Timolol

Timolol
Clinical data
Trade names	Betimol, Blocadren, Istalol, Timoptic, others
AHFS/Drugs.com	Maleate Monograph; eent Monograph
MedlinePlus	a684029
License data	US DailyMed: Timolol;
Pregnancy; category	AU: C; ;
Routes of; administration	By mouth, topical (eye drop)
Drug class	Beta blocker
ATC code	C07AA06 (WHO) S01ED01 (WHO) C07BA06 (WHO) C07DA06 (WHO); Combination: S01ED51 (WHO);
Legal status
Legal status	CA: ℞-only; UK: POM (Prescription only); US: ℞-only;
Pharmacokinetic data
Bioavailability	60%
Metabolism	Liver (80%, mainly CYP2D6)
Onset of action	15–30 min
Elimination half-life	2.5–5 hours
Duration of action	24 hours
Excretion	Kidney
Identifiers
	IUPAC name (S)-1-(tert-Butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol;
CAS Number	26839-75-8 ;
PubChem CID	33624;
IUPHAR/BPS	565;
DrugBank	DB00373 ;
ChemSpider	31013 ;
UNII	5JKY92S7BR;
KEGG	D08600 ; as salt: D00603 ;
ChEBI	CHEBI:9599 ;
ChEMBL	ChEMBL499 ;
CompTox Dashboard (EPA)	DTXSID4023674 ;
ECHA InfoCard	100.043.651
Chemical and physical data
Formula	C13H24N4O3S
Molar mass	316.42 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC(C)(C)NCC(O)COc1nsnc1N1CCOCC1;
	InChI InChI=1S/C13H24N4O3S/c1-13(2,3)14-8-10(18)9-20-12-11(15-21-16-12)17-4-6-19-7-5-17/h10,14,18H,4-9H2,1-3H3/t10-/m0/s1 ; Key:BLJRIMJGRPQVNF-JTQLQIEISA-N ;
	(verify)

Timolol is a beta blocker medication used either by mouth or as eye drops.^[3]^[5] As eye drops it is used to treat increased pressure inside the eye such as in ocular hypertension and glaucoma.^[3] By mouth it is used for high blood pressure, chest pain due to insufficient blood flow to the heart, to prevent further complications after a heart attack, and to prevent migraines.^[5]

Common side effects with the drops is irritation of the eye.^[3] Common side effects by mouth include tiredness, slow heart beat, itchiness, and shortness of breath.^[5] Other side effects include masking the symptoms of low blood sugar in those with diabetes.^[3] Use is not recommended in those with asthma, uncompensated heart failure, or COPD.^[3] It is unclear if use during pregnancy is safe for the fetus.^[6] Timolol is a non-selective beta blocker.^[3]

Timolol was patented in 1968, and came into medical use in 1978.^[7] It is on the World Health Organization's List of Essential Medicines.^[8] Timolol is available as a generic medication.^[3]^[9] In 2021, it was the 163rd most commonly prescribed medication in the United States, with more than 3 million prescriptions.^[10]^[11]

Medical uses

By mouth

In its by mouth or oral form, it is used:

to treat high blood pressure
to prevent heart attacks
to prevent migraine headaches^[12]

The combination of timolol and the alpha-1 blocker prazosin has sedative effects.^[13]

Eye drops

In its eye drop form it is used to treat open-angle and, occasionally, secondary glaucoma.^[3]^[14] The mechanism of action of timolol is probably the reduction of the formation of aqueous humor^[3] in the ciliary body in the eye. It was the first beta blocker approved for topical use in treatment of glaucoma in the United States (1978).^[15] When used by itself, it depresses intraocular pressure (IOP) 18–34% below baseline within first few treatments. However, there are short-term escape and long-term drift effects in some people. That is, tolerance develops. It may reduce the extent of the daytime IOP curve up to 50%. The IOP is higher during sleep. Efficacy of timolol in lowering IOP during the sleep period may be limited.^[16]^[17]^[18] It is a 5–10× more potent beta blocker than propranolol. Timolol is light-sensitive; it is usually preserved with 0.01% benzalkonium chloride (BAC), but also comes BAC-free. It can also be used in combination with pilocarpine, carbonic anhydrase inhibitors^[19] or prostaglandin analogs.^[20]

A Cochrane review compared the effect of timolol versus brimonidine in slowing the progression of open angle glaucoma in adults but found insufficient evidence to come to conclusions.^[21]

On the skin

In its gel form it is used on the skin to treat infantile hemangiomas.^[22]

Contraindications

The medication should not be taken by individuals with:^[23]

An allergy to timolol or any other beta-blockers
Asthma or severe chronic obstructive bronchitis
A slow heart rate (bradycardia), or a heart block
Heart failure^[24]

Side effects

The most serious possible side effects include cardiac arrhythmias and severe bronchospasms.^[23] Timolol can also lead to fainting, congestive heart failure, depression, confusion, worsening of Raynaud's syndrome and impotence.^[23]

Side effects when given in the eye include: burning sensation, eye redness, superficial punctate keratopathy, corneal numbness.^[25]^[14]

Formulations

It is available in tablet and liquid formulations.^[23]^[25]

For ophthalmic use, timolol is also available combined:

with carbonic anhydrase inhibitors:
- timolol and brinzolamide
- timolol and dorzolamide
with α₂ agonists:
- timolol and brimonidine
with prostaglandin analogs:
- timolol and latanoprost
- timolol and travoprost

Brand names

Timolol is marketed under many trade names worldwide.^[1] Timolol eye drops are marketed under the brand name Istalol among others.^[26]^[27]

References

^ ^a ^b "Timolol". Drugs.com. Archived from the original on 7 March 2016. Retrieved 28 December 2016.
^ "Product monograph brand safety updates". Health Canada. February 2024. Retrieved 24 March 2024.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k "Timolol eent". The American Society of Health-System Pharmacists. Archived from the original on 28 December 2016. Retrieved 8 December 2016.
^ Volotinen M, Turpeinen M, Tolonen A, Uusitalo J, Mäenpää J, Pelkonen O (July 2007). "Timolol metabolism in human liver microsomes is mediated principally by CYP2D6". Drug Metabolism and Disposition. 35 (7): 1135–1141. doi:10.1124/dmd.106.012906. PMID 17431033. S2CID 794764.
^ ^a ^b ^c "Timolol Maleate". The American Society of Health-System Pharmacists. Archived from the original on 28 December 2016. Retrieved 8 December 2016.
^ "Timolol ophthalmic Use During Pregnancy". The American Society of Health-System Pharmacists. Archived from the original on 28 December 2016. Retrieved 28 December 2016.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 460. ISBN 9783527607495. Archived from the original on 28 December 2016.
^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ "Competitive Generic Therapy Approvals". U.S. Food and Drug Administration (FDA). 29 June 2023. Archived from the original on 29 June 2023. Retrieved 29 June 2023.
^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
^ "Timolol - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
^ Marcus DA, Bain PA (27 February 2009). Effective Migraine Treatment in Pregnant and Lactating Women: A Practical Guide. シュプリンガー・ジャパン株式会社. pp. 141–. ISBN 978-1-60327-438-8. Archived from the original on 5 November 2017. Retrieved 14 November 2010.
^ Atkin T, Comai S, Gobbi G (April 2018). "Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery". Pharmacol Rev. 70 (2): 197–245. doi:10.1124/pr.117.014381. PMID 29487083. S2CID 3578916.
^ ^a ^b "Timolol Ophthalmic". MedlinePlus. 15 April 2017. Retrieved 31 December 2019.
^ Sambhara D, Aref AA (January 2014). "Glaucoma management: relative value and place in therapy of available drug treatments". Therapeutic Advances in Chronic Disease. 5 (1): 30–43. doi:10.1177/2040622313511286. PMC 3871276. PMID 24381726.
^ Liu JH, Kripke DF, Weinreb RN (September 2004). "Comparison of the nighttime effects of once-daily timolol and latanoprost on intraocular pressure". American Journal of Ophthalmology. 138 (3): 389–95. doi:10.1016/j.ajo.2004.04.022. PMID 15364220.
^ Liu JH, Medeiros FA, Slight JR, Weinreb RN (March 2009). "Comparing diurnal and nocturnal effects of brinzolamide and timolol on intraocular pressure in patients receiving latanoprost monotherapy". Ophthalmology. 116 (3): 449–54. doi:10.1016/j.ophtha.2008.09.054. PMID 19157559.
^ Liu JH, Slight JR, Vittitow JL, Scassellati Sforzolini B, Weinreb RN (September 2016). "Efficacy of Latanoprostene Bunod 0.024% Compared With Timolol 0.5% in Lowering Intraocular Pressure Over 24 Hours". American Journal of Ophthalmology. 169: 249–257. doi:10.1016/j.ajo.2016.04.019. PMID 27457257.
^ Strohmaier K, Snyder E, Adamsons I (July 1998). "A multicenter study comparing dorzolamide and pilocarpine as adjunctive therapy to timolol: patient preference and impact on daily life". Journal of the American Optometric Association. 69 (7): 441–51. PMID 9697378.
^ "Ganfort 0.3 mg/ml + 5 mg/ml eye drops, solution - Summary of Product Characteristics (SmPC)". (emc). 20 February 2020. Retrieved 1 March 2020.
^ Sena DF, Lindsley K (January 2017). "Neuroprotection for treatment of glaucoma in adults". The Cochrane Database of Systematic Reviews. 1 (1): CD006539. doi:10.1002/14651858.CD006539.pub4. PMC 5370094. PMID 28122126.
^ Novoa M, Baselga E, Beltran S, Giraldo L, Shahbaz A, Pardo-Hernandez H, et al. (April 2018). "Interventions for infantile haemangiomas of the skin". The Cochrane Database of Systematic Reviews. 2018 (4): CD006545. doi:10.1002/14651858.CD006545.pub3. PMC 6513200. PMID 29667726.
^ ^a ^b ^c ^d "Timolol Maleate tablet". DailyMed. 17 August 2006. Retrieved 1 December 2019.
^ "Package leaflet: Information for the user Timolol" (PDF). hpra.ie.
^ ^a ^b "Betimol- timolol solution". DailyMed. 18 March 2010. Retrieved 1 December 2019.
^ "Generic Istalol Availability". Drugs.com. Retrieved 20 June 2019.
^ "Istalol". Drugs.com. 1 August 2018. Retrieved 19 July 2019.