.  
Atropine Sulfate *
 (Adverse Effect Reported)

The Elephant Formulary
© 2003-06 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D.
Published by Elephant Care International -
www.elephantcare.org


Elephant specific information, if available, is in blue.

Chemistry - The prototype tertiary amine antimuscarinic agent, atropine sulfate is derived from the naturally occurring atropine. It is a racemic mixture of d-hyoscyamine and l-hyoscyamine. The l- form of the drug is active, while the d- form has practically no antimuscarinic activity. Atropine sulfate occurs as colorless and odorless crystals, or white, crystalline powder. One gram of atropine sulfate is soluble in approximately 0.5 ml of water, 5 ml of alcohol, or 2.5 ml of glyc­erin. Aqueous solutions are practically neutral or only slightly acidic. Commercially available injections may have the pH adjusted to 3.0 - 6.5. Atropine may also be known as dl-hyoscyamine .

 

Storage/Stability/Compatibility - Atropine sulfate tablets or soluble tablets should be stored in well-closed containers at room temperature (15-30°C). Atropine sulfate for injection should be stored at room temperature; avoid freezing.

 

Atropine sulfate for injection is reportedly compatible with the following agents: ben­zquinamide HCl, butorphanol tartrate, chlorpromazine HCl, cimetidine HCl (not with pentobarbi­tal), dimenhydrinate, diphenhydramine HCl, dobutamine HCl, droperidol, fentanyl citrate, glycopyrrolate, hydromorphone HCl, hydroxyzine HCl (also w/meperidine), meperidine HCl, mor­phine sulfate, nalbuphine HCl, pentazocine lactate, pentobarbital sodium (OK for 5 minutes, not 24 hours), perphenazine, prochlorperazine edisylate, promazine HCl, promethazine HCl (also w/meperidine), and scopolamine HBr.

 

Atropine sulfate is reported physically incompatible with norepinephrine bitartrate, metaraminol bitartrate, methohexital sodium, and sodium bicarbonate. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluents used and it is suggested to consult specialized references for more specific information.

 

Pharmacology - Atropine, like other antimuscarinic agents, competitively inhibits acetylcholine or other cholinergic stimulants at postganglionic parasympathetic neuroeffector sites. High doses may block nicotinic receptors at the autonomic ganglia and at the neuromuscular junction. Pharmacologic effects are dose related. At low doses salivation, bronchial secretions, and sweating (not horses) are inhibited. At moderate systemic doses, atropine dilates and inhibits accommodation of the pupil, and increases heart rate. High doses will decrease GI and urinary tract motility. Very high doses will inhibit gastric secretion.

 

Uses/Indications - The principal veterinary indications for systemic atropine include:

1)   Preanesthetic to prevent or reduce secretions of the respiratory tract

2)   Treat sinus bradycardia, sinoatrial arrest, incomplete AV block

3)   As an antidote for overdoses of cholinergic agents (e.g., physostigmine, etc.)

4)   As an antidote for organophosphate or muscarinic mushroom intoxication

5)   Hypersialism

6)   Treatment of bronchoconstrictive disease

 

Pharmacokinetics - Atropine sulfate is well absorbed after oral administration, IM injection, inhalation, or endotracheal administration. After IV administration, peak effects in heart rates occur within 3-4 minutes.

 

Atropine is well distributed throughout the body and crosses into the CNS, across the placenta, and can distribute into the milk in small quantities.

 

Atropine is metabolized in the liver and excreted into the urine. Approximately 30-50% of a dose is excreted unchanged into the urine. The plasma half-life in humans has been reported to be between 2-3 hours.

 

Contraindications/Precautions - Atropine is contraindicated in patients with narrow-angle glaucoma, synchiae (adhesions) between the iris and lens, hypersensitivity to anticholinergic drugs, tachycardias secondary to thyrotoxicosis or cardiac insufficiency, myocardial ischemia, unstable cardiac status during acute hemorrhage, GI obstructive disease, paralytic ileus, severe ulcerative colitis, obstructive uropathy, and myasthenia gravis (unless used to reverse adverse muscarinic effects secondary to therapy).

 

Antimuscarinic agents should be used with extreme caution in patients with known or suspected GI infections. Atropine or other antimuscarinic agents can decrease GI motility and prolong retention of the causative agent(s) or toxin(s) resulting in prolonged symptoms. Antimuscarinic agents must also be used with extreme caution in patients with autonomic neuropathy.

 

Antimuscarinic agents should be used with caution in patients with hepatic or renal disease, geriatric or pediatric patients, hyperthyroidism, hypertension, CHF, tachyarrhythmias, prostatic hypertrophy, or esophogeal reflux. Systemic atropine should be used cautiously in horses as it may decrease gut motility and induce colic in susceptible animals. It may also reduce the arrhythmogenic doses of epinephrine. Use of atropine in cattle may result in inappetance and rumen stasis which may persist for several days.

 

Adverse Effects/Warnings - Adverse effects are basically extensions of the drug’s pharmacologic effects and are generally dose related. At usual doses effects tend to mild in relatively healthy patients. The more severe effects listed tend to occur with high or toxic doses. GI effects can include dry mouth (xerostomia), dysphagia, constipation, vomiting, and thirst. GI effects may include urinary retention or hesitancy. CNS effects may include stimulation, drowsiness, ataxia, seizures, respiratory depression, etc. Ophthalmic effects include blurred vision, pupil dilation, cycloplegia, and photophobia. Cardiovascular effects include sinus tachycardia (at higher doses), bradycardia (initially or at very low doses), hypertension, hypotension, arrhythmias (ectopic complexes), and circulatory failure.

 

Overdosage - For signs and symptoms of atropine toxicity see adverse effects above. If a recent oral ingestion, emptying of gut contents and administration of activated charcoal and saline cathartics may be warranted. Treat symptoms supportively and symptomatically. Do not use phenothiazines as they may contribute to the anticholinergic effects. Fluid therapy and standard treatments for shock may be instituted.

 

The use of physostigmine is controversial and should probably be reserved for cases where the patient exhibits either extreme agitation and is at risk for injuring themselves or others, or for cases where supraventricular tachycardias and sinus tachycardias are severe or life-threatening. The usual dose for physostigmine (human) is: 2 mg IV slowly (for average sized adult) If no response, may repeat every 20 minutes until reversal of toxic antimuscarinic effects or cholinergic effects takes place. The human pediatric dose is 0.02 mg/kg slow IV (repeat q10 minutes as above) and may be a reasonable choice for initial treatment of small animals. Physostigmine adverse effects (bronchoconstriction, bradycardia, seizures) may be treated with small doses of IV atropine.

 

Drug Interactions - The following drugs may enhance the activity of atropine and its derivatives: antihistamines, procainamide, quinidine, meperidine, benzodiazepines, phenothiazines. The following drugs may potentiate the adverse effects of atropine and its derivatives: Primidone, disopyramide, nitrates, long-term corticosteroid use (may increase intraocular pressure). Atropine and its derivatives may enhance the actions of nitrofurantoin, thiazide diuretics, sympathomimetics. Atropine and its derivatives may antagonize the actions of metoclopramide.

 

Doses -

Horses:

For treatment of bradyarrhythmias due to increased parasympathetic tone:

a)   0.02 mg/kg IV (Muir and McGuirk 1987a)

b)   0.045 mg/kg parenterally (Hilwig 1987)

 

As a bronchodilator:

a)   5 mg IV for a 400-500 kg animal (Beech 1987)

 

For organophosphate poisoning:

a)   Approximately 1 mg/kg given to effect IV (use mydriasis and absence of salivation as therapy endpoints), may repeat every 1.5 - 2 hours as required subcutaneously (Oehme 1987)

b)   0.22 mg/kg, 1/4th of the dose administered IV and the remainder SQ or IM (Package Insert; Atropine Injectable, L.A. - Fort Dodge)

 

 

Elephants:

a) *Adverse effect reported: An  Asian elephant became agitated following the IV administration of atropine (0.05 mg/kg) administered IV 90 minutes after azaperone was given. Summary below (Gross et.al. 1994).

 

b) 150 mg atropine and 6 mg etorphine were administered simultaneously IM to a 3500 kg female African elephant on two occasions (Dunlop et.al. 1988).

 

c) Following induction with 8 mg etorphine IV, a 3050 kg female Asian elephant was given 120 mg atropine IV to decrease secretions (Mihm et.al. 1988).

 

d) Following induction with 7 mg etorphine IM, an African elephant (approx. 3000 kg) was given 90 mg atropine IM (Briggs et.al. 1988).

 

e) Atropine (0.04 mg/kg) administered IV corrected a second degree AV heart block in an African elephant under general anesthesia (Heard et.al. 1988).

 

f) The administration of 4 to 5 mg/100 kg body weight is advised for elephants that lie down after xylazine has been given to prevent hypostatic congestion and counter cardiodepressant effects (Schmidt, 1986).

 

g)  Three adult male Asian elephants were given atropine (0.04-0.05 mg/kg) IM following induction with etorphine (1 mg/450 kg of body weight). (Byron et.al. 1985).

 

h) An adult female Asian elephant (approx. 3500 kg) was given 450 mg atropine (0.11 mg/kg) IM/SQ 38 minutes following induction with 600 mg xylazine (Schmidt, 1983). (Author’s (Mikota) note: At 0.11 mg/kg, the calculated dose of atropine for a 3500 kg elephant would be 385 mg).

 

Elephant References:

a) Gross,M.E., Clifford,C.A., and Hardy,D.A. 1994. Excitement in an elephant after intravenous administration of atropine. Journal of the American Veterinary Medical Association 205:(10):1437-1438   Summary: A 28-year-old Asian elephant (Elephas maximus) was anaesthetized for cesarean section to remove a dead calf. The elephant was sedated with azaperone (0.35 mg/kg), and atropine (.05 mg/kg) was administered i.v. 90 minutes later in preparation for induction of anaesthesia with etorphine HCl. Within a minute of the injection of atropine the elephant began swaying kicking, moving in an agitated manner around the stall and refused to obey commands. When the behavior did not abate after 30 minutes, azaperone (0.018 mg/kg) was administered IM.  The elephant became calm and responsive to commands within 15 minutes.  The authors suggest drug interaction with azaperone, toxicosis due to the dead calf and species differences as possible causative factors.

b) Dunlop,C.I., Hodgson,D.S., Cambre,R.C., and Kenney,D. 1988. Prolonged isoflurane anesthesia of an adult elephant on two occasions. Veterinary Surgery 17:(3):167-168 

c) Mihm,F.G., Machado,C., and Snyder,R. 1988. Pulse oximetry and end-tidal CO2 monitoring of an adult Asian elephant. Journal of Zoo Animal Medicine 19:106-109  Abstract: The adequacy of ventilation during etorphine anesthesia of a 20-yr-old Asian elephant (Elephas maximus) was monitored with a pulse oximeter to measure arterial hemoglobin oxygen saturation (SaO2) and a CO2 analyzer to measure end-tidal CO2 concentrations (PetCO2).  Immediately after the first anesthetic induction, SaO2 values of 45% were noted while the animal was breathing room air at a rate of 6/min.  The SaO2 readings increased to 93% 15 min after administration of 5 liters/min of oxygen via the trunk.  Seven arterial blood gas samples obtained during two anesthetics, and once while unanesthetized, provided PaO 2 and PaCO2 values which compared favorably with SaO2 and PetCO2 .  In the anesthetized animal, PaO2 ranged between 31 and 70 mmHg while SaO2 values were 70-95%.  At the same time, measurements of PaCO2 ranged from 42 to 57 mmHg while values of PetCO2 ranged from 35 to 57 mmHg.  Pulse oximetry and end-tidal CO2 monitoring are easy to apply and should increase the safety of anesthesia for these animals.

d) Briggs,M., Schmidt,M., Black,D., Roach,R., Opdahl,J., Stark,G., Owens,D., and Driver,M. 1988. Extraction of an infected tusk in an adult African elephant. J Am Vet Med Assoc 192:(10):1455-1456  Abstract: An 18-year-old African elephant was determined to have a nonrepairable crack in its left tusk. Treatment included extraction of the tusk, using rotational and extractional forces, and administration of antibiotics, followed by 1 year of flushing the opened tusk cavity with warm tap water. Two years after surgery, the elephant was healthy, and the tusk cavity was 80% filled with normal tissue.

e) c) Heard,D.J., Kollias,G.V., Webb,A.I., Jacobson,E.R., and Brock,K.A. 1988.  Use of halothane to maintain anesthesia induced with etorphine in juvenile African elephants.  Journal of the American Veterinary Medical Association 193:254-256  Excerpts: Sixteen 3- to 5-year-old African elephants were anesthetized one or more times for a total of 27 diagnostic and surgical procedures.  Xylazine (0.1 ± 0.04 mg/kg of body weight, mean ± SD) and ketamine (0.6 ± 0.13 mg/kg) administered IM induced good chemical restraint in standing juvenile elephants during a 45-minute transport period before administration of general anesthesia.  After IM or IV administration of etorphine (1.9 ± 0.56 micrograms/kg), the mean time to lateral recumbency was 20 ± 6.6 and 3 ± 0.0 minutes, respectively.  The mean heart rate, systolic blood pressure, and respiration rate during all procedures was 50 ± 12 beats/min, 106 ± 19 mm of Hg, and 10 ± 3 breaths/min, respectively. 

Cardiac arrhythmias were detected during 2 procedures.  In one elephant paroxysmal ventricular tachycardia was detected and the procedure terminated when the arrhythmia failed to stabilize after multiple doses of lidocaine (1 mg/kg, IV).  In another elephant, second degree atrioventricular block returned to normal sinus rhythm after IV administration of atropine (0.04 mg/kg).

In one elephant, low mean blood pressure (54 mm of Hg) responded to reduction in halothane (vaporizer setting 1 to 0.75%) and slow infusion of dobutamine HCl ((250 mg/1,000 ml) given to effect. The systolic blood pressure increased to 90 mm of Hg and remained high with a continuous infusion of dobutamine (5 µg/kg/min). Immediately after induction in another elephant, profound respiratory depression (< 1breath/minute) and palpably weak arterial pulse were identified.  Intravenous administration of diprenorphine at half the recommended reversal dose resulted in improvement of respiration and palpable arterial pulse, without the elephant developing signs of complete anesthetic reversal.  

Alterations in systolic blood pressure, ear flapping, and trunk muscle tone were useful for monitoring depth of anesthesia.  Results indicated that halothane in oxygen was effective for maintenance of surgical anesthesia in juvenile African elephants after induction with etorphine.  Note: A correction appeared in a later volume 193(6): p.721.

f) Schmidt,M.J., 1986. Proboscidea (Elephants). In: Fowler,M.E. (Editor), Zoo and wild animal medicine. W.B. Saunders, Philadelphia,PA, USA pp. 884-923

g) Byron,H.T., Olsen,J., Schmidt,M.J., Copeland,J.F.Jr., and Byron,L. 1985. Abdominal surgery in three adult male Asian elephants. Journal of the American Veterinary Medical Association 187:(11):1236-1237 

h) Schmidt,M.J. 1983. Antagonism of xylazine sedation by yohimbine and 4-aminopyridine in an adult Asian elephant (Elephas maximus). Journal of Zoo Animal Medicine 14:94-97 
Abstract: Heavy xylazine sedation was successfully antagonized by intravenous injection of yohimbine and 4-aminopyridine (4-AP) in an adult female Asian elephant (Elephas maximus) prior to euthanasia.  A total xylazine dose of 1,200 mg intramuscularly plus 600 mg intravenously (approximately 0.33 mg/kg body weight) was given resulting in heavy sedation.  After 50 minutes of deep recumbent sedation, 425 mg yohimbine and 1,000 mg of 4-AP were administered intravenously.  Xylazine sedation was antagonized and the elephant was up and walking around within 5 minutes of antagonist administration.  The elephant remained standing for other 3 hours; at which point euthanasia was performed.

Monitoring Parameters - Dependent on dose and indication

1)   Heart rate and rhythm

2)   Thirst/appetite; urination/defecation capability

3)   Mouth/secretions dryness

 

Client Information - Parenteral atropine administration is best performed by professional staff and where adequate cardiac monitoring is available. If animal is receiving atropine tablets, allow animal free access to water and encourage drinking if dry mouth is a problem.

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times -

 

Veterinary-Approved Products: Atropine is approved for use in dogs, cats, horses, cattle, sheep, and swine. No information is available regarding meat or milk withdrawal. Atropine products are available by prescription only.

Atropine Sulfate for Injection

0.5 mg/ml 30 ml, 100 ml vials

2 mg/ml 100 ml vial

15 mg/ml (Organophosphate Tx) 100 ml vial

 

Human-Approved Products:

Atropine Sulfate for Injection

0.05 mg/ml in 5 ml syringes

0.1 mg/ml in 5 and 10 ml syringes

0.3 mg/ml in 1 ml  and 30 ml vials

0.4 mg/ml in 1 ml amps and 1, 20, and 30 ml vials

0.5mg/ml in 1 & 30 ml vials and 5 ml syringes

0.8 mg/ml in 0.5 & 1 ml amps and 0.5 ml syringes

1 mg/ml in 1 ml amps & vials and 10 ml syringes

 

Atropine Sulfate Tablets

0.4 mg in 100’s

 

Also see the monograph for atropine sulfate for ophthalmic use in the appendix

 

 

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