INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY EVALUATION

ANTIDOTES FOR POISONING BY

ORGANOPHOSPHORUS PESTICIDES

Monograph on Atropine
First draft by
ANDREW J. HEATH MD PhD1
Revised and updated by
Robin McKeown PhC2 August 2002, Geneva, Switzerland
Peer Reviewed by
Professor M. Balali-Mood MD PhD3, Dr A. Dewan4 and Professor Fengsheng He5
at
National Poisons Centre, Penang, Malaysia, 18-20 December, 2002.
1

now at: Protherics PLC, Runcorn, UK

Pharmacist-in-Charge, ACT Poisons Information Service, Canberra, Australia

Director, Medical Toxicology Centre, Mashad, Iran

Deputy Director, National Institute of Occupational Health, Ahmedabad, India

Chinese Centre for Disease Control and Prevention, Beijing, China

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Table of Contents

1. Introduction

2. Name and chemical formula

2.1 Names

2.2 Synonyms

2.3 IUPAC name

2.4 CAS number

2.5 Empirical formula

2.6 Relative molecular mass

2.7 Conversion tables

3. Physico-chemical properties

3.1 Melting point

3.2 Physical state

3.3 Solubility

3.4 Optical properties

3.5 pKa

3.6 pH

3.7 Stability in light

3.8 Reactivity

3.9 Pharmaceutical incompatibilities

3.10 Proprietary names and manufacturers

3.11 Other

4. Pharmaceutical formulation and synthesis

4.1 Synthesis

4.2 Manufacturing processes

4.3 Pharmaceutical formulation

5. Analytical methods

5.1 Quality control of antidote

5.2 Methods for identification of antidote

5.3 Methods for analysis of atropine in biological samples

5.4 Methods for analysis of the toxic agent in biological samples

6. Shelf life

7. General properties

7.1 Mode of antidotal activity

8. Animal studies

8.1 Pharmacodynamics

8.2 Pharmacokinetics

8.3 Toxicology

9. Volunteer studies

9.1 Pharmacodynamics

9.2 Pharmacokinetics

10. Clinical studies - clinical trials

11. Clinical studies - case reports

11.1 Dose and duration of atropine sulphate therapy

11.2 Route of administration

11.3 Assessment of optimal atropinization

11.4 Adverse effects of atropine therapy

11.5 Role of other anticholinergic agents

11.6 Clinical atropine toxicity

11.7 Drug interactions

12. Summary of evaluation and recommendations

12.1 Indications

12.2 Advised routes and doses

12.3 Other consequential or supportive therapy

12.4 Controversial issues and areas of use where there is

insufficient information to make recommendations

12.5 Proposals for further studies

12.6 Adverse effects

12.7 Restrictions for use

13. Model information sheet

13.1 Uses

13.2 Dosage and route

13.3 Precautions/contraindications

13.4 Pharmaceutical incompatibilities and drug interactions

13.5 Adverse effects

13.6 Use in pregnancy and lactation

13.7 Storage

14. References

1. Introduction
Atropine is the best-known member of a group of drugs known as muscarinic antagonists,
which are competitive antagonists of acetylcholine at muscarinic receptors. This naturally
occurring tertiary amine was first isolated from the Atropa belladonna plant by Mein in 1831
(Weiner, 1985). Although atropine earlier enjoyed widespread use in the treatment of peptic
ulcer, today it is mostly used in resuscitation, anaesthesia, and ophthalmology, usually as the
more soluble sulphate salt. By competitively blocking the action of acetylcholine at
muscarinic receptors, atropine may act as a specific antidote. As such, it may also be used to
counteract adverse parasympathomimetic effects of pilocarpine, or neostigmine administered
in myasthenia gravis. It is a specific antidote for the treatment of poisoning with
organophosphorus and carbamate insecticides and organophosphorus nerve agents. Although
other anticholinergic agents (such as dexetimide) with different distribution kinetics may
have advantages in rodent models (Lullmann et al., 1982), the role of atropine in the
treatment of organophosphate poisoning is essentially unchallenged, though there is
controversy concerning the dose of atropine necessary for optimal therapy in
organophosphate poisoning.
Atropine is also useful in treating muscarine poisoning following ingestion of fungi of the
Clitocybe and Inocybe species.
If the dose of atropine is titrated correctly, it has few serious side effects when used in
organophosphate poisoning. Patients who are hypoxic, however, are at risk of developing
ventricular tachycardia or fibrillation if given atropine. It is important, therefore, to correct
hypoxia by clearing airways, administering oxygen and, if necessary, mechanically
ventilating the patient before giving atropine (Hase et al., 1984; Matthew & Lawson, 1970;
Heath & Meredith, 1992).

2. Name and chemical formula

2.1 Names:
Atropine and atropine sulphate

2.2 Synonyms
atropine
Atropin (German); eyeules; DL-hyoscyamine (atropine consists of a mixture of equal parts of
D- and L-hyoscyamine); atropinum; 2-phenylhydracrylic acid-3-alpha-tropanyl ester; betaphenyl-t-oxypropionsaeure-tropyl-ester (German); 1-alpha-H,5-alpha-tropan-3-alphaOL()tropate (ester); DL-tropanyl-2-hydroxy-1-phenylpropionate; tropic acid3-alphatropanyl ester; DL-tropyltropate; (1R,3r,5S,8r)-Tropan-3-yl(RS)-tropate, tropine tropate
(Budavari,1996; Sax, Lewis,1992)
atropine sulphate

Atropina solfato (Italy); atropina sulfato (Spain, Argentina); atropine sulphate (USA); atropin
siran (Czech); atropinsulfas; atropinsulfat (Germany); sulphate datropine (France); 1-alphaH,5-alpha-H-tropan-3-alpha-OL-()-tropate (ester), sulfate (2:1) salt; dl-tropanyl-2-hydroxy1-phenylpropionate sulphate
(Sax, Lewis,1992)

2.3 IUPAC name

atropine
benzeneacetic acid, alpha-(hydroxymethyl)-8-methyl- 8-azabicyclo{3.2.1}oct-3-yl ester endo
-()atropine sulphate
benzeneacetic acid, alpha- (hydroxymethyl)-8-methyl-8-azabicyclo{3.2.1}oct-3-yl ester endo
-()-, compounds, sulfate (2:1) (salt)

2.4 CAS number:

51-55-8 (atropine)
55-48-1 (atropine sulphate anhydrous) (USP, 2002).
5908-99-6 (atropine sulphate monohydrate) (Parfitt, 1999)

2.5 Empirical formula

atropine

C17H23NO3

atropine sulphate monohydrate

(C17H23NO3)2,H2SO4 .H2O (Parfitt, 1999)

2.6 Relative molecular mass

atropine

289.38

atropine sulphate monohydrate

694.82 ((Budavari, 1996)

atropine sulphate anhydrous

676.82

2.7 Conversion tables

atropine

1 mmol

= 289 mg

1g

= 3.46 mmol

1mol/L

= 0.289g/ml

1mg/L

= 3.46mol/L

atropine sulphate anhydrous

1 mmol

= 676.82mg

1g

= 1.48 mmol

1 mol/L

= 0.677g/ml

1 mg/L

= 0 1.48 mol/L

atropine sulphate monohydrate

1 mmol

= 694.82 mg

1g

= 1.44 mmol

1 mol/L

= 0.695g/ml

1 mg/L

= 1.44 mol/L

3. Physico-chemical properties
3.1 Melting point
atropine:
Atropine sublimes under high vacuum at 93 to 110 oC and has a melting point of 114 to 116
o
C. (Budavari, 1996)
atropine sulphate monohydrate:
This salt has a melting point of 190 to 194 oC (Budavari, 1996).

3.2 Physical state

atropine:
Atropine occurs as white crystals or crystalline powder.
atropine sulphate:
Atropine sulphate occurs as odourless, very bitter, colourless crystals or white crystalline
powder (Parfitt,1999, Budavari, 1996).

3.3 Solubility
atropine:
Atropine has low solubility in water (approximately 1g atropine in 455ml water and 1 g
atropine in 90ml water at 80 C). One gram is soluble in 2 ml alcohol, 2.5ml alcohol at 60C,
27 ml of glycerol, 25ml ether and 1 ml chloroform (Budavari, 1996)
atropine sulphate monohydrate

Atropine sulphate is very soluble in water. One gram dissolves in 0.4 ml water. One gram
dissolves in 5 ml cold alcohol and 2.5 ml boiling alcohol, in 2.5 ml glycerol, 420 ml
chloroform and 3,000 ml ether.(Budavari, 1996)

3.4 Optical properties:

atropine
atropine is optically inactive.
atropine sulphate
atropine sulphate is almost inactive optically (Budavari, 1996).

3.5. pKa
atropine:
9.8 (McEvoy, 2002)

3.6. pH
atropine:
A saturated solution of atropine in water is alkaline (Parfitt,1999).
atropine sulphate:
A 2% solution in water has a pH of 4.5 to 6.2 (Parfitt,1999).

3.7. Stability in light

atropine:
Atropine should be protected from light, and stored in airtight containers (Parfitt, 1999).
atropine sulphate:
Atropine sulphate is slowly affected by light (McEvoy, 2002). It should be protected from
light and stored in airtight containers (Parfitt, 1999).

3.8. Reactivity
atropine:
When heated to decomposition, toxic fumes of oxides of nitrogen are emitted (Sax , Lewis,
1992).
atropine sulphate:

Atropine sulphate effloresces when exposed to dry air (McEvoy, 2002). When heated to
decomposition, toxic fumes of oxides of nitrogen and sulphide are emitted (Sax, Lewis 1992).

3.9. Pharmaceutical incompatibilities

atropine:
No information available
atropine sulphate
Atropine sulphate is reported to be physically incompatible with noradrenaline bitartrate,
metaraminol bitartrate and sodium bicarbonate injections. A haze or precipitate may form
within 15 minutes when the injection is mixed with methohexital sodium solution (McEvoy,
2002). Immediate precipitation occurs when cimetidine and pentobarbital sodium together are
mixed with atropine sulphate in solution, while a precipitate will form within 24 hours if
atropine sulphate is mixed with pentobarbital sodium alone (Trissell, 2001). Thiopental
sodium and atropine sulphate injected together at Y-sites will form white particles in the
solution immediately (Trissell, 2001). A haze will form in 24 hours then a precipitate at 48
hours if flucloxacillin sodium and atropine sulphate are stored together at 30 C, while no
change is seen at 15C (Trissell, 2001).
Incompatibilities between atropine sulphate and hydroxybenzoate preservatives have
occurred, with a total loss of atropine in 2-3-weeks (Parfitt, 1999). Atropine sulphate is
incompatible with other alkalis, tannin, salts of mercury or gold, vegetable decoctions or
infusions, borax, bromides and iodides (Budavari, 1996).

3.10. Proprietary names and manufacturers

atropine:
Atropen (Meridian, USA) (McEvoy, 2002);
Atropinol (Winzer, Denmark) (Index Nominum 2000)
atropine sulphate:
Atropair (Pharmafair, USA); Atropine Aguettant( Aguettant, France),
Atropine Meram (Cooper, France); Atropine Opthadose(Ciba-Geigy, Belgium); Atropine
SDU Faure(Ciba Vision, Suisse); Atropinium sulfuricum Streuli(Streuli, Suisse);
Atropinum sulfuricum AWD(ASTA Medica, Denmark); Atropisol(Ciba Vision, Canada,
Iolab, USA);
Atropocil(Edol, Portugal); Atropt(Sigma, Australia);
Atrosol(Adilna Turkey); I-Tropine(Americal, USA);
Isopto Atropine(many countries); Liotropina(SIFI, Italy);

Midrisol(Abdi Ibrahim, Turkey); Noxenur S(Galenika, Denmark);

Sal-Tropine(Hope, USA);Skiatropine(Cjauvin, France, Suisse); Stellatropine(Stella,
Belgium, Luxembourg); Tropyn Z(Zafiro, Mexico)

3.11. Other
There are no data available concerning the specific gravity or refractive index of atropine or
its salt.

4. Pharmaceutical formulation and synthesis

4.2. Manufacturing processes
Atropine is usually prepared by extraction from the plants Atropa belladonna (deadly
nightshade), Datura stramonium (Jimson weed) or Duboisia myoporoides (McEvoy, 2002).
This extracted atropine is a combination of D and L hyoscyamine. Both these isomers may
bind to muscarinic receptors (Berghem et al, 1980) although the pharmacological activity is
thought to be due almost entirely to L hyoscyamine (McEvoy, 2002).

4.3. Pharmaceutical formulation

atropine
Atropine is available as a sterile solution with a citrate buffer, glycerin and phenol as
preservative, in a self-injecting device for administration into the muscular tissue of the outer
thigh. It can be administered through clothing if necessary. The content is 1.67 mg atropine
(equivalent to 2 mg atropine sulphate) in 0.7 ml (Atropen Meridian Technologies) (Byrd,
2002, Copenhaver, 1994).
atropine sulphate
Atropine sulphate is available as a sterile solution in normal saline or water for injection from
several manufacturers (including Astra, Abbott, Elkins-Sinn and IMS) (McEvoy, 2002). The
preservatives parabens and sulphites, (McEvoy 2002) may be found in injectable products.
Atropine sulphate is usually available in concentrations of 0.25-0.5 mg/ml, although some
countries, such as Portugal and Germany, have a 10 mg/ml solution for use in
organophosphate poisoning. Atropine sulphate injections may be adjusted to a pH of 3 to 6.5
with sulphuric acid (McEvoy 2002).
Oral forms (tablets) are also available (McEvoy, 2002).

4.1. Synthesis
atropine
The alkaloid, atropine, is an organic ester which may be prepared synthetically by combining
tropine and tropic acid (McEvoy 2002), but is usually obtained by extraction from some
solanaceous plants (Parfitt,1999).

5. Analytical methods
5.1. Quality control of antidote.
atropine
Assay (USP, 2002)
400 mg of atropine, accurately weighed, is dissolved in 50 ml of glacial acetic acid and one
drop of crystal violet TS is added. This is titrated with 0.1 N perchloric acid VS to a green
endpoint. A blank determination is performed and any necessary correction made. Each ml of
0.1N perchloric acid should be equivalent to 28.94 mg of C17H23NO3.
Limit of foreign alkaloids and other impurities (USP, 2002)
A solution of atropine in methanol is prepared containing 20 mg per ml, and, by quantitative
dilution of a portion of this solution with methanol, a second solution of atropine is prepared
containing 1 mg per ml. Then, 25 L of the first (20 mg per ml) atropine solution, 1 L of the
second (1 mg per ml) atropine solution and 5 L of a methanol solution of USP Atropine
Sulfate RS containing 24 mg per ml is applied to a suitable thin layer chromatographic plate,
coated with an 0.5 mm layer of chromatographic silica gel. The spots are allowed to dry, and
the chromatogram developed in a solvent system consisting of a mixture of chloroform,
acetone and diethylamine (5:4:1), until the solvent front has removed about three quarters of
the length of the plate. The plate is removed from the developing chamber, the solvent front is
marked and the solvent allowed to evaporate. The spots on the plate are located by spraying
with potassium iodoplatinate TS: the Rf value of the principal spot obtained from each test
solution should correspond to that obtained from the Reference Standard solution: no
secondary spot obtained from the first atropine solution should exhibit intensity equal or
greater than the principal spot obtained from the second atropine solution (0.2%).
atropine sulphate
Assay (USP, 2002)
1 g of atropine sulphate, accurately weighed, is dissolved in 50 ml of glacial acetic acid, then
titrated with 0.1 N perchloric acid VS, determining the endpoint potentiometrically. A blank
determination is performed and any necessary corrections made. Each ml of 0.1 N perchloric
acid should be equivalent to 67.68 mg of (C17H23NO3)2 . H2SO4.
Assay (BP, 2000)
0.500 g of atropine sulphate is dissolved in 30 ml of anhydrous acetic acid R, warming if
necessary. The solution is cooled then titrated with 0.1M perchloric acid and the end-point
determined potentiometrically (2. 2. 20). 1 ml of 0.1M perchloric acid should be equivalent to
67.68 mg of C34H48N2O10S.
Assay (PPRC, 2000)

0.5 g of accurately weighed atropine sulfate is dissolved in a mixture of 10 ml of glacial

acetic acid and 10 ml of acetic anhydride, one to two drops of crystal violet IS is added and
the solution titrated with perchloric acid (0.1 mol/L) VS until the colour is changed to pure
blue. A blank determination is performed and any necessary corrections made. Each ml of
perchloric acid (0.1 mol/L) VS should be equivalent to 67.68 mg of (C17H23NO3)2 .H2SO4.
Limit of other alkaloids (USP, 2000)
150 mg atropine sulphate is dissolved in 10 ml water. To 5 ml of this solution is added a few
drops of platinic chloride TS: no precipitate should be formed. To the remaining 5 ml of the
solution, 2 ml of 6 N ammonium hydroxide is added and shaken vigorously: a slight
opalescence may develop but no turbidity should be produced.
Limit of foreign alkaloids and decomposition products (BP, 2000)
The substance should be examined by thin-layer chromatography (2. 2. 27) using silica gel G
R as the coating substance. Solutions should be made up as follows:
Test solution. 0.2 g of the substance to be examined is dissolved in methanol R and diluted to
10 ml with the same solvent.
Reference solution (a). 1 ml of the test solution is diluted to 100 ml with methanol R.
Reference solution (b). 5 ml of reference solution (a) is diluted to 10 ml with methanol R.
To the plate is applied separately 10 l of each solution. These are developed over a path of
10 cm using a mixture of 90 volumes of acetone R, 7 volumes of water R and 3 volumes of
concentrated ammonia R. The plate is dried at 100 C to 105 C for 15 minutes. It is allowed
to cool then sprayed with dilute potassium iodobismuthate solution R until the spots appear.
Any spot in the chromatogram thus obtained with the test solution, apart from the principal
spot, should not be more intense than the spot in the chromatogram obtained with reference
solution (a) (1.0 per cent) and not more than one such spot should be more intense than the
spot in the chromatogram obtained with reference solution (b) (0.5%).
Limit of apoatropine (BP, 2000)
0.10 g atropine sulphate is dissolved in 0.01M hydrochloric acid and diluted to 100 ml with
the same acid. The absorbance is determined (2. 2. 25) at 245 nm. The specific absorbance
should not be greater than 4.0, calculated with reference to the anhydrous substance (about
0.5 per cent).
atropine sulphate injection
Chromatographic methods of assay are described in USP, 2002 and BP, 2000.
The pH of atropine sulphate injection USP, 2002 should be between 3.0 and 6.5. It should
contain not more than 55.6 USP Endotoxin units per milligram of atropine sulfate and it
should meet the standard requirements for USP, 2002 injections.

5.2. Methods for identification of antidote

Atropine
(USP, 2002)
Infrared absorption spectrophometric identification testing is one method by which atropine
can be identified:
Atropine 30 mg then 36 mg of USP atropine sulphate RS are dissolved in individual 60 ml
separators with the aid of 5 ml portions of water. To each separator is added 1.5 ml of 1 N
sodium hydroxide solution and 10 ml of chloroform. This is shaken for 1 minute, the layers
allowed to separate and the chloroform extracts filtered through separate filters of about 2 g
of anhydrous granular sodium sulfate supported on pledgets of glass wool. Each aqueous
layer is extracted with two additional 10 ml portions of chloroform. These are filtered and
combined with the respective main extracts. The chloroform solutions are evaporated under
reduced pressure to dryness, then each residue is dissolved in 20 ml of carbon disulfide. The
infrared absorption spectrum, determined in a 1 mm cell of the solution obtained from the test
specimen, should exhibit maxima only at the same wavelengths as that of the solution
obtained from the Reference Standard.
Atropine sulphate
(BP, 2000)
First identification tests A, B and E
Second identification tests C, D, E and F.
A. An aqueous solution should show almost no optical rotation
B. The sample is examined by infrared absorption spectrophotometry (2. 2. 24) then
compared with the spectrum obtained with atropine sulphate CRS
C. About 50 mg of the test specimen is dissolved in 5 ml of water R, then added to 5 ml picric
acid solution R. The precipitate, when washed with water R, then dried at 100 C to 105 C
for 2 hours, should melt (2. 2. 14) at 174 C to 179 C.
D. To about 1 mg of test specimen is added 0.2 ml of fuming nitric acid R, which is
evaporated to dryness in a water bath. The residue is dissolved in 2 ml of acetone R. Then,
0.1 ml of a 30 g/L solution of potassium hydroxide R in methanol is added. A violet colour
should develop.
E. Reactions of sulphates (2. 3. 1) is given by the test specimen
F. Reaction of alkaloids (2. 3. 1) is given by the test specimen
Atropine sulphate injection
(BP, 2000)

A The method for thin-layer chromatography, Appendix 111 A, using silica gel G as the
coating substance and a mixture of 50 volumes of chloroform, 40 volumes of acetone and 10
volumes of diethylamine as the mobile phase is carried out. Applied separately to the plate
are 5 l of each of the following solutions:
For solution (1), a volume of the injection containing 5mg of Atropine Sulphate is evaporated
to dryness on a water bath, the residue is triturated with 1 ml of ethanol (96%), allowed to
stand and the supernatant liquid used.
Solution (2), containing 0.5% w/v of atropine sulphate BPCRS in ethanol (96%) is heated at
105 C for 20 minutes after removal of the plate, allowed to cool and sprayed with dilute
potassium iodobismuthate solution.
The spot in the chromatogram obtained with solution (1) should correspond to that in the
chromatogram obtained with solution (2).
B In the Assay, the chromatogram obtained with solution (1) should exhibit a peak with the
same retention time as the peak due to atropine sulphate in the chromatogram obtained with
solution (2)

5.3. Methods for analysis of atropine in biological samples

Atropine may be assayed accurately in plasma using a radioimmunoassay technique
(Wurzburger et al., 1977; Berghem et al., 1980). Atropine concentrations down to 0.1-0.9
mg/L can be measured with good accuracy and reliability using reversed phase liquid
chromatography (Fell et al., 1979), GC-MS assay (Hinderling et al., 1985), mass
fragmentography (Palmer et al., 1981), or radioreceptor assay (Metcalfe, 1981; Aaltonen et
al., 1984).

5.4. Methods for analysis of the toxic agent in biological samples

Various methods have been described for the detection of organophosphates in biological
fluids. However, most often, measurement of erythrocyte (or plasma) acetylcholinesterase
activity is used as an indirect measurement of the degree of enzyme inhibition (see section 4
in overview chapter).

6. Shelf life
atropine
When stored protected from light, atropine in a self-injecting kit can have a shelf life of 5
years. (Byrd, 2002). The self-injector kit should be stored between 15 and 30 C (McEvoy,
2002) and may freeze at temperatures below 29 F. Frozen injectors are still usable after
being thawed if they do not appear to be frozen or cracked (Copenhaver, 1994). Atropine
should be preserved in airtight, light-resistant containers (USP, 2002).
atropine sulphate

Atropine sulphate should be stored in single or multiple-dose containers, preferably glass, at a

temperature of less than 40 C (preferably between 15 to 30 C). It should be protected from
light (McEvoy, 2002) and stored in airtight containers.(USP, 2002). Freezing should be
avoided (McEvoy, 2002). The shelf-life is 24 months from the date of manufacturing if kept
under the above conditions (personal communication, Abbott Laboratories, 1989).

7. General properties
7.1. Mode of antidotal activity
Atropine is a muscarinic cholinergic blocking agent. It competitively blocks parasympathetic,
postganglionic nerve endings from the action of acetylcholine and other muscarinic agonists.
Atropinic drugs have little effect at nicotinic receptor sites. Large doses of atropine produce
only partial block of autonomic ganglia and have almost no effect at the neuromuscular
junction.
Small doses of atropine depress sweating and salivary and bronchial secretion. Atropine is
particularly useful in relieving bronchoconstriction and salivation induced by
anticholinesterases. Doses required to inhibit gastric secretion are invariably accompanied by
dry mouth and ocular disturbances. At higher doses, the heart rate increases as the effects of
vagal stimulation are blocked (Kentala et al.,1990). When given alone atropine has little
effect on blood pressure, although it can block completely the hypotensive and vasodilatory
effects of choline esters. Larger doses decrease the normal tone and amplitude of contractions
of the bladder and ureter, thereby inhibiting micturition. Atropine inhibits both the tone and
motility of the gut, reducing peristalsis.
Unlike scopolamine, small doses of atropine have little depressant action on the central
nervous system. However, in toxic doses, atropine initially causes central excitation
(exhibited as restlessness, confusion, hallucinations, and delirium) followed by central
depression with coma and death. Both atropine and scopolamine shift the EEG to slow
activity, reducing the voltage and frequency of the alpha rhythm. Atropine normalizes
increased EEG activity due to isoflurophate (Longo, 1966). For many years, the central
anticholinergic effects of the belladonna alkaloids in reducing tremor were the mainstay of
therapy for Parkinson's disease.
Large doses of atropine impair accommodation, causing dilation of the pupil and blurred
vision. The normal pupillary response to light or upon convergence may be completely
abolished. These ocular effects may be seen after oral, systemic, or local administration of the
drug (Weiner, 1985).
The peripheral antimuscarinic effects of atropine may not be the only antidotal property of
the drug in organophosphate poisoning. Atropine may also be of value in treating acute
dystonic reactions occasionally observed in acute organophosphate poisoning (Joubert et al.,
1984; Joubert & Joubert, 1988; Smith, 1977; Wedin, 1988). Patients with extrapyramidal
signs have been noted to have abnormally low plasma and red blood cell cholinesterase
activities, producing an excess of acetylcholine relative to dopamine (Wedin, 1988).
However, there is little clinical evidence available on the possible anticonvulsive effects of
atropine in man.

8. Animal studies
8.1. Pharmacodynamics
This section will review briefly animal work relevant to the use of atropine, whether
administered alone or in combination with an oxime, in the management of organophosphate
poisoning. It is necessary, when reviewing animal data, to ensure that the dose of atropine
given was sufficient to influence outcome. Another problem in extrapolating animal data to
man is that many animal models evaluate mortality up to 24 hours, after only one injection of
an antidote or antidotes given immediately following exposure to an organophosphorus
compound, a model not likely to be mimicked in clinical practice.
Given the importance of adequate supportive therapy in the clinical setting, and particularly
the importance of a patent airway, it is surprising that many studies do not state whether such
treatment was employed, even when large animals such as buffalo calves (weighing 100-150
kg) were used (Gupta, 1984).
8.1.1. Antidotal effect of atropine
Sanderson (1961) studied the effect of intraperitoneally administered atropine (17.4 mg/kg)
given alone, or combined with oximes, on the survival of rats poisoned orally by ten different
organophosphates, excluding dimethoate. Atropine alone prevented the development of
toxicity. Although the numbers of rats in each group were small (n = 6) and statistical
analysis was not performed, this study demonstrated that atropine treatment alone did
reduced mortality.
Stein & Neill (1985) studied the survival rate of rats poisoned orally by dimethoate (600
mg/kg) after treatment with either atropine or hyoscine, 1 mg/kg intraperitoneally (i.p.) and
repeated hourly for up to 12 h. Compared to non-treated controls, no effect on survival was
observed and the authors concluded that atropine and hyoscine were equally ineffective.
However, their conclusions were most probably invalid, since the dose of atropine used was
inadequate for the species studied (Sanderson, 1985). In a previous study, Sanderson & Edson
(1959) had demonstrated that atropine (17.4 mg/kg i.p. every 4 hours) was effective in
reducing the mortality in dimethoate-poisoned rats.
Schoene et al. (1988) studied the efficacy of atropine administered prior to dosing with
paraoxon in mice. Atropine was administered 5, 20, 40 and 60 minutes before
organophosphate administration and was found to reduce mortality significantly. The
"efficacy half-life" of the antidote was approximately twice the half-life of the antidote in
blood. Although the sensitivity of the atropine assay used in this study was not satisfactory,
this does not detract from the significant life-saving effect of atropine in this experimental
study.
In calves poisoned with intravenous dichlorvos, atropine was shown to reverse the respiratory
effects of the organophosphate (Likeux et al., 1986). The organophosphate-induced reduction
in dynamic lung compliance, arterial oxygen tension, increase in total pulmonary resistance,
work of breathing and alveolar arterial oxygen gradient were reversed by atropine. Atropine
may therefore, reverse changes in ventilation-perfusion inequalities resulting from uneven
distribution of ventilation, caused by acetylcholine-mediated airway constriction (Slocombs

& Robinson, 1987). Atropine had no effect on muscle fasciculation or plasma cholinesterase
inhibition.
In monkeys, Lipp (1976) investigated the effect of atropine on soman-induced respiratory
depression. An immediate increase in heart rate was accompanied by a gradual increase in
respiratory rate. Only after low doses of organophosphate is a relationship demonstrable
between the antimuscarinic and protective effects of atropine pre-treatment (Green et al.,
1977). Large doses of atropine counteract the convulsive effects of massive organophosphate
poisoning. This effect is not related to the degree of muscarinic blockade.
In a study in rats, Pazdernik et al. (1986) investigated the effect of atropine pre-treatment on
local cerebral glucose utilization during seizures induced with soman. High-dose atropine (10
mg/kg) was found, like diazepam, to reduce local cerebral glucose utilization and thus reduce
brain damage. The protective effect of atropine in organophosphate poisoning may therefore
be far more than simple muscarinic blockade.
Support for an anticonvulsant action of atropine has been presented by McDonough et al.
(1987) who found that atropine pre-treatment prevented the development of convulsions and
brain damage induced by soman or VX injected directly into the amygdala. The results
indicated that the nerve agents were not directly neurotoxic, that peripherally induced
hypoxia or anoxia were unlikely mechanisms of the neuropathology, and that the brain
damage produced by these compounds was primarily seizure-mediated.
Chronic exposure to certain organophosphates may induce changes in the pharmacodynamics
of atropine, thus influencing the response of the animal to atropine therapy. Atropine has been
shown to produce myoclonus and stereotyped responses in rats (related to enhanced
serotonergic and dopaminergic activity) following DFP (isoflurophate) exposure (Fernando et
al., 1985). In rats challenged 6 to 72 hours after single doses of sarin or soman, myoclonus
was markedly enhanced (Fernando et al., 1986), suggesting rapid development of
hypersensitivity to antimuscarinic agents. Furthermore, repeated DFP administration caused a
specific decrease in muscarinic receptors and 14C choline uptake in the striatum and ileal
longitudinal muscle of guinea pigs (Yamada et al., 1983), a change associated with a more
than 50% depression of tissue acetylcholinesterase activity. The concept of a down regulation
of muscarinic receptors after chronic soman administration has also been corroborated by
Modrow & McDonough (1986), who, using a behavioural model in rats, found
supersensitivity to atropine.
Matsubara & Horikoshi (1983) observed that atropine alone increased the survival rate by 20
to 40% in rats given a normally lethal dose of fenitrothion.
8.1.2. Atropine and oximes
Although the role of atropine in organophosphate poisoning is clear, our knowledge of the
kinetics and dynamics of atropine and oximes when employed in combined therapy is very
limited. In one study in mice, Clement et al. (1988) noted that soman increased the terminal
half-life and volume of distribution (Vd) of the oxime HI-6 (asoxime chloride). Atropine
increased the clearance of HI-6 with no effect on Vd. These changes in oxime kinetics were
probably the result of haemodynamic changes.

In fenitrothion-poisoned rats, Matsubara and Horikoshi (1983) studied the effect of various
antidotes on 72-hour lethality. When using 100% lethal doses of this organophosphate (800
mg/kg orally), atropine (20 mg/kg i.p.) alone was more effective than oxime (pralidoximine
(2-PAM), 50 mg/kg i.p.) alone, and significantly (p < 0.05) increased the survival ratio up to
40% (survival of 6/10 compared with 0/10 in controls). The effect of 2-PAM alone was not
significant (survival of 2/10) at this dose of fenitrothion. At the 500 mg/kg dose of the
organophosphate (OP), the effect of both antidotes alone upon survival was significant as
compared to controls. The optimal therapy (800 mg/kg of OP), however, was the repeated
and combined administration of atropine and 2-PAM resulting in 90% survival and
considerable alleviation of the features of toxicity (survival of 9/10; 0/10 in controls).
Gupta (1984) studied the effect of atropine, 2-PAM and diazepam in buffalo calves poisoned
orally with sublethal (100 mg/kg) or minimal lethal doses (125 mg/kg) of malathion, which
produced severe tremors and convulsions within 40 to 60 minutes. The antidotes were
administered parenterally either alone or in combination at the time of peak malathion
toxicity (within 1 hour) and were assessed for their ability to reduce signs of cholinergic
toxicity. A combination of atropine (0.5 mg/kg, 1/4 IV and 3/4 IM) and 2-PAM (20 mg/kg IV)
reversed the clinical evidence of malathion toxicity within 15 minutes. Atropine alone was
less effective (survival - 4/5; survival with the combination - 5/5; survival of controls - 0/3)
and did not reverse malathion-induced biochemical changes. In contrast, administration of 2PAM (10-30 mg/kg IV ) or diazepam (0.5-1.0 mg/kg IV) alone accentuated malathion
toxicity when sublethal doses were given (0/9 and 0/12 survived, respectively, compared to
3/3 in controls). In this experimental setting, the combination of atropine sulphate and 2-PAM
was claimed to be the most effective antidotal treatment in acute malathion poisoning
(sublethal doses) as judged from the rapid disappearance of toxic features. The survival ratio
for the latter combination (5/5) was the same as for the combination of atropine and diazepam
(5/5, controls - 0/3).
In the experimental study by Sanderson (1961) discussed in section 8.1.1, no beneficial
potentiation between oxime and atropine could be demonstrated for the ten organophosphate
insecticides tested when the organophosphate was given orally, and the combination was less
effective than atropine alone in azinphos-methyl (gusathion), azinphos-ethyl (ethylgusathion), demeton and morphothion poisoning. Beneficial potentiation between oxime and
atropine did occur when morphothion was given intraperitoneally. Sanderson (1961)
suggested that combined treatment with atropine and oxime may be deleterious when the
animals are given the organophosphate orally because reduced peristalsis slows the
absorption of the organophosphate beyond the most effective concentrations of the antidotes
given parenterally. The study by Gupta (1984), described above did not, however,
demonstrate this negative effect of combined oxime and atropine therapy.
Ligtenstein & Moes (1991) studied the synergism of atropine (37.5 mg/kg ip) and oxime (HI6) pre-treatment (50 mg/kg ip) in rats administered two different cholinesterase inhibitors
subcutaneously, one with a mixed central/peripheral mode of action (S-diethylaminoethyl-0cyclohexyl-methylphosphonothioate) and its methiodide derivate with an almost entirely
peripheral effect. LD50 was assessed after 24 hours. In both cases, HI-6 alone was found to be
more effective than atropine alone, significantly reducing convulsions and lethality (factor of
5 and 70, highest for the peripheral agent). Atropine alone had only a slight protective effect
against the mixed central/peripheral agent and no beneficial effect against the other. The
explanation offered for this observation was that the beneficial effect of atropine was
mediated through central mechanisms, the peripheral parasympatholytic effect being

negligible in counteracting lethality. The combination of atropine and oxime had an

extremely significant synergistic effect on reducing lethality (LD50 increased from 16 ug/kg to
no deaths at 5 mg/kg) when the toxicant had a mixed central/peripheral action, whereas no
significant synergistic effect was observed when the toxicant had a peripheral action. The
authors explanation for this observation was that under the former circumstances, the
acetylcholinesterase reactivation in the respiratory neuromuscular synapse by the oxime, was
supplemented by the central action of atropine, which improved respiratory control at the
level of the central nervous system.
Clement (1994) studied the effect of atropine (17.4 mg/kg, i.p.) alone, or combined with 2PAM, obidoxime and HI-6, administered 5 min before mice were poisoned by a combination
of sarin and cyclohexyl methylphosphonofluoridate (cyclosarin or GF) administered
subcutaneously. Atropine alone failed to reduce lethality but combined with either oxime the
lethality was significantly reduced as judged by 24 hour ED50 values.
An experimental study of sarin poisoning in rats (Shiloff & Clement, 1987) compared the
efficacy of HI-6, obidoxime and pralidoxime as antidotes when combined with atropine. H16 was found to be most efficacious, followed by pralidoxime and obidoxime. These
conclusions were however based on a single dose regimen of sarin and of atropine. This may
be important, since the optimal combination of atropine with an oxime may depend upon the
severity of the poisoning. Response surface methods, which provide an assessment of the
entire dose-response surface for all inherent variables, were used to optimize treatment
therapies in soman intoxication (Carter et al., 1985). These workers showed in guinea pigs
that the level of soman exposure altered the nature of the atropine/pralidoxime interaction. At
low exposure levels, optimal treatment was with atropine alone. As soman toxicity increased,
pralidoxime became important and the optimal dose of atropine required initially decreased
slightly, but then again increased when soman was given in high doses.
8.1.3. Atropine and oxime synergy with other therapeutic agents
8.1.3.1. Physostigmine and Pyridostigmine (Carbamates)
In animal experiments, both physostigmine (Albuquerque et al., 1985; Deshpande et al.,
1986; Harris et al., 1978 & 1980) and pyridostigmine (Berry & Davies, 1970; Dellinger,
1988; Jones et al., 1985) pre-treatment has been shown to reduce atropine and pralidoxime
requirements. Carbamates, such as physostigmine, that pass the blood-brain barrier may
protect from organophosphate toxicity by reducing the organophosphate-induced rise in total
brain acetylcholine, thereby restoring neural function (Harris et al., 1980). The optimal
atropine/pralidoxime dose combination has been shown to be a function of the challenge
level of soman and pyridostigmine (Jones et al., 1985). The protective effect of these
carbamates may involve several mechanisms other than cholinesterase inhibition. It is of
interest that, for example, physostigmine, in addition to its anticholinesterase activity,
interacts with multiple sites at the acetylcholine receptor (Albuquerque et al., 1985).
Deshpande et al. (1986) studied the synergistic effect of atropine following pre-treatment
with physostigmine in an experimental study in the rat. These workers found that
physostigmine pre-treatment 30 minutes prior to injection of sarin reduced mortality to 28%.
When it was co-administered with atropine, mortality fell to 4%.

Prophylactic use of these carbamates may be important for defence forces expecting to be
attacked with nerve agents. Pre-treatment, or treatment, with these carbamates has no present
place in the treatment of organophosphate insecticide poisoning in man.
8.1.3.2. Diazepam
The anticonvulsant effect of diazepam has been demonstrated in rats treated with soman
(Pazdernik et al., 1986) and in the monkey (Lipp, 1973). In quinalphos-poisoned rats, pretreatment with atropine and diazepam decreased the acute toxicity of the insecticide 3.3 times
(Bokonjic et al., 1987). This positive effect was further enhanced by a continuous infusion of
pralidoxime, which maintained pralidoxime concentrations between 1- 5.4 g/L. In a study of
rats poisoned with fluostigmine and pre-treated with atropine and diazepam, the subsequent
administration of diazepam had no effect on the course of the poisoning (Rump et al., 1976).
In the study by Gupta (1984) using minimal lethal doses of malathion, the combination of
atropine and diazepam (0.75 mg/kg IV) prevented death (5/5 animal survived compared to
0/3 of controls) and the development of cholinergic signs of toxicity, except for weak
muscular fasciculation persisting for 30 to 60 minutes. Diazepam alone accentuated toxicity.
8.1.3.3. Clonidine
In a study in mice, Buccafusco & Aronstam (1986) showed that pre-treatment with the
centrally-acting alpha-C-2 adrenergic agonist clonidine protected against several of the
centrally-mediated toxic effects of soman, increasing survival rates. Furthermore, there was a
synergistic effect on survival rates when clonidine was combined with atropine. At protective
doses, clonidine not only blocked acetylcholine release but non-competitively inhibited
acetylcholinesterase activity. It also inhibited ligand binding to cortical muscarinic receptors.
Clearly, clonidine has multiple effects and should be the subject of further experimental
study.
8.1.3.4. Calcium channel blockers
This group of drugs, together with phenytoin (but not other anticonvulsants used in the
study), may also offer protection against organophosphate toxicity (Dretchen et al., 1986). In
mice, pre-treatment with phenytoin, verapamil, nifedipine, nitrendipine or nimodipine
increased the LD50 of DFP. This may be due to a protective action on central respiratory
centres and peripheral nicotinic sites.
8.1.3.5. Other agents
The effects of antidotal therapy on neuronal RNA content have been studied by Doebler et al.
(1983). Soman produced a virtually complete inhibition of acetylcholinesterase activity and
moderate decline in neuronal RNA content. Atropine pre-treatment together with pralidoxime
reduced RNA levels but increased acetylcholinesterase activity. Thus, no precise relationship
exists between the restoration of neuronal acetylcholinesterase (AChE) and AChE activity.
The effects on neuronal RNA metabolism may, rather, reflect alterations in acetylcholine
sensitivity; if this is so, then manipulation of acetylcholine responsiveness may be a further
mechanism for therapeutic intervention. Sterling et al. (1988) studied two drugs found to
inhibit presynaptic acetylcholine synthesis in vitro. In a rat model, pre-treatment with Nhydroxyethylnapthylvinylypyridine (NHENVP) or N-allyl-3 quinuclidinol was found to
protect rats from soman toxicity, enhancing the effects of atropine and pralidoxime.

Thus the effects of atropine, pralidoxime and other drugs that synergistically decrease
organophosphate toxicity are complex and as yet, not elucidated fully. Although there are
promising new therapeutic approaches, the clinical usefulness of clonidine, calcium channel
blockers and presynaptic blockade of acetylcholine synthesis is not yet known.

8.2. Pharmacokinetics
The extensive information obtained from clinical studies, and the problems of extrapolating
data obtained from different animal species, limits the need for animal data on
pharmacokinetics.
Studies in anaesthetized monkeys show that mean plasma concentrations after intraosseous
administration correspond to those found two minutes after intravenous administration. Both
the intraosseous and endotracheal routes are acceptable alternatives if intravenous access is
delayed or unavailable (Prete et al., 1987).

8.3. Toxicology
The following LD50 values are given for acute toxicity (Sax, Lewis 1992)

Species

Route

Atropine
LD50 (mg/kg)

Atropine sulphate
LD50 (mg/kg)

Rat

Mouse

Oral

500

600

Intravenous

73

Intramuscular

920

intraperitoneal

280

215

Oral

75

468

Intravenous

30

31

8.3.1. Mutagenicity testing

Atropine caused non-specific aggregation of chromosomes, considered to be of no
cytogenetic danger (Vrba,197I, Davies 1985).
Atropine sulphate was assessed as negative in the Ames assay, using one or more Salmonella
typhimurium standard strains (TA98, TA100, TA1535, TA1537 and TA1538) ( Ramel et al,
1986).
8.3.2. Carcinogenicity testing
Atropine may promote experimental carcinogenesis in rat stomach caused by N-methyl-Nnitro-N- nitrosoguanidine (Tatsuka et al.1989). In a long-term trial of 858 rats by Schmahl
and Habs, (1976) atropine was not found to be carcinogenic.
8.3.3. Teratogenicity testing
Chick eggs were injected with 0.6 to 1.5mg atropine during the interval of 4 to 12 days
incubation. No defects were produced (Shepard, 1980).
Atropine given to rat dams from days 7 to 19 of gestation resulted in avoidance learning
deficits in their pups compared to controls. Findings suggested that prenatal exposure to
sympatholytic drugs may produce adverse effects on the behavioural development of pups
(Matsuhashi et al.1984).
8.3.4. Behavioural toxicology
In microencephalic rats, compared to normal controls the magnitude of deficits in learning
the Morris water maze increased as a function of atropine dose, suggesting that learning and
memory may be related to changes in the number and/or function of muscarinic cholinergic
receptors (Lee et al 1990). Behavioural alterations have been noted amongst the offspring of
rats treated during pregnancy with atropine (Watanabe et al 1985).

9. Volunteer studies
The pharmacokinetic data and basic pharmacodynamic data in man are given in this section
although some information may be derived from case reports.

9.1. Pharmacodynamics
There is a clear temporal relationship between the plasma concentrations of atropine after
intramuscular injection (Berghem et al., 1980), and the time course of the cardiac accelerating
effect of the drug (Sidell et al., 1970). This does not hold true for all pharmacological effects;
for example, the saliva reducing effect is more delayed, peaking at 100 minutes after an
intramuscular injection (Murrin, 1973). The effect of atropine on pupillary dilation and near
point vision reaches a maximum only six hours after administration (Mirakhur, 1978).
Furthermore, studies in both adults (Sjovall et al., 1984a) and children (Sjovall et al., 1984b)

report no correlation between a single serum atropine concentration and both subjective and
objective responses.

9.2. Pharmacokinetics
9.2.1. Absorption
Oral absorption. Atropine is absorbed irregularly from the gastrointestinal tract, and more
slowly than with parenteral dosing (Dollery, 1991). In adults, atropine is absorbed mainly
from the duodenum and jejunum rather than the stomach. Maximum radioactivity, using 3Hatropine, was found one hour after an oral dose (Beermann et al, 1971). Absorption of orally
administered atropine may be delayed if atropine has been previously administered, as shown
by Hardison et al (1979): a 38% increase in small bowel transit time was observed following
intramuscular injection of atropine.
In children, who received atropine 0.03mg/kg orally, peak plasma concentrations occurred at
90 minutes with only 10-20% occupancy of muscarine-2 subtype receptors. By contrast, after
0.02mg/kg intramuscular administration, peak was at 25 minutes with 60-70% receptor
occupancy (Gervais et al, 1997). Following an oral dose of 0.03mg/kg atropine, a mean
maximum serum concentration of 6.7nmol/L occurred at two hours in children, compared
with 5.7 nmol/L at 30 minutes after intramuscular administration (Saarnivaara et al, 1985).
Rectal absorption. In children, rectal absorption of atropine is slower than absorption from
the intramuscular route. Peak plasma concentrations of 0.7g/L occurred after 15 minutes,
following rectal administration of atropine, compared with 2.4 g/L, five minutes after
intramuscular dosing (Olsson et al, 1983). Peak plasma concentrations after rectal dosing in
children below 15kg in weight were lower than in older children (but not to a clinically
significant degree) and plasma concentrations declined faster (Bejersten et al, 1985).
Sublingual absorption. Oral sublingual atropine absorption was considered to be "of minor
clinical significance" compared to absorption after intramuscular or subcutaneous
administration. Absorption from the sublingual route was variable and low in pregnant
women at full term given 0.02mg/kg to 0.07mg/kg compared to intramuscular or
subcutaneous administration of 0.02mg/kg (Kanto & Pihlajamaki, 1986). A 7-month child in
asystole received a sublingual injection of atropine 0.15mg (with adrenaline) with return of
sinus rhythm and pulse (Rothrock et al, 1993).
Inhalation. Inhalation of atropine sulphate from a pressurized metered-dose inhaler resulted
in peak serum concentrations of 4.9 g/L, 6.1 g/L and 7.9 g/L from administration of
1.7mg, 3.4mg and 5.2mg respectively. By comparison, a 1.67mg intramuscular injection of
atropine free base (equivalent to 2mg atropine sulphate) gave a mean peak concentration of
8.4 g/L (Kehe et al, 1992).
Ocular absorption. Some absorption of atropine can occur from the lower cul-de-sac of the
eye (Lahdes et al, 1988). Peak plasma concentration was reached within 8 minutes after
instillation of a 1% atropine solution.
Dermal absorption. Limited absorption occurs from the intact skin (Hardman, 1996).

Intramuscular absorption. Intramuscular absorption of atropine and atropine sulphate

depends on the method of injection, the site of injection (Friedl et al, 1989) and the
pharmaceutical form. Exercise may increase the rate of absorption (Kamimori et al, 1990).
Atropine and atropine sulphate reach peak plasma levels when injected intramuscularly in
about 30 minutes (Berghem et al, 1980, Saarnivaara et al, 1985, Gervais et al, 1997). In
pregnant women at full term, however, mean peak plasma levels were reached at 1.59 hours,
following a dose of 0.01mg/kg (Kanto et al, 1981). Absorption may be faster if atropine is
injected into the deltoid muscle rather than the gluteal or vastus lateralis muscles (AliMelkkila et al, 1993). A study using time to peak heart rate to seek differences between routes
of administration and pharmaceutical forms, found that intravenous administration was most
rapid (5 5 minutes) compared to intramuscular administration of citrate buffered atropine in
a modified syringe (26 + 13 minutes [sic]), citrate buffered atropine ( 40 + 15 minutes[sic]),
or atropine sulphate (56 20minutes) (Martin et al, 1980).
Subcutaneous absorption. There was no significant difference in the rate of absorption of
doses (0.02mg/kg atropine) given intramuscularly or subcutaneously to full term pregnant
women (Kanto & Pihlajamaki, 1986).
Endotracheal absorption. Optimal drug doses and absorption parameters for administration
by the endotracheal route are unknown (The American Heart Association, 2000) but
medications should be administered at 2 to 2.5 times the recommended intravenous dose, and
diluted before use in 10ml saline or distilled water in adults (Emergency Cardiac Care
Committee, 1992). In children with normal cardiac status, Howard & Bingham (1990) found
that there was no difference between effect on heart rate or speed of onset with either
intravenous atropine sulphate 0.025mg/kg dilute in 2ml saline, given at the same time as 2ml
saline endotracheally or twice the dose (ie 0.05mg/kg) of atropine given endotracheally at the
same time as 2ml intravenously. After studying 50 patients using dose titration with
endotracheal atropine, it was considered that if atropine must be given by the endotracheal
route in an emergency, then 0.03mg/kg or more may be comparable to the effect of
0.01mg/kg given intravenously (Lee et al, 1989). Any route of vascular administration was
considered preferable to the endotracheal route (The American Heart Association, 2000).
Intraosseous administration. Animal studies with atropine (Prete et al, 1987) have shown
similar actions and drug concentrations after intraosseous administration to those after
intravenous administration (Emergency Cardiac Care Committee, 1992). Establishment of an
intraosseous route in children 6 years old or younger has been suggested, if venous access
cannot be achieved. Intraosseous administration has been used in older children & adults, and
has also been considered preferable to the endotracheal route (The American Heart
Association, 2000).
9.2.2. Distribution
After intravenous dosing, atropine distributes rapidly with only 5% remaining in the blood
compartment after five minutes (Berghem et al., 1980). Initial distribution half-life is
approximately one minute (Kanto & Klotz, 1988). Elimination kinetics can be fitted to a twocompartment model after therapeutic doses. The apparent volume of distribution (Vd) is 1-1.7
L/kg with a clearance of 5.9-6.8 ml/kg/minute and a half-life of 2.6-4.3 hours in the
elimination phase (Kanto et al, 1981; Aaltonen et al., 1984; Virtanen et al., 1982).

Atropine rapidly crosses the placenta, with apparent fetal uptake. No distribution into the
amniotic fluid was found in one study (Kanto et al, 1981) but significant distribution in
another (Kanto et al. 1987). In one study, concentrations in the umbilical vein were 93% of
the maternal level five minutes after an intravenous injection (Kivalo & Saarikoski, 1977).
Small quantities of atropine are stated to appear in breast milk but there is little data to
support this (atropine may also impair milk production, although this is not conclusively
documented) (Dollery, 1991)
Penetration into human lumbar cerebrospinal fluid was less complete, particularly after a
single intravenous injection (Virtanen et al., 1982). It has been speculated that the
cerebrospinal fluid (CSF) represents a "deep" compartment with slow drug penetration
(Kanto & Klotz, 1988). Nonetheless, atropine penetration is assumed to be greater into the
central nervous system than into lumbar cerebrospinal fluid (CSF), compatible with the wellknown central anticholinergic effects of the drug.
Penetration of atropine into the eye after both local and systemic administration is slow and
incomplete.( Morton Grant W, 1986, Friedl et al 1988)
9.2.3. Elimination
After intravenous dosing, atropine elimination fits a two-compartment model with an intrinsic
clearance of 5.9-6.8 ml/kg/min and a plasma half-life of 2.6-4.3 hours in the elimination
phase (Kanto et al., 1981; Aaltonen et al., 1984; Virtanen et al., 1982).
The elimination half-life of atropine is longer in children less than two years of age, and in
the elderly. In children, this is due to an increased volume of distribution (Vd), increasing the
half-life up to 5-10 hours in the neonate. In the elderly (70 years and older), the half-life may
be prolonged from 10 to 30 hours due to reduced clearance. These changes do not appear to
be sex-related. Not only the kinetics, but also the dynamics may change with age, making
both the younger and older patient more sensitive to a given dose (Berg et al., 1959; Smith et
al., 1979). Patients with Downs syndrome may exhibit abnormally greater cardioaccelerator
response to intravenously administered atropine (Harris & Goodman 1969) while patients
with albinism may have decreased susceptibility to some of the actions of atropine (Parfitt,
1999; Maciejasz, 1971). The mechanisms for these differences are unclear.
Atropine is metabolized in the liver by microsomal monooxygenases. HPLC separation of
urine has identified 5 compounds: atropine, noratropine, tropine, atropine-N-oxide(equatorial
isomer), and tropic acid (Van der Meer et al., 1983). Thus, atropine is partly metabolized and
partly excreted unchanged in the urine, the unchanged portion being approximately 50% (Van
der Meer et al, 1986). Since biliary excretion is negligible, the hepatic plasma clearance of
519147 ml/min represents metabolism. Hepatic blood clearance and extraction ratio were
476136 ml/min and 0.32, respectively. The elimination of atropine is, therefore, partly flowdependent (Hinderling et al., 1985). Following an intravenous injection, 57% of the dose is
found in the urine as unchanged atropine and 29% as tropine. Since the renal plasma
clearance (656118 ml/min) was found to approach the renal plasma flow (71238 ml/min),
tubular excretion may occur. Thus, both liver and renal disease can be expected to influence
the kinetics of atropine (Hinderling et al., 1985).

10. Clinical studies - clinical trials

The first report of atropine being used as an antidote for acetylcholinesterase inhibitors was
by Fraser in 1870 (Holmstedt, 1972; 1985), who used atropine to counteract the effect of
physostigmine on the pupil. Although the clinical efficacy of atropine in organophosphate
poisoning is well known (Bardin et al., 1987; Chew et al., 1971; DuToit et al., 1981; Hayes et
al., 1978; Hirschberg & Lerman, 1984; Kipling & Cruickshank, 1985; Minton & Murray,
1988; Namba et al., 1971; Richards, 1964; Senanayake & Karalliedde, 1987; Zilker & Hibler,
1996; Zweiner & Ginsburg, 1988), no controlled prospective studies have been published.
This evaluation is therefore based mainly on case reports and retrospective case studies as
presented in section 11. Two non-controlled clinical studies are discussed briefly below.
Finkelstein et al. (1989) performed a non-controlled prospective study of severe
organophosphate poisoning. In this study of 53 adult patients, relatively low doses of atropine
(2 mg intravenous bolus, then the same dose at intervals of 10 min or more) were
administered, adjusted as necessary to the severity of tracheobronchial secretions and
bronchospasm. All 53 patients were mechanically ventilated and obidoxime was also given.
Although it is not possible to quantitate any beneficial effect from atropine administration
alone in these severely poisoned patients, atropine treatment appeared to counteract the
muscarinic features and thereby the pulmonary complications.
De Silva et al. (1992) compared the treatment of moderate to severe organophosphate
poisoning from a period when pralidoxime was not available in Sri Lanka (atropine given
alone to 21 patients) with a period when both atropine and pralidoxime were available (24
patients). Their conclusion, that atropine alone may be sufficient in such cases, was heavily
criticized by Johnson et al. (1992). The observed beneficial effect of atropine, however,
remained unchallenged.

11. Clinical studies - case reports

There are numerous case reports on the use of atropine in organophosphate poisoning. To
provide a better overview of the data, this section is divided into subheadings as follows.

11.1. Dose and duration of atropine sulphate therapy

The optimal dose of atropine sulphate required to manage moderate and severe
organophosphate poisoning is controversial. Recommendations for initial intravenous dosing
range from 1 mg in adults and 0.01 mg/kg in children as a "test dose" up to 5 mg in adults,
(Ganendran, 1974; Kipling & Cruickshank, 1985; LeBlanc et al., 1986), and 0.05 mg/kg in
children (Borowitz, 1988; Dutta et al., 1977; Lund & Monteagudo 1986; Mortenson, 1986).
Larger doses may, however, be necessary: in a retrospective study of 37 paediatric patients,
Zweiner & Ginsburg (1988) found that one third of patients required at least 0.05 mg/kg
before any decrease in cholinergic activity was observed. In one adult, up to 15 mg was given
as a single bolus (Worrell, 1975). Most cases of mild-moderate organophosphate poisoning
require no more than a total of 5-50 mg atropine.
A small number of patients appear to have required massive quantities of atropine, sometimes
for prolonged periods, in particular those poisoned with highly lipid-soluble compounds, such
as fenthion (Borowitz, 1988). Total doses of atropine as high as 3911 mg (Warriner et al.,
1977), 11 443 mg (Hopmann & Wanke, 1974) and 19 590 mg (Goulsousidis & Kokkas,
1985) have been given to patients, who recovered from their severe poisoning. LeBlanc et al

(1986) describe a case treated with 30 000 mg of atropine over 5 weeks (LeBlanc et al.,
1986). Relapse during therapy also appears to be more common with highly lipophilic
organophosphates (Borowitz, 1988; DuToit et al., 1981; Hayes et al., 1978; LeBlanc et al.,
1986; Milby, 1971; Warriner et al., 1977; Worrell, 1975; Yoshida et al., 1987). Because of the
risk of relapse, patients should be weaned off atropine slowly (Ganendran, 1974). If large
quantities of atropine sulphate are given, care should be taken to avoid using formulations
containing preservatives such as chlorbutanol or benzyl alcohol.

11.2. Route of administration

In order to cater for the sometimes large doses of atropine required to treat organophosphate
poisoning some manufacturers produce larger ampoules, containing 10-100 mg of atropine
(Berman & Bertoldi, 1985). It may be more practicable to administer large doses by
intravenous infusion rather than by intermittent bolus injections (Bardin et al., 1987;
Borowitz, 1988; Chew et al., 1971; DuToit et al., 1981; LeBlanc et al., 1986). Intravenous
infusion may save time, produce less fluctuation in plasma atropine concentrations and make
weaning much easier. On the other hand, because administration by infusion may result in
less frequent assessments, it is much easier for a patient to develop atropine toxicity while on
an infusion than when receiving bolus injections. Moreover, it should be remembered that the
half-life of atropine (up to 4 hours or longer in children and the elderly) necessitates using a
bolus dose as well as adjusting the drip rate if a rapid increase in the degree of atropinization
is required.
In an emergency situation, it may be necessary to give atropine before intravenous or
intraosseous access can be established. The endotracheal route has therefore been used, when
vascular access was not available. Atropine was given endotracheally to a 16-month-old child
with a carbamate overdose (Garbner, 1987). The child responded rapidly to 1.0mg, and a total
of 2.5 mg atropine was given by this route. The optimal dose requirements for the
endotracheal route have not yet been established, however.
Oral administration of atropine has been reported as being useful for stable patients on
intravenous therapy for several days or weeks, who need slow weaning (Worrell, 1975).
Atropine given intramuscularly in some specialized injectors may have faster onset of action
than other forms of intramuscular injection. The recommended dose for nerve agent exposure
in adult, otherwise healthy patients with mild to moderate symptoms is 2 to 4 mg (McEvoy,
2002).
Initial doses of both atropine and atropine sulphate administered to adults and children by the
intramuscular route appear to be similar to those given intravenously (McEvoy 2002,
Copenhaver 1994, Parfitt 1999, Dollery 1991), although onset of action will be slower after
intramuscular injection (Martin et al 1980).

11.3. Assessment of optimal atropinization

An evaluation of adequate atropine dosing is made clinically, by noting a decrease in
cholinergic (muscarinic) signs or symptoms. Atropine has no effect on red blood cell or
plasma cholinesterase activity.

The decision as to whether more atropine is required, or whether the patient can be weaned, is
essentially clinical. The degree of atropinization may be indicated by dryness of the mouth
and tracheobroncheal secretion, pupil size, heart rate, and flushing (Milby, 1971; Senanayake
& Karalliedde, 1987). Tachycardia and mydriasis can be unreliable indicators, however, since
both may also result from nicotinic stimulation in severely poisoned patients (Ganendran,
1974; Hirschberg & Lerman, 1984; Worrell, 1975). Tachycardia may also reflect hypoxia
caused by pulmonary hypersecretion and bronchospasm. The use of atropine is not, therefore,
contraindicated in a patient with tachycardia: as the patients oxygenation improves the pulse
rate will usually slow (Fjarli et al.,1998, Zweiner & Ginsburg, 1988).
Mann (1967) noted that 10% of organophosphate-poisoned patients did not have miosis.
Pupil constriction that reverses following atropine administration, however, does appear to be
a reliable indicator (Garbner, 1987).
The most sensitive measure of adequate atropinisation appears to be repeated evaluation of
the quantity of secretions (Bardin et al., 1987; Dean et al., 1967; DuToit et al., 1981).
When weaning patients who have been treated for several days, atropine should be continued
for at least 24 hours after symptoms have subsided (Bardin et al., 1987).

11.4. Adverse effects of atropine therapy

Atropine toxicity was noted on at least one occasion in 16 of 61 patients (26%) (Bardin et al.,
1987). Hirschberg & Lerman (1984) in a retrospective, multicentre study noted overatropinization in three of 232 cases. The dose of atropine should be reduced if the patient
shows signs of atropine toxicity such as fever, or delirium
If atropine is administered to hypoxic patients there is a risk of ventricular tachycardia or
fibrillation (Hase et al., 1984; Matthew & Lawson, 1970). In this situation, atropine should be
given at the same time as the patient is oxygenated (Zavon, 1974).
Prolonged atropinization may cause paralytic ileus (DuToit et al., 1981). Paralytic ileus was
also reported in an infant with Downs syndrome who was being treated with topical atropine
(Marshall et al.,1989).
In a case reported by LeBlanc et al. (1986), rigidity was observed for up to 10 days following
weaning after a five-week period of therapy. Mydriasis, but no other pharmacological effects,
was noted in a neonate, whose mother had been given atropine for organophosphate
poisoning before the birth (Shah et al,1995).
Other adverse effects of atropine, not necessarily associated with treatment of
organophosphorus insecticide poisoning, include precipitation of glaucoma (Berdy et al.
1991) and hypersensitivity reactions (anaphylaxis) (Aguilera et al., 1988).

11.5. Role of other anticholinergic agents

Both n-methylatropine and glycopyrrolate bromide have been used in organophosphate
poisoning in man. De Kort et al., (1988) reported a case where 69 mg of n-methylatropine
nitrate was used. Gerkin & Curry (1987) gave 5850 mg of atropine sulphate and 124 g
pralidoxime in a case of methyl parathion poisoning. In an attempt to use an anticholinergic

with a longer duration of action, 510 mg glycopyrrolate bromide was then given. The large
amount of bromide involved resulted in an elevated plasma bromide concentration. Thus the
risk of bromide intoxication may restrict the use of large quantities of glycopyrrolate bromide
in organophosphate poisoning.
A single case has been described of an adult male who had ingested chlorpyrifos and was
treated with ipratropium when six days of intravenous atropine had failed fully to control
respiratory distress. Ipratropium was given by endotracheal administration of an aerosol mist
of 0.5mg diluted to 2 ml. A total of 409 mg of atropine had been given before commencement
of ipratropium. The patient received a total of 7mg of ipratropium over a period of 5 days,
commencing at 0.5mg every six hours for the first day. Tachycardia and mydriasis were
observed as side effects at the beginning of treatment. Respiratory distress was alleviated, but
intraoral salivary secretions continued unabated (Shemesh et al.1988). Ipratropium has less of
an inhibitory effect on mucociliary clearance, compared with atropine, thus, its use avoids the
increased accumulation of lower airways secretions in patients with airways disease
(Hardman, 1996).
All of the above drugs are quaternary derivatives that do not penetrate the blood-brain barrier.
Thus they are ineffective against the CNS toxicity of organophosphates.

11.6. Clinical atropine toxicity

Poisoning can occur following oral, ocular, respiratory or parenteral exposure. There are
numerous case reports of atropine poisoning from plants from antiquity through to the
present. In a case of jimsonweed poisoning (Datura stramonium), a four-year-old boy
presented with confusion, hallucinations, ataxia, and tachycardia. Symptoms developed three
hours after ingestion, recovery took two days (Schumacher, 1965). In a 65-year-old man, 3
mg of atropine from Atropa belladonna leaves mistaken for burdock (Arctium lappa) leaves,
produced not only peripheral atropinization but also a central anticholinergic syndrome with
restlessness, hyperactivity, and dysphasia. Symptoms resolved within 24 hours with
symptomatic therapy (Wood & Haq, 1971).
Mild atropine toxicity, with a central anticholinergic syndrome, may also occur after
"normal" dosing, as the prolonged half-life of atropine with increasing age puts the older
patient at risk (Beech et al., 1987).
Arthurs & Davies (1980) reported three children overdosed with atropine following a
thousand-fold error in dosage. During the first 12 hours, the children were sedated and
disoriented. They became increasingly restless as a central anticholinergic syndrome persisted
for two days, requiring large quantities of diazepam for sedation; the pupils remained dilated
for a week.
In a review of nine cases of accidental poisoning with oral drops (Eumydrin, atropine
methonitrate), Meerstadt (1982) reported toxicity with atropine dosages ranging from 0.393.55 mg/kg. One patient, a 6-week-old boy, presented with fever, irritability, warm dry skin,
inspiratory stridor, cyanosis of the hands and feet, and dilated and unresponsive pupils.
Recovery was uneventful.
Following an accidental oral overdose of 0.3 mg/kg atropine in two small children,
Saarnivaara et al. (1985) reported maximum serum levels of 29 and 15.6 mg/L at 2 to 2.5

hours, concentrations normally found in the distribution phase following an intravenous bolus
of a therapeutic dose. Symptoms of toxicity resolved uneventfully within eight hours. In
three-year old children, deaths have been reported following ocular applications as low as 1.6
and 2 mg (Heath, 1950; Morton, 1939) and oral doses of 100 mg (Legroux, 1962), although
one patient recovered following an estimated ingestion of 1 g (Alexander et al., 1946).

11.7. Drug interactions

Intramuscular atropine may slow small bowel transit time by approximately 38% (Hardison
et al 1979), which in turn determines enterohepatic cycling frequency. Gastric emptying may
also be delayed by atropine (Dollery, 1991). Thus, the pharmacokinetics and/or efficacy of
oral drugs co administered with atropine may be changed, as may the response of drugs that
undergo enterohepatic circulation.
Changes in drug efficacy have occurred with levodopa (decreased effect) (Algeri et al., 1976)
and amantidine (hallucinations) (Postma & Tilburg, 1975), when anticholinergics were given
concomitantly. Pre-treatment with the calcium channel blocker, verapamil has increased the
tachycardia produced by atropine in healthy volunteers.(Meyer et al, 1991).
Other drugs with anticholinergic effects, such as tricyclic antidepressants, some
antihistamines, phenothiazines, disopyramide and quinidine, will have additive peripheral and
central nervous system anticholinergic activity if given with atropine (Dollery, 1991). Tertiary
amine muscarinic receptor antagonists used as antispasmodics, such as dicyclomine,
oxyphencyclimine, flavoxate and oxybutynin will also act similarly, as will quaternary
ammonium muscarinic receptor antagonists, for example, ipratropium, methscopolamine and
homatropine (Hardman, 1996).
The muscarinic actions of parasympathomimetic drugs such as carbachol, bethanecol and
pilocarpine are blocked by atropine (Hardman, 1996).
The action of anticholinesterase agents such as physostigmine, neostigmine, edrophonium,
ambenonium and pyridostigmine can be antagonised at muscarinic receptor sites by atropine
(Hardman, 1996) and vice versa, according to dose size.

12. Summary of evaluation and recommendations

Atropine is the drug of choice for the treatment of the muscarinic symptoms and signs of
poisoning with anticholinesterase agents (organophosphate or carbamate), particularly
excessive salivation and lacrimation, bronchoconstriction and hypersecretion, pulmonary
oedema and bradycardia. Animal studies have shown that atropine alone significantly reduces
mortality and counteracts features of toxicity due to most anticholinesterase insecticides. In
several clinical case reports the administration of atropine is clearly associated with a
reduction of cholinergic features and a favourable outcome.
In most experimental studies, a reduction in cholinergic features has been demonstrated by
the concomitant administration of atropine and an oxime, although a significant further
reduction in mortality has not always been demonstrated from the use of combined therapy.
An unequivocal synergism from combination therapy in reducing mortality can be achieved
experimentally following exposure to organophosphorus insecticides with a mixed

central/peripheral mode of action. In clinical case reports the combination of atropine and an
oxime has usually, but not always, been associated with a favourable outcome.

12.1. Indications
Based on experimental studies and clinical case reports, atropine sulphate is the
anticholinergic drug of choice for the initial management of organophosphate poisoning
whenever cholinergic features are present. The decision to treat should be based on the
clinical evaluation of the patient, especially the bronchial hypersecretion, rather than on any
laboratory tests.

12.2. Advised routes and doses

Based on clinical evidence, atropine is best given intravenously as bolus injections to dry the
secretion as quickly as possible. The initial adult dose in an unknown or mild
anticholinesterase poisoning is 1-2 mg repeated every 5 to 10 minutes until the desired
clinical response is achieved. In a severe organophosphate poisoning atropine must be given
at much higher doses to dry the secretion. Atropine may then be repeated or increased in
increments at 15 to 30 minute intervals to maintain the signs of atropinization. Since repeated
dosing is required, a constant infusion of atropine to maintain atropinization is more practical.
When a constant atropine infusion is used the patient should be examined at least very 1 to 2
hours
For diagnosis in children, an intravenous dose of 0.015mg/kg can be administered, while
watching for signs of atropinization (mouth dryness, dilated pupils, tachycardia). For a
therapeutic intravenous dose in symptomatic children, 0.015 to 0.05mg/kg can be given every
fifteen minutes as needed.
If intravenous access is not available, the drug can be given by the intraosseous, endotracheal,
intramuscular, or subcutaneous routes. If a rapid effect is required, case reports have shown
that atropine sulphate can be given effectively by the endotracheal route. The dose
requirements are unclear, however, and may be at least 2 to 2.5 times the intravenous dose.
Based on pharmacokinetic studies in monkeys, the intraosseous route may also be considered
in children. The intraosseous dose of atropine is similar to the intravenous dose. Doses of
intramuscular or subcutaneous atropine sulphate are similar to intravenous doses also, but
onset time is longer (about 30 minutes), and more variable.
The dose of atropine should be titrated against a reduction in secretions, especially bronchial
secretions, rather than against heart rate (tachycardia) or pupil size (miosis). No maximum
atropine dose per hour or per 24 hours can be given as this depends entirely on the severity of
the intoxication (dose and type of organophosphate). Atropine treatment may have to be
continued for many days.
For patients who develop CNS signs of atropine toxicity such as agitation, hallucination and
confusion, treatment should be discontinued until the CNS signs disappeared. Patients should
be weaned from atropine treatment slowly, particularly if they have received atropine over
several days.

12.3. Other consequential or supportive therapy

There is evidence from many animal studies of a significant synergistic effect from
combination therapy with an oxime and atropine. Animal data also indicate that the addition
of diazepam is beneficial for the control of seizures, though significantly reduced lethality has
not been demonstrated.
Sodium bicarbonate infusion to induce blood alkalinization (maintain arterial blood pH
between 7.45 and 7.55) in a controlled clinical trial of human organophosphate poisoning
revealed significant therapeutic effects (Balali-Mood et al, 2002).

12.4. Controversial issues and areas of use where there is insufficient

information to make recommendations
There appears to be no controversy as to the benefit of atropine in reversing cholinergic
features in organophosphate poisoning. Although the optimal dose of atropine (see section
12.2) is the dose which prevents bronchial hypersecretion, there appears to be little evidence,
as yet, to confirm which route of administration is the most effective in an emergency if
venous access is not available.

12.5. Proposals for further studies

Very little is known regarding the optimal dose and pharmacokinetics of atropine in relation
to the dose of oximes, the severity of poisoning, and the properties of a particular
organophosphate. This is clearly a field worthy of further study.
No controlled clinical study has documented the effect of atropine in human
organophosphorus insecticide poisoning. Based on the data reviewed in this monograph, such
a study would be considered unethical to perform. Further studies are, however, warranted to
confirm the optimal route of administration if venous access is not available.

12.6. Adverse effects

Signs of over-atropinization are infrequent but may include mydriasis, tachycardia and a
central anticholinergic syndrome with restlessness, hyperactivity and delirium.

12.7. Restrictions for use

There appear to be no restrictions for the use of atropine in organophosphate-poisoned
patients with excess cholinergic features. However, special care must be taken under the
following circumstances:
In the hypoxic patient clearing the airway and sufficient oxygenation of the patient must be
ensured to avoid clinically significant cardiac arrhythmias.
In warm environments, the body temperature should be monitored because of atropine
inhibition of sweating. External cooling measures may be necessary.

13. Model information sheet

13.1. Uses

Atropine sulphate is indicated for the treatment of anticholinesterase agents (organophosphate

and carbamate poisonings) and whenever cholinergic features need to be counteracted.

13.2. Dosage and route

Adults: 1-2 mg bolus given intravenously in an unknown or mild anticholinesterase
poisoning. Repeated as often as every 5-10 minutes as required to reduce (bronchial)
secretions. In moderate and severe organophosphate poisonings, much larger doses are
required.
Children: At least 0.015 mg/kg bolus should be given intravenously; then 0.015 to 0.05
mg/kg every 15 minutes as needed. Intraosseous, endotracheal, intramuscular or
subcutaneous routes should be used if venous access is not available.
No maximum dose of atropine can be given as this depends on the severity of the
organophosphate poisoning.

13.3. Precautions/contraindications
Cyanotic (hypoxic) patients should be oxygenated and if necessary intubated at the same time
as atropine is administered, to avoid ventricular tachyarrhythmias.
If an infusion is used, the risk of over-atropinization should be avoided by regular review of
the rate of infusion, particularly in patients with liver or kidney disease, in children and in the
elderly.
In warm environments, patients should be kept cool and body temperature monitored as
atropine inhibits sweating.

13.4. Pharmaceutical incompatibilities and drug interactions

Anti-AChE agents, such as the organophosphorus insecticides, are synergistic with the
depolarizing blocking agents, such as succinylcholine. The latter is therefore best avoided in
these patients as is also other parasympathomimetic therapy.

13.5. Adverse Effects

Atropine administration should be discontinued if over-atropinization is observed.
Possible hypersensitivity to cholinergic stimulation (tremors, rigidity) after prolonged
atropine therapy may occur.

13.6. Use in pregnancy and lactation

Pregnancy is no contraindication to therapy as the organophosphate poisoning represents a
greater threat to the fetus than atropine.

13.7. Storage

Atropine sulphate injection preparations should be stored at 15-30oC and protected from light.
Under these conditions, the shelf life of atropine sulphate for injection is two years. Atropine
in autoinjectors, protected from light and stored between 15 and 30 C, have a shelf life of 5
years.

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