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-
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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