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Propranolol

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 Main brand names, main 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 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   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
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 keletal 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 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
12. Additional information
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    PROPRANOLOL

    International Programme on Chemical Safety
    Poisons Information Monograph 441
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Propranolol

        1.2  Group

             Beta-blocker
             Beta-adrenergic receptor blocking agent
             Class II antiarrhythmic drug

        1.3  Synonyms

             1-isopropylamine-3-(1-naphtylhoxy)-2 propanol;
             1-isopropylamine-3-(alpha naphthoxy)-2 propanol-hydrochloride;
             Propanolol;
             1-isopropylamino-3-(1-naphthyloxy)propan-2-ol;
             1-isopropylamino-3-(1-naphthyloxy)propan-2-olhydrochloride;
             Dociton;
             ICI 45520;
             Inderal;
             Inderal hydrochloride;
             Inderol;
             Propranolol hydrochloride;
             Propranolon hydrochloride;

        1.4  Identification numbers

             1.4.1  CAS number

                    525-66-6

             1.4.2  Other numbers

                    318-98-9
                    AY - 64043
                    ICI - 45520
                    NCS - 91523
                    RTECS: UB 7500000 propranolol base
                    RTECS: UB 7525000 propranolol hydrochloride

        1.5  Main brand names, main trade names

             Angilol (United Kingdom); Arcablock-Retard-Capsules
             (Austria); Apsolol (United Kingdom); Avlocrdyl (France);
             Bedranol (Switzerland - United Kingdom); Beprane (France);

             Berkolol (United Kingdom); Beta-Neg (Italy); Betaryl
             (France); Beta-tablinen (Germany); Blocardyl (Argentina);
             Cardinol  (Australia); Cadispare (South Africa); Caridolol
             (Japan); Corotrend (Switzerland); Deralin (Australia,Israel);
             Detensol  (Canada); Dideral (Turkey); Dociton (Germany);
             Efektolol  (Germany); Elbrol (Germany); Euprovasin (Italy);
             Frekven  (Denmark; Norway; Sweden); Herzbase (Japan); Herzul
             (Japan); Ikopal (Iceland); Indéral (Argentina; Australia;
             Belgium; Canada; Denmark; Italy, Japan; Nether Lands; Norway;
             South Africa; Sweden; Switzerland; United Kingdom; United
             States of America); Inderalici (Italy); Indobloc (Germany);
             Kemi (Japan); Nedis (Argentina); Noloten (Argentina);
             Novopralol (Canada); Obsidan (Germany); Oposim (Argentina);
             Pranolol (Norway); Prano-puren (Germany); Prolol (Australia);
             Pronovan (Norway); Propabloc (Germany); Propalong
             (Argentina); Propanur (Germany); Propra-ratiopharm (Germany);
             Pur bloka (South Africa); Pylapron (Japan); Reducor (Turkey);
             Rexigen (South Africa); Sagittol (Germany); Sawatal (Japan);
             Sumial (Spain); Tensiflex (Argentina); Teenol (Japan); Tonum
             (Italy). 

        1.6  Manufacturers, Importers

             No data available.

    2.  SUMMARY

        2.1  Main risks and target organs

             Beta-blockers compete with endogenous and/or exogenous
             beta-adrenergic agonists. Propranolol is not cardioselective
             and it has no intrinsic sympathomimetic activity. It has
             membrane stabilizing properties and is highly lipid soluble.
             At toxic doses, propranolol has a pronounced negative
             chronotropic and inotropic effect and also a quinidine-like
             effect on the heart.
    
             The cardiovascular system is the main target organ. 
             Propranolol decreases sinus rate, atrio-ventricular
             conduction, intraventricular conduction and cardiac
             contractility.  Central nervous system toxicity (coma and
             convulsions) may also occur because of its high
             liposolubility.

        2.2  Summary of clinical effects

             Toxicity occurs within 1 to 2 hours following ingestion
             but the delay in onset may vary according to the
             formulation.
    

             Symptoms may include:
    
             * Cardiovascular disturbances: bradycardia, atrioventricular
               block of varying degrees, intraventricular block,
               hypotension, cardiogenic shock, pulmonary oedema
    
             * Neurological symptoms: coma and convulsions 
    
             * Respiratory depression and apnoea.
    
             * Cardiovascular collapse and apnoea may occur suddenly. 
               Patients with underlying cardiovascular disease are
               predisposed to the adverse cardiac effects of propranolol. 
               Propranolol may induce bronchospasm in asthmatic
               patients.

        2.3  Diagnosis

             Nausea, vomiting, bradycardia and hypotension are the
             early features of propranolol poisoning. In severe cases
             coma, convulsions, shock and respiratory depression may be
             present.
    
             Blood pressure monitoring and ECG are the relevant
             investigations to detect cardiotoxicity.  The ECG may show
             bradycardia, AV block, widened QRS complex and bundle branch
             block.
    
             Measurement of propranolol concentration may be helpful for
             diagnosis but is not useful for clinical management.

        2.4  First aid measures and management principles

             Patients with propranolol poisoning should be monitored
             closely preferably in an intensive care unit.
    
             Monitor vital signs: ECG, blood pressure, respiration
    
             Treatment may include:
    
             * gastric lavage, emesis only after immediate ingestion, oral
               activated charcoal.
    
             * supportive treatment of respiratory failure by artificial
               ventilation.
    
             * symptomatic treatment for convulsions with diazepam, and
               shock with dopamine or norepinephrine.
    
             * atropine in case of symptomatic bradycardia
    

             * isoproterenol and/or glucagon act as antidote and should be
               administered if atrioventricular block or shock are
               present.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Synthetic substance.

        3.2  Chemical structure
    
    STRUCTURAL FORMULA 1
    
             Propranolol:   C16H21NO2
    
             Molecular Weight = 259.35
    
             Propranolol hydrochloride:    C16H21NO2HCl
    
             Molecular Weight = 295.84

        3.3  Physical properties

             3.3.1  Colour

                    White

             3.3.2  State/form

             3.3.3  Description

                    White, odourless crystalline powder. Soluble 1
                    in 20 of water or alcohol; slightly soluble in
                    chloroform; practically insoluble in ether.
    
                    Only stable at acidic pH; decomposes rapidly when
                    alkaline. Solutions are most stable at pH 3; in
                    aqueous solutions propranolol decomposes with
                    oxidation of the isopropylamine side-chain 
                    (Martindale). Propranolol is a racemic mixture of
                    dextrorotary and levorotary forms.

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    No data available.

             3.4.2  Storage conditions

                    Store in well-closed containers, protect from light.

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    Cardiovascular diseases
    
                    Propranolol, a non cardioselective beta-blocker, is
                    mostly used in the treatment of hypertension, angina,
                    for the prevention of re-infarction in patients who
                    have suffered from myocardial infarction. It is also
                    used to control symptoms of anxiety and in the
                    treatment of supraventricular tachycardia,
                    hypertrophic obstructive cardiomyopathy and tetralogy
                    of Fallot.
    
                    Endocrine disorders
    
                    In hyperthyroidism and thyrotoxic crisis; together
                    with alpha blocking agents in the preoperative
                    treatment of phaeochromocytoma.
    
                    Hepatic diseases
    
                    Prevention of haemorrhage in portal hypertension
    
                    Neurological disorders
    
                    Propranolol has also been used in the treatment of
                    extrapyramidal disorders and in the prophylaxis of
                    migraine headache.
    

                    Anxiety disorders
    
                    Propranolol may be used in acute stress reactions,
                    somatic anxiety and panic reactions, but its value is
                    questioned (Reynolds, 1993).

        4.2  Therapeutic dosage

             4.2.1  Adults

                    Propranolol dosing should be initiated at low
                    doses and gradually increased until the desired
                    therapeutic effect is achieved.
    
                    Oral administration
    
                    In cardiovascular diseases: the initial dose of 40 mg
                    twice daily, may be increased at weekly intervals to a 
                    maintenance dose of 160 to 260 mg daily (some patients
                    require 320 mg daily).
    
                    In prevention of haemorrhage due to portal
                    hypertension: 20 mg twice daily.
    
                    In migraine headache: 40 to 120 mg daily 
    
                    Intravenous administration
    
                    The optimal dose is 1 to 3 mg (inject slowly: 1
                    mg/minute maximum). The total dose should not exceed 5
                    to 10 mg.

             4.2.2  Children

                    Oral administration
    
                    0.25 to 0.5 mg/kg/24 hours administered in divided
                    doses (3 or 4 times daily up to 1 mg/kg/24 hours) 
    
                    Intravenous administration
    
                    0.025 to 0.05 mg/kg; 3 or 4 times daily under ECG
                    control
    
                    Caution: Propranolol should never be discontinued
                    abruptly in patients with coronary artery disease. 
                    Gradually decrease the dosage.

        4.3  Contraindications

             Absolute: asthma, congestive cardiac failure,
             atrio-ventricular block, bradycardia (below 50/minute),
             treatment with amiodarone.
    
             Relative: Raynaud's disease, diabetes mellitus.

    5.  ROUTES OF ENTRY

        5.1  Oral

             Ingestion is the most frequent cause of poisoning

        5.2  Inhalation

             No case has been reported.  The effect of 10 mg
             propanolol given by nasal route is rapid and equivalent to
             the intravenous route (Hussain et al., 1980). 

        5.3  Dermal

             No data available.

        5.4  Eye

             No data available.

        5.5  Parenteral

             No case of overdoses has been reported. Cardiovascular
             symptoms have been reported after therapeutic
             administration.

        5.6  Other

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             After oral administration, propranolol is almost
             completely and rapidly absorbed from the gastrointestinal
             tract. However, because of the high first-pass metabolism and
             hepatic tissue binding, the absolute bioavailability is only
             about 30% and varies greatly between individuals. Peak plasma
             concentration occurs one to two hours after administration
             (Frishman et al., 1979; Goodman & Gilman, 1985).
    

             After administration of the sustained release formulation,
             the peak plasma concentration occurs 7 hours after
             absorption.

        6.2  Distribution by route of exposure

             About 90 to 95 % of the drug is bound to plasma proteins.
    
             The volume of distribution is 300 L/1.73 M2 or 3.9 L/kg
             (approximately 200 L in an adult).
    
             Propranolol is highly lipophilic: it crosses the blood-brain
             barrier and the placenta: the ratio of concentration in the
             blood between the foetus and the mother is 1.5.

        6.3  Biological half-life by route of exposure

             After oral administration, propranolol undergoes
             saturable kinetics.
    
             The plasma half-life is 3 to 6 hours and is about 12 hours
             with the sustained release forms. The total body clearance is
             800 mL/minute/1.73 m2.
    
             After overdose, the plasma half-life is prolonged. Halloran
             and Phillips (1981) reported a half-life of 16 hours. In two
             cases reported by Tzen War Chen et al. (1986), the half-life
             was 13.8 (ingestion of 3.12 g) and 8.3 hours (ingestion of
             0.28 g).  In five cases studied by Jaeger et al. (1990), the
             mean plasma half-life was mean 10.5 hours (range: 5.1 to
             17).

        6.4  Metabolism

             Propranolol is extensively metabolized by the liver. At
             least one of the metabolites, the 4-hydroxypropranolol, is
             biologically active. The hepatic metabolism is saturable and
             bioavailability may be increased in overdoses.

        6.5  Elimination by route of exposure

             After a single oral dose, propranolol is completely
             eliminated in 48 hours, mainly by hepatic metabolism. Less
             than 0.5 % is excreted unchanged in urine.  The renal
             clearance is 12 mL/kg/minute. About 20% of the dose is
             eliminated in urine mainly as glucuronide conjugates.
    
             Propranolol is excreted in breast milk at a concentration of
             50% that of blood.
    

             Dialysis clearance is about 20 mL/minute with a blood flow of
             250 mL/minute.

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    Propranolol is a non cardioselective
                    beta-blocker with no intrinsic sympathomimetic.  It
                    has membrane stabilizing activity and is highly lipid
                    soluble.  At toxic doses, propranolol has a pronounced
                    negative chronotropic and inotropic effect and a
                    quinidine-like effect on the heart: the result is a
                    reduction of the heart rate, a decrease of the
                    sino-atrial and atrioventricular conduction, a
                    prolongation of the intraventricular conduction and a
                    decrease of cardiac output. Blockade of beta-2
                    receptors may cause bronchospasm and hypoglycaemia.
                    Given its high lipid solubility, propranolol crosses
                    the blood-brain barrier and may cause coma and
                    convulsions (Langemeijer et al., 1986; de Wildt et
                    al., 1984).

             7.1.2  Pharmacodynamics

                    Beta-blocking agents compete with endogenous
                    and/or exogenous beta-adrenergic agonists. Their
                    specific effects depend on their selectivity for
                    beta-1 receptors (located in the heart) or beta-2
                    receptors (located in bronchi, blood vessels, stomach,
                    gut, uterus). Beta-blockers are classified according
                    to their cardioselectivity, membrane stabilizing
                    effect, intrinsic sympathomimetic effect and lipid
                    solubility (Critchley & Ungar, 1989; Ellenhorn &
                    Barceloux, 1988; Frishman & Sivermon, 1979; Frishman,
                    1979; Goodman & Gilman, 1985; Weinstein, 1984).
    
                    At therapeutic doses, propranolol slightly decreases
                    heart rate (15%), supraventricular conduction and
                    cardiac output (15 to 20%) (Johnson et al., 1969). 
                    Cardiac work and oxygen consumption are also
                    decreased.  Propranolol decreases the secretion of
                    renin.
    
                    The pharmaceutical form of propranolol is a racemate:
                    the dextrorotary isomer accounts for most of the
                    beta-blocking effect, whereas the levorotary isomer
                    has a predominantly membrane stabilizing
                    effect.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Propranolol toxicity shows
                             individual variations which may be due to an
                             underlying cardiac disease, to the ingestion
                             of other cardiotoxic drugs and to variations
                             in first-pass metabolism.
    
                             The toxic dose is about 1 g. In 104 cases
                             reported in literature the mean toxic (but
                             non lethal) dose was 1.75 g (Gross 1991)
                             although survival has been reported after
                             ingestion of 5 to 8 g (Lagerfeldt & Matell,
                             1982; Tynan et al., 1981).  Khan & Miller
                             (1985) reported survival of a 28-year-old man
                             following ingestion of 3 g.
    
                             The minimal lethal dose reported was 1.6 g in
                             a 57-year-old man (Auzepy et al., 1983). The
                             mean lethal dose in 17 cases reported in the
                             literature was 5.85 g although there is wide
                             interindividual variation (Gross,
                             1991).

                    7.2.1.2  Children

                             Ingestion of 70 mg by a 2-year-old
                             child produced drowsiness, 2nd degree
                             atrioventricular block and hypoglycaemia of
                             0.14 g/L (Hesse & Pedersen, 1973). Ingestion
                             of 100 mg by a 5-year-old child produced
                             drowsiness, delirium and hallucinations (Eibs
                             et al., 1982). An ingestion of 400 to 1,200
                             mg by a 3-year-old boy was uneventful after
                             early induced vomiting: the plasma level was
                             2.29 µg/L (Artman et al., 1982).

             7.2.2  Relevant animal data

                    In mouse the LD50 are:
    
                    565 mg/kg after oral route
                    22 to 35 mg/kg after intravenous route
                    107 mg/kg after intraperitoneal route 
                    (RETCS, 1985)

             7.2.3  Relevant in vitro data

                    No data available.

        7.3  Carcinogenicity

             No data available.

        7.4  Teratogenicity

             No confirmed reports of teratogenic effect.

        7.5  Mutagenicity

             No data available.

        7.6  Interactions

             Decreased bioavailability
    
             Antacids decrease the gastric absorption of propranolol. 
             Barbiturates, phenytoïn and rifampicin increase the
             first-pass clearance of propranolol by hepatic enzyme
             induction  (Sotanieni et al., 1979).
    
             Increased bioavailability
    
             Plasma propranolol concentrations may be increased up to 50%
             by histamine H2 antagonists and oral contraceptives, which
             decrease hepatic metabolism by enzyme inhibition.
    
             Diminished pharmacodynamic effects
    
             Non-steroidal anti-inflammatory drugs decrease the
             antihypertensive effect of propranolol. Nifedipine might
             exacerbate the symptoms of beta-blocker withdrawal.
    
             Enhanced pharmacodynamic effects
    
             Digitalis, amiodarone, verapamil and diltiazem may increase
             bradycardia due to propranolol. Verapamil, prenylamine,
             flecainide and disopyramide enhance the negative inotropic
             effect of propranolol.

        7.7  Main adverse effects

             Numerous adverse effects during propranolol treatment
             have been reported (Reynolds, 1993; Drugdex, 1991; Dukes,
             1984; Meyler et al., 1974; Goodman & Gillman, 1985).
    

             * Cardiovascular: sinus bradycardia, atrioventricular block,
               hypotension, increase of left ventricular failure,
               cardiogenic shock, intermittent claudication.
    
             * Respiratory: bronchospasm, exacerbation of asthmatic
               symptoms in known asthmatics, pulmonary oedema.
    
             * Central nervous system: depression, psychosis, convulsions,
               hallucinations.
    
             * Musculoskeletal: muscle weakness, aggravation of myasthenia
               gravis, peripheral neuropathy.
    
             * Gastrointestinal: vomiting, diarrhoea, dry mouth.
    
             * Endocrine and metabolic: hypoglycaemia, hyperkalaemia,
               hypothyroidism, sexual dysfunction (impotence).
    
             * Dermatological: urticaria, exfoliative dermatitis.
    
             * Haematological: agranulocytosis (immunologic reaction),
               thrombocytopenia.
    
             * Teratogenicity: a case of tracheoesophageal fistula in a
               newborn of a mother treated with propranolol during the
               pregnancy has been reported by Campbell, 1985. However, a
               teratogenic effect of propranolol has not been
               confirmed.
    
             * Pregnancy: hypoglycaemia and lethargy have been reported in
               newborn from mothers treated with propranolol before
               delivery.
    
             * Others: propranolol treatment may potentiate anaphylactic
               shock.

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                             Toxic ingredient: liquids, capsules,
                             scene residues
                             In case of ingestion:
                             Vomitus: total amount
                             Gastric aspirate: total amount (or gastric
                             lavage: first portion: 100 mL)
                             Whole blood without additives: 10 mL
                             Urine: random specimen: 50 mL

                    8.1.1.2  Biomedical analyses

                             Plasma (lithium heparin as
                             anticoagulant) or serum and urine for
                             standard biochemical analyses.

                    8.1.1.3  Arterial blood gas analysis

                             Heparinized arterial blood sample
                             (in severe cases).

                    8.1.1.4  Haematological analyses

                             Anticoagulated blood (e.g. EDTA) for
                             standard haematological analyses and
                             differential blood picture.

                    8.1.1.5  Other (unspecified) analyses

                             No further materials.

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                             Some authors suggest the use of
                             antioxidants (ascorbic acid, sodium
                             metabisulphite) as stabilizers for
                             4-hydroxypropranolol, but loss appears to be
                             insignificant in samples stored at -30°C
                             without additives (Fu & Mason,
                             1989).

                    8.1.2.2  Biomedical analyses

                             No special requirements, but as
                             usually performed.

                    8.1.2.3  Arterial blood gas analysis

                             No special requirements, but as
                             usually performed.

                    8.1.2.4  Haematological analyses

                             No special requirements, but as
                             usually performed.

                    8.1.2.5  Other (unspecified) analyses

                             Serum, urine and other materials in
                             a refrigerator (4°C).

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                             Some authors suggest the use of
                             antioxidants (ascorbic acid, sodium
                             metabisulphite) as stabilizers for
                             4-hydroxypropranolol, but loss appears to be
                             insignificant in samples stored at -30°C
                             without additives (Fu & Mason,
                             1989).

                    8.1.3.2  Biomedical analyses

                             No special requirements, but as
                             usually performed.

                    8.1.3.3  Arterial blood gas analysis

                             No special requirements, but as
                             usually performed.

                    8.1.3.4  Haematological analyses

                             No special requirements, but as
                             usually performed.

                    8.1.3.5  Other (unspecified) analyses

                             Not applicable.

        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

                             Sodium, potassium, chloride,
                             calcium, magnesium Glucose, amylase, creatine
                             kinase, creatinine (urea)
                             Optional: bicarbonate (or total CO2), uric
                             acid

                    8.3.1.2  Urine

                    8.3.1.3  Other fluids

                             No dedicated test.

             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

             Measurement of serum electrolytes, glucose, creatinine
             and urea nitrogen, and arterial blood gases are useful to
             optimize supportive care.

        8.5  Overall Interpretation of all toxicological analyses and
             toxicological investigations

             Analysis of Materials
    
             Propranolol can be detected and identified in materials by a
             number of simple techniques.  Marquis and Mandelin's test
             both give a green-blue reaction (Moffat et al., 1986).  The
             spectrum in methanol gives deltamax at 290 nm (A| = 240), 306
             nm (A| = 143), and 319 nm (A| = 86); the pattern in dilute
             acid is similar.  Thin layer chromatography is useful for
             propranolol analysis, and the drug can be visualized as a
             green-blue spot with Mandelin's reagent.  The Rf is 0.50 in

             both methanol / ammonia (100:1.5) and in ethyl acetate /
             methanol / ammonia (85:15:5) (Moffat et al., 1986).  Gas
             chromatography is also useful, and the retention index for
             propranolol is 2150 on OV1, SE30, SE54, HP5 or similar; FID
             gives sufficient sensitivity for residues, but
             nitrogen-phosphorus detection gives improved sensitivity and
             specificity.  GCMS may also be used for underivatized
             propranolol, although the spectrum is not characteristic.
    
             Analysis of Biological Specimens
    
             Analysis in body fluids is fairly straightforward, although
             quantitative analysis is only rarely indicated.  There are no
             commercially-available immunoassay kits which respond to
             propranolol.  For detection in urine or plasma an extraction
             into a polar solvent is required (e.g. methyl tert-butyl
             ether, dichloromethane:iso-propanol or ethyl acetate) from
             basic buffer, and recovery from urine may be improved by
             salting out.  Urinalysis is best performed by thin layer
             chromatography.  The Rf of propranolol is 0.50 in both
             methanol / ammonia (100:1.5) and in ethyl acetate / methanol
             / ammonia (85:15:5) with a positive iodoplatinate and a
             green-blue Mandelin's response.  The 4-hydroxy metabolite is
             at Rf 0.50 in methanol / ammonia (100:1.5), and 0.40 in ethyl
             acetate / methanol / ammonia (85:10:5), and has a
             characteristic pale blue response with iodoplatinate, and a
             red response to Marquis reagent (personal experience). Gas
             chromatography of urine generally shows only propranolol
             (retention index 2150 on OV1, SE30, SE54, HP5 or similar) and
             sometimes the 4-hydroxy-metabolite at retention index 2650
             (see below under advanced methods).  Nitrogen-phosphorus
             detection is required for low therapeutic amounts, or mass
             spectrometry methods are suitable.
    
             Quantitative analysis of toxic concentrations in serum may be
             performed by direct fluorimetry.  Drug is extracted from
             alkalinized plasma (potassium carbonate) into toluene and
             re-extracted into acetic acid (0.005M) in ethylene glycol (50
             g/L). Excitation is at 290 nm, and emission measured at 358
             nm with a sensitivity of 0.003 mg/L from 1 mL sample (Rao et
             al., 1978; Baselt, 1987).  Other authors prefer scanning the
             emission pattern to identify potential interferences from
             quinidine and other fluorescing compounds (Kraml & Robinson,
             1978).  The method can also be used to quantitate
             4-hydroxypropanolol at 320 nm excitation and measuring
             emission at 510 nm with a sensitivity of 0.015 mg/L (Rao et
             al., 1978; Baselt, 1987).  Most frequently quantitation in
             plasma is performed by HPLC with fluorescence detection which
             gives excellent sensitivity (sub-therapeutic concentrations
             on less than 0.1 mL); excitation at 205 to 215 nm, emission
             measured at 340 nm.  Methylpropranolol, benzimidazole or

             flecainide can be used as internal standard.  HPLC of
             propranolol can best be achieved with silica columns with
             organic mobile phases containing modifiers such as
             camphorsulfonic acid or ammonium sulphate (Bhamra et al.,
             1985; Rognerud & Ou, 1989).  For simultaneous measurement of
             propranolol and 4-hydroxypropanolol, reverse-phase systems
             are required and chromatography is slower.  Sensitivity is
             reduced (0.01 mg/L) due to the difference in emission
             wavelength for the two compounds (Sood et al., 1988; Fu &
             Mason, 1989). Some authors suggest the use of antioxidants
             (ascorbic acid, sodium metabisulphite) as stabilizers for
             4-hydroxypropranolol, but loss appears to be insignificant in
             samples stored at -30°C without additives, although loss may
             occur during the extraction procedure (Fu & Mason, 1989). 
             Gas chromatographic methods are less often used, but are
             described electron capture after derivatization with
             pentafluoropropionic anhydride / pyridine (1 minute at 70°C)
             (Kates & Jones, 1977) or trifluoroacetic anhydride / benzene
             / trimethylamine for 5 min at 50°C (Walle, 1974) or TFAA in
             toluene for 60 minutes at room temperature (Jack & Laugher,
             1985).  Isothermal analysis may be performed at 200 to 250°C
             depending on the column and conditions.  Detection limits are
             0.001 to 0.005 mg/L.  None of the GC methods report data for
             4-hydroxypropranolol.
    
             Advanced Methods of Analysis
    
             Several more complex methods describe the screening urine for
             a range of ß-blockers using GCMS of TMS derivatives (Dunasia
             & Houghton, 1991), or for simultaneous analysis of
             propranolol and its full pattern of metabolites by GLC (Walle
             & Gaffney, 1972) or HPLC (Harrison et al., 1985).  Methods
             are currently available for separation of the R- and 
             S- enantiomers of propranolol, all of which use HPLC with
             fluorescence detection.  Separation is achieved either on
             chiral columns (Herring & Johnson, 1993), or on conventional
             columns after diastereoisomerization with a chiral reagent
             (Pham-Huy et al., 1994; Toyo'oka et al., 1997), or after
             addition of a chiral selector to the mobile phase (Karlsson &
             Pettersson, 1989).  Some of these methods also measure the
             4-hydroxy metabolite.
    
             Toxicity is only poorly correlated with serum propranolol
             concentrations, and measurement of vital signs gives a more
             reliable index of intoxication.  Survival has been reported
             in a patient with a plasma concentration of 4.8 mg/L (Gross,
             1991).  However, the following table of typical
             concentrations is given for guidance:
    

                                                                        
                                               mg/L          µmol/L
             Peak (2 hours) after single oral
             dose (1.2 mg/kg)                  0.03 to 0.05  0.12 to 0.19
             Steady-state in therapy           0.03 to 0.15  0.12 to 0.58
             Toxicity apparent                 > 0.5         > 1.93
             Life threatening toxicity         > 2.0         > 7.72
             4-hydroxypropranolol              10% of propranolol
             propranolol glucuronide           600% of propranolol
             naphthoxylacetic acid             1000% of propranolol
                                                                        
    
             Measurement of serum electrolytes, glucose, creatinine and
             urea nitrogen, and arterial blood gases are useful to
             optimize supportive care.

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The severity of propranolol poisoning is due to
                    its cardiotoxicity and depends on the dose ingested,
                    the presence of underlying cardiac disease and
                    concomitant ingestion of other cardiotoxic drugs.
    
                    Symptoms and signs appear within one to two hours and
                    may include the following:
    
                    * Cardiovascular effects: bradycardia, hypotension,
                      cardiogenic shock. The ECG may show nodal rhythm,
                      atrioventricular block and QRS widening
    
                    * CNS effects: lethargy, coma and convulsions,
                      mydriasis
    
                    * Hypoventilation resulting from severe shock

             9.1.2  Inhalation

                    No data available.

             9.1.3  Skin exposure

                    No data available.

             9.1.4  Eye contact

                    No data available.

             9.1.5  Parenteral exposure

                    Cardiovascular effects: bradycardia,
                    hypotension, cardiogenic shock. The ECG may show nodal
                    rhythm, atrioventricular block and QRS widening CNS
                    effects: lethargy, coma and convulsions, mydriasis
                    Hypoventilation resulting from severe shock.

             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

                    No data available.

             9.2.5  Parenteral exposure

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Patients who survive 48 hours after acute poisoning or
             who have not developed cardiac arrest before admission are
             likely to recover. Death may occur from cardiac asystole
             which is favoured by hypoxaemia.
    
             The prognosis depends on the dose ingested and is worse in
             patients with an underlying cardiac disease and in those who
             have ingested other cardiotoxic drugs (Critchley & Ungar,
             1989; Ellenhorn & Barceloux, 1988; Weinstein, 1984).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Acute:
    
                    Cardiovascular symptoms are the major features of
                    propranolol poisoning.
    
                    Bradycardia is the commonest symptom (present in 60 to
                    90% of cases) and occurs soon after ingestion.
    
                    Hypotension is observed in about 50 to 70% of the
                    cases. Hypotension and shock are due to decreased
                    cardiac output and vasodilatation (Amundson & Brodine,
                    1988).
    
                    Cardiac arrest may occur within 1 to 2 hours of
                    ingestion. Cardiac arrest has been reported to occur
                    in 45 minutes following the ingestion of 9.4 g of
                    propranolol by a 60-year-old man (Jones et al.,
                    1982).
    
                    ECG changes are always present in symptomatic
                    poisoning: sinus or nodal bradycardia,
                    atrioventricular block (1st to 3rd degree) are the
                    most common.  Widening of the QRS interval, bundle
                    branch block or increased QT interval are less
                    frequently observed.
    
                    Chronic: No data available.

             9.4.2  Respiratory

                    Acute:
    
                    Respiratory depression and apnoea is mostly associated
                    with severe shock and is due to cerebral hypoxia (Hong
                    et al., 1983).
    
                    Pulmonary oedema may occur, especially in patients
                    with a previous compromised cardiac function.
    
                    Bronchospasm may occur in susceptible patients.
    
                    Chronic: No data available.

             9.4.3  Neurological

                    9.4.3.1  CNS

                             Acute:
    
                             Lethargy, drowsiness, agitation, delirium,
                             hallucinations and mydriasis may be
                             observed.
    
                             Coma is usually only seen in patients with
                             cardiovascular collapse.
    
                             Convulsions have been reported after
                             ingestion of large doses (Das & Ferris, 1988;
                             Frishman et al., 1979; Tynan et al., 1981). 
                             Convulsions may be due to hypotension or to a
                             direct effect of propranolol (membrane
                             stabilizing effect).
    
                             Chronic:
    
                             Fatigue, CNS depression, hallucinations and
                             psychosis have been reported.

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             Acute: Effects of beta-receptor blockade.
    
                             Chronic: Effects of beta-receptor blockade.

                    9.4.3.4  keletal and smooth muscle

                             Acute: No data available.
    
                             Chronic: Muscular fatigue may be observed.

             9.4.4  Gastrointestinal

                    Acute: vomiting, nausea may be seen; spasm of
                    the lower oesophageal sphincter has been reported in 2
                    cases  (Panos et al., 1986; Laake et al., 1981).  A
                    case of mesenteric ischaemia following propranolol
                    overdose has been reported (Pettei et al., 1990).
    
                    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

                    No data available.

             9.4.9  Eye, ear, nose, throat: local effects

                    Acute: Mydriasis and diplopia may be noted.
    
                    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

                             Metabolic acidosis may occur in
                             severe poisoning with shock.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Hypokalaemia (Peterson et al.,
                             1984) or a hyperkalaemia (Delacour et al.,
                             1986) have been reported rarely.

                    9.4.12.3 Others

                             Hypoglycaemia (0.14 and 0.5 g/L)
                             was reported in two cases of poisoning in
                             children (Hesse & Pedersen, 1973).

             9.4.13 Allergic reactions

                    No data available.

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Pregnancy: No data available.
    
                    Breast-feeding: No data available.
    
                    Enzyme deficiencies: No data available.

        9.5  Other

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Patients with propranolol poisoning should be monitored
             closely, preferably in an intensive care unit.
    
             Make a proper assessment of airway, breathing, circulation
             and neurological status of the patient.
    
             Monitor ECG, blood pressure and respiration.
    
             Treatment may include:
    
             * gastric lavage, oral activated charcoal, emesis, only after
               immediate ingestion
    
             * supportive treatment for respiratory failure by artificial
               ventilation; symptomatic treatment for convulsions with
               diazepam, and shock with dopamine or norepinephrine
    

             * atropine in case of symptomatic bradycardia
    
             * isoproterenol and/or glucagon if atrioventricular block or
               shock are present

        10.2 Life supportive procedures and symptomatic/specific treatment

             Sinus bradycardia may be treated with intravenous
             atropine 1 to 2 mg in adults (10 to 30 µg/kg in
             children).
    
             Isoproterenol is the drug of choice conduction disturbances. 
             Administer as a continuous infusion, beginning at a dose of
             0.3 µg/kg/minute and progressing in 0.2 µg/kg/minute
             increments as needed.
    
             Glucagon may also be used but it is usually less efficient
             than isoproterenol.
    
             Transvenous cardiac pacing may be indicated if severe
             bradycardia does not respond to isoproterenol or
             glucagon.
    
             Hypertonic sodium solutions (molar sodium lactate or
             bicarbonate) may be indicated if there is a widening of the
             QRS interval (due to the membrane stabilizing effect).
    
             If hypotension and shock does not respond to isoproterenol
             and glucagon, dopamine or norepinephrine are indicated
             (Halloran & Phillips, 1981; Weinstein, 1984). If shock does
             not improve, haemodynamic study by a Swan-Ganz catheter
             should be performed in order to assess the treatment.
    
             An intra-aortic balloon pump has been used in a 17-year-old
             woman who had ingested 8 g propranolol and developed shock
             which did not respond to isoproterenol, adrenaline and
             glucagon (Lane et al., 1987).
    
             If cardiac arrest perform external cardiac massage and
             mechanical ventilation with oxygen. Adrenaline is indicated:
             1 to 4 mg intravenous in an adult, 0.25 to 0.5 mg by
             intratracheal route in a child.
    
             Respiratory depression should be treated by artificial
             ventilation.  Bronchospasm may require treatment with beta-2
             agonists or aminophylline.
    

             If convulsions persist despite the correction of hypotension,
             they may be treated by diazepam or clonazepam, neither of
             which have a negative inotropic effect.
    
             Metabolic acidosis should be treated with sodium
             bicarbonate.
    
             Correct hypo- or hyperkalaemia.
    
             Give intravenous glucose if hypoglycaemia is present.

        10.4 Decontamination

             Emesis
    
             Emesis may only be indicated in cases of recent ingestion. 
             However, it has been reported that induced emesis has
             precipitated severe bradycardia and hypotension because it
             increases the vagal tone (Soni et al., 1983; Smith et al.,
             1986).  Because cardiotoxic symptoms may appear rapidly and
             suddenly, emesis induced by syrup of ipecac is not
             recommended.
    
             Gastric lavage
    
             Gastric lavage may also precipitate bradycardia and
             hypotension. Therefore it should be performed under strict
             ECG and blood pressure monitoring. Because of the rapid
             absorption of propranolol, gastric lavage should be performed
             within 4 hours of ingestion.
    
             Oral activated charcoal
    
             Activated charcoal should be administered following gastric
             lavage. Repeated doses may interfere with the enterohepatic
             recirculation of propranolol. The efficiency of oral
             activated charcoal has been documented for atenolol, nadolol,
             pindolol and sotalol but not for propranolol (Neuvonen &
             Olkkola, 1988).

        10.5 Elimination

             Forced diuresis
    
             Forced diuresis is not recommended because only a very small
             amount of propranolol is excreted in urine.
    
             Haemodialysis, Haemoperfusion
    
             Considering the pharmacokinetics of propranolol, enhanced
             elimination by haemodialysis or haemoperfusion is useless and
             not recommended (see section 6).

        10.6 Antidote treatment

             10.6.1 Adults

                    Atropine
    
                    Although atropine has been frequently used in the
                    cases reported in literature, it is the least
                    effective treatment (Weinstein, 1984). Atropine may
                    only abolish the increased vagal stimulation and is
                    ineffective in severe bradycardia.
    
                    Atropine may be used in sinus bradycardia: administer
                    1 to 2 mg intravenous in adults.  If bradycardia does
                    not respond give isoproterenol.
    
                    Isoproterenol
    
                    Isoproterenol is a beta agonist which will
                    competitively antagonize the effects of the beta
                    blocker. It is indicated for the treatment of
                    conduction disturbances and shock. Administer
                    isoproterenol in continuous infusion. Begin at a dose
                    of 0.3 µg/kg/minute and progress in 0.2 µg/kg/minute
                    increments as needed. In several reports isoproterenol
                    was ineffective, but this was certainly due to
                    inadequate dosage (Critchley & Ungar, 1989). High
                    doses may be administered until the beta-blocking
                    effect is reversed (Rang & Dale, 1987).  In the cases
                    reported by Halloran & Phillips (1981) and Lagerfeldt
                    & Matell (1976), doses of 25 to 74 µg/minute were
                    given. Massive propranolol ingestions reportedly
                    require doses of isoproterenol up to 200 µg/minute
                    (Agura et al., 1986) and even 800 µg/minute (Tynan et
                    al., 1981) for effective treatment.
    
                    Prenalterol
    
                    Prenalterol (a beta-agonist) was used successfully for
                    refractory hypotension unresponsive to glucagon and
                    vasopressor in a case of massive propranolol overdose
                    (Kulling et al., 1983). The recommended  dose is 5 to
                    10 mg followed by an infusion of 5 mg/hour. Doses up
                    to 50 and 100 mg may be required.
    
                    Glucagon
    
                    Glucagon has positive inotropic and chronotropic
                    effects which are thought to be mediated by the
                    activation of the adenylcyclase system independently
                    of beta-adrenoreceptors (Kosinski & Malindzak, 1973).
                    It has been reported that glucagon increases

                    myocardial contractility in patients refractive to
                    isoproterenol. The dose required for a significant
                    myocardial action is much higher than that used to
                    stimulate gluconeogenesis. This may result in side
                    effects like nausea and vomiting. The initial dose is
                    50 to 150 µg/kg (5 to 10 mg) intravenously over one
                    minute, followed by an infusion of 1 to 5 mg/hour.
                    (Illingworth, 1979; Kosinski & Malindzak, 1973;
                    Parmley, 1971; Robson, 1980; Ward & Jones,
                    1976).

             10.6.2 Children

                    Doses should be adapted according to the body
                    weight. No particular dosage regimen for
                    isoproterenol, prenalterol or glucagon have been
                    recommended for propranolol poisoning in
                    children.

        10.7 Management discussion

             All patients with an history of acute ingestion of
             propranolol should have an ECG and be monitored for at least
             6 hours.
    
             Patients can be managed outside intensive care unit if there
             is a history of recent ingestion and no cardiotoxic effects
             are present.
    
             If symptoms of cardiotoxicity are present transfer the
             patient to an intensive care unit and monitor vital signs and
             biochemical parameters.
    
             Keep the patient in the intensive care unit until cardiotoxic
             symptoms have disappeared.
    
             A patient who presented with cardiotoxic effects and seizures
             after propranolol overdose did not respond to adrenaline,
             atropine, fluids and bicarbonate. Intravenous calcium
             chloride produced a dramatic restoration of blood pressure
             and a narrowing of the QRS complexes. After a bolus of 1 g
             intravenous, calcium chloride was given by an infusion 0.08 g
             per minute, which was reduced to 0.005 g per minute according
             to the ECG pattern and the blood pressure level. The authors
             believe that calcium may have a role to play in the treatment
             of propranolol overdose (Brimacombe et al., 1991).

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             After poisoning with 800 mg propranolol, a 65-year-old
             man was admitted two hours after ingestion. He was comatose
             and had bradycardia (50/minute) and shock.  The patient was
             treated by artificial ventilation, atropine (ineffective),
             isoproterenol (40 µg/hour) and recovered after 12 hours. Peak
             serum propranolol concentration was 1536 µg/l and serum
             half-life was 6.6 hours (Ducret et al., 1973).
    
             Poisoned with 8 g propranolol, a 14-year-old girl was
             admitted 35 minutes following ingestion. Her blood pressure
             was 130/70 mm Hg and pulse was 34/minute.  Ten minutes after
             induced emesis by ipecac the patient developed sudden
             hypotension and convulsions. ECG showed a second degree
             atrioventricular block and a right bundle-branch block.
             Treatment consisted of artificial ventilation, external
             cardiac massage, atropine 1.2 mg intravenous, isoproterenol
             0.4 mg intravenous and calcium gluconate 1 g intravenous.
             Blood pressure increased to 110/70 mmHg with isoproterenol at
             a rate of 0.8 mg/minute. Isoproterenol was discontinued seven
             hours following admission and the patient was extubated
             (Tynan et al., 1981).
    
             Agura et al. reported (1986) acute poisoning in a 40-year-old
             woman. The cardiogenic shock did not improve with atropine 
             (1 mg), adrenaline (1 mg), isoproterenol (16 to 20
             µg/minute), dopamine (15 to 20 µg/minute) and noradrenaline
             (10 to 12 µg/minute). Blood pressure and heart rate were only
             restored by glucagon (10 mg intravenous then 5 mg/hour) and
             high doses of isoproterenol (160 to 200 µg/minute).
    
             Elkharrat & Bismuth (1982) reported 25 cases of propranolol
             poisoning (1 to 2.5 g). Symptoms were present in 40 % of the
             cases: sinus bradycardia in 25%, atrioventricular block in
             20%, hypotension in 10% and shock in 5%. No mortality or
             sequelae were noted.
    
             Refractory hypotension following propranolol overdose was
             treated with, in addition to isoprenaline and glucagon,
             extracorporeal circulatory support using femoral vein 
             - femoral artery bypass (McVey & Corke, 1991).

    12. Additional information

        12.1 Specific preventive measures

             No data available.

        12.2 Other

             No data available.

    13. REFERENCES

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        overdose: successful treatment with high dose isoproterenol and
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        Amundson DE, Brodine SK  (1988). A fatal case of propranolol
        poisoning.  Drug Intell Clin Pharm 22: 781-782.
    
        Artman M, Grayson M, Boerth R (1982). Propranolol in children:
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        Auzepy Ph, Boukara N, Richard Ch, Giudicelli JF (1983).
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        14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
            ADDRESS(ES)

             Authors:   L. Tritsch, M. Dahlet, Ph, Sauder,
                        J. Kopferschmitt, F.  Flesch, A. Jaeger. 
                        Service de Réanimation Médicale et Centre
                        Anti Poisons 
                        CHU, Pavillon Pasteur 
                        67091 Strasbourg Cedex
                        France
    
                        Tel: 33-88161144
                        Fax: 33-88161330

             Date:      27 March 1991
    
             Peer
             Review:    Adelaide, Australia, April 1991
    
             Finalized
             IPCS:      May 1994
    
             Author
             Section 8: Dr S. Dawling
                        Center for Clinical Toxicology
                        Vanderbilt University Medical Center
                        501 Oxford House
                        1161 21st Avenue South
                        Nashville, TN 37232-4632
                        United States of America

                        Tel:    1-615-9360760
                        Fax:    1-615-9360756
                        E-mail: sheila.dawling@mcmail.vanderbilt.edu
    
             Date:      March 1998
    
             Editor:    Mrs J. Duménil
                        International Programme on Chemical Safety
    
             Date:      May 1999
    


    See Also:
       Toxicological Abbreviations