Formoterol: Antagonism

Gliclazide: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Glipizide: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Glisoxepide: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Glyburide: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Glycodiazine: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Indomethacin: Risk of inhibition of renal prostaglandins

Insulin Glargine: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Isoproterenol: Antagonism

Ketoprofen: The NSAID, Ketoprofen, may antagonize the antihypertensive effect of Timolol.

Ketorolac: The NSAID, Ketorolac, may antagonize the antihypertensive effect of Timolol.

Lidocaine: The beta-blocker, timolol, may increase the effect and toxicity of lidocaine.

Lumiracoxib: The NSAID, Lumiracoxib, may antagonize the antihypertensive effect of Timolol.

Meclofenamic acid: The NSAID, Meclofenamate, may antagonize the antihypertensive effect of Timolol.

Meloxicam: The NSAID, Meloxicam, may antagonize the antihypertensive effect of Timolol.

Methyldopa: Possible hypertensive crisis

Methysergide: Ischemia with risk of gangrene

Nabumetone: The NSAID, Nabumetone, may antagonize the antihypertensive effect of Timolol.

Naproxen: The NSAID, Naproxen, may antagonize the antihypertensive effect of Timolol.

Orciprenaline: Antagonism

Oxaprozin: The NSAID, Oxaprozin, may antagonize the antihypertensive effect of Timolol.

Oxtriphylline: Antagonism of action and increased effect of theophylline

Pipobroman: Antagonism

Pirbuterol: Antagonism

Piroxicam: Risk of inhibition of renal prostaglandins

Prazosin: Risk of hypotension at the beginning of therapy

Procaterol: Antagonism

Repaglinide: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Salbutamol: Antagonism

Salmeterol: Antagonism

Sulindac: The NSAID, Sulindac, may antagonize the antihypertensive effect of Timolol.

Terazosin: Increased risk of hypotension. Initiate concomitant therapy cautiously.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Timolol. Consider alternate therapy or monitor for therapeutic/adverse effects of Amytriptyline if Timolol is initiated, discontinued or dose changed.

Terbutaline: Antagonism

Theophylline: Antagonism of action and increased effect of theophylline

Tiaprofenic acid: The NSAID, Tiaprofenic acid, may antagonize the antihypertensive effect of Timolol.

Tolazamide: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Tolbutamide: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Tolmetin: The NSAID, Tolmetin, may antagonize the antihypertensive effect of Timolol.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Verapamil: Additive effects of decreased heart rate and contractility may occur. Increased risk of heart block.