Insulin
| 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
Insulin
1.2 Group
Antidiabetic agent
1.3 Synonyms
Amorph IZS
Amorphous IZS
Biphasic Insulin
Cryst IZS
Crystalline IZS
Extended Insulin Zinc Suspension
Globin Insulin
Globin Insulin with zinc
Globin Zinc Injection Insulin
Globin Zinc Insulin
GZI
Injectio Insulini Protaminati cum zinco
Insulin cum zinco (crystallisati) suspension
Insulin Hydrochloride
Insulin Injection
Insulin lente
Insulin semilente
Insulin Ultralente
Insulin zinc suspension (mixed)
Insulin zinci crystallisati suspension injectabilis
Insulini cum zinco (Amorphi) suspension injectabilis
Insulini cum zinco suspensio composita
Insulini Isophani Protaminati Suspension injectabilis
Insulini Solution Injectabilis
Insulini Zinci Injectabilis Mixta
Insulini zinci protaminati injectio
Insulini zinci protaminati suspension injectabilis PZI
Isophane Insulin
Isophane Insulin (NPH)
Isophane Insulin Suspension
Isophane Protamine Insulin Injection
IZS
Neutral Insulin
NPH Insulin
Ordinary Insulin
Prompt Insulin Zinc Suspension
Protamine zinc injection
Regular Insulin
Soluble Insulin
Unmodified Insulin
1.4 Identification numbers
1.4.1 CAS number
9004-10-8
1.4.2 Other numbers
53027-39-7
8049-62-5
8063-29-4
9004-17-5
9004-21-1
1.5 Brand names, Trade names
Acid Insulin Injection
Hypurin Soluble (CP)
Regular Iletin (Lily USA)
Highly purified Animal Insulins
Actrapid MC (Novo UK, Favillon UK)
Hypurin Neutral (Weddel UK)
Neusulin (Wellcome UK)
Nuso Neutral Insulin (Boots UK, Evans Medical UK,
Wellcome UK)
Velosulin (Nordisk UK, Leo UK)
Velosulin Cartridge (Nordisk, Wellcome)
Quicksol Boots
Human Sequence Insulins
Human Actrapid (Novo)
Human Actrapid Purified (Novo)
Human Velosulin (Nordisk, Wellcome)
Humaline (Lily)
Highly Purified Animal Insulins
Insulin zinc suspension Lente (Evans)
Hypurin Lente (CP)
Lentard MC (Novo)
Tempulin (Boots)
Human sequence insulins
Human monotard (Novo)
Humulin Lente (Lily)
Semitard MC (Novo)
Human Sequence Insulins
Human ultratard (Novo)
Humulin zinc (Lily)
Rapitard MC (Noro)
Manufacturers - Boots, Evans Medical UK, Wellcome UK.
Highly Purified Animal Insulins
Isophane Insulin Injection (Evans)
Hypurin Isophane (CP)
Insulatard (Nordisk, Wellcome)
Monophane (Boots)
Mixed Highly Purified Animal Insulins
Initard 50/50 (Nordisk, Wellcome)
Mixtard 30/70 (Nordisk, Wellcome)
Human Sequence Insulins
Human Insulatard (Nordisk, Wellcome)
Human Protaphane (Novo)
Humulin (Lily)
Mixed Human Sequence Insulins
Human Actraphane (Noro)
Human Initard 50/50 (Nordisk, Wellcome)
Human Mixtard 30/70 (Nordisk, Wellcome)
Humulin M1 (Lily)
Humulin M2 (Lily)
Humulin M3 (Lily)
Humulin M4 (Lily)
Hypurin Protamine Zinc (Weddel UK)
Also Marketed in Great Britain by Boots, Wellcome, Evans
Medical and Weddel
Other Proprietary Names
Protamine Zinc and Iletin
1.6 Manufacturers, Importers
Local agents
Insulin Hayleys (Boots)
Morrison Son & Jones (Novo)
Robert Hall & Co. (Nordisk)
2. SUMMARY
2.1 Main risks and target organs
Hypoglycaemia is the main risk of insulin overdose. The brain
relies on glucose as its source of energy and hypoglycaemia
may lead to coma, convulsions and even death.
2.2 Summary of clinical effects
Hypoglycaemia:
The early symptoms of hypoglycaemia are weakness, hunger,
giddiness, pallor, sweating, sinking feeling in the stomach,
palpitations, irritability, nervousness, headache and tremor.
Symptoms resemble those of sympathetic stimulation.
Later, symptoms such as depression or euphoria, inability to
concentrate, blurring of vision, drowsiness, lack of judgement
and self control and amnesia may be present due to
neuroglycopenia. Other features are hemiplegia, ataxia,
tachycardia, diplopia and paraesthesia.
If untreated the condition progresses to convulsions, coma and
death.
In the precoma stage, Babinski reflex is often present.
Pupils are often dilated but react to light. Later pupils are
constricted and no longer react to light. Hypokalaemia may be
present.
Speed of onset of hypoglycaemia varies with the preparation of
insulin used. Symptoms do not usually appear unless the blood
glucose concentration falls below 3.5 mmol/l. Convulsions can
occur if the blood glucose concentration falls below 2 mmol/l.
In diabetic patients with chronic hyperglycaemia, symptoms of
hypoglycaemia may occur at higher blood glucose
concentrations. A few patients may develop hypoglycaemic coma
without prior warning symptoms.
Other effects:
Non-specific local reactions such as allergic reactions,
atrophy of fat or induration and hypertrophy sometimes occur
at the site of injection (usually not a problem with highly
purified insulins).
2.3 Diagnosis
Early symptoms include weakness, hunger, giddiness, pallor,
sweating, sinking feeling in the stomach, palpitations,
irritability, nervousness, headache and tremor.
Later, depression or euphoria, inability to concentrate,
blurring of vision, drowsiness, lack of judgement and self
control and amnesia occur. Other features are hemiplegia,
ataxia, tachycardia, diplopia and paraesthesia.
If untreated the condition progresses to convulsions, coma and
death.
In the precoma stage, Babinski reflex is often present.
Pupils are often dilated but react to light. Later pupils are
constricted and no longer react to light. Hypokalaemia may be
present.
Estimation of blood glucose level: (see 2.3.1)
Estimation of plasma insulin is usually not relevant. The
serum potassium concentration should be measured explicitly.
Determination of urinary glucose and ketones for diabetic
ketoacidosis.
Serum creatinine, blood urea and serum electrolytes to asses
renal function.
2.4 First aid measures and management principles
If patient is conscious and cooperative - Oral glucose or 3-4
lumps of sugar should be given with water. This could be
repeated in 15 minutes or earlier if symptoms recur. This
should be supplemented by one or more carbohydrate meals until
the patient improves.
If unconscious or uncooperative - Intravenous glucose or
intramuscular glucagon should be given at once. Hospital
admission comes later. 50ml of 50% dextrose should be given
IV.
NB - It is very important to advise patients and relatives
regarding the prevention of hypoglycaemia. They should know
the warning symptoms of hypoglycaemia.
Correction of hypoglycaemia is the most important aspect of
management. If consciousness is impaired even after
correction of hypoglycaemia, cerebral oedema should be
suspected. Cerebral oedema should be treated with mannitol
and corticosteroids.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Extracted from beta cells of the islets of Langerhans of pork
or beef pancreas and purified by crystallisation.
It is also made biosynthetically by recombinant DNA technology
using Escherichia coli or semisynthetically by enzymatic
modification of porcine material.
3.2 Chemical structure
Molecular weight: 6000
Consists of two chains, A and B, of amino acids, joined
together by two disulphide bonds. Insulin is synthesised from
a single chain precursor named proinsulin. On conversion of
human proinsulin to insulin, 4 basic amino acids and the
remaining connector or C peptide is removed by proteolysis.
The resultant insulin molecule has 2 chains. The acidic or A
chain with glycine at the amino terminal residue and the basic
or B chain consisting of 30 amino acids with phenylalanine at
the amino terminus. An even larger molecule prepoinsulin has
been identified as a precursor of proinsulin.
Insulin can exist as a dimer, monomer or hexamer. Two
molecules of Zn2+ are coordinated in the hexamer which is
stored as granules in the beta cell.
The biologically active form of the hormone is the monomer.
The porcine hormone is most similar to man and differs only by
the substitution of an alanine residue for threonine at the
carboxy terminus of the B chain. Bovine insulin differs by
three amino acids and therefore is more antigenic than porcine
insulin.
3.3 Physical properties
3.3.1 Properties of the substance
White or almost white crystalline powder.
Slightly soluble in water. Practically
insoluble in alcohol, chloroform and ether.
Soluble in dilute solution of mineral acids and
with degradation in solutions of alkali
hydroxide.
3.3.2 Properties of the locally available formulation
Insulin Injection
This may be prepared by dissolving crystalline insulin
containing not less than 23 units/mg in water for
injections containing a suitable substance to render the
injection iso-osmotic with blood; hydrochloric acid to
adjust the pH to 3 to 3.5; and a suitable bactericide.
The USP specifies sterile, acidified or neutral solution
of insulin USP containing 40, 80, 100 or 500 units per
ml as well as 1.4 - 1.8% w/v of glycerol and 0.1 - 0.25%
(W/V) of phenol or cresol.
pH of acidified injection 2.5 - 3.5
pH of neutral injection 7 - 7.8
Insulin injection is a colourless injection or straw
coloured liquid practically free from solid matter which
deposits on standing. Contains not more than 40 g
zinc/100 units of insulin. Sterilised by filtration and
kept in multidose containers.
Neutral insulin BP
Sterile buffered solution of bovine or porcine insulin
of potency not less than 23 units/mg; pH 6.6 - 8
colourless liquid. Contains not more than 20 g
zinc/100 units of insulin and a suitable bactericide.
Available in multidose containers.
Insulin Zinc Suspension BP
Sterile buffered suspension of mammalian insulin in the
form of a complex obtained by addition of zinc chloride.
Insulin is in a form insoluble in water. Prepared by
mixing 3 volumes of insulin zinc suspension (amorphous)
and 7 volumes of insulin zinc suspension (crystalline).
Contains 40, 80, or 100 units/ml. White suspension
available in multidose containers. pH 6.9 - 7.5.
Complies with a test for prolongation of insulin effect.
Insulin Zinc Suspension BP (Amorphous)
Sterile buffered suspension of mammalian insulin in the
form of a complex obtained by addition of zinc chloride.
Prepared fromcrystalline insulin containing not less
than 23 u almost colourless suspension in which the
particles have no uniform shape and rarely exceed 2 m
in dimension; pH 6.9 - 7.5. Iso-osmotic with blood.
Containing suitable bactericide, the preparation
contains 40 and 80 units/ml.
U.S.P. describes a sterile suspension of insulin U.S.P.
in buffered water for injection is modified by addition
of zinc chloride so that the solid phase of suspension
is amorphous. Contains 40, 80 or 100 units/ml.
Also contain sodium acetate 0.15 - 0.17%, sodium
chloride 0.65 - 0.75%, methyl hydroxy benzoate 0.09 -
0.11% and for each 100 units of insulin, 120 - 250 g of
zinc. pH 7.2-7.5
Insulin zinc suspension (crystalline) BP
Sterile buffered suspension of bovine insulin to which
zinc chloride is added. Crystalline form is insoluble
in water.
Prepared from crystalline insulin containing not more
than 23 units/mg.
White or almost colourless suspension. Particles are
mainly crystalline. Majority of crystals having a
maximum diameter greater than 10 m.
pH 6.9 - 7.5 Iso-osmotic with blood. Preparation
contains 40 and 80 units/ml.
U.S.P. - Sterile suspension of insulin contain 40, 80,
100 units/ml. Contains sodium acetate, sodium chloride
and methyl hydroxybenzoate (Concentration same as for
amorphous insulin) and zinc 120 - 250 ug. pH 7.2 - 7.5.
Biphasic Insulin BP
Sterile buffered suspension of crystals of bovine
insulin containing not less than 23 units/mg. in a
solution of porcine insulin of similar potency. White
suspension. pH 6.6 - 7.2 iso-osmotic with blood.
Contained 27.5 - 37.5 ug zinc for each 100
units/insulin. Quarter of insulin in soluble form.
Multidose glass container.
Globin zinc Insulin BP
Sterile preparation of mammalian insulin in the form of
a complex obtained by addition of suitable globin and
zinc chloride.
USP specification: Insulin modified by addition of zinc
and globin obtained from beef blood, 40, 80, 100
units/ml. Colourless liquid pH 3 - 3.8; iso-osmotic with
blood. Each 100 units of insulin also contains 3.6 - 4
mg of globin and 250 - 350 g zinc.
USP specification: Also contains as preservatives phenol,
glycerol and cresol. Multidose container.
Isophane Insulin
Sterile buffered suspension of insulin in the form of a
complex obtained by addition of suitable protamine.
Prepared from crystalline insulin.
pH 6.9 - 7.5 iso-osmotic with blood.
Contains for each 100 units of insulin, 300 - 600 g
protamine sulphate and not more than 40 g zinc, a
suitable bactericide and sodium phosphate as buffering
agent.
USP specification: Sterile suspension of zinc insulin
crystalline and protamine sulphate in buffered water for
injection. Solid phase contain crystals of insulin
protamine and zinc; 40, 80, 100 units/ml. Contains
glycerol, metacresol, phenol sodium phosphate and zinc.
Protamine Zinc Insulin
Sterile buffered suspension of mammalian insulin to
which protamine and zinc chloride are added.
White suspension. pH 6.9 - 7.5 iso-osmotic with blood.
Contains for each 100 units of insulin, 1 - 1.7 mg of
protamine sulphate and zinc chloride equivalent to 200
per g of zinc, 10 - 11 mg of sodium phosphate.
USP specification: Buffered sterile suspension to which
zinc chloride and protamine sulphate are added. 40, 80,
100 units/ml. Also contain glycerol, cresol, phenol,
sodium phosphate for each 100 units of insulin in
addition to protamine and zinc.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
Up to 2 years at storage conditions of 2° - 8°C
3.4.2 Shelf-life of the locally available formulation
Up to 2 years at storage conditions of 2° - 8°C
3.4.3 Storage conditions
Store at 2° - 8°C. Avoid freezing.
3.4.4 Bioavailability
To be added by PCC using the monograph
3.4.5 Specific properties and composition
To be added by PCC using the monograph
4. USES
4.1 Indications
(a) Diabetes mellitus
(b) Complications of diabetes mellitus
eg. Hyperglycaemic ketoacidotic coma
Hyperglycaemic hyperosmolar non-ketotic coma
(c) Hyperkalaemia
(d) Insulin hypoglycaemia can be used as a test of anterior
pituitary function and to test completeness of vagotomy in
reducing gastric secretion.
4.2 Therapeutic dosage
4.2.1 Adults
Blood sugar < 16.5 mmol/l (300 mg%): 20 units.
Blood suger 11 - 16.5 mmol/l (200 - 300 mg%): 10 units.
4.2.2 Children
Dose is than adjusted according to the usual monitoring
of blood and/or urine glucose. Daily dose increments
should be 4 units. When stabilised, two-thirds of the
daily dose is generally given 30 minutes before
breakfast and one-third 30 minutes before the evening
meal.
If only one injection per day is required, 10 - 14 units
of an intermediate-acting insulin can be given. Dose
increment is 4 units given on alternate days. Soluble
or neutral may be added or special mixed insulins used
according to the patient's response.
4.3 Contraindications
Absolute Hypoglycaemia
Relative Allergic reactions may occur to beef or porcine
insulins.
Precautions: Differing immunological response to bovine and
porcine insulin have been reported and hypoglycaemia has been
reported in patients changing from bovine to porcine insulin.
Care is recommended to avoid inadvertant change of insulin
from one species to another. Care may be necessary in
changing over to a highly purified insulin.
The hypoglycaemia caused by insulin may be enhanced by alcohol,
monoamine oxidase inhibitors and propranolol and other beta
blockers. Propranolol may mask the symptoms of hypoglycaemia.
NB - Any deterioration in renal function and severe hepatic
disease may reduce insulin clearance and may result in
hypoglycaemia.
5. ROUTES OF ENTRY
5.1 Oral
When taken orally insulin has no hypoglycaemic effect since it
is inactivated in the gastrointestinal tract (Reynolds, 1982)
5.2 Inhalation
Not relevant
5.3 Dermal
Not relevant
5.4 Eye
Not relevant
5.5 Parenteral
Insulin is administered by subcutaneous, intramuscular or
intravenous injections and poisoning can occur only through
this route.
5.6 Other
Not relevant
6. KINETICS
6.1 Absorption by route of exposure
Insulin must be injected SC, IM or IV. It is absorbed into
the blood and peak plasma insulin concentration with
subcutaneous insulin occurs at 60 - 90 min. Absorption is
slower if there is peripheral vascular disease or smoking, and
faster if the patient is vasodilated eg. by a hot bath or
ultraviolet exposure or exercise.
Any changes in mode of administration either accidentally (eg.
accidental IM or IV injection) or deliberately (eg. constant
subcutaneous insulin infusion) may potentiate the absorption
and action of insulin, leading to hypoglycemia. Severe
hypoglycaemia may occur during constant infusion and several
deaths have been reported (Paterson et al, 1983).
Absorption of insulin from injection site affected by insulin
lipodystrophy is very unpredictable and rapid absorption may
lead to hypoglycaemia.
6.2 Distribution by route of exposure
A fraction of endogenous or exogenous insulin in plasma may be
associated with certain proteins but the bulk appears to
circulate in blood and lymph as the free hormone. The volume
of distribution of insulin approximates the volume of
extrecellular fluid.
Insulin is inactivated in the liver and kidneys (about 40% in
a single passage). About 10% appear in the urine.
6.3 Biological half-life by route of exposure
The plasma half-life is:
intravenous injection 10 minutes
subcutaneous injection 4 hours
intramuscular injection 2 hrs.
6.4 Metabolism
Metabolism occurs mainly in the liver and kidneys; 10% of the
dose appears in the urine. Insulin is normally filtered at
the glomeruli and then completely reabsorbed or destroyed at
the proximal tubule. In patients with impaired renal tubular
function, urinary clearance approaches glomerular filtration
rates. 50% of insulin that reaches the liver via the portal
vein is destroyed in a single passage, never reaching the
general circulation. Proteolytic degradation of insulin
occurs both at cell surfaces and in the lysosomes. A
proteolytic enzyme that degrades insulin has been purified
from muscle. An enzyme, glutathione insulin transhydrogenase,
which utilises reduced glutathione to reduce disulfide bridges
of insulin and produce separate chains, has been implicated.
Severe impairment of renal function appears to affect the rate
of disappearance of circulating insulin to a greater extent
than does hepatic disease.
6.5 Elimination by route of exposure
About 10% of the drug appears in urine.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Insulin in overdose causes hypoglycaemia. Hypoglycaemia
deprives the brain of substrate glucose upon which it is
almost exclusively dependent for its oxidative
metabolism. During insulin coma, oxygen consumption in
the human brain decreases by nearly half.
A prolonged period of hypoglycaemia causes irreversible
damage to the brain as evidenced in experimental animals
by histological changes in the cortex, basal ganglia and
rostral parts of the medulla. Convulsions, coma, mental
retardation, hemiparesis, ataxia, incontinence, aphasia,
choreiform movements, and parkinsonism may occur in man.
7.1.2 Pharmacodynamics
Insulin binds to a receptor on the surface of the target
cell and probably also enters the cell in this state.
The receptors vary in number inversely with the insulin
concentration to which they are exposed.
The receptor becomes phosphorylated on addition of
insulin and ATP. The cellular mechanism of action of
insulin after combination with the receptor is
uncertain; the complex may activate a "second
messenger" which in turn causes the release of third
messenger Ca++ ions. Insulin also has a membrane effect
in increasing gluose uptake and utilization, especially
by muscle and adipose tissue. Its effects include the
following:
a) Reduction in blood sugar due to increased glucose
uptake in the peripheral tissues which convert it to
glycogen or fat, and reduction of hepatic output
(diminished breakdown of glycogen and diminished
gluconeogenesis). When blood glucose falls below renal
threshold (180 mg/100 ml or 10 mmol/l) glycosuria ceases
as does the osmotic diuresis of water and electrolytes.
Polyuria and excessive thirst are thus alleviated. If
blood glucose falls much below normal levels, appetite
is stimulated.
b) Other metabolic effects: Insulin stimulates the
transit of amino acids and potassium into the cells.
Insulin regulates utilization of carbohydrate and energy
products and enhances protein synthesis.
c) Insulin increases concentrations of the active form
of the enzyme pyruvate dehydrogenase. Hence pyruvate is
oxidized or converted to fat and is unavailable for
glucose formation. In addition to enhanced synthesis of
fat, insulin increases the activity of membrane bound
lipoprotein lipase which makes fatty acids derived from
circulating lipoproteins available to the cell.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
In most normal adults, 0.1 - 0.2 Units/kg
intravenously is sufficient to cause profound
hypoglycaemia. However, in insulin dependent
diabetics, it is not possible to indicate the
amount of insulin necessary to cause toxicity
because the level of hypoglycaemia and its
duration are the important factors. For example,
patients who have taken 80 to 500 times of the
normal dose taken for suicidal purposes have
recovered (Martin et al, 1977).
7.2.1.2 Children
No data available.
7.2.2 Relevant animal data
No data available.
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
Development of cancer at the site of long term insulin
injection has been reported. (Eisenbad and Walter, 1975).
7.4 Teratogenicity
Congenital malformations occurred in 17 of 117 babies born to
diabetic mothers taking insulin at the time of conception (Pay
and Insley, 1976).
7.5 Mutagenicity
No data available.
7.6 Interactions
Alcohol, beta blockers, salicylates, oxytetracycline and
monoamine oxidase inhibitors potentiate the hypoglycaemic
effects of insulin. Bezafibrate and clofibrate may improve
glucose tolerance and have an additive effect. Corticosteroids,
corticotrophin, diazoxide, diuretics like bumetanide,
furosemide and thiazides and oral contraceptives antagonise
the effects of insulin. Lithium may occasionally impair
glucose tolerance.
7.7 Main adverse effects
(a) Hypoglycaemia - symptoms are directly related to duration
and depth of hypoglycaemia. Initial sympathetic overactivity
is followed by signs of neuroglycopenia.
(b) Non specific local reactions at site of injection eg.
pain, oedema.
(c) Allergic reactions
(d) Lipoatrophy or induration and hypertrophy at the site of
injection is asociated with chronic use.
(e) Insulin resistance.
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
Type of Plasma Insulin a) Bioassay
b) Immunoassay
Plasma insulin estimated by bioassay is called
insulin-like activity (ILA) and plasma insulin
estimated by immunoassay is called
immunoreactive insulin (IRI); ILA and IRI differ
qualitatively and quantitatively. In vivo
bioassays depend on lowering of blood glucose in
rabbits or production of convulsions in mice.
Several in vitro methods have become popular due
to high degrees of sensitivity and relative
simplicity of execution. One method is based on
the capacity of insulin to increase the glycogen
content and glucose uptake of rat diaphragm.
Adipose tissue assays are based on the capacity
of insulin to stimulate glucose metabolism by
the epididymal fat pad of the rat or by a
suspension of isolated fat cells.
The sensitivity of radio-immunoassay is greater
than that of other assays.
The following could be determined by radio-
immunoassay.
a. Total immunoreactive insulin (IRI)
b. NEIRI - nonextracted immunoreactive
plasma insulin
c. Free plasma insulin ('Free' IRI)
d. I125 insulin binding in vitro
e. Acute insulin sensitivity (KITT)
f. Half-time of immunoreactive insulin
disappearance (Gilman and Goodman, 1985;
Martin et al, 1977).
Blood glucose estimation
Concentration of plasma IRI of normal
persons after an overnight fast is under 20
microunits/ml.
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
Not relevant
9.1.2 Inhalation
Not relevant
9.1.3 Skin exposure
Not relevant
9.1.4 Eye contact
Not relevant
9.1.5 Parenteral exposure
0.4 units of monocomponent insulin injected
subcutaneously three times a day into each quadrant of a
pitted scar did not cause hypoglycaemia (Amroiwalla,
1977). Insulin toxicity causes hypoglycaemic symptoms.
9.1.6 Other
9.2 Chronic poisoning
9.2.1 Ingestion
Not relevant
9.2.2 Inhalation
Not relevant
9.2.3 Skin exposure
Not relevant
9.2.4 Eye contact
Not relevant
9.2.5 Parenteral exposure
Not relevant
9.2.6 Other
Not relevant
9.3 Course, prognosis, cause of death
Symptoms do not usually appear unless the blood glucose
concentration falls below 3.5 mmol/l. Convulsions can occur
if the blood glucose concentration falls below 2 mmol/l. Mild
hypoglycaemia is usually relieved rapidly by ingestion of
carbohydrates.
Even when the level of consciousness is impaired, parenteral
admiistration of glucose or glucagon will lead to full
recovery. Sometimes brain damage is irreversible.
Severe or prolonged neuroglycopenia may respond only slowly to
restoration of the plasma glucose concentration as concomitant
cerebral oedema may itself depress the level of consciousness.
Prolonged hypoglycaemia may cause irreversible cerebral
damage as manifested by chronically impaired cognitive
functions, convulsions and hemiparesis, eventually causing
death.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Acute - Hypoglycaemia promotes the release of adrenalin
which causes palpitations and tachycardia. When
hypoglycaemia is severe, angina, arrhythmias, premature
beats and coronary thrombosis may occur.
9.4.2 Respiratory
Shallow breathing is present in severe, prolonged
hypoglycaemic coma.
9.4.3 Neurological
9.4.3.1 CNS
Signs of neuroglycopenia due to prolonged
hypoglycaemia include intellectual impairment,
irrational behaviour, blurring of vision,
diplopia, headache, confusion, abnormal and
often aggressive behaviour, mental retardation,
hemiparesis, ataxia, incontinence, aphasia,
choreiform movements, parkinsonism, epilepsy,
convulsions, drowsiness and coma.
9.4.3.2 Peripheral nervous system
Numbness of lips, nose or fingers.
9.4.3.3 Autonomic nervous system
Initial sympathetic overactivity is observed due
to hypoglycaemia as a result of the release of
adrenaline.
Symptoms include anxiety, hunger, sweating,
weakness, pallor, palpitations and tremors.
9.4.3.4 Skeletal and smooth muscle
9.4.4 Gastrointestinal
No data available.
9.4.5 Hepatic
No data available.
9.4.6 Urinary
9.4.6.1 Renal
No data available.
9.4.6.2 Other
Urinary incontinence.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
Cutaneous bullae occur due to prolonged coma (similar to
those associated with barbiturate poisoning).
Lipodystrophy - Fat atrophy and hypertrophy usually
occur with prolonged use of non purified insulins.
9.4.9 Eye, ear, nose, throat: local effects
Eye - Pupils are initially dilated and react to light.
Later pupils are constricted and cease to react to
light.
9.4.10 Haematological
Hypercoagulation has been reported.
9.4.11 Immunological
Immediate hypersensitivity: this occurs most frequently
during first few weeks of therapy. Following an
injection a 'wheal and flare' response occurs around
injection site within 2 hours. Local swelling is
maximal at 6 - 12 hrs but the reaction usually settles
within 24 - 48 hrs.
Rarely, a widespread general hypersensitivity reaction
with widespread urticaria, gastrointestinal
disturbances and angioneurotic oedema will occur.
Immediate hypersensitivity is mediated by IgE
antibodies.
Delayed hypersensitivity may occur shortly after
introducing insulin therapy.
Erythema occurs around injection site 2 - 24 hrs after
injection and settles slowly over 2 - 3 days. Rarely,
local residual scarring may occur.
Type IV hypersensitivity is mediated by lymphocytes.
These reactions subside spontaneously and are rarely
generalized but occasionally they may persist and
necessitate a change in insulin therapy. Most cases
occur with non-highly purified bovine insulin.
Acute anaphylaxis to insulin is extremely rare.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Hypoglycaemic coma may lead to respiratory
depression and anoxia with consequent
acidosis.
9.4.12.2 Fluid and electrolyte disturbances
Hyperinsulinaemia may itself cause
hypokalaemia and hypoglycaemia provokes the
release of adrenalin, which may also cause
hypokalaemia
9.4.12.3 Others
9.4.13 Allergic reactions
see 9.4.11.
9.4.14 Other clinical effects
9.4.15 Special risks
Hypoglycaemia, severe in 17 cases, occurred during the
first 6 hours of life in 22 of 34 infants born to
diabetic mothers who received insulin. Clinical
features were present only in two (Martin et al, 1975).
Pregnancy: It is unclear whether insulin causes
congenital malformations, though diabetes certainly
does. Neonatal hypoglycaemia is caused by neonatal
pancreatic hyperstimulation when diabetic mothers have
been hyperglycaemic. Alcohol is an important risk
factor - and most cases of death from insulin have been
associated with alcohol.
9.5 Other
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Correction of hypoglycaemia and the maintenance of normal
blood glucose concentration are the most important aspects
in management. In conscious, cooperative patients, oral
therapy with a few lumps of sugar or glucose is adequate.
Patients who have large subcutaneous depots of insulin
continue to absorb it over several days, and may need
glucose infusions.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Venous blood glucose concentration is measured on a
fresh sample taken into a tube containing fluoride-
acetate. A volume of 1-2 ml of whole blood is
sufficient. If measurement is likely to be delayed,
the sample should be stored at 4°C, though even at
this temperature there is some glucose consumption.
Where assay within a few hours is impossible, a
reliable result can be obtained by separating the
plasma and then freezing it at -20°C.
Diagnosis of hypoglycaemia is suggested by a low
glucose oxidase strip reading.
Insulin assay is not helpful in patients with
antibodies, unless free insulin concentration can be
measured.
10.2.2 Biomedical analysis
The blood glucose concentration should be measured.
Hypokalaemia can be detected by assay of serum
potassium.
10.2.3 Toxicological analysis
Refer to section 8.
10.2.4 Other investigations
10.3 Life supportive procedures and symptomatic/specific
treatment
If the patient is conscious and cooperative, give oral
glucose or sucrose (3-4 sugar lumps) and repeat after 15
minutes or earlier if symptoms recur. This should be
supplemented by a carbohydrate meal until blood sugar is
stable.
If the patient is unconscious or uncooperative, give 50 ml
of 50% dextrose (25 g of glucose) IV. If there is no
response within 15 minutes repeat the dose; glucagon 1 mg IM
or IV or SC is a less reliable alternative. This can also be
repeated but failure of the first glucagon injection is
unlikely to be followed by success with further doses.
For children give approximately 1 ml/kg of 50% glucose and
repeat if there is no response. A 10% glucose infusion via
a peripheral vein may be enough, but commonly 20% glucose
has to be given by the central vein.
If the patient is still unconscious despite this treatment
and blood sugar is normal or above normal then cerebral
oedema is likely and should be treated with 20% mannitol.
(Unless contraindicated due to cardiovascular disease).
Blood glucose concentration should be measured every 15 - 30
minutes and the rate of infusion altered to keep the blood
glucose concentration within the range of 5 - 10 mmol/l.
Give dexamethasone 10 mg IV followed by 16 mg daily in four
divided doses. Give oxygen.
Treatment with parenteral dextrose at doses up to 25 g/hr
may be necessary for protracted periods, depending on the
preparation of insulin injected. Initially, 1% - 20%
solution via a large central vein may be necessary to
supplement oral carbohydrate ingestion.
Occasionally neurological deficits recover after several
days if full supportive care is maintained.
Frequent blood sugar estimations (venous or capillary) may
be necessary, particularly initially, according to the
clinical condition. Plasma insulin estimations do not help
in the management.
Treat hypokalaemia with potassium supplements. Intravenous
potassium chloride 20 - 60 mEq per litre of fluid may be
given.
10.4 Decontamination
Not relevant
10.5 Elimination
Not relevant
10.6 Antidote treatment
10.6.1 Adults
No specific antidotes are available
10.6.2 Children
No specific antidotes are available
10.7 Management discussion
Glucagon 1 mg IM is useful to correct hypoglycaemia.
However, there is a risk that glucagon-induced insulin
secretion may be a complication (Marri et al, 1968).
Excision of the skin and fat of an insulin injection site
under a local anaesthetic has been performed in the
management of insulin overdose (McIntyre et al, 1986).
Hypoglycaemia may develop later than predicted from the
duration of action of various insulin preparations (Haskell
and Stapezyriski, 1983).
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Kaminer and Robbins (1988) reported a case of a 16 year old
girl with insulin-dependent diabetes mellitus who gave
herself an injection of 600 units of regular insulin in a
suicidal attempt. She lost consciousness for 12 hours and
was found confused and disoriented. She recovered fully.
Martin et al (1977) reported a case of a young man with a
prior history of depressive illness who was found
unconscious about 12 hours after self-administration of
about 1,600 units of NPH insulin along with a large amount
of alcohol and barbiturates. Despite the intravenous
administration of a large amount of glucose and 20% fructose
solution, hypoglycaemia recurred and his conscious state
deteriorated after an episode of respiratory obstruction.
He did not require further insulin for 6 days by which time
the blood glucose level had risen to 15 mmol/l. Improvement
in his conscious state was slow and he had evidence of
marked mental impairment and emotional lability.
11.2 Internally extracted data on cases
11.3 Internal cases
12. Additional information
12.1 Availability of antidotes
12.2 Specific preventive measures
Patients should be advised regarding the correct dose and
injection technique. They should have an adequate knowledge
of early features of hypoglycaemia so that they can take
glucose or sugar immediately.
12.3 Other
13. REFERENCES
Amroliwalla FK (1977). Br Med J 1: 1389 - 90
British National Formulary (1988). British Medical Association
and the Pharmaceutical Society of Great Britain.
Dukes MNG (1988). Meyler's Side Effects of Drugs. Amsterdam,
Elsevier Scientific Publishers.
Eisenbad E, Walter RM (1975). J Am Med Ass 233: 985.
Gilman AG, Goodman LS, Rall TW, Murad F (1985) ed. In: The
Pharmacological Basis of Therapeutics 7th Ed. Pergamon. p 1490 -
1504.
Haskell RJ, Stapezynski JS (1983). Intravenous glucose for the
treatment of intentional insulin overdoses. Ann Emerg Med 12:
260.
Kaminer Y, Robbins DR (1988). Attempted suicide by insulin
overdose in insulin-dependent diabetic adolescents. Paediatrics
81: 526 - 528.
Laurence DR, Bennett PN. Clinical Pharmacology. Churchill
Livingstone. Edinburgh.
McIntyre AS, Woolf VJ, Burnhem WR (1986). Local excision of
subcutaneous fat in the management of insulin overdose. Br J
Surg 73: 538.
Martin FIR, Hansen N, Warne GL (1977). Attempted suicide by
insulin overdose in insulin-requiring diabetics. Med J Austr 1:
58-60.
Martin FIR et al (1975). Arch Dis Child 130: 998
Paterson KR, Paice BJ, Lawson DH, (1983). Undesired effects of
insulin therapy. Adv Drug React Ac Pois Rev 2: 219-234
Pay IR, Insley J (1976). Arch Dis Child 51: 935
Reynolds JEF (1982) ed. Martindale, The Extra Pharmacopoeia. 28th
ed. The Pharmaceutical Press, London. p. 2025.
Trevor M. Avery's Drug Treatment. 3rd ed. ADIS Press. Auckland.
p. 530-535
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Author(s):Dr Ravindra Fernando
Dr (Mrs) Geetha Fernando
National Poisons Information Centre
General Hospital
Colombo 8
Sri Lanka
Tel: 94-1-94016
Fax: 94-1-599231
Date: April 1990
Reviewer: Dr R. Ferner
West Midlands Poisons Unit
Dudley Road Hospital
Birmingham B18 7QH
United Kingdom
Tel: 44-21-5543801
Fax: 44-21-5236526
Date: February 1991
Peer review: Adelaide, Australia, April 1991