Atropine
An alkaloid which may be obtained from solanaceous plants,
or prepared by synthesis.
White needle-like crystals or, white crystalline powder. Solu-
ble 1 in 460 of water. I in 2 of alcohol, 1 in 1 of chloroform,
1 in 25 of ether, and 1 in 90 of water at 80°. A saturated solu-
tion in water is alkaline to phenolphthalein. Store in airtight
containers. Protect from light.
Antimuscarinic drugs such as atropine are competitive inhibitors of the actions of acetylcholine at the muscarinic receptors of autonomic effector sites innervated by parasympathetic (cholinergic postganglionic) nerves; they are also inhibitors of the action of acetylcholine on smooth muscle lacking cholinergic innervation. They have been described as parasympatholytic, atropinic, atropine-like, and as anticholinergic, although the latter term should encompass compounds that also have antinicotinic actions.
Atropine Sulphate
Odourless colourless civstils or while crystalline powder. It
effloresces in dry air. Soluble 1 in 0.5 of water, 1 in 2.5 of
boiling water. I in 5 of alcohol, 1 in 2.5 of glycerol: practical-
ly insoluble in ether. A 2% solution in water has a pH of 4.5
to 6.2. Store in airtight containers. Protect from light.
Incompatibilities. Incompatibility between atropine sul-
phate and hydroxybenzoate preservatives has been observed,
resulting in a total loss of the atropine in 2 to 3 weeks.
Adverse Effects
The pattern of adverse effects seen with atropine and
other antimuscarinics can mostly be related to their
pharmacological actions at muscarinic and, at high
doses, nicotinic receptors. These effects
are dose-related and are usually reversible when
therapy is discontinued. The peripheral side-effects
of atropine and other antimuscarinics are a conse-
quence of their inhibitory effect on muscarinic re-
ceptors within the autonomic nervous system. At
therapeutic doses, adverse effects include dryness of
the mouth with difficulty in swallowing and talking,
thirst, reduced bronchial secretions, dilatation of the
pupils (mydriasis) with loss of accommodation (cy-
cloplegia) and photophobia, flushing and dryness of
the skin, transient bradycardia followed by tachy-
cardia, with palpitations and arrhythmias, and diffi-
culty in micturition, as well as reduction in the tone
and motility of the gastro-intestinal tract leading to
constipation. Some of the central side-effects of at-
ropine and other tertiary antimuscarinics seen at tox-
ic doses (see below) may also occur at therapeutic
doses.
In overdosage, the peripheral effects become more
pronounced and other symptoms such as hyperther-
mia, hypertension, increased respitatory rate, and
nausea and vomiting may occur. A rash may appear
on the face or upper trunk. Toxic doses also cause
CNS stimulation marked by restlessness, confusion,
excitement, ataxia, incoordination, paranoid and
psychotic reactions, hallucinations and delirium.
and occasionally seizures. However, in severe intox-
ication, central stimulation may give way to CNS
depression, coma, circulatory and respiratory fail-
ure, and death.
There is considerable variation in susceptibility to
atropine; recovery has occurred even after I g,
whereas .deaths have been reported from doses of
100 mg or less for adults and 10 mg for children.
Quaternary ammonium antimuscarinics, such as at-
ropine methobromide or methonitrate and propan-
theline bromide, have some ganglion-blocking
activity so that high doses may cause postural hypo-
tension and impotence: in toxic doses non-depolar-
ising neuromuscular block may be produced.
Systemic toxicity may be produced by the instilla-
tion of antimuscarinic eye drops, particularly in
children and in the elderly. Prolonged administra-
tion of atropine to the eye may lead to local irrita-
tion, hyperaemia, oedema, and conjunctivitis. An
increase in intra-ocular pressure may occur, espe-
cially in patients with angle-closure glaucoma.
Hypersensitivity to atropine is not uncommon and
may occur as conjunctivitis or a skin rash.
Effects on body temperature. Atropine can cause hyper-
thermia as a result of inhibition of sweating. This may be at-
tenuated by atropine's ability to dilate cutaneous blood
vessels. However, there has been a report of hypothermia in a
14-year-old feverish patient following intravenous adminis-
tration of atropine.
For reports of fatal heat stroke in patients receiving an an-
timnscarinic and an antipsychotic concomitantly.
Effects on the CNS. Relatively recent references to the
CNS toxicity of atropine describe a toxic psychosis and an
increase in frequency of seizures In both instances the ef-
fects followed the administration of atropine (alone or with
hyoscine hydrobromide and phenylephrine hydrochloride) as
eye drops.
Effects on the eyes. In addition to the expected ocular ef-
fects of atropine there have been instances of acute angle-clo-
sure glaucoma in patients receiving nebulised atropine,
Effets on the gastro-intestinal tract. A report of para-
lytic ileus in a 77-year-old man with Parkinson's disease who
had been receiving atropine sulphate by mouth to control ex-
cess salivation.
Effects on the heart. Atropine sulphate to a total of 1 mg
per 70 kg body-weight given intrevenously to 79 patients be-
fore surgery produced arrhythmias in over 20% of patients but
particularly frequently in the young. Atrioventricular disso-
ciation was the most common disturbance in adults and in
children atrial rhythm disturbances were common. In another
study premedication including atropine or glycopyrronium
given intramuscularly resulted in a significantly greater inci-
dence of tachycardia during anaesthetic induction and intuba-
tion compared with controls who received no antimuscarinic
drug. Patients who received glycopyrronium also had a higher
incidence of tachycardia during surgery than the controls. No
significant difference in bradycardia or extrasystoles was
found in the atropine- or the glycopyrronium-treated patients.
Atrial fibrillation has been reported in 2 elderly glaucoma pa-
tients following post-surgical application of atropine oint-
ment or eye drops to the eye.
Effects on mental function. A study in patients with Par-
kinson's disease and healthy control subjects suggested that
although short-term memory was impaired in patients receiv-
ing long-term antimuscarinic therapy the effect was reversible
on discontinuation.
Hypersensitivity. A report of anaphylactic shock develop-
ing in a 38-year-old woman following in intravenous injec-
tion of atropine.
Overdosage. Reports of atropine poisoning or overdosage
have included a respiratory therapist who had given 10 atro-
pine sulphate aerosol treatments in the preceding 24 hours
and children who had taken overdoses of a preparation con-
taining diphenoxylate and atropine.
Treatment of Adverse Effects
If overdoses of atropine have been taken by mouth
the stomach should be emptied. Activated charcoal
has also been suggested to reduce absorption. Sup-
portive therapy should be given as required.
Physostigmine has been tried for antimuscarinic
poisoning but such use can be hazard-
ous and is not generally recommended. Diazepam
may be given to control marked excitement and con-
vulsions: phenothiazines should not be given as they
may exacerbate antimuscarinic effects.
Precautions
Atropine needs to be used with caution in children
and the elderly (who may be more susceptible to its
adverse effects), in patients with or at risk of urinary
retention (including those with prostatic enlarge-
ment), and in those with paralytic ileus or pyloric
stenosis. In patients with ulcerative colitis its use
may lead to ileus or megacolon, and its effects on the
lower oesophageal sphincter may exacerbate reflux.
Caution is generally advisable in any patient with
diarrhoea. It should not be given to patients with
myasthenia gravis except to reduce adverse mus-
carinic effects of an anticholinesterase.
Atropine should not be given to patients with angle-
closure glaucoma or with a narrow angle between
the iris and the cornea, since it may raise intra-ocular
pressure and precipitate an acute attack. Acute an-
gle-closure glaucoma has been reported in patients
receiving nebulised atropine. Some recommend that
atropine eye drops should not be used in infant!
aged less than 3 months du? to the possible associa-
tion between the induced cyclopipgia and the devel-
opment of amblyopia. Systemic reactions have
followed the absorption of atropine from eye drops
overdosage is less likely if the eye ointment is used
In the event of blurred vision, following topical ad
ministration of atropine to the eye, patients should
not drive or operate machinery. Systemic adminis
tration of antimuscarinics may also cause blurred vi
sion, dizziness, and other effects that may impair;
patient's ability to perform skilled tasks such a
driving.
Because of the risk of provoking hyperthemua atro
pine should not be given to patients, especially chil
dren, when the ambient temperature is high. It
should also be used cautiously in patients with fever
Atropine and other antimuscarinics need to be used
with caution in conditions characterised by tachy
cardia such as thyrotoxicosis, heart failure, and in
cardiac surgery, where they may further accelerate
the heart rate. Care is required in patients with acute
myocardial infarction, as ischaemia and infarction may be made worse, and in patients with hypertension.
Atropine may cause confusion, especially in the elderly. Reduced bronchial secretion caused by systemic administration of atropine may be associated with the formation of mucous plugs, In the treatment of parkinsonism, increases in dosage and transfer to other forms of treatment should be gradual and antimuscarinic should not be withdrawn abruptly. Minor reactions may be controlled by reducing the dose until tolerance has developed. Persons with Down's syndrome appear to have an increased susceptibility to some of the actions of atropine, whereas those with albinism may have a reduced susceptibility.
Interactions
The effects of atropine and other antimuscarinics may be enhanced by the concomitant administration of other drugs with antimuscarinic properties, such as amantadine, some antihistamines, phenothiazine antipsychotics, and tricyclic antidepressants. Inhibition of drug-metabolising enzymes by MAOIs may possibly enhance the effects of antimuscarinics. The reduction in gastric motility caused by antimuscarinics may affect the absorption of other drugs. Antimuscarinics and parasympathomimetics may counteract each others effects.
Pharmacokinetics
Atropine is readily absorbed from the gastro-intesti-nal tract; it is also absorbed from mucous membranes, the eye, and to some extent through intact skin. It is rapidly cleared from the blood and is distributed throughout the body. It crosses the blood-brain barrier. It is incompletely metabolised in the liver and is excreted in the urine as unchanged drug and metabolites. A half-life of about 4 hours has been reported. Atropine crosses the placenta and traces appear in breast milk. Quaternary ammonium salts of atropine, such as the methonitrate, are less readily absorbed after oral administration. They are highly ionised in body fluids and being poorly soluble in lipids they do not readily cross the blood-brain barrier.
Pregnancy. Studies of the pharmacokinetics of atropine in mother and fetus in late pregnancy indicated that atropine rapidly crosses the placenta. However, whereas peak concentrations of atropine in fetal cord blood were reached about 5 minutes after intravenous administration, the maximum effect on fetal heart rate occurred after about 25 minutes.
Uses and Administration
Atropine is a tertiary amine antimuscarinic alkaloid with both central and peripheral actions. It is usually given as the sulphate. It first stimulates and then depresses the CNS and has antispasmodic actions on smooth muscle and reduces secretions, especially salivary and bronchial secretions; it also reduces perspiration, but has little effect on biliary or pancreatic secretion. Atropine depresses the vagus and thereby increases the heart rate. When given by mouth atropine reduces smooth-muscle tone and diminishes gastric and intestinal motility but has little effect on gastric secretion in usual therapeutic doses. Quaternary ammonium derivatives. such as the methonitrate, have less effect on the CNS but strong ganglion-blocking activity. Atropine is used for a variety of purposes, including: in anaesthetic practice as a premedicant and to counteract the muscarinic effects of anticholinesterases such as neostigmine and other parasympathomimetics; as
an antispasmodic in gastro-intestinal disorders: as in adjunct to opioid analgesics for the symptomatic relief of biliary or renal_colic; to treat bradycardia; to treat or prevent bronchospasm: and in the treatment of poisoning with mushrooms that contain muscarine and in organophosphorus pesticide poisoning. Atropine is used topically as a mydriatic and cycloplegic in ophthalmology.
See below for details on dosage and administration of atropine and its derivatives.
Anaesthesia.
Atropine has been given as a premedicant before general anaesthesia to diminish the risk of vagal inhibition of the heart and to reduce salivary and bronchial secretions. For premedi-cation 300 to 600 ng of atropine sulphate may be given by subcutaneous or intramuscular injection, usually 30 to 60 minutes before anaesthesia. Alternatively 300 to 600 ug of atropine sulphate may be given intravenously immediately before induction of anaesthesia. Atropine sulphate may also be given in combination with up to 10 mg morphine sulphate by subcutaneous or intramuscular injection about an hour before anaesthesia. Suitable paediatric premedication doses of atropine sulphate are: 100 ug subcutaneously for children weighing up to 3 kg; 200 Mg for children weighing 7 to 9 kg; 300 ng for children weighing 12 to 16 kg; 400 ug for children weighing 20 to 27 kg; 500 ug for children weighing 32 kg; and 600 Mg for children weighing 41 kg.
To counteract the muscarinic effects of anticholinesterases when they are used to reverse the effects of competitive muscle relaxants, atropine sulphate 0.6 to 1.2 mg is given by intravenous injection before or with the anticholinesterase.
Anoxic seizures. A reflex anoxic seizure is a paroxysmal event triggered by a noxious stimulus which, by vagal stimulation, causes pronounced bradycardia or cardiac arrest and consequent relative cerebral ischaemia.1 Certain features of the attack may lead to a misdiagnosis of epilepsy. To avoid confusion with epileptic seizures, reflex anoxic seizures have also been called white or type 2 breath holding attacks. Depending on the degree of vagal hypersensitivity or noxious stimulus attacks may occur infrequently or several times a day.
Infants and young children are mainly affected, however, the condition usually resolves by early childhood. It is generally benign and children do not suffer cardiac or cerebral damage. Treatment is seldom necessary, but atropine has been advocated to prevent vagal hypersensitivity in those children with frequent, persistent attacks. As alropine may require frequent administration with an attendant risk of overdosage. transder-mal hyoscine has been tried as an alternative.-
Cardiac disorders. Atropine depresses the vagus and thereby increases the heart rate. It is therefore used in a variety of disorders or circumstances in which bradyarrhythmias occur. It is frequently used in sudden onset bradyarrhythmias and although it may also be employed for the initial treatment of chronic arrhythmias, cardiac pacing is generally preferred for long-term control. Examples of acute use include the prevention and treatment of arrhythmias associated with anaesthesia (see above), the treatment of other drug-induced arrhythmias, and in cardiac arrest due to asystole. Atropine sulphate has been used in the management of bradycardia of acute myocardial infarction: however, caution is required, as atropine may exacerbate ischaemia or infarction in these patients. European and US authorities have published standards and guidelines for cardiopulmonary resuscitation and emergency cardiac care, including recommendations on the use of atropine. The dosage of atropine sulphate, and the frequency at which doses are repeated, varies according, to the severity of the condition. In asystole, the recommended adult dose of atropine in the European guidelines is 3 mg given intravenously once only, although it is stated that the evidence for benefit is equivocal;1 in the USA the dose is 1 mg intravenously which is repeated in 3 to 5 minutes if asystole continues.2 The European guidelines do not consider that atropine is necessary for the management of paediatric asystole.3 In bradycardia. atropine is given in doses of 0.5 to 1.0 mg intravenously repeated every 3 to 5 minutes to a total dose of 0.04 mg per kg body-weight.- If an intravenous line cannot be established, atropine can be given via an endotracheal tube.
Colic pain. Atropine has been used as an adjunct to opioid analgesics for symptomatic relief of biliary or renal colic.
Eye disorders. Atropine is used to produce mydriasis and cycloplegia for ophthalmic examination. Dilatation of the pupil occurs in half an hour following one local application and lasts for a week or more: marked paralysis of accommodation is obtained in 1 to 3 hours with recovery in 6 to 12 days. However, other antimuscarinics such as cyclopentolate. homatropine, or tropicamide may be preferred because they have a more rapid onset and shorter duration of action than atropine. Atropine is also used in the management of uveitis and iritis, and in strabismus. It is used in the treatment of iritis and uveitis to immobilise the ciliary muscle and iris and to prevent or break down adhesions. Because of its powerful cycloplegic action atropine is also used in the determination of refraction in children below the age of 6 and in children with convergent strabismus.
In the treatment of inflammatory eye disorders such as uveitis or iritis, the dose of atropine sulphate for adults is I or 2 drops of a 0.5 or 1 % solution instilled into the eye(s) up to four times daily. The dose in children is 1 or 2 drops of a 0.5% solution (or one drop of a 1% solution) instilled up to three times daily. For refraction in adults the dose is one drop of a 1% solution of atropine sulphate; this may be instilled either twice daily for 1 or 2 days before the procedure or on a single occasion one hour before the procedure. In children the dose for refraction is 1 or 2 drops of a 0.5% solution (or one drop of a 1% solution) instilled twice daily for 1 to 3 days before the procedure, with a further dose given one hour before the procedure. An ophthalmic ointment of atropine sulphate 1% may be preferred for children under 5 years of age and particularly in infants under 3 months of age who are at increased risk of systemic effects with eye drops. Some recommend that atropine sulphate should not be used in the eyes of children younger than 3 months of age due to a -possible association between the cycloplegia produced and the development of amblyopia.
Atropine borate has also been used in ophthalmic preparations.
Gastro-intestinal disorders.
Antimuscarinics may be used in gastro-intestinal disorders because of their marked inhibitory effect on gastro-intestinal motility and their amisecretory effects. Atropine (as the sulphate or quaternary derivatives such as the methobromide or methonitrate) has been used to reduce smooth-muscle tone and diminish motility. but has little effect on gastric secretion at usual therapeutic doses (about 200 ug of atropine sulphate). It has been tried as an adjunct to the treatment of gastric and duodenal ulcers and the antispasmodic action of atropine has been used to facilitate radiological examination of the gut. Atropine sulphate has also been used in the treatment of irritable bowel syndrome. Atropine oxide hydrochloride is also used for gastro-intestinal disorders.
Poisoning. Atropine is used in the management of overdosage or poisoning due to various substances with muscarinic actions. It is used to overcome the effects of accumulation of acetylcholine produced by anticholinesterase compounds including organophosphorus pesticides,chemical warfare nerve gases, and parasympathomimetics such as neostigmine. It is also used to antagonise the effects of cholinomi-metic substances in the treatment of overdosage with parasympathomimetics such as bethanechol and in the treat' ment of poisoning with mushrooms that contain muscarine. Atropine blocks the action of these compounds at muscarinic receptors reversing bradycardia and decreasing tracheobron-chial secretions, bronchoconstriction, intestinal secretions, and intestinal motility.
In the treatment of poisoning with organophosphorus pesticides or chemical warfare nerve gases atropine may be given to adults in an initial dose of 2 mg or more intramuscularly or intravenously every 10 to 30 minutes until muscarinic effects disappear or signs of atropine toxicity are seen but depending on the severity of the symptoms injections have been given as often as every 5 minutes in some centres. In moderate to severe poisoning a state of atropinisation is usually maintained for at least 2 days and continued for as long as symptoms are evident. In severely poisoned patients this may entail prolonged treatment As large amounts of atropine may be required it is important to use a preservative-free preparation to avoid the potential toxicity associated with administration of
excess quantities of preservatives such as benzyl alcohol or
chlorobutanol. Since atropine is ineffective against any nico-
tinic effects of these compounds a cholinesterase reactivator
such as pralidoxime may be used as an adjunct.
The use of atropine in poisoning or overdosage with other
compounds having muscarinic actions is similar to that for
organophosphorus pesticides but the duration of treatment
necessary is usually shorter. An initial dose of 0.5 to 1 mg
given subcutaneously or intravenously and repeated every 2
hours may be adequate for overdosage with cholinomimetics
such as bethanechol.
Respiratory tract disorders. Although atropine is a po-
tent bronchodilator its use in the management of reversible
airways obstruction has largely been replaced by other an-
timuscarinics. It is sometimes used in combina-
tion preparations with antihistamines and decongestants for
the symptomatic relief of symptoms of the common cold.