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 70°C (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 15°C; 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 µg/kg/min progressing in 5-10 µg/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