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 µg
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.
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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.