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Isosorbide Dinitrate

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Isosorbide Dinitrate
     1.2 Group
       Vasodilator, anti-anginal
     1.3 Synonyms
       1,4:3,6 - Dianhydro - D-glucitol dinitrate
       1,4:3,6 - Dianhydrosorbitol 2,5 - dinitrate
       Dinitrosorbide
       Sorbide Dinitrate
       Sorbide Nitrate
     1.4 Identification numbers
       1.4.1 CAS number
             87-33-2
       1.4.2 Other numbers
             Diluted Isosorbide Dinitrate (BP*, USP**) 9245 -2
             Isosorbide Dinitrate 9244-5
             RTECS LZ4385000
     1.5 Brand names, Trade names
       Cedocard-5, Cedocard-10, Cedocard-20, Cedocard Retard, 
       Cedocard IV (Tillotts, UK), Isoket, Isoket 10, Isoket 20, 
       Isoket Retard, Isoket 0.1% (Schwartz, UK), Isordil, Isordil 
       Tembids (Ayerst,UK), Sorbichew, Sorbitrate (Stuart, UK), 
       Vascardin (Nicholas, UK), Soni-Slo (Lipha Rona, UK); Conducil, 
       Corosorbide, Maycor, Sigillum, Surantol, Vasodilat 
       (Argentina); Carvasin, Isotrate (Australia); Sorbidilat 
       (Belgium); Coronex (Canada); Risordan (France); Cardis, 
       Corovliss, IsoMack, Maycor, Nitrol, Nitrosorbon, Sorbidilat, 
       Vermicet (Germany); Carvasin, Nitrosorbide, (Italy);  Directan,
        Nitrol (Japan); Isorbid (Mexico);  Sorbaugil (Norway, 
       Sweeden); IsoMack, Myorexon, Sorbidilat (Switzerland); 
       Dilatrate - SR, Iso-Bid, Iso-D, Isotrate,  Sorbide, Sorquad, 
       Vasotrate (USA).
     1.6 Manufacturers, Importers
       Local Agents: Vascardin- Chemical Industries (Ceylon) Ltd.; 
       Isordil - George Stuart (Agencies) Ltd.; Sorbitrate - Hemas 
       (Drugs) Ltd.;  Angitrit - Unichem Laboratories Ltd., Bombay, 
       Ghaziabad; Isotrate - Torrent Laboratories Pvt. Ltd., 
       Ahmedabad.
    2. SUMMARY
     2.1 Main risks and target organs
       Vasodilatation and hypotension (with their accompanying 
       complications) are the main risks with overdose of isosorbide 
       dinitrate.  Heart and blood vessels are the target organs.  
       Methaemoglobinaemia can occur.
     2.2 Summary of clinical effects
       Features of poisoning may appear within few minutes to one 
       hour or more after exposure.  Tachycardia, hypotension 
       followed by bradycardia and collapse, throbbing headache, 
       dizziness, restlessness, syncope, convulsions and coma could 
       occur.  Some of the other features that can be seen include 
       vomiting, diarrhoea, cyanosis and methaemoglobinaemia.  
       Respiratory failure may occur in severe cases.
     2.3 Diagnosis
       Clinical diagnosis is based on the history of exposure, and 

       signs and symptoms observed: tachycardia, hypotension, 
       throbbing headache, flushing of the face.
                 
       Blood gas analysis and concentration of methaemoglobin may be 
       helpful in diagnosis and to assess the severity.
     2.4 First aid measures and management principles
       First-aid measures - Induce emesis if the drug was ingested 
       within the last four hours. Give plenty of oral fluids.
                 
       Management principles - Monitor vital signs, blood pressure, 
       and respiration.  In severe cases continuous cardiac 
       monitoring is useful. Patients with severe acute isosorbide 
       dinitrate overdose should be admitted to an intensive care 
       unit.  Treatment includes emesis, gastric aspiration and/or 
       lavage, administration of oxygen and assisted respiration.  
       Keep head in low position.  Intravenous fluid to expand 
       intravascular volume and IV dopamine/dobutamine are useful 
       therapeutic measures.  Methaemoglobinaemia (above 30%) should 
       be treated with methylene blue 1-2 g/kg IV.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       It is a synthetic substance prepared from sorbitol.
       
       Diluted Isosorbide dinitrate is a mixture of isosorbide 
       dinitrate (usually 20-50%) with lactose,  mannitol, or 
       excipients added to minimize the risk of explosion.  It may 
       contain up to 1% of a suitable stabilizer such as ammonium 
       phosphate.  
     3.2 Chemical structure
       Formula C6H8N2O8
       Molecular weight 236.1
     3.3 Physical properties
       3.3.1 Properties of the substance
             Isosorbide dinitrate is a fine white to ivory-
             white odourless crystalline solid.  It is 
             sparingly soluble in water (1.0g/900ml); freely 
             soluble in acetone, chloroform, alcohol and 
             ether.  
             
             Melting Point 70C (Windholz, 1976).
             
             See section 3.1. (Additives incorporated to 
             minimize risk of explosion).    
       3.3.2 Properties of the locally available formulation
             No data available.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             No data available.
       3.4.2 Shelf-life of the locally available formulation
             No data available.
       3.4.3 Storage conditions
             Store in air tight containers in a cool place.  Non-
             pharmaceutical formulations should not be exposed to 
             temperatures exceeding 15C; protect
             from light (Reynolds, 1989).
       3.4.4 Bioavailability

             To be completed
       3.4.5 Specific properties and composition
             No data available.
    4. USES
     4.1 Indications
       Isosorbide dinitrate is used principally in the 
       management of patients with ischaemic heart disease.  It 
       reduces the number, duration and severity of episodes of 
       angina pectoris. Exercise tolerance  is increased  and 
       the  requirements for nitroglycerin are reduced.  It is 
       effective in all forms of angina, (i.e. stable effort 
       angina, mixed angina, unstable angina and vasospastic or 
       variant angina).
                  
       It is used in acute myocardial infarction in control of 
       ischaemic pain, reduction of elevated blood pressure and 
       in the treatment of pulmonary oedema and congestive 
       cardiac failure.
       
       It is also useful in the treatment of severe 
       hypertension. The iv infusion can be used for precise 
       control of blood pressure. 
       
       It is used to control blood pressure during general 
       anaesthesia when precise control of blood pressure is 
       important.  It may also be used in oesophageal spasm.
       
       Apart from the well-documented uses, its vasodilator and 
       smooth muscle relaxant property might be useful in 
       managing patients with pulmonary hypertension and portal 
       hypertension. (Needleman et al., 1985).
     4.2 Therapeutic dosage
       4.2.1 Adults
             For relief of acute attacks of angina, sublingual 
             isosorbide dinitrate is effective in doses ranging from 
             2.5-10 mg.
             
             In long term management of ischaemic heart disease (with 
             or without cardiac failure) the oral dose range may vary 
             from 30-160 mg/day.
             
             If necessary, it may be further increased to about 240 
             mg/day.  By the intravenous route 2-10 mg/hour can be 
             infused.
       4.2.2 Children
             Dosage not established.
     4.3 Contraindications
       Hypersensitivity to isosorbide dinitrate.
       Pre-existing methaemoglobinaemia.
       Marked anaemia.
       Head trauma, cerebral haemorrhage.
       
       Precautions: Hypotension; Glaucoma.
    5. ROUTES OF ENTRY
     5.1 Oral
       Oral entry and absorption through gastro-intestinal tract is 

       the most frequent route of intoxication.  Absorption can occur 
       sublingually.  
     5.2 Inhalation
       No data available.
     5.3 Dermal
       A preliminary report of experience with isosorbide dinitrate 
       cream is available (Reynolds, 1989).
     5.4 Eye
       Not relevant.
     5.5 Parenteral
       Intoxication may occur in patients treated with intravenous 
       isosorbide dinitrate.
     5.6 Other
       Unknown.
    6. KINETICS
     6.1 Absorption by route of exposure
       Oral 
                 
       Isosorbide  dinitrate is readily absorbed from the oral mucosa 
       and has a short duration of action.  Following oral 
       administration it is well absorbed from the gastrointestinal 
       tract.  In view of its first pass effect and short plasma half 
       life, slow release formulations are available.  Sublingual 
       administration produces maximal concentration of the drug in 
       plasma within 6 minutes. (Gossellin et al, 1984).
             
       Dermal       
       
       Isosorbide dinitrate is also absorbed through the skin from an 
       ointment base (Reynolds, 1989).
       
       The bioavailability of isosorbide dinitrate is about 29% 
       following oral or sublingual dosing (Reynolds, 1989).
     6.2 Distribution by route of exposure
       No data available.
     6.3 Biological half-life by route of exposure
       The terminal elimination half-life of isosorbide dinitrate is 
       54.7 minutes, 48.8 minutes and 47.7 minutes respectively 
       following IV injection, sublingual and oral administration 
       (Reynolds, 1989).
       _______________________________________________________________
       _
       Medication     Recommended Onset of     Peak        Duration
                      Dosage (mg) Action      Action
                                  (Min)        (Min)
       _______________________________________________________________
       _
          Sublingual  2.5-10mg    5-20 min    15-60 min     45-120 
       min
          Oral        10-60mg     15-45 min   45-120 min    2-6 hours
       _______________________________________________________________
       _
       (Shane et al, 1978)
       
     6.4 Metabolism
       The major route of metabolism of isosorbide dinitrate in man 

       is by enzymatic denitration followed by formation of 
       glucuronides.  The primary initial metabolites, isosorbide-2-
       mononitrate and isosorbide-5-mononitrate have longer half-
       lives (2-5 hours) and are presumed to be responsible, at least 
       in part, for the therapeutic efficacy of isosorbide  
       dinitrate.  A substantial amount of drug can be metabolized 
       due to the "first pass" effect.
     6.5 Elimination by route of exposure
       Largely excreted in urine as isosorbide glucuronide (Gosselin 
       et al., 1984).
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             Isosorbide dinitrate has dilator properties on vascular 
             smooth muscle in virtually all vascular beds.  Nitrates 
             dilate veins, arteries, and, in high concentrations, 
             arterioles. The beneficial effects in therapeutic doses 
             and the effects seen with overdose are attributable to 
             the physiologic consequences of systemic venous and 
             arteriolar vasodilation.  Cardiac preload, systemic 
             blood pressure and systemic vascular  resistance all 
             show a progressive decrease. A state of hypotension, 
             circulatory collapse and shock may result (Cohn and 
             Franciosa, 1977).  Methaemoglobinaemia may occur 
             following overdose of isosorbide dinitrate or during 
             therapy (Arsura et al, 1984).
       7.1.2 Pharmacodynamics
             Organic nitrates can activate guanylate cyclase and 
             increase the synthesis of guanosine 3', 5' - 
             monophosphate (cyclic GMP) in smooth muscle and other 
             tissues.  The reactive free radical nitric oxide (NO) is 
             formed which interacts with and activates guanylate 
             cyclase.
             
             A cyclic GMP-dependent protein kinase is stimulated with 
             alteration in the state of phosphorylation of various 
             proteins in smooth muscle.  These events lead to 
             dephosphorylation of myosin light chains, and in turn to 
             relaxation of smooth muscle.  Vasodilatation ensues 
             (Murad et al, 1979). 
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     It is not known what dose of the drug is 
                     associated with symptoms of overdose or what 
                     dose of the drug would be life-threatening. 
                          
                     Taking repeated high oral doses (30mg 4 
                     times/day) increases the risk of developing 
                     hypotension, tachycardia, tolerance and cross-
                     tolerance to nitroglycerin.  Most serious is the 
                     potential for developing a form of life-
                     threatening organic nitrate dependence (Gosselin 
                     et al, 1981).
             7.2.1.2 Children
                     No data available.

       7.2.2 Relevant animal data
             The acute oral LD50 of isosorbide dinitrate in rats was 
             found to be approximately 1100 mg/kg of body weight.  
             Animal experiments indicate that approximately 500 times 
             the usual therapeutic dose would be required to produce 
             such toxic symptoms in humans.
       7.2.3 Relevant in vitro data
             Unknown.
     7.3 Carcinogenicity
       None.
     7.4 Teratogenicity
       No data available.
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       Several important interactions may occur with other 
       cardiovascular drugs.
       
       Severe postural hypotension has been observed in patients 
       given isosorbide dinitrate and hydralazine for chronic cardiac 
       failure.
       Undue dizziness and faintness may occur with sublingual 
       nitrates and 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, tricyclic antidepressants and other drugs with 
       anticholinergic effects may prevent dissolution of sublingual 
       isosorbide dinitrate tablets by causing dry mouth.  
       
       The effects of acetylcholine, epinephrine and histamine can be 
       antagonized by isosorbide dinitrate.
       
       An enhanced hypotensive effect may be seen with alcohol.
       
       Isosorbide dinitrate may show cross tolerance with other   
       nitrates (glyceryl trinitrate etc.) (AMA Drug Evaluations).
     7.7 Main adverse effects
       The toxic effects of the nitrates are 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 are seen, especially in 
       elderly patients.  Rarely severe bradycardia has been 
       reported.  Throbbing headache is quite common.  This symptom 
       is likely to recede as tolerance develops.  Peripheral oedema 
       is also frequently seen.  Transient hypoxaemia with 
       precipitation of angina is seen occasionally.  Transient 
       cerebral ischaemic episodes unrelated to changes in blood 
       pressure are rarely seen.  It is therefore advisable to 
       initiate treatment with small doses in patients with 
       cerebrovascular disease.  Methaemoglobinaemia may be seen 
       after therapeutic doses.

                 
       Weakness, transient dizziness, restlessness and collapse may 
       occur. Cutaneous flushing, perspiration and exfoliative 
       dermatitis have all been reported.  Nausea and vomiting are 
       not frequent (McDevitt and MacConnaelie, 1988).
       
       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 complete and may occur with one 
       type of nitrate therapy and not with others; disappearance of 
       the throbbing headache is a useful sign. 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 sides of the 
       circulation pertaining to the development of tolerance is not 
       clear. By providing a long (approximately 8 hours) nitrate-
       free interval, the development of tolerance may be avoided or 
       reduced.  Decreasing the number of daily doses of isosorbide 
       dinitrate also helps to achieve this effect.  Sustained-
       release preparations are more likely to produce tolerance than 
       the short-acting preparations (Abrams, 1988).
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)

             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Signs of overdosage may include the following:  
             hypotension, persistent and throbbing headache, vertigo, 
             palpitations, visual disturbances, and perspiring skin 
             (later becoming cold and cyanotic), nausea, vomiting, 
             colicky and even bloody diarrhoea) and syncope.  In 
             severe cases, methaemoglobinaemia with cyanosis and 
             anoxia, initial hyperpnoea, dyspnoea and slow breathing, 
             slow pulse, moderate fever, cerebral symptoms of 
             confusion, and coma followed by clonic convulsions and 
             possibly death due to circulatory collapse may occur.
       9.1.2 Inhalation
             Not applicable.
       9.1.3 Skin exposure
             No data available.
       9.1.4 Eye contact
             No data available.
       9.1.5 Parenteral exposure
             Symptoms include headache, dizziness, flushing of skin, 
             vomiting, marked fall in blood pressure, 
             methaemoglobinaemia and coma.       
             
             (The preparation is for use as an intravenous infusion 
             after dilution only.  It is not for direct IV 
             injection.)
       9.1.6 Other
             Unknown.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Unknown.
       9.2.2 Inhalation
             Not relevant.
       9.2.3 Skin exposure
             Unknown.
       9.2.4 Eye contact
             Not relevant.
       9.2.5 Parenteral exposure
             Unknown.
       9.2.6 Other

             Unknown.
     9.3 Course, prognosis, cause of death
       Practically all the toxic features are due to reduction of 
       blood pressure.  If the blood pressure is maintained recovery 
       is likely.  Death could occur from shock and respiratory 
       failure.
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Sudden fall in blood pressure, syncope, palpitation and 
             tachycardia are the features of poisoning.
       9.4.2 Respiratory
             Cyanosis may occur due to methaemoglobinaemia.  Initial 
             hyperpnoea followed by dyspnoea and slow breathing leads 
             to respiratory failure.
       9.4.3 Neurological
             9.4.3.1 CNS
                     Throbbing headache, dizziness, confusion, visual 
                     disturbances, convulsions and coma are features 
                     of CNS toxicity.
             9.4.3.2 Peripheral nervous system
                     Unknown.
             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.
       9.4.4 Gastrointestinal
             Nausea, vomiting, colicky pains and diarrhoea.
       9.4.5 Hepatic
             Unknown.
       9.4.6 Urinary
             9.4.6.1 Renal
                     Unknown.
             9.4.6.2 Other
                     Unknown.
       9.4.7 Endocrine and reproductive systems
             Unknown.
       9.4.8 Dermatological
             Sweating and coldness of the skin.
       9.4.9 Eye, ear, nose, throat: local effects
             Unknown.
       9.4.10 Haematological
              Haemolysis occurred in two patients with glucose-6-
              phosphate dehydrogenase deficiency during treatment 
              with isosorbide dinitrate (Aderka et al, 1983).
                             
              Methaemoglobinaemia is a common toxic feature.
       9.4.11 Immunological
              Unknown.
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       Metabolic acidosis can occur due to 
                       circulatory collapse.
              9.4.12.2 Fluid and electrolyte disturbances
                       Fluid and electrolyte loss may occur due to 
                       vomiting and diarrhoea.

              9.4.12.3 Others
                       Unknown.
       9.4.13 Allergic reactions
              Unknown.
       9.4.14 Other clinical effects
              Unknown.
       9.4.15 Special risks
              Unknown.
     9.5 Other
       Unknown.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Patients with isosorbide dinitrate overdose should be 
         admitted to an intensive care unit.  Because cardiovascular 
         collapse may  occur rapidly, IV lines, oxygen, and 
         monitoring of vital signs are the first priorities.  
         Treatment depends on the dose ingested and the state of the 
         patient.  It includes gastric lavage and supportive 
         treatment with inotropic and vasopressor drugs, sodium 
         bicarbonate, oxygen and artificial ventilation, if 
         necessary.  Blood gas analysis is needed. If 
         methaemoglobinaemia is suspected, the methaemoglobin level 
         should be measured.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                Samples of vomitus or gastric lavage material may be 
                preserved  for subsequent toxicological studies.
         10.2.2 Biomedical analysis
                Haemoglobin percentage, arterial blood gases and 
                methaemoglobin concentration blood glucose and blood 
                urea nitrogen levels should be measured.
         10.2.3 Toxicological analysis
                Not relevant for clinical management.
         10.2.4 Other investigations
                Electrocardiogram.
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         Make a proper assessment of airway, breathing, circulation 
         and neurological status of the patient.
         
         Monitor vital signs, electrocardiogram, central venous 
         pressure and blood pressure.
         
         Correct hypotension and shock.  Elevate the foot end of the 
         bed.  Administer IV fluids. If no response, administer 
         dopamine 2-5 g/kg/min progressing in 5-10 g/kg/min 
         increments depending on the response. The intravascular 
         volume should be monitored with CVP or Swan Ganz catheter 
         pressure measurements.
         
         Maintain a clear airway. If necessary, support ventilation 
         using appropriate mechanical device and administer oxygen. 
         
         If clinical features of methaemoglobinaemia are present 
         administer 100% oxygen. Advise strict bed rest.  If 

         methaemoglobinaemia persists or if the methaemoglobin level 
         is over 30% give 1% methylene blue solution 0.1-0.2 ml/kg (1 
         to 2 mg/kg) IV over 5 minutes.  The same dose may be 
         repeated within 1 hour if there is no improvement.
         
         If convulsions are present give diazepam 5 - 10mg IV and 
         repeat if necessary.
      10.4 Decontamination
         Emesis: if consciousness is not impaired and the drug has 
         been ingested in the last 4 hours, induce emesis by giving 
         syrup of ipecac at the following doses:
         
         6-18 months:  10 ml
         18 months to 12 years:   15 ml
         adults:  30 ml
         
         This should be followed by 1-2 glasses of water. Repeat 
         after 15 minutes if no response.  If ipecac is not available 
         or if the patient has not responded in 5 minutes after the 
         second dose, or in an adult, perform gastric lavage.  This 
         should be performed within the first few hours of ingestion 
         if it is to be effective.
      10.5 Elimination
         The usefulness of forced diuresis, haemoperfusion and 
         dialysis has not been established.  These techniques are 
         unlikely to be useful, given the pharmacokinetic 
         characteristics of isosorbide dinitrate.
      10.6 Antidote treatment
         10.6.1 Adults
                No specific antidote is available for isosorbide 
                dinitrate. Methylene blue is the antidote for 
                methaemoglobinaemia.
         10.6.2 Children
                No specific antidote is available.
      10.7 Management discussion
         Purgatives may be given if patients have taken slow-release 
         preparations.  After emesis or lavage activated charcoal 
         might be useful.
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         No data available on isosorbide dinitrate.
      11.2 Internally extracted data on cases
         To be added by the centre.
      11.3 Internal cases
         To be added by the centre.
    12. Additional information
      12.1 Availability of antidotes
         No specific antidote is available.
      12.2 Specific preventive measures
         First aid sheet
         
         Isosorbide dinitrate is a drug used in the management of 
         ischaemic or coronary heart disease.
         
         Flushing of the face, dizziness, rapid pulse, throbbing 
         headache, vomiting, restlessness, low blood pressure, 

         coldness of the skin, difficulties with respiration are some 
         of the features of poisoning that could be seen.
         
         If the patient become symptomatic, therapeutic use of this 
         drug should be stopped and careful observation necessary.
         
         Induce vomiting by tickling the back of the throat if the 
         drug was taken orally. Give adequate fluids.  Take the 
         patient to a hospital immediately along with the collected 
         vomitus and the remaining drugs.
      12.3 Other
         No data available.
    13. REFERENCES
    Abrams J, Nitrates In: Frishman, WH, Weiner, DA, ed.  Medical 
    Clinics of North America, Philadelphia, WB Saunders Company, 72: 
    (1) 1-36.   
    
    Aderka D, Garfinkel D, Bograda H et al, (1983). Isosorbide 
    dinitrate induced haemolysis in G6PD-deficient subjects. Acta 
    Haemat, 69: 63-64. 
    
    AMA Drug Evaluations. Antianginal drugs, 6th Edition pp 463-481. 
    
    Arsura E, Lichstein E, Guadagnino U et al, (1984). Methaemoglobin 
    levels produced by organic nitrates in patients with coronary 
    artery disease.  J Clin Pharmacol, 24: 160-164. 
    
    British National Formulary No. 15 (1988). British Medical 
    Association and The Pharmaceutical Society, Gt. Britain. 95-97.
    
    Cohn JN, Franciosa JA, (1977). Vasodilator Therapy of Cardiac 
    failure.  New Eng J Med 297:27-31 and 254-258. 
    
    Dowd AL, (1989). Physicians Desk Reference (PDR), 2314.
              
    Gosselin RE, Smith RP, Hodge HC, (1984). Ed. Clinical Toxicology 
    of Commercial Products, U.S.A., Williams and Wilkins.
    
    McDevitt DC, MacConnaelie, (1988).  Antianginal and B-
    adrenoceptor blocking drugs.  Dukes, M.N.G., ed. In Meyler's Side 
    Effects of Drugs.  The Netherlands,  Amsterdam,  Elsevier, 359-
    389. 
    
    Murad F, Arnold WP, Mittal CK, Branghler JM, (1979). Properties 
    and regulation of guanylate cyclase and some proposed functions 
    for cyclic GMP.  Adv. Cyclic Nucleotide Res, 11: 175-204.
    
    Needleman P, Corr PB, Johnson EM (Jr), (1985). Drugs used for the 
    treatment of angina: organic nitrates, calcium channel blockers, 
    and B-adrenergic antagonists.  In: Goodman and Gilman's The 
    Pharmacological Basis of Therapeutics, Gilman, AG, Goodman, LS, 
    Rall, TW, Murad, F, ed. New York, Macmillan Publishing Company, 
    806-826.
    
    Reynolds JEF, (1982) Ed. Martindale, The Extra Pharmacopoeia, 
    London, The Pharmaceutical Press, 1623.

    
    Reynolds JEF, (1989).  Ed Martindale The Extra Pharmacopoeia, 
    London, The Pharmaceutical Press, 1503.
    
    Shane SJ, Iazzetta JJ, Clisholer AW, Berka JF, Leung D, (1978). 
    Plasma concentrations of isosorbide dinitrate and its metabolites 
    after chronic oral dosage in man.  Br J Clin Pharmacol, 6: 37-41.
    
    Windholz M, (1976). The Merck Index, U.S.A., Merck & Co., Inc. 
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Author:   Dr Ravindra Fernando/Dr R.L. Jayakody 
              The National Poisons Information Centre, 
              General Hospital 
              Kynsey Road
              Colombo 
              Sri Lanka 
    
    Date:     August 1990
    
    Peer Review:   Newcastle-upon-Tyne, January 1991
    
    Update:   Dr R. Fernando, June 1994



    See Also:
       Toxicological Abbreviations