INTOX Home Page

Timolo

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)


    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Timolol
     1.2 Group
       beta-blocker; adrenergic beta-receptor blocking agent, 
       Class II antiarrhythmic drug
     1.3 Synonyms
       Timolol maleate
       MK-950
       (-)-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole
     1.4 Identification numbers
       1.4.1 CAS number
             26839-75-8
       1.4.2 Other numbers
             Timolol maleate : 26921-17-5
     1.5 Brand names, Trade names
       Betim (Denmark; Netherlands; Leo, Norway; Lovens, Sweden; Leo, 
       UK; Belgim); Blocadren (Frosst, Australia; Belgium; Frosst, 
       Canada; Merck Sharp & Dohme, Italy; Netherlands; Merck Sharp & 
       Dohme, Norway; Merck Sharp & Dohme, South Africa; Spain ; MSD, 
       Sweden; MSD Switzerland; MSD, UK; MSD, USA); Blocanol 
       (Finland); Chibro-Timoptol (Germany); Cusimolol (Cusi, Spain); 
       Oftan-Timolol (NAF, Norway); Proflax (Merck Sharp & Dohme, 
       Argentina); Temserin (Frosst, Germany; Greece); Tenopt (Sigma, 
       Australia); Tiloptic (Israel); Timacor (Denmark; Merck Sharp & 
       Dohme-Chibret, France); Timolide (USA); Timolol (UK); Timoptic 
       (Merck Sharp & Dohme, Canada; Chibret, Switzerland; Merck 
       Sharp & Dohme, USA; Austria); Timoptol (Frosst, Australia; 
       Merck Sharp & Dohme-Chibret, France; Chibret, Germany; Merck 
       Sharp & Dohme, Italy; Netherlands; New Zealand; South Africa; 
       Merck Sharp & Dohme, UK, Belgium).
     1.6 Manufacturers, Importers
    2. SUMMARY
     2.1 Main risks and target organs
       Beta-blocking agents exert their effects by competing with 
       endogenous and/or exogenous beta-adrenergic agonists. Timolol 
       is a non-cardioselective beta-blocker (it has similar affinity 
       for beta1 and beta2 receptors) and it has no intrinsic 
       sympathomimetic or membrane stabilising effect. The main risks 
       might be an impairment of atrioventricular conduction and a 
       negative inotropic effect (Critchley and Ungar, 1989; Frishman,
        1981)
     2.2 Summary of clinical effects
       Only one case of acute poisoning after ingestion of 300 mg 
       timolol in a  24 year-old man has been reported. The patient 
       showed moderate toxic  symptoms:  drowsiness, vertigo, 
       headache, and first degree atrioventricular  block which was 
       treated with atropine 1 mg and isoproterenol 5 mg. The  
       patient recovered without sequelae (Tisserand, 1982).
       
       Adverse systemic effects have been reported in patients 
       treated with timolol  eye drops.
     2.3 Diagnosis
       Symptoms are those anticipated from beta-blockade and include 
       heart block, drowsiness, headache and vertigo.There is, 

       however, little reported  experience of ovedose with timolol. 
       
       Timolol may be measured in plasma but plasma concentrations 
       are not known to be useful for the clinical management of the 
       patient.
     2.4 First aid measures and management principles
       Patients with poisoning by ingestion of timolol should be 
       monitored  closely, preferably in an intensive care unit.
            
       Monitor vital signs: ECG, blood pressure, respiration.
            
       Treatment may include:
       
       emesis, gastric lavage, oral activated charcoal
       
       atropine for symptomatic bradycardia, isoproterenol and/or 
       glucagon for  atrioventricular block or hypotension
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Synthetic
     3.2 Chemical structure
       C13H24N4O3S
       
       Molecular weight: 316.42
     3.3 Physical properties
       3.3.1 Properties of the substance
             White, odourless powder. 
             Melting point: 201.5-202.5 °C. 
             Soluble 1 in 15 of water, 1 in 21 of alcohol, 
             and 1 in 40 of  chloroform; soluble in methanol; 
             practically insoluble in ether. 
             A 2% solution in water has a pH of 3.8 to 4.3. 
             Ophthalmic preparations have a pH of 6.5 to 7.5. 
             
             (Reynolds, 1989; Merck Index, 1983)
       3.3.2 Properties of the locally available formulation
             See section 3.3.1.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             No data available.
       3.4.2 Shelf-life of the locally available formulation
             No data available.
       3.4.3 Storage conditions
             Store in well-closed containers. Ophthalmic solutions 
             should  be protected from light.
       3.4.4 Bioavailability
             No data available.
       3.4.5 Specific properties and composition
             No data available.
    4. USES
     4.1 Indications
       Oral administration
       
       Timolol has been used in the treatment of hypertension, angina
       pectoris, cardiac arrhythmias, migraine and for the 
       reduction of mortality  following myocardial infarction.

       Ocular administration
       
       Ophthalmic solutions of timolol are used in the treatment of 
       glaucoma to  reduce intraocular pressure.
     4.2 Therapeutic dosage
       4.2.1 Adults
             Ophthalmic solutions: The dose for glaucoma is 1 drop of 
              0.25% solution in each eye twice daily.  Dosage may be 
             increased to  1 drop of 0.5% solution twice daily.
                  
             Oral doses in hypertension are 15 to 60 mg daily.
             
             No dose adjustment is required in renal failure or in 
             patients  undergoing dialysis.
       4.2.2 Children
             Timolol is not recommended in children. The paediatric 
             dose  is unknown.
     4.3 Contraindications
       Timolol is contraindicated in patients with asthma, 2nd and 
       3rd degree AV block, and cardiogenic shock.
       
       Timolol should be used cautiously in patients with chronic 
       obstructive pulmonary diseases, sinus bradycardia, cardiac 
       failure,  myasthenia gravis, Raynaud's syndrome.
       
       Timolol should not be administered with other beta-blockers.
    5. ROUTES OF ENTRY
     5.1 Oral
       Poisoning after ingestion of timolol tablets may occur but 
       only one  case has been actually reported.
     5.2 Inhalation
       No data available.
     5.3 Dermal
       No case reported.
     5.4 Eye
       Systemic toxic symptoms may occur after treatment with
       timolol eye drops.
     5.5 Parenteral
       No data available.
     5.6 Other
       No data available.
    6. KINETICS
     6.1 Absorption by route of exposure
       Oral
       
       Timolol is almost completely (90%) absorbed from the 
       gastrointestinal tract.  The peak plasma concentration occurs 
       0.5-3 hours after ingestion (Fourtillan  et al, 1981). Timolol 
       is subject to a moderate first pass effect (Tocco et  al, 
       1975).
       
       Ocular
       
       The onset of the ocular hypotensive action occurs after 10-20 
       minutes and  lasts for at least 24 hours. (Zimmerman & Kaufman,

        1977b). Timolol is  absorbed systemically; serum 
       concentrations are 2-5  g/l (Affrime et al,  1980; Alvan et al,
        1980).
     6.2 Distribution by route of exposure
       Oral
       
       Bioavailability is about 60 % (Wilson et al, 1982).
       
       Apparent volume of distribution is 1.3 - 1.7 L/kg (Vermeij et 
       al, 1978;  Wilson et al, 1982)
       
       Plasma protein binding is approximately 10%.
       
       Timolol crosses the placenta
       
       Ocular
       Timolol is distributed in conjunctiva, cornea, sclera, iris, 
       aqueous humor,  liver, kidney and lung.
            
       Transdermal
       
       After cutaneous application of timolol ointment, 50 to 60 % is
       abosrbed systemically (Vlasses et al, 1985)
     6.3 Biological half-life by route of exposure
       Oral
       
       After oral administration, the half-life is 2.5 - 5 hours 
       (Tocco et al,  1975; Vermeij et al, 1978; Else et al, 1978; 
       Ishizaki and Tawara, 1978). The  half-life varies according to 
       genetic differences in hepatic metabolism:  half-lives of 3.7 
       and 7.5 hours were reported in extensive and poor  
       metabolisers, respectively (McGourty et al, 1985). The total 
       body clearance  is 463 ml/kg/hr (Wilson et al, 1982).
     6.4 Metabolism
       Oral
       
       Timolol is extensively metabolized in the liver by hydrolytic 
       cleavage of the morpholino ring with subsequent oxidation. 
       Following an oral dose, 80 % is metabolized and 20% is 
       eliminated unchanged in urine (Tocco et  al, 1975). Metabolism 
       is dependent on genetic polymorphism.
     6.5 Elimination by route of exposure
       Oral:     Kidney
       
       About 20% of the dose is eliminated unchanged in the urine and 
       40 to 60% as  metabolites (Tocco et al, 1975).
       
       Breast milk
       
       Timolol is present in breast milk but the total amount of 
       timolol ingested  by an infant who is breast feeding is 
       unlikely to cause any clinical  effects. Following a maternal 
       oral dose, the milk/plasma ratio is 0.80. 
       
       Ocular:   Breast milk
       

       Following ocular instilation, the concentration in breast milk 
       was  approximatively 6 times higher (5.6 ng/ml) than in serum 
       (0.93 ng/ml)  (Lustgarten and Podos, 1983). However, the total 
       amount of timolol ingested  by an infant who is breast feeding 
       is unlikely to cause any clinical  effects.
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             At toxic doses, timolol may exert a pronounced negative  
             chronotropic and negative inotropic cardiac effect.
       7.1.2 Pharmacodynamics
             The exact mechanism whereby timolol reduces ocular 
             pressure   is still not known. The most likely action is 
             by decreasing the  secretion of aqueous humor
             (Zimmerman et al, 1977)
             
             At therapeutic doses, timolol slightly decreases heart 
             rate,  supraventricular conduction and cardiac output.
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     Only one case of acute poisoning with timolol  
                     (after ingestion of 300 mg) has been reported; 
                     this  patient showed moderately severe symptoms 
                     (Tisserand,  1982).
             7.2.1.2 Children
                     An 18 month-old girl developed bradycardia,  
                     respiratory depression and cyanosis 30 minutes 
                     after the  administration of timolol eye drops 
                     (Williams and Ginther,  1982).
       7.2.2 Relevant animal data
             The oral LD50 is 1190 mg/kg in mice and 900 mg/kg in 
             rats  (RTECS, 1980).
       7.2.3 Relevant in vitro data
             No data available.
     7.3 Carcinogenicity
       No data available.
     7.4 Teratogenicity
       No epidemiological studies of congenital abnormalities among 
       infants  born to women treated with timolol during pregnancy 
       have been reported.
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       Sinus bradycardia has been reported after concomitant 
       treatment with  timolol eye drops and quinidine.
     7.7 Main adverse effects
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens

             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
                     Routine biochemical investigations (i.e. sodium, 
                      potassium, creatinine and/or urea, glucose).
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
             Should be obtained on admission.
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
             Following a single oral dose of 20 mg, the mean peak 
             plasma  concentration is 83 microgram/l (range: 50 - 
             103) (Fourtillan et al,  1981). The plasma concentration 
             required for beta-blocking  activity is estimated to be 
             5 - 10 microgram/l.
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Only one case of acute poisoning of timolol following  
             ingestion of 300 mg in a 24 year-old man has been 
             reported. The  patient showed moderately severe symptoms,
              including drowsiness,  vertigo, headache, first-degree 
             atrioventricular block (Tisserand,  1982).
       9.1.2 Inhalation
             No data available.
       9.1.3 Skin exposure

             No data available.
       9.1.4 Eye contact
             Adverse systemic effects have been reported after 
             treatment  with ophtalmic solutions of timolol. See 
             section 7.7.
       9.1.5 Parenteral exposure
             No data available.
       9.1.6 Other
             No data available.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             No data available.
       9.2.2 Inhalation
             No data available.
       9.2.3 Skin exposure
             No data available.
       9.2.4 Eye contact
             Dryness of the eye has been reported in a man treated by 
              timolol 75 mg daily (Frais and Batley, 1979)
             
             Corneal anaesthesia was observed in a patient treated 
             with timolol  eye drops (Calissendorff, 1981).
       9.2.5 Parenteral exposure
             No data available.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       Only one case of acute poisoning following ingestion of 300 mg 
       timolol  in a 24 year-old man has been reported. The patient 
       showed moderately severe  symptoms:  drowsiness, vertigo, 
       headache, first degree atrioventricular  block which was 
       treated by atropine 1 mg and isoproterenol 5 mg. The patient   
       recovered without sequelae (Tisserand, 1982). No deaths have 
       been reported.
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Acute 
             
             First-degree atrioventricular block has been reported 
             after  ingestion of 300 mg; blood pressure was
             120/80 mmHg and the heart rate was 58/min (Tisserand, 
             1982).
             
             Bradycardia, hypotension, atrioventricular block and 
             congestive  cardiac failure may occur after 
             administration of timolol.
             
             Chronic: No data available.
       9.4.2 Respiratory
             Acute 
             
             Reversible respiratory arrest was observed in a 62-year-
             old woman  after instillation of timolol eye drops 
             (Botet et al, 1986) and may  occur after oral
             administration.
             

             Bronchospasm may occur in susceptible patients after 
             administration  of timolol. 
             
             Chronic: No data available.
       9.4.3 Neurological
             9.4.3.1 CNS
                     Acute
                     
                     Drowsiness, vertigo, headache have been reported 
                     in one  case after ingestion of 300 mg 
                     (Tisserand, 1982).
                     
                     Fatigue, confusion, depression, hallucinations 
                     have been  reported after administration of 
                     timolol.
                     
                     Chronic: No data available.
             9.4.3.2 Peripheral nervous system
                     Acute
                     
                     Worsening of myasthenia gravis may occur after  
                     administration of timolol.
                     
                     Chronic: No data available.
             9.4.3.3 Autonomic nervous system
                     Acute: Effects of beta-blockade.
                     
                     Chronic: Effects of beta-blockade.
             9.4.3.4 Skeletal and smooth muscle
                     No data available.
       9.4.4 Gastrointestinal
             Acute
             
             Abdominal pain, nausea, vomiting and diarrhoea may occur 
             after  administration of timolol orally or as eye drops.
             
             Chronic: No data available.
       9.4.5 Hepatic
             No data available.
       9.4.6 Urinary
             9.4.6.1 Renal
                     No data available.
             9.4.6.2 Other
                     No data available.
       9.4.7 Endocrine and reproductive systems
             No data available.
       9.4.8 Dermatological
             Acute: Urticaria may be observed.
             
             Chronic: No data available.
       9.4.9 Eye, ear, nose, throat: local effects
             Acute
             
             Eyelid erythema and oedema has been reported following 
             ocular  administration.
             

             Chronic: No data available.
       9.4.10 Haematological
              No data available.
       9.4.11 Immunological
              No data available.
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       No data available.
              9.4.12.2 Fluid and electrolyte disturbances
                       Hyperkalaemia has been reported.
              9.4.12.3 Others
                       No data available.
       9.4.13 Allergic reactions
              No data available.
       9.4.14 Other clinical effects
              Sexual dysfunction following usual doses of topical 
              ocular  timolol has been reported and may also occur 
              after oral  administration.
       9.4.15 Special risks
              Timolol is eliminated in breast milk but the total 
              amount  of timolol ingested by an infant who is breast 
              feeding is unlikely  to cause clinical effects.
              
              No epidemiological studies of congenital anomalies 
              among infants  born to women treated with timolol 
              during pregnancy have been  reported.
     9.5 Other
       No data available.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Patients with poisoning by ingestion of timolol should be 
         monitored  preferably in an intensive care unit.
         
         Monitor vital signs: ECG, blood pressure, respiration.
         
         Treatment may include:
         
         emesis, gastric lavage, oral activated charcoal
         
         atropine for symptomatic bradycardia, isoproterenol and/or 
         glucagon for  atrioventricular block or hypotension
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
         10.2.2 Biomedical analysis
         10.2.3 Toxicological analysis
                Measurement of plasma timolol concentrations is not 
                useful  for the clinical management.
         10.2.4 Other investigations
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         See also monograph on PROPRANOLOL.
         
         Cardiovascular disturbances:
         
         Sinus bradycardia may be treated with intravenous atropine.

         
         Isoproterenol is the drug of choice for the treatment of 
         atrioventricular  block. Hypotension may require 
         administration of isoproterenol or glucagon.
         
         Respiratory:
         
         Bronchospasm may be treated with beta-2-agonists or 
         aminophylline.
      10.4 Decontamination
         Although emesis, gastric lavage and oral activated charcoal 
         have not  been evaluated in timolol poisoning but they may 
         be indicated in poisoning  by ingestion.
      10.5 Elimination
         The efficacy of forced diuresis has not been evaluated.
         
         The elimination of timolol is not significantly enhanced by 
         haemodialysis or  peritoneal dialysis and these procedures 
         cannot be recommended.
      10.6 Antidote treatment
         10.6.1 Adults
         10.6.2 Children
      10.7 Management discussion
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         Tisserand (1982) reported a case of acute poisoning after 
         ingestion of  300 mg of timolol in a 24 year-old man. The 
         patient developed moderately  severe symptoms, including 
         drowsiness, vertigo, headache, first degree  
         atrioventricular block. Treatment included atropine 1 mg and 
         isoproterenol 5  mg. The patient recovered without any 
         complications.
      11.2 Internally extracted data on cases
      11.3 Internal cases
    12. Additional information
      12.1 Availability of antidotes
         No data available.
      12.2 Specific preventive measures
         No data available.
      12.3 Other
         No data available.
    13. REFERENCES
    Affrime MB et al (1980). Dynamics and kinetics of ophthalmic 
    timolol.
    Clin Pharmacol Ther 27: 471 
    
    Alvan G (1980). Absorption of ocular timolol. Clin 
    Pharmacokinetics
    5: 95.
    
    Botet C, Grau J, Benito P et al (1986). Timolol ophthalmic 
    solution and respiratory  arrest. Ann Intern Med 105: 306.
    
    Calissendorff B (1981).  Corneal anesthesia after treatment with 
    maleate, a case  report.  Acta Ophthalmologica 59: 347.
    

    Cheymol G, Biour M (1985).  Données récentes sur les effets 
    indésirables des  inhibiteurs bêta-adrénergiques. Thérapie 40: 
    423-8. 
    
    Critchley JAJH, Ungar A (1989).  The management of acute 
    poisoning due to  beta-adrenoceptor antagonists. Med Toxicol 4: 
    32-45.
    
    Drugdex, Micromedex Inc., 1991.
    
    Dukes MNG (1984). Side Effects of Drugs, Annual 8. Elsevier, 
    Amsterdam. 
    
    Else et al (1978).  Eur J Clin Pharmacol 14: 431.
    
    Fourtillan JB, Courtois P, Lefebvre MA et al (1981).  
    Pharmacokinetics of oral  timolol studied by mass fragmentography 
    Eur J Clin Parmacol 19: 193-196.
    
    Frais MA, Baley TJ (1979). Ocular reaction to timolol maleate. 
    Postgrad Med J 55:  884. 
    
    Fraunfelder FT, Meyer SM (1987). Systemic reactions to ophthalmic 
    drug preparations.   Med Toxicol 2: 287-293.
    
    Frishman WH (1982).  Atenolol and timolol, two new systemic beta-
    adrenoceptor  antagonists. New Eng J Med 306: 1456-1462.
    
    Ishizaki T, Tawara K (1978). Eur J Clin Pharmacol 14: 7 
    
    Lustgarten JS, Podos SM (1983). Topical timolol and the nursing 
    mother. Arch  Ophthalmol 101: 1381-1382.
    
    Lustgarten JS (188). Topical timol-induced arthropathy. Am J 
    Ophthalmol 105: 687-688.
    
    Reynolds JEF (1989). Martindale, The Extra Pharmacopoeia. The 
    Pharmaceutical Press.   London.
    
    McGourty JC, Silas JH, Fleming JJ et al (1985). Pharmacokinetics 
    and beta-blocking  effects of timolol in poor and extensive 
    metabolizers of debrisoquine. Clin Pharmacol  Ther 38: 409-413.
    
    Merck Index (1983). An encyclopedia of chemicals, drugs and 
    biologicals, 10th ed,  Merck Inc. 
    
    RTECS, (1980). Registry of Toxic Effects of Chemical Substances.
    Lewis RL (ed). 
    
    Tisserand D (1982). Intoxications volontaires aiguës par les beta-
    bloquants. A propos  de 19 cas. Thèse Méd., Nancy I. 
    
    Tocco DJ et al (1975). Physiological disposition of and 
    metabolism of timolol in man  and laboratory animals. Drug Metab 
    Dispos 3: 361.
    

    Vermeij P et al (1978). The disposition of timolol in man. J 
    Pharm Pharmacol 30: 53. 
    
    Vlasses PH, Ribeiro LGT, Rotmensch HH et al (1985). Initial 
    evaluation of transdermal  timolol: serum concentrations and beta-
    blockade. J Cardiovascular Pharmacol 7:  245-250.
    
    Williams T, Ginther WH. Hazard of ophthalmic timolol. New Eng J 
    Med 306:  1485-1486.
    
    Wilson TW, Firor WB, Johnson GL et al (1982). Timolol and 
    propranolol:
    bioavailability, plasma concentrations and beta-blockade. Clin 
    Pharmacol Ther 32:   676-685.
    
    Zimmerman T, Kaufman H (1977a). Timolol: a beta-adrenergic 
    blocking agent for the  treatment of glaucoma. Arch Ophthalmol 
    95: 601.
    
    Zimmerman T, Kaufman H (1977b). Timolol: dose response and 
    duration of action. Arch  Ophthalmol 95: 605.
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Authors:  Jaeger A., Flesch F. Kopferschmitt J., Sauder Ph.
              Service de Réanimation Médicale et Centre Anti-Poisons  
                              
              CHU, Pavillon Pasteur
              1 Place de l'Hôpital
              67091 Strasbourg Cédex
              France
    
              Tel: 33-88161144
              Fax: 33-88161330
    
    Date:     28 March 1991
    
    Peer Review: Adelaide, Australia, April 1991