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Glyceryl trinitrate

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
   1.7 Presentation, Formulation
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
         3.3.1.1 Colour
         3.3.1.2 State/Form
         3.3.1.3 Description
      3.3.2 Properties of the locally available formulation(s)
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation(s)
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
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 AND BIOMEDICAL INVESTIGATIONS
   8.1 Sample
      8.1.1 Collection
      8.1.2 Storage
      8.1.3 Transport
   8.2 Toxicological/Analytical Methods
      8.2.1 Test for active ingredient
      8.2.2 Test for biological sample
   8.3 Other Laboratory Analyses
      8.3.1 Haemotological investigations
      8.3.2 Biochemical investigations
      8.3.3 Arterial blood gas analysis
      8.3.4 Other relevant biomedical analyses
   8.4 Interpretation
   8.5 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 Central nervous system (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 Adult
      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)
    1. NAME

       1.1 Substance 

           Glyceryl trinitrate (BAN) 

           (British Pharmacopoeia Commission, 1994)

       1.2 Group    

           ATC classification index

           Cardiac therapy (C01)/Myocardial therapy (C01D)/Anti-anginal 
           vasodilators (C01DA). 

           (WHO, 1992)

       1.3 Synonyms 

           Nitroglycerin (USAN, 1994)
           Trinitroglycerin
           Glonoin
           Trinitrin
           GTN
           Nitroglycerol

           (Reynolds, 1993)

       1.4 Identification numbers

           1.4.1 CAS number

                 55-63-0

           1.4.2 Other numbers

                 RTECS

                 QX2100000

       1.5 Brand names, Trade names

           To be completed by each Centre using local data.

       1.6 Manufacturers, Importers

           To be completed by each Centre using local data

       1.7 Presentation, Formulation

           Different presentations and formulations are available, e.g. 

           Tablets for sublingual use: 0.15 to 0.6  mg
           Sustained release tablets: 1 to 13 mg
           Solution for intravenous  use: 0.8 mg/mL and 

           5 mg/mL solutions
           Ointment 2%
           Transdermal system: 12.5 to 104 mg
           Aerosol spray 0.3 to 0.4 mg metered dose

           (To be completed by each Centre using local data)
    
    2. SUMMARY
         
       2.1 Main risks and target organs

           Toxic effects of glyceryl trinitrate are caused by 
           vasodilatation and methaemoglobinaemia. 

           Venous and arterial vasodilatation causes lowering of blood 
           pressure leading to shock.  Heart, blood vessels and red 
           blood cells are the target organs in glyceryl trinitrate 
           poisoning. 

       2.2 Summary of clinical effects
                      
           Features of poisoning may appear within a few minutes to one 
           hour or more after exposure.  There is tachycardia and 
           hypotension followed by bradycardia and collapse. 

           Flushing of the face, headache, dizziness, restlessness, 
           syncope, convulsions and coma may be present. 

           Some of the other features are vomiting, diarrhoea, cyanosis 
           and methaemoglobinaemia and respiratory failure. 
           
           Effects of glyceryl trinitrate are enhanced by alcohol. 

       2.3 Diagnosis

           Clinical diagnosis may be difficult to obtain, as the early 
           flushing of the skin disappears when hypotension develops. 
                            
           A venous blood sample should be collected to determine 
           methaemoglobin levels in cyanotic patients.  In severe 
           poisoning arterial blood gas analysis is indicated.  

       2.4 First aid measures and management principles

           If the patient becomes symptomatic, therapeutic use of this 
           drug should be stopped and careful observation necessary. 

           Induce vomiting if the drug was ingested recently. Give 
           adequate fluids.  Take the patient to a hospital immediately 
           with the remaining drug. 

           Patients with severe acute glyceryl trinitrate overdose 
           should be admitted to an intensive care unit. 

           Keep patient in head low position.
           
           Monitor vital signs, blood pressure, and respiration.  In 
           severe cases continuous cardiac monitoring is useful. 

           Treatment may include gastric aspiration and/or lavage, and 
           administration of oxygen. 

           In severe hypotension, intravenous fluid to expand 
           intravascular volume and/or intravenous dopamine/dobutamine, 
           or other pressor agents such as epinephrine (adrenaline) or 
           norepinephrine (noradrenaline) are indicated. 

           Artificial ventilation may be necessary.

           Methaemoglobinaemia should be treated with methylene blue, 1% 
           solution 0.1 ml/kg intravenously or l mg/kg intravenously. 
           
    3. PHYSICO-CHEMICAL PROPERTIES
         
       3.1 Origin of the substance

           This is prepared by the nitration of anhydrous glycerol with 
           a mixture of nitric and fuming nitric acids. 
                
       3.2 Chemical structure

           Structural formula

           CH2 - ONO2
           |
           CH  - ONO2
           |   
           CH2 - ONO2

           Molecular formula 

           C3H5(O.NO2)3

           Molecular weight  

           227.1
                   
           Chemical names

           Propane-1,2,3-triol trinitrate

           1,2,3-Propanetriol trinitrate

           (Reynolds, 1993; Budavari, 1989)

       3.3 Physical properties

           3.3.1 Properties of the Substance 
           
                 3.3.1.1 Colour

                         Colourless

                 3.3.1.2 State/Form

                         Slightly volatile, oily liquid
                         
                 3.3.1.3 Description
                              
                         Odourless
                
                         Sweet, aromatic and pungent taste.  

                         The melting points of labile form and the 
                         stable form are 2.8 C and 13.5 C 
                         respectively. 

                         The pure substance explodes at 218 C, but the 
                         tablets are not explosive. 

                         Vapour pressure: at 20 C = 0.00026 mm 
                                          at 93 C = 0.31 mm 

                         Solubility:  One gram dissolves in 800 ml 
                         water, in 4 g ethanol, in 18 g methanol, in 
                         120 g carbon disulfide. 

                         Miscible with ether, acetone and chloroform 
                         (Reynolds, 1982; Windholz, 1976) 

           3.3.2 Properties of the locally available formulation(s) 

                 To be completed by each Centre using local data. 

       3.4 Other characteristics

           3.4.1 Shelf-life of the substance

                 Glyceryl trinitrate tablets are unstable unless they 
                 are stored under air-tight conditions and protected 
                 from light.  

                 They are subject to considerable loss of potency when 
                 in contact with packaging components such as adhesive 
                 labels, cotton and rayon fillers and plastic bottles 
                 and caps.  

                 It is recommended that glyceryl trinitrate tablets B.P. 
                 should be labelled with an indication that they should 
                 be discarded after eight weeks after the package has 
                 been opened. 
                              
                 It is also suggested that glyceryl trinitrate tablets 
                 should be dispensed only in glass containers sealed 

                 with a foil lined cap without cotton wool wadding 
                 (Reynolds, 1989). 
                   
           3.4.2 Shelf-life of the locally available formulation(s) 

                 To be completed by each Centre using local data. 
                              
           3.4.3 Storage conditions 

                 Store in air tight containers. Protect from light. 

           3.4.4 Bioavailability

                 To be completed by each Centre using local data. 

           3.4.5 Specific properties and composition

                 The pure substance explodes on rapid heating or on 
                 percussion (not the tablets). 

    4. USES

       4.1 Indications

           4.1.1 Indications

                 Prophylaxis and treatment of angina and left 
                 ventricular failure. 

                 Control of hypertension during cardiac surgery. 

                 Congestive cardiac failure unresponsive to usual 
                 therapy. 

           4.1.2 Description

                 Not relevant

       4.2 Therapeutic dosage

           4.2.1 Adults 

                  Sublingual 

                 300 to 600 micrograms, may be repeated as required. 
                              
                  Buccal

                 1 to 5 mg three times a day (angina). 

                 5 to 10 mg three times a day (congestive cardiac 
                 failure). 

                  Aerosol spray

                 1 to 2 metered doses sprayed on oral mucosa (preferably 
                 on or under the tongue) and the mouth is then closed.  
                 A metered dose contains 300 to 400 micrograms. 

                  Oral

                 2.5 to 10 mg as sustained release tablets, two to three 
                 times daily. 

                  Intravenous injection

                 Doses starting at 20 to 25 micrograms/minute (to be 
                 adjusted according to response). 
                              
                  Transdermal

                 Patches containing 5 to 10 mg - one patch applied to 
                 fresh area of skin every day but removed during part of 
                 the day. 

                 2% ointment - Half to 2 inches of ointment applied 3 to 
                 4 times a day. 

                 (Reynolds, 1993)
                              
           4.2.2 Children  

                 No specific recommended dose for children.
                              
                 In congestive heart failure - The dosage schedule for 
                 intravenous glyceryl trinitrate is not well established 
                 but 0.5 to 20 micrograms/kg/min (maximum 60 
                 micrograms/kg/min) has been suggested (Friedman & 
                 George, 1984). 

       4.3 Contraindications

           Hypotensive conditions.

           Head injury. 

           Severe anaemia. 

           Cerebral haemorrhage.

           Use with caution in patients predisposed to closed-angle 
           glaucoma. 

           Intravenous administration contraindicated in constrictive 
           pericarditis and uncorrected hypovolaemia. 

    5. ROUTES OF ENTRY

       5.1 Oral 

           Toxic effects can occur by ingestion.  

       5.2 Inhalation

           Inhalation of dust may cause toxic effects (Windholz, 1976). 

       5.3 Dermal

           Toxic effects may occur when absorbed through skin. Prolonged 
           skin contact can cause skin eruptions (Windholz, 1976). 

       5.4 Eye

           Unknown.
           
       5.5 Parenteral

           Toxic effects can occur by the administration of excessive 
           intravenous doses. 

       5.6 Other

           Unknown

    6. KINETICS

       6.1 Absorption by route of exposure

           Oral

           Glyceryl trinitrate is readily absorbed from the oral mucosa 
           but rapidly metabolized so that it has only a fleeting 
           duration of action. 

           It is also readily absorbed from the gastrointestinal tract, 
           but owing to extensive first-pass metabolism in the liver its 
           bioavailability is reduced. 

           A study involving 5 healthy persons indicated a 
           bioavailability of less than 1% following administration by 
           mouth of glyceryl trinitrate capsule and oral solution. 
           However the weakly pharmacologically active dinitrate meta-
           bolites reached relatively high concentrations after oral 
           glyceryl trinitrate administration and it was suggested that 
           these metabolites may be responsible for the activity of oral 
           glyceryl trinitrate (Noonan & Benet, 1986). 

           Dermal

           Glyceryl trinitrate is also absorbed through the skin from an 
           ointment base (Reynolds, 1982). 

       6.2 Distribution by route of exposure

           The time to peak concentration depends on the route of 
           administration; it occurs after 2 minutes, 40 minutes and one 
           hour after sublingual, oral and dermal administration 
           respectively.  

           Volume of distribution of nitroglycerin is 2.1 to 
           4.5 litres/kg  (Goodman & Gilman, 1985). 

           Bioavailability is 38% after sublingual and 1% for
           oral administration.

       6.3 Biological half-life by route of exposure

           It has a very short plasma half life.  Clearance of 
           nitroglycerin is 140 to 320 ml/min/kg (Goodman & Gilman 
           1985). Elimination half-life of nitroglycerin is 1.7 to 2.9 
           minutes (Goodman & Gilman 1985). 

           When glyceryl trinitrate was given sublingually peak plasma 
           concentrations appeared within 4 minutes and at least half of 
           the intact glyceryl trinitrate was cleared from the blood in 
           1 to 3 minutes (Reynolds, 1982). 
                      
           Peak plasma concentration following dermal application of 45 
           mg nitroglycerin ointment occurred in about 1 hour (Baselt, 
           1982). 

       6.4 Metabolism

           Glyceryl trinitrate is metabolized by hydrolysis to 
           dinitrates and the mononitrate (Reynolds, 1982). 

           The half-life for dinitrate metabolites is about 40 minutes 
           (Noonan & Benet, 1986), i.e. approximately 20 times that of 
           glyceryl trinitrate. 

       6.5 Elimination by route of exposure
                      
           In 10 healthy volunteers given glyceryl trinitrate 560 g 
           sublingually, about 22% of the administered dose was excreted 
           in the urine after 24 hours mainly as the mononitrate 
           (Reynolds, 1982). 
         
    7. PHARMACOLOGY AND TOXICOLOGY

       7.1 Mode of action

           7.1.1 Toxicodynamics

                 Glyceryl trinitrate has dilator properties on vascular 
                 smooth muscle in virtually all vascular beds. The 
                 beneficial effects in therapeutic doses and the effects 
                 seen with overdose are attributable to the physiologic 

                 consequences of systemic venous and arteriolar 
                 vasodilatation.  The cardiac preload, systemic blood 
                 pressure and systemic vascular resistance all show a 
                 progressive decrease. A state of hypotension and 
                 circulatory collapse and shock may result. 

                 Methaemoglobinaemia may occur in patients following an 
                 overdose or after therapy. 
                   
           7.1.2 Pharmacodynamics

                 Glyceryl trinitrate relaxes smooth muscle including 
                 vascular smooth muscle, and reduces systolic blood 
                 pressure.  It is thought that the anti-anginal effect 
                 mainly depends on reducing myocardial oxygen demand by 
                 means of peripheral vasodilatation which causes 
                 decreased venous return permitting a reduction in left 
                 ventricular volume and energy expenditure. 

                 The effect of glyceryl trinitrate in relaxing coronary 
                 vessels is not considered to increase appreciably 
                 coronary blood flow (Reynolds, 1982). 

       7.2 Toxicity

           7.2.1 Human data

                 7.2.1.1 Adults

                         The minimum lethal dose of glyceryl trinitrate 
                         is not exactly known.  Severe intoxication has 
                         been reported after ingestion of 24 mg 
                         (Windholz, 1976) but doses up to 1200 mg have 
                         been tolerated with only slight effects. 

                              
                         Fatal dose of glyceryl trinitrate has been 
                         recorded as 2 g (Dreisbach, 1987). 

                         Patients with hypotension are intolerant to 
                         glyceryl trinitrate and doses as low as 0.24 mg 
                         have produced nausea, vomiting, syncope and 
                         collapse (Baselt, 1982). 

                 7.2.1.2 Children

                         No data available.
    
           7.2.2 Relevant animal data

                 Minimum oral lethal dose in rats is 80 to 100 mg/kg 
                 (Windholz, 1976). 

           7.2.3 Relevant in vitro data

                 Not available.

       7.3 Carcinogenicity

           Not known.

       7.4 Teratogenicity

           Not known.
            
       7.5 Mutagenicity

           Not known.

       7.6 Interactions

           Alcohol enhances the effects of glyceryl trinitrate.

           Undue dizziness and faint feeling may occur when sublingual 
           nitrates are taken with beta-adrenoceptor blocking drugs. 

           Complete AV block has been reported after use of sublingual 
           nitrates in patients receiving lignocaine by infusion.  Even 
           cardiac asystole may occur. 

           Disopyramide (by producing dryness in mouth) may  prevent 
           dissolution of sublingual isosorbide  dinitrate tablets. This 
           may also occur with tricyclic antidepressants. 

           Delayed dissolution of glyceryl trinitrate tablets in 
           patients with dry mouths has been reported in a patient 
           taking imipramine (Robbins, 1983) and in another patient 
           treated with atropine (Kimchi, 1984).  The use of the lingual 
           spray rather than a sublingual tablet has been suggested to 
           overcome the problem (Reynolds, 1989). 

           A patient developed resistance to the effects of heparin on 
           two occasions directly after intravenous administration of 
           glyceryl trinitrate.  The interactions could not be 
           attributed to propylene glycol in the solvent since 
           resistance also occurred during administration of a for-
           mulation of glyceryl trinitrate without propylene glycol 
           (Reynolds, 1989). 

           Explosion flush has been observed in patients with 
           transdermal patch when electric defibrillation was performed. 
            
       7.7 Main adverse effects

           The toxicity of the nitrates is unaffected  by the chemical 
           form or by the route of  administration  and all the nitrates  
           have a common profile of adverse effects. 

           Hypotension, reflex tachycardia and palpitations may occur. 
           Postural hypotension and syncope is seen, especially in 
           elderly patients.  Rarely severe bradycardia has been 
           reported.  Throbbing headache is quite common.  This symptoms 
           is likely to recede as tolerance develops.  Peripheral oedema 
           is also frequently seen. 

           Transient hypoxemia with precipitation of angina is seen  
           occasionally.  Transient cerebral ischaemic episodes 
           unrelated to changes in blood pressure are rarely seen. 
           Hence,in patients with cerebrovascular disease, it is advised 
           to initiate treatment with small doses. Methaemoglobinaemia 
           may be seen after therapeutic doses. 

           Nitrate Tolerance

           Although tolerance has long been associated with nitrates, 
           its clinical implications are not clear.  Tolerance is best 
           defined as a decreasing pharmacological effect over time, 
           often with a need for an increasing dose to achieve a given 
           action. 

           Tolerance may be partial or incomplete and may occur to  one 
           aspect of nitrate therapy and not to others. Disappearance of 
           the throbbing headache is useful. However, due to an 
           attenuation of the antihypertensive effect, these agents are 
           not useful in the long term management of hypertension.  The 
           part played by the arterial and venous side of the 
           circulation pertaining to the  development  of tolerance is 
           not clear. By having a long (approximately 8 hours) nitrate 
           free interval, the development of tolerance may be avoided or 
           reduced. Decreasing the number of daily doses of glyceryl 
           trinitrate also helps to achieve this effect. Sustained  
           release preparations are more likely to produce tolerance 
           than the short acting preparations. 

    8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

       8.1 Sample

           8.1.1 Collection

                 Samples of blood should be collected in air tight clean 
                 bottles for toxicological analysis and to determine 
                 methaemoglobinemia levels. 

           8.1.2 Storage

                 -

           8.1.3 Transport

                 -

       8.2 Toxicological/Analytical Methods
     
           Plasma glyceryl trinitrate can be analyzed by electron - 
           capture gas chromatography (Wei and Reid, 1979). 

           8.2.1 Test for active ingredient

                 -

           8.2.2 Test for biological sample

                 -

       8.3 Other Laboratory Analyses
    
           8.3.1 Haemotological investigations
    
                 Methaemoglobin level should be determined if cyanosis 
                 is present. 
    
           8.3.2 Biochemical investigations

                 -

           8.3.3 Arterial blood gas analysis

                 - In severe poisoning arterial blood gas analysis is 
                 indicated 

           8.3.4 Other relevant biomedical analyses

                 -

       8.4 Interpretation

           Methaemoglobinemia can be fatal if the level is over 60%. 
         
       8.5 References

           (In section 13).
    
    9. CLINICAL EFFECTS

       9.1 Acute poisoning 

           9.1.1 Ingestion 

                 Poisoning following oral ingestion is uncommon unless 
                 large doses are ingested. 
                      
                 Nausea, vomiting, abdominal cramps, headache, flushing 
                 of skin, mental confusion, delirium, bradycardia, slow 
                 respiratory rate and convulsions are the features of 
                 poisoning.  

                 Cyanosis may be present due to methaemoglobinaemia.  

                 Death may occur following shock or, rarely, respiratory 
                 failure. 

           9.1.2 Inhalation 

                 Headache, flushing of the skin, vomiting, dizziness, 
                 hypotension, cyanosis, convulsions, coma and 
                 respiratory failure may occur following inhalation. 

           9.1.3 Skin exposure 

                 Toxic effects are same as inhalation.
         
           9.1.4 Eye contact 

                 Unknown.

           9.1.5 Parenteral exposure 

                 Toxic effects same as for inhalation.
                      
           9.1.6 Other 

                 Unknown.

       9.2 Chronic poisoning

           9.2.1 Ingestion 

                 Repeated administration may cause toxic effects similar 
                 to acute poisoning. 

           9.2.2 Inhalation 

                 Workers dealing with glyceryl trinitrate show marked 
                 tolerance to repeated exposure, but since this 
                 tolerance disappears rapidly, a short absence from 
                 exposure may lead to severe poisoning from amounts that 
                 were previously safe (Dreisbach, 1987). 

           9.2.3 Skin exposure 

                 Erythroderma has been reported on prolonged skin 
                 contact (Reynolds, 1982). 

           9.2.4 Eye contact 

                 Unknown.
                 
           9.2.5 Parenteral exposure 

                 Unknown.

           9.2.6 Other 

                 Weakness, low blood pressure and a feeling of warmth 
                 occurred in an 81 year old woman who used glyceryl 
                 trinitrate plasters prescribed for chest pain to treat 
                 backache (Reynolds, 1989). 

       9.3 Course, prognosis, cause of death

           Practically all the immediate signs and symptoms are due to 
           reduction of blood pressure and usually appear within a few 
           minutes to one hour after exposure to glyceryl trinitrate. 

           If the blood pressure is maintained recovery is likely 
           (Dreisbach, 1987).  Death could occur from shock and 
           respiratory failure. 

       9.4 Systematic description of clinical effects

           9.4.1 Cardiovascular

                  Acute

                 Hypotension may occur from vasodilatation (Baselt, 
                 1982; Khan & Carleton, 1981).  There is compensatory 
                 tachycardia (Baselt, 1982). 

                 A marked fall of blood pressure is one of the principal 
                 manifestations in glyceryl trinitrate poisoning. 

                 In more severe cases intense throbbing in the head is 
                 accompanied by visible carotid pulsations and 
                 pulsations all over the body even in the tips of 
                 fingers. 
    
                 In very severe poisoning the signs are not entirely to 
                 lowering of the blood pressure.  The heart muscle is 
                 affected directly and the heart beats are weakened 
                 (Rabinowitch, 1944). 

                 Syncope is another feature that could occur.
    
                 Clinical manifestation may be modified in special 
                 circumstances. However, bradycardia has been observed 
                 in patients with sick sinus node syndrome or patients 
                 taking beta blocking drugs (Khan & Carleton, 1981). 

                 Acute myocardial infarction due to coronary vasospasm 
                 has been described following withdrawal from industrial 
                 exposure to glyceryl trinitrate (Przybojewski & Heyns, 
                 1983). 

                 Left ventricular function deteriorated in a 34 year old 
                 male with alcoholic cardiomyopathy and liver 
                 dysfunction following 0.25 inch glyceryl trinitrate 

                 paste applied to skin over abdomen spread over a 6 
                 square inch area.  Pulsus alternans began about 30 
                 minutes after the paste application and resolved 
                 shortly after its removal and leg elevation 
                 (Chandraratna et al., 1979). 
                              
                 Paradoxical angina occurred after injection of glyceryl 
                 trinitrate into the left coronary artery in one patient 
                 (Reynolds, 1989). 
                              
                 Complete heart block occurred after sublingual 
                 administration of glyceryl trinitrate in a patient with 
                 no evidence of cardiac ischaemia or underlying heart 
                 disease (Reynolds, 1989). 
                              
                 Asystole occurred following the administration of 
                 glyceryl trinitrate 0.3 mg sublingually to a 33 year 
                 old patient (Reynolds, 1989). 
    
                 Chronic 

                 No changes in heart function or pulse rhythm were 
                 detected after chronic occupational exposure. There was 
                 a slight fall of blood pressure which returned to 
                 normal after resting a few hours (Munch et al., 1965). 
                              
                 Syncope and palpitations have also been reported. 

           9.4.2 Respiratory
           
                  Acute  

                 Cyanosis is usually due to methaemoglobinaemia. 
                 However, impairment of respiration may occur in severe 
                 cases and could lead to fatal respiratory failure. 
    
                 Bronchitis has also been reported (Rabinowitch, 1944). 

                  Chronic  

                 Cyanosis due to methaemoglobinaemia may occur. 

           9.4.3 Neurological

                 9.4.3.1 Central nervous system (CNS) 
                
                          Acute 

                         Central nervous reactions such as throbbing 
                         headache, dizziness, delirium, convulsions and 
                         coma are the common features seen. 
                              
                         Mental disturbances occur apparently consequent 
                         on severe headache and vary from mild 
                         confusional states to mania. 
                      
                         Ingestion of alcohol may aggravate quarrelsome 
                         and destructive mania (Rabinowitch, 1944). 
    
                         Tremors of the hands are common (Rabinowitch, 
                         1944). 

                 9.4.3.2 Peripheral nervous system
     
                          Acute  
            
                         Unknown.

                          Chronic 

                         Pain, paraesthesia and weakness in the limbs 
                         developed in a person who had been handling 
                         dynamite (Nitroglycerin) (Jacob & Maroun, 
                         1969). 

                 9.4.3.3 Autonomic nervous system

                         Unknown.

                 9.4.3.4 Skeletal and smooth muscle

                         All the cardiovascular effects are due to 
                         relaxation of smooth muscles of blood vessels. 
    
                          Acute 

                         Poisoning could cause nausea, vomiting, colicky 
                         pains and diarrhoea. 

                          Chronic 

                         Nausea, vomiting.

           9.4.4 Gastrointestinal
    
                 Unknown

           9.4.5 Hepatic

                 Unknown.

           9.4.6 Urinary

                 9.4.6.1 Renal

                         Direct nephrotoxicity is not known. Polyuria 
                         has been reported (Rabinowitch, 1944). 

                 9.4.6.2 Other 

                         Unknown.

           9.4.7 Endocrine and reproductive systems

                 Unknown.

           9.4.8 Dermatological

                  Acute

                 Flushing of skin, sweating and coldness of the skin can 
                 occur. 

                 Allergic contact dermatitis has been reported after 
                 local application (Rosenfeld & White 1984). Patients 
                 with a transdermal patch may be at risk of burns when 
                 exposed to microwave ovens (Murray, 1984). 

                  Chronic

                 Prolonged contact on the skin produces eruptions 
                 (Reynolds, 1982). 

           9.4.9 Eye, ear, nose, throat: local effects

                 Dry throat may occur (Rabinowitch, 1944).

                 Transient loss of vision may occur prior to acute toxic 
                 effects from glyceryl trinitrate over exposure.  
                 (Rabinowitch, 1944). 

           9.4.10 Haematological

                   Acute 
                              
                  Methaemoglobinaemia is a common toxic feature. 
            
                   Chronic 

                  Methaemoglobinaemia can occur.

                  Haemolytic anaemia has been reported in
                  patients with G6PD deficiency (Aderka 1983). 

           9.4.11 Immunological

                  Unknown.

           9.4.12 Metabolic

                  9.4.12.1 Acid-base disturbances 

                           Circulatory collapse could cause metabolic 
                           acidosis. 

                  9.4.12.2 Fluid and electrolyte disturbances 
                              
                           Vomiting and diarrhoea may disturb the fluid 
                           and electrolyte balance of the body. 

                  9.4.12.3 Others

                           No data available.

           9.4.13 Allergic reactions

                  Allergic contact dermatitis caused by glyceryl 
                  trinitrate ointment has been reported (Reynolds, 
                  1989). 

           9.4.14 Other clinical effects

                  Unknown.

           9.4.15 Special risks

                  Haemolytic anaemia has been reported in patients with 
                  G6PD deficiency (Aderka 1983). 

       9.5 Other

           No data available.

       9.6 Summary 
       
    10. MANAGEMENT

        10.1 General principles

             Treatment should be based on clinical symptoms rather than 
             on analytical data. 

             Ingestion 
                              
             In cases of massive overdose consider removal of ingested 
             glyceryl trinitrate by emesis or gastric lavage followed by 
             activated charcoal, if patient seen within 1 to 2 hours of 
             ingestion. 

             Maintain blood pressure. 

             Skin contact 

             Remove poison from the skin by scrubbing with soap and 
             water. 
             
        10.2 Relevant laboratory analyses 

             10.2.1 Sample collection

                    Samples of gastric lavage material may be preserved 
                    for subsequent toxicological studies. 

             10.2.2 Biomedical analysis

                    Measure methaemoglobin level, arterial blood gases, 
                    electrolytes, blood glucose and blood urea in 
                    patients with clinical signs of poisoning. 
                              
             10.2.3 Toxicological analysis

                    Not relevant for clinical management.

             10.2.4 Other investigations

                    ECG should be performed.

        10.3 Life supportive procedures and symptomatic/specific
             treatment 

             Observation and monitoring 
     
             Monitor pulse, respiration, blood pressure, 
             electrocardiogram and central venous pressure. 

             Hypotension and shock 

             Elevate the foot end of the bed.  Administer intravenous 
             fluids.  If no response, administer dopamine 2 to 5 
             micrograms/kg/min progressing in 5 to 10 micrograms/kg/min 
             increments depending on the response. Other pressor agents, 
             such as epinephrine (adrenaline) or norepinephrine 
             (noradrenaline) may be also be necessary. 
                      
             The intravascular volume should be attended to with CVP or 
             Swan-Ganz catheter pressure measurements. 
                      
             Passive movements of the extremities may aid venous return. 

             Respiratory depression

             Administer oxygen and artificial ventilation if necessary. 

             Methaemoglobinaemia 

             If clinical features of methaemoglobinaemia are present 
             give 100% oxygen. Advise strict bed rest. 

             If it still persists or if the methaemoglobin levels are 
             over 30% give methylene blue 1% solution  0.1  mL/kg 
             intravenously over 5 minutes.  The same dose may be 
             repeated within 1 hour if there is no improvement. 
                
             Convulsions 

             If convulsions are present give diazepam 5 to 10 mg 
             intravenously  and repeat if necessary. 

        10.4 Decontamination

             Ingestion 
         
              Emesis

             If the drug has been ingested recently induce emesis with 
             syrup of ipecacuanha, BP, followed by 1 to 2 glasses of 
             water.  Dose for adults and children over 12 years is 30 mL 
             and for children under 12 years  15 mL. 
                
              Gastric lavage

             Gastric lavage is useful in severe poisoning.

             Skin contact

             Remove the poison from the skin by washing thoroughly with 
             soap and water. 
                
        10.5 Elimination

             Usefulness of forced diuresis, haemoperfusion and dialysis 
             in the elimination of glyceryl trinitrate has not been 
             established. 

             These techniques are probably of no value, given the 
             pharmacokinetic data. 
             
        10.6 Antidote treatment
     
             10.6.1 Adult

                    No specific antidote for glyceryl trinitrate is 
                    available.  Methylene blue is the antidote for 
                    methaemoglobinaemia. 

             10.6.2 Children

                    No specific antidote for glyceryl trinitrate is 
                    available.  Methylene blue is the antidote for 
                    methaemoglobinaemia. 

        10.7 Management discussion

             Not relevant
             
    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Case 1

             An 80-year-old man developed intractable hypotension and 
             bradycardia in spite of treatment with dopamine 42 hours 
             after taking one hundred 4 mg tablets of glyceryl 
             trinitrate, and died 8 hours later from cardiac arrest 
             (Marshall & Eckland, 1980). 

             Case 2

             An obese 47 year old woman in a suicidal gesture ingested 
             24 mg nitroglycerine (60 therapeutic doses).  When seen at 
             hospital 15 minutes later she was convulsing and 
             semicomatose without cyanosis.  

             The systolic blood pressure was moderately elevated 
             (150/80) mmHg and the pulse rate 104/min.  The respiratory 
             rate of 24 increased gradually over several hours to a 
             level of 120 per minute. 

             Breathing finally became cheyne-stokes in character. 
             Convulsions subsided promptly, perhaps because of the 
             intramuscular administration of amylobarbital (only 40 mg) 
             and consciousness was regained in 3 to 4 hours.  At this 
             time however she became apnoeic and was placed in a 
             respirator. With the restoration of spontaneous breathing 
             hyperventilation returned.  About 7 hours after the 
             ingestion the more common symptoms of numbness, tingling, 
             excitement, headache and flushing were noted.  Recovery was 
             eventually complete (Gosselin et al., 1984). 

             Case 3
         
             Demey et al, (1988) reported of severe hyper-osmolality, 
             lactic acidosis, central nervous system depression, and 
             haemolysis in 72 year old woman with impaired renal 
             function who received large amounts of propylene glycol 
             intravenously as a solvent for infusions of glyceryl 
             trinitrate.  She was treated with haemodialysis and 
             hypertonic saline was administered to prevent a sudden drop 
             in osmolality.  It was considered that the haemolysis 
             probably occurred caused because red blood cells and 
             propylene glycol 50% solution were administered through the 
             same intravenous line (Reynolds, 1989). 
    
        11.2 Internally extracted data on cases

             No data available.

        11.3 Internal cases

             To be completed by each Centre using local data.

    12. ADDITIONAL INFORMATION

        12.1 Availability of antidotes

             No specific antidote is available.
                
        12.2 Specific preventive measures

             Not relevant
            
        12.3 Other

             No data available.

    13. REFERENCES

        Aderka D, Garfinkel D, Bograd H, et al.  (1983) Isosorbide
        dinitrate-induced hemolysis in G6PD-deficient subjects. Acta
        Haemat, 69: 63-64.

        Baselt RC  (1982)  Disposition of toxic drugs and chemicals in
        man. Davis, CA, Biomedical Publications, pp 560 - 562.

        British Pharmacopoeia Commission (1994) British approved names
        1994. London, HMSO, 

        Budavari S ed. (1989) The Merck Index: an encyclopedia of
        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey,
        Merck and Co., Inc.  p 1045.

        Chandraratna PA, Langevin E, Langevin J  (1979)  Pulsus
        Alternans induced by glyceryl trinitrate paste in patients with
        alcoholic cardiomyopathy,  Br. Med. J., 41: 354 - 355.

        Demey HE, Daelemans RA, Verpooten Ga, De Broe ME, Van Campenhout
        CM, Lakiere FV, Schepens PJ, & Bossaert LL (1988) Propylene
        glycol induced side effects during intravenous nitroglycerin
        therapy. Intensive Care Med, 14(3): 221-226.

        Dreisbach RH (1987) Handbook of poisoning: Prevention,
        diagnosis and treatment. Los Altos, California, Appleton and
        Lange, p 384.

        Fleeger CA ed. (1993) USAN 1994: USAN and the USP dictionary
        of drug names. Rockville, MD, United States Pharmacopeial
        Convention, Inc., p 465. 

        Friedman WF & George BL (1984)  New concepts and drugs in the
        treatment of congestive heart failure. Pediatr Clin N Am, 
        31: 1197-1227.
    
        Gilman AG, Rall TW, Nies AS & Taylor P eds.(1990) Goodman and 
        Gilman's the pharmacological basis of therapeutics, 8th ed. New
        York, Pergamon Press, pp 1154-1155Goodman &  Gilman, (1985). The
        Pharmacological Basis of Therapeutics, New York, MacMillan
        Publishing Company. pp 1700

        Gosselin RE, Smith RP, Hodge HC  (1984) Clinical toxicology of
        commercial products. 5th ed., Baltimore, MD, Williams and
        Wilkins.

        Jacob JC & Maroun FB  (1969)  Peripheral Neuropathy in a
        person sensitive to dynamite. Canad. Med. Ass. J., 101: 623-625. 

        Kimchi A (1984)  Dry mouth and delayed dissolution of
        nitroglycerine (letter).  New England J. Med., 310: 1122.

        Khan AH & Carleton RA (1981) Nitroglycerin induced hypotension
        and bradycardia. Arch. Intern. Med., 141: 984.

        Marshall JB & Ecklund RE  (1980)  Methaemoglobinaemia from
        overdose of nitroglycerin. J.Am. med. Ass., 224: 330.

        Munch JC, Friedland B, Shepard M (1965)  Glyceryl Trinitrate
        I. Acute Toxicity. Industr. Med. Surg., 34: pp 143, 146.

        Munch JC, Friedland B, Shepard M (1965) Glyceryl Trinitrate
        II. Chronic Toxicity. Industr. Med. Surg., pp 940 - 943.

        Murad F, Arnold WP, Mittal CK, Brarghler JM (1979)  Properties
        and regulation guanclate cydose and some proposed functions for
        cyclic GMP. Adv Cyclic Nucleotide Res, 11: 175-204.

        Murray KB  (1984)  Hazard of microwave ovens to transdermal
        delivery system.  N Engl J Med, 310: 721.
     
        Noonan PK & Benet LZ (1986)  The bioavailability of oral
        nitroglycerin. J. Pharm. Sci, 75: 241 - 243.

        Przybojewski JZ & Heyns MH (1983) Acute myocardial infarction
        due to coronary vasospasm secondary to industrial nitroglycerin
        withdrawal. S. Afr. Med. J., 64: 101 - 104.

        Rabinowitch IM (1944)  Acute Nitroglycerine Poisoning.  The
        Canadian Medical Association Journal, 50: 199-201.

        Reynolds JEF ed.  (1982)  Martindale the extra pharmacopoeia. 
        28th ed., London, The Pharmaceutical Press, pp 1620-1623.

        Reynolds JEF  ed.  (1989)  Martindale the extra pharmacopoeia.
        29th ed., London, The Pharmaceutical Press pp 1499-1502.

        Reynolds JEF  ed.  (1993)  Martindale the extra pharmacopoeia.
        30th ed., London, The Pharmaceutical Press pp 1020-1023.

        Robbins LJ (1983)  Dry mouth and delayed dissolution of
        sublingual nitroglycerine (letter).  New England J. Med., 309:
        985.

        Rosenfeld AS & White WB (1984)  Allergic contact dermatitis
        secondary to transdermal nitroglycerin. Am Heart F, 108:1061-
        1062.

        Wei JV & Reid PR (1979)  Quantitative determination of
        trinitroglycerin in human plasma. Circulation, 59: 588 - 592.

        WHO (1992) Anatomical Therapeutic Chemical (ATC)
        classification index. Oslo, WHO Collaborating Centre for Drug
        Statistics Methodology, p 24.

        Windholz M ed. (1976)  The Merck Index: an encyclopedia of
        chemicals, drugs, and biologicals. Rahway, New Jersey, Merck and
        Co., Inc.

    14. AUTHOR(S), REVIEWER(S), DATE(S)(INCLUDING UPDATES, COMPLETE
        ADDRESS(ES)

        Author(s)             Dr. Ravindra Fernando
                              National Poisons Information Centre
                              Faculty of Medicine
                              Kynsey Road
                              Colombo 8
                              Sri Lanka

                              Miss Deepthi Widyaratne
                              (as above)

        Tel                   94-1-94016
        Fax                   94-1-599231

        Date                  August 1990

        Peer Review           Drs Ferner, Fernando, Temple and Jaeger 
                              Newcastle-upon-Tyne, United Kingdom, 
                              January 1991. 
    


    See Also:
       Toxicological Abbreviations