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Identification
Name Timolol
Accession Number DB00373 (APRD00229, DB08625)
Type small molecule
Groups approved
Description

A beta-adrenergic antagonist similar in action to propranolol. The levo-isomer is the more active. Timolol has been proposed as an antihypertensive, antiarrhythmic, antiangina, and antiglaucoma agent. It is also used in the treatment of migraine disorders and tremor. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Timolol maleate
  • Timololum [INN-Latin]
Brand names
  • Apo-Timol
  • Apo-Timop
  • Aquanil
  • Betim
  • Betimol
  • Blocadren
  • Istalol
  • Novo-Timol
  • Nu-Timolol
  • Phoxal-timolol
  • Proflax
  • Temserin
  • Tenopt
  • Tim-AK
  • Timacar
  • Timacor
  • Timopic
  • Timoptic
  • Timoptic in Ocudose
  • Timoptic OcuDose
  • Timoptic-XE
  • Timoptol
Brand name mixtures
  • Combigan (Brimonidine Tartrate + Timolol Maleate)
  • Cosopt (Dorzolamide Hydrochloride + Timolol Maleate)
  • Timolide Tab (Hydrochlorothiazide + Timolol Maleate)
  • Timpilo 2 (Pilocarpine Hydrochloride + Timolol Maleate)
  • Timpilo 4 (Pilocarpine Hydrochloride + Timolol Maleate)
  • Xalacom (Latanoprost + Timolol Maleate)
Categories
  • Antihypertensive Agents
  • Adrenergic beta-Antagonists
  • Anti-Arrhythmia Agents
CAS number 26839-75-8
Weight Average: 316.42
Monoisotopic: 316.156911344
Chemical Formula C13H24N4O3S
InChI Key InChIKey=BLJRIMJGRPQVNF-JTQLQIEISA-N
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
Plain Text
IUPAC Name
tert-butyl[(2S)-2-hydroxy-3-{[4-(morpholin-4-yl)-1,2,5-thiadiazol-3-yl]oxy}propyl]amine
SMILES
CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Ethers
Substructures
  • Hydroxy Compounds
  • Aliphatic and Aryl Amines
  • Thiadiazoles
  • Ethers
  • Amino Alcohols
  • Heterocyclic compounds
  • Aromatic compounds
  • Morpholines
  • Alcohols and Polyols
Pharmacology
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.
Pharmacodynamics 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.
Absorption Bioavailability is about 60%
Volume of distribution Not Available
Protein binding ~10%
Metabolism

Primarily hepatic (80%) via the cytochrome P450 2D6 isoenzyme.
Route of elimination Timolol and its metabolites are primarily excreted in the urine.
Half life 2.5-5 hours
Clearance Not Available
Toxicity LD50=1190 mg/kg (oral, mice), LD50=900 mg/kg (oral, rat). Symptoms of overdose include drowsiness, vertigo, headache, and atriventricular block.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Santen oy
  • Falcon pharmaceuticals ltd
  • Aton pharma inc
  • Ista pharmaceuticals
  • Akorn inc
  • Bausch and lomb pharmaceuticals inc
  • Bausch and lomb inc
  • Falcon pharmaceuticals inc
  • Fdc ltd
  • E fougera div altana inc
  • Hi tech pharmacal co inc
  • Novex pharma
  • Pacific pharma inc
  • Pacific pharma
  • Wockhardt ltd
  • Merck research laboratories div merck co inc
  • Mylan pharmaceuticals inc
  • Quantum pharmics ltd
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Usl pharma inc
  • Watson laboratories inc
Packagers
Dosage forms
Form Route Strength
Liquid Ophthalmic
Solution Ophthalmic
Solution / drops Ophthalmic
Tablet Oral
Prices
Unit description Cost Unit
Betimol 0.5% Solution 15ml Bottle 152.24 USD bottle
Timolol maleate powder 107.1 USD g
Betimol 0.5% Solution 10ml Bottle 106.88 USD bottle
Betimol 0.25% Solution 15ml Bottle 93.56 USD bottle
Timoptic-XE 0.5% Gel Forming Solution 5ml Bottle 85.09 USD bottle
Timoptic 0.5% Solution 10ml Bottle 83.2 USD bottle
Timoptic-XE 0.25% Gel Forming Solution 5ml Bottle 65.37 USD bottle
Betimol 0.5% Solution 5ml Bottle 63.43 USD bottle
Timolol Maleate 0.5% Gel Forming Solution 5ml Bottle 60.84 USD bottle
Timoptic 0.5% Solution 5ml Bottle 59.8 USD bottle
Timolol Maleate 0.25% Gel Forming Solution 5ml Bottle 59.71 USD bottle
Betimol 0.25% Solution 5ml Bottle 55.56 USD bottle
Timolol Maleate 0.5% Solution 15ml Bottle 50.7 USD bottle
Betimol 0.25% Solution 10ml Bottle 49.99 USD bottle
Timolol Maleate 0.5% Gel Forming Solution 2.5ml Bottle 46.74 USD bottle
Timolol Maleate 0.25% Solution 15ml Bottle 43.68 USD bottle
Timoptic 0.25% Solution 5ml Bottle 43.06 USD bottle
Istalol 0.5% eye drops 36.43 USD ml
Timolol Maleate 0.5% Solution 10ml Bottle 33.58 USD bottle
Timolol Maleate 0.25% Solution 10ml Bottle 28.87 USD bottle
Timoptic-XE 0.25% Gel Forming Solution 2.5ml Bottle 23.99 USD bottle
Timolol Maleate 0.5% Solution 5ml Bottle 17.68 USD bottle
Timolol Maleate 0.25% Solution 5ml Bottle 15.6 USD bottle
Timoptic-xe 0.5% eye solution 13.6 USD ml
Timoptic-xe 0.25% eye solution 11.51 USD ml
Betimol 0.5% eye drops 10.15 USD ml
Betimol 0.25% eye drops 9.19 USD ml
Timoptic 0.5% eye drops 8.63 USD ml
Timoptic 0.25% eye drops 7.32 USD ml
Timoptic-Xe 0.5 % Long Acting Gellan Solution 4.64 USD ml
Timoptic 0.5% ocudose drops 4.57 USD each
Timoptic-Xe 0.25 % Long Acting Gellan Solution 3.88 USD ml
Timoptic 0.25% ocudose drops 3.8 USD each
Timoptic 0.5 % Solution 3.63 USD ml
Timolol 0.5% eye drops 3.24 USD ml
Timolol 0.25% eye drops 2.78 USD ml
Apo-Timop 0.5 % Solution 1.95 USD ml
Mylan-Timolol 0.5 % Solution 1.95 USD ml
Pms-Timolol 0.5 % Solution 1.95 USD ml
Sandoz Timolol Maleate 0.5 % Solution 1.95 USD ml
Apo-Timop 0.25 % Solution 1.62 USD ml
Mylan-Timolol 0.25 % Solution 1.62 USD ml
Pms-Timolol 0.25 % Solution 1.62 USD ml
Sandoz Timolol Maleate 0.25 % Solution 1.62 USD ml
Timolol maleate 20 mg tablet 0.94 USD tablet
Hydrocortisone 2.5% lotion 0.6 USD ml
Apo-Timol 20 mg Tablet 0.59 USD tablet
Novo-Timol 20 mg Tablet 0.59 USD tablet
Timolol maleate 10 mg tablet 0.51 USD tablet
Timolol maleate 5 mg tablet 0.41 USD tablet
Apo-Timol 10 mg Tablet 0.3 USD tablet
Novo-Timol 10 mg Tablet 0.3 USD tablet
Nu-Timolol 10 mg Tablet 0.3 USD tablet
Apo-Timol 5 mg Tablet 0.19 USD tablet
Novo-Timol 5 mg Tablet 0.19 USD tablet
Nu-Timolol 5 mg Tablet 0.19 USD tablet
Aquanil hc 1% lotion 0.12 USD ml
Aquanil cleanser 0.03 USD ml
Patents
Country Patent Number Approved Expires
United States 6174524 1999-09-26 2019-09-26
United States 5231095 1993-07-27 2010-07-27
Properties
State solid
Melting point 201.5-202.5 oC
Experimental Properties
Property Value Source
water solubility 2.74 mg/mL PhysProp
logP 1.2 PhysProp
Caco2 permeability -4.85 [ADME Research, USCD] BiGG
pKa 3.9 Various sources
Predicted Properties
Property Value Source
water solubility 2.69e-01 g/l ALOGPS
logP 1.44 ALOGPS
logP 1.34 ChemAxon Molconvert
logS -3.07 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 7 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 79.74 ChemAxon Molconvert
rotatable bond count 7 ChemAxon Molconvert
refractivity 83.92 ChemAxon Molconvert
polarizability 33.75 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Link
External Links
Resource Link
KEGG Compound C07141 Link_out
PubChem Compound 33624 Link_out
PubChem Substance 46507733 Link_out
ChemSpider 31013 Link_out
ChEBI 39465 Link_out
ChEMBL 39465 Link_out
Therapeutic Targets Database DAP000088 Link_out
PharmGKB PA451690 Link_out
HET TIM Link_out
Drug Product Database 812455 Link_out
RxList http://www.rxlist.com/cgi/generic3/timololgfs.htm Link_out
Drugs.com http://www.drugs.com/cdi/timolol-drops.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Timolol Link_out
ATC Codes
  • C07AA06
  • S01ED01
AHFS Codes
  • 52:92.00
  • 24:24.00
PDB Entries Not Available
FDA label show (471.4 KB)
MSDS show (73.5 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Beta-1 adrenergic receptor

Pharmacological action: yes
Actions: antagonist

Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity

Organism class: human
UniProt ID: P08588 Link_out
Gene: ADRB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Nieminen T, Uusitalo H, Maenpaa J, Turjanmaa V, Rane A, Lundgren S, Ropo A, Rontu R, Lehtimaki T, Kahonen M: Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol. A pilot study. Eur J Clin Pharmacol. 2005 Dec;61(11):811-9. Epub 2005 Nov 17. Pubmed
  3. Varma DR, Shen H, Deng XF, Peri KG, Chemtob S, Mulay S: Inverse agonist activities of beta-adrenoceptor antagonists in rat myocardium. Br J Pharmacol. 1999 Jun;127(4):895-902. Pubmed
  4. Hirooka K, Kelly ME, Baldridge WH, Barnes S: Suppressive actions of betaxolol on ionic currents in retinal ganglion cells may explain its neuroprotective effects. Exp Eye Res. 2000 May;70(5):611-21. Pubmed
  5. Bhattacharyya BJ, Lee E, Krupin D, Hockberger P, Krupin T: (-)-Isoproterenol modulation of maxi-K(+) channel in nonpigmented ciliary epithelial cells through a G-protein gated pathway. Curr Eye Res. 2002 Mar;24(3):173-81. Pubmed
  6. Wang T, Kaumann AJ, Brown MJ: (—)-Timolol is a more potent antagonist of the positive inotropic effects of (—)-adrenaline than of those of (—)-noradrenaline in human atrium. Br J Clin Pharmacol. 1996 Aug;42(2):217-23. Pubmed

2. Beta-2 adrenergic receptor

Pharmacological action: yes
Actions: antagonist

Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine

Organism class: human
UniProt ID: P07550 Link_out
Gene: ADRB2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Fuchsjager-Mayrl G, Markovic O, Losert D, Lucas T, Wachek V, Muller M, Schmetterer L: Polymorphism of the beta-2 adrenoceptor and IOP lowering potency of topical timolol in healthy subjects. Mol Vis. 2005 Sep 23;11:811-5. Pubmed
  3. Rotmensch HH, Vlasses PH, Feinberg JA, Abrams WB, Ferguson RK: Comparisons of beta-adrenergic blocking properties of S- and R-timolol in humans. J Clin Pharmacol. 1993 Jun;33(6):544-8. Pubmed
  4. Borger P, Hoekstra Y, Esselink MT, Postma DS, Zaagsma J, Vellenga E, Kauffman HF: Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Am J Respir Cell Mol Biol. 1998 Sep;19(3):400-7. Pubmed
  5. Van der Graaf PH, Saxena PR, Shankley NP, Black JW: Exposure and characterization of the action of noradrenaline at dopamine receptors mediating endothelium-independent relaxation of rat isolated small mesenteric arteries. Br J Pharmacol. 1995 Dec;116(8):3237-42. Pubmed
  6. Ferro A, Hall JA, Dickerson JE, Brown MJ: A prospective study of the effects of prolonged timolol therapy on alpha- and beta-adrenoceptor and angiotensin II receptor mediated responses in normal subjects. Br J Clin Pharmacol. 1997 Mar;43(3):301-8. Pubmed
  7. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed

3. Lysozyme

Pharmacological action: unknown

Helps to release the mature phage particles from the cell wall by breaking down the peptidoglycan

Organism class: viral
UniProt ID: P00720 Link_out
Gene: E
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed
Enzymes

1. Cytochrome P450 2D6

Actions: substrate

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C19

Actions: substrate

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: substrate

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Terao T, Hisanaga E, Sai Y, Tamai I, Tsuji A: Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier. J Pharm Pharmacol. 1996 Oct;48(10):1083-9. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on July 14, 2011 16:14

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.