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Oxytocin

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 - A nonapeptide hypothalamic hormone stored in the posterior pituitary (in mammals), oxytocin occurs as a white powder that is soluble in water. The commercially available preparations are highly purified and have virtually no antidiuretic or vasopressor activity when administered at usual doses. Oxytocin potency is standardized according to its vasopressor activity in chickens and is expressed in USP Posterior Pituitary Units. One unit is equivalent of approximately 2.0 - 2.2 micrograms of pure hormone.

 

Commercial preparations of oxytocin injection have their pH adjusted with acetic acid to 2.5-4.5 and multi-dose vials generally contain chlorbutanol 0.5% as a preservative.

 

Storage/Stability/Compatibility - Oxytocin injection should be stored at temperatures of less than 25°C, but should not be frozen. Some manufacturers recommend storing the product under refrigeration (2-8°C), but some products have been demonstrated to be sta­ble for up to 5 years if stored at less than 26°C.

 

Oxytocin is reportedly compatible with most commonly used intravenous fluids and the following drugs: chloramphenicol sodium succinate, metaraminol bitartrate, netilmicin sulfate, sodium bicarbonate, tetracycline HCl, thiopental sodium and verapamil HCl.

 

Oxytocin is reportedly incompatible with the following drugs: fibrinolysin, nore­pinephrine bitartrate, prochlorperazine edisylate and warfarin sodium. Compatibility is de­pendent upon factors such as pH, concentration, temperature and diluents used. It is sug­gested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).

 

Pharmacology - By increasing the sodium permeability of uterine myofibrils, oxytocin stimulates uterine contraction. The threshold for oxytocin-induced uterine contraction is reduced with pregnancy duration, in the presence of high estrogen levels and in patients al­ready in labor.

 

Oxytocin can facilitate milk ejection, but does not have any galactopoietic properties. While oxytocin only has minimal antidiuretic properties, water intoxication can occur if it is administered at too rapid a rate and/or if excessively large volumes of electrolyte-free intravenous fluids are administered.

 

Uses/Indications - In veterinary medicine, oxytocin has been used for induction or en­hancement of uterine contractions at parturition, treatment of postpartum retained placenta and metritis, uterine involution after manual correction of prolapsed uterus in dogs, and in treating agalactia.

 

Pharmacokinetics - Oxytocin is destroyed in the GI tract and, therefore, must be adminis­tered parenterally. After IV administration, uterine response occurs almost immediately. Following IM administration, the uterus responds generally within 3-5 minutes. The dura­tion of effect in dogs after IV or IM/SQ administration has been reported to be 13 minutes and 20 minutes, respectively. While oxytocin can be administered intranasally, absorption can be erratic.

Oxytocin is distributed throughout the extracellular fluid. It is believed that small quantities of the drug cross the placenta and enter the fetal circulation.

 

In humans, the plasma half-life of oxytocin is about 3-5 minutes. In goats, this value has been reported to be about 22 minutes. Oxytocin is metabolized rapidly in the liver and kidneys and a circulating enzyme, oxytocinase can also destroy the hormone. Very small amounts of oxytocin are excreted in the urine unchanged.

 

Contraindications/Precautions - Oxytocin is considered to be contraindicated in animals with dystocia due to abnormal presentation of fetus(es), unless correction is made. When used prepartum, oxytocin should be used only when the cervix is relaxed naturally or by the prior administration of estrogens (Note: Most clinicians avoid the use of estrogens, as natural relaxation is a better indicator for the proper time to induce contractions).

 

In humans, oxytocin is considered to be contraindicated in patients with significant cephalopelvic disproportion, unfavorable fetal positions, in obstetrical emergencies when surgical intervention is warranted,  severe toxemia or when vaginal delivery is contraindi­cated. Oxytocin is also contraindicated in patients who are hypersensitive to it. Nasally administered oxytocin is contraindicated in pregnancy. Before using oxytocin, treat hypoglycemia or hypocalcemia if present.

 

Adverse Effects/Warnings - When used appropriately at reasonable dosages, oxytocin rarely causes significant adverse reactions. Most adverse effects are as a result of using the drug in inappropriate individuals (adequate physical exam and monitoring of patient are essential) or at too high doses (see Overdosage below). Hypersensitivity reactions are a possibility in non-synthetically produced products. Repeated bolus injections of oxytocin may cause uterine cramping and discomfort.

 

Overdosage - Effects of overdosage on the uterus depend on the stage of the uterus and the position of the fetus(es). Hypertonic or tetanic contractions can occur leading to tumul­tuous labor, uterine rupture, fetal injury or death.

 

Water intoxication can occur if large doses are infused for a long period of time, espe­cially if large volumes of electrolyte-free intravenous fluids are concomitantly being ad­ministered. Early symptoms can include listlessness or depression. More severe intoxica­tion symptoms can include coma, seizures and eventually death. Treatment for mild water intoxication is stopping oxytocin therapy and restricting water access until resolved. Severe intoxication may require the use of osmotic diuretics (mannitol, urea, dextrose) with or without furosemide.

 

Drug Interactions - If sympathomimetic agents are used concurrently with oxytocin, post-partum hypertension may result. Monitor and treat if necessary. Oxytocin used con­comitantly with cyclopropane anesthesia can result in hypotension, maternal sinus brady­cardia with atrioventricular dysrhythmias. One case in humans has been reported where thiopental anesthesia was delayed when oxytocin was being administered. The clinical significance of this interaction has not been firmly established.

 

Doses -

Horses:

To augment or initiate uterine contractions during parturition in properly evaluated mares:

a)   20 Units IM causes slow, quiet foaling;

40 - 60 Units IM produces, quiet, safe foaling within an hour;

100 Units or more will result in rapid completion of a more active foaling;

IV (bolus) doses of 2.5 - 10 Units may be used to initiate parturition. (Hillman 1987)

b)   For induction: If cervix is dilated at least 2 cm (internal measurement): 40 - 60 Units given as IV bolus, delivery should occur within 90 minutes.

If the cervix is closed or less than 2 cm dilated: give oxytocin in 10 unit incre­ments IV at 15-30 minute intervals. If the cervix dilates, but no signs of labor are shown, give additional oxytocin of 40 - 60 Units. (Carleton and Threlfall 1986)

To aid in removal of retained placenta:

a)   Oxytocin Bolus: 30 - 40 Units IM at intervals of 60-90 minutes. If parturition occurred more than 24 hours prior to oxytocin, doses up to 80 - 100 Units IM may be used. Alternatively, IV doses of 30 - 60 Units may be used until an ade­quate response is detected via rectal palpation of the uterus.

Oxytocin Infusion:       Add 80 - 100 Units oxytocin to 500 ml normal saline and begin IV infusion. Adjust rate of infusion according to mare’s reactions. Slow rate if mare exhibits symptoms of excessive abdominal pain. Retained placenta generally expelled within 30 minutes. Gentle traction may help speed up expul­sion. If several days have past since parturition, doses of up to 300 Units (administered rapidly) may be necessary to activate uterine motility. (Held 1987)

 

For mild to moderate cases of acute post-partum metritis:

a)   20 Units IM 3-4 times a day for 2-3 days (Hameida, Gustafsson, and Whitmore 1986)

 

For obstetrical use in mares:

a)   100 Units IV, IM or SQ (Package Insert; Oxytocin Injection—Anthony Products)

 

 

Elephants:

For dystocia:

a) Oxytocin for labor induction in elephants should be used judiciously. To induce labor, give 20-30 IU IM or IV as the initial dose; increase if needed every 20-30 minutes in increments of 20-30 IU.  For milk letdown, give 40-60 IU intravenously.  Give one injection only when needed for the calf to nurse or to collect milk for bottle feeding (Schmitt, 2001).

 

b) See abstract below for guidelines on oxytocin use (Schaftenaar, et.al. 2001).

 

c) 5-20 mg IV with or without prior estrogenation. Repeated doses have been unrewarding in producing a primary delivery and lack of productive response to oxytocin after cessation of natural labor signals the existence of a serious dystocia (Foerner, 1999).

 

d) A 17- year-old Asian elephant in labor for almost 9 hours was treated with 20 ml of oxytocin 0.5% vol/wt intravenously along with 500 ml of dextrose 5%.  A healthy calf was delivered within 16 minutes from the time of initiation of the infusion (Raju et.al. 1997).

 

e) An Asian cow was given 50 IU of oxytocin (0.013 mg/kg) SC which induced strong uterine contractions.  When this dose was repeated SC but failed to elicit delivery, the same dose was given IV.  Uterine contractions followed almost immediately and lasted about 30 minutes. Although a vaginal vestibulotomy was eventually performed, the author felt the dose of 50 IU to be correct as higher doses may have carried the risk of a uterine rupture or displacement of the placenta (Schaftenaar, 1996).

 

For retained placenta:

f) Intermittent oxytocin therapy on days 2-14 postpartum failed to result in the expulsion of a retained placenta and produced only transient abdominal contractions and minimal increases in milk letdown.  On day 15, 10 mg estradiol cypionate was administered i.m. followed by 200 IU oxytocin i.v.  An additional 10 IU oxytocin was administered i.v. on day 16 and the placenta was palpable within the vaginal vault on day 17 (Murray et.al. 1996).

 

Elephant References:

a) Schmitt,D.L. 2001. Riddle’s Elephant and Wildlife Sanctuary Elephant Birth Protocol. www.elephantcare.org/protodoc_files/birthpro.pdf

b) Schaftenaar,W., Hildebrandt,T.B., Flugger,M., Goritz,F., Schmitt,D., and West,G.  2001. Guidelines for veterinary assistance during the reproduction process in female elephants. Proceedings American Association of Zoo Veterinarians, American Association of Wildlife Veterinarians, Association of Reptilian and Amphibian Veterinarians, and the National Association of Zoo and Wildlife Veterinarians Joint Conference. Pages: 348-355  Abstract: In February 2000, a group of European zoo veterinarians met at Tierpark Hagenbeck, Hamburg to evaluate a questionnaire about 31 parturitions in Asian elephants.  The results were presented at the 40th International Symposium on Diseases of Zoo and Wild Animals.  The results were combined with the experiences of some North-American zoo veterinarians, which resulted in the protocol presented in this paper.  The protocol may serve as a guideline for institutions that wish to breed elephants. The proper application of the recommendations given in these guidelines should increase the reproductive success in elephants.  It is the moral obligation of everyone who is responsible for the  management and breeding of elephants to consider utilizing the guidelines as they may apply to their situation and to collect data that may help increase our knowledge. The breeding process in elephants requires monitoring of several parameters in both males and females. The most crucial parameters are the determination of the estrous cycle through progesterone and, perhaps, LH assay, evaluation of the genital tract in both sexes, determination of the number of fetuses and finally, parturition.  The first part of the paper will mention briefly the tools that can be used in female elephants to achieve these goals.  The second part describes a protocol for veterinary intervention in elephant parturition.  Additional excerpt: The calf should be born within 2 hours after rupture of the fetal membranes.  If not, veterinary intervention should take place according to the following schedule. Two hours after rupture of the membranes or 120 hours after progesterone drop, collect a blood samples for calcium determination.  Store an EDTA and heparin sample for Herpes virus diagnosis (both cells and plasma in freezer after separation).  Perform a rectal palpation, transrectal ultrasonographic examination, transrectal massage of the pelvic area with two arms for at least 10 minutes (keep hands gripped together and press with the wrists or the palmer sides of the hands against the pelvic roof and the genital tract).  This may stimulate labor activities.  Care must be taken not to damage the rectal wall, which may get very edematous.  Insert at least one catheter IV.  To stimulate further relaxation of the cervix, the parenteral administration of estrogens may be considered.  However, no data are available for elephants.  Administer 50 IU oxytocin IM or SC if there is (some) relaxation of the cervix.  Four hours after rupture  of membranes or 122 hours after progesterone drop, treat for hypocalcemia if applicable.  Perform a rectal palpation, transrectal ultrasongraphic examination, and transrectal massage of the pelvic area and give 50 IU of oxytocin IM or SC.  If parts of the fetus are in the pelvic canal, the dose may be increased to 100 IU, given IM.  Six hours after rupture of the membranes or 124 hours after progesterone drop, perform a rectal palpation, transrectal ultrasonographic examination, check blood Ca level again, and perform transrectal massage of the pelvic area.  If no progress was made, prepare everything to perform a vaginal vestibulotomy.  Administer 100 IU of oxytocin in a 1-hr infusion.  Eight hours after rupture of he membranes or 126 hr after progesterone drop, perform a rectal palpation, transrectal ultrasongraphic examination, and transrectal massage of the pelvic area.  If no  progress was made, perform a vaginal vestibulotomy. See original article for further details.

c) Foerner,J.J., 1999. Dystocia in the elephant. In: Fowler,M.E. and Miller.R.E. (Editors), Zoo and Wild Animal Medicine: Current Therapy 4. W.B. Saunders, Philadelphia; USA pp. 522-525

d) Raju,R., Rao,B.S.G., Khadri,S.M., and Asha,D. 1997. Chemical manipulation of delayed parturition in captive Asiatic elephant at Mysore Zoo. Indian Forester 123:(10):910-916

e) Schaftenaar,W.  1996. Vaginal vestibulotomy in an Asian elephant (Elephas maximus). Proceedings American Association of Zoo Veterinarians. Pages: 434-439
Abstract: Due to its dimensions, dystocia in elephants presents a difficult problem.  This paper describes the delivery of a dead calf by surgical intervention.  A vestibulotomy was performed under local anesthesia.  Complications in wound healing resulted in a permanent fistula of the vestibulum.  The difficulties in decision making and the interpretation of clinical signs are discussed.

f) Murray,S., Bush,M., and Tell,L.A. 1996. Medical management of postpartum problems in an Asian elephant (Elephas maximus) cow and calf. Journal of Zoo and Wildlife Medicine 27:(2):255-258  Abstract: An 18-yr old female Asian elephant (Elephas maximus) gave birth to a 120-kg female calf following 22 mo of gestation.  Immediately after parturition, the cow became agitated and aggressive towards the calf.  Before the keepers were able to safely intervene and remove the calf, the cow stepped on the calf's head and right front leg.  Within 30 min, the cow calmed down, allowing the calf's safe reintroduction under close keeper supervision and control.  The cow had a retained placenta, poor mammary development, and low milk production.  The calf's injuries, in combination with the cow's low milk production, impeded the calf's ability to nurse and gain weight.  Within 10 days, the calf lost 10% of its weight.  Serum protein electrophoresis indicated failure of passive transfer of maternal immunoglobulin.  On day 10, the calf received a transfusion of concentrated immunoglobulin extracted and concentrated from the cow's previously banked plasma.  On day 13, the calf developed a urinary tract infection, as diagnosed by white blood cells and bacteria in the urine.  Following immunoglobulin administration and antibiotic therapy, clinical signs slowly resolved and the calf gained weight.  The cow passed the fetal membranes during parturition, but the placenta was retained.  Despite prophylactic systemic antibiotics and vaginal flushing, the cow became depressed and developed a leukocytosis and anemia.  A mucopurulent vaginal discharge and ventral edema were noted on day 3, and milk production was minimal.  Because decreased milk production has been reported as a common sequel to retained placenta, efforts were focused on removing the placenta.  Intermittent oxytocin therapy on days 2-14 did not result in expulsion of the placenta and produced only transient abdominal contractions and minimal increases in milk letdown.  On day 15, 10 mg estradiol cypionate was administered i.m. followed by 200 IU oxytocin i.v.  An additional 10 IU oxytocin was administered i.v. on day 16.  The friable placenta was palpable within the vaginal vault on day 17.  The remaining placenta was removed by gentle traction applied by a modified weighted pressure cuff.  Once the placenta was removed, the cow's clinical problems slowly resolved and the calf continued to gain weight.

Monitoring Parameters -

1)   Uterine contractions, status of cervix

2)   Fetal monitoring if available and indicated

 

Client Information - Oxytocin should only be used by individuals able to adequately monitor its effects.

 

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

 

Veterinary-Approved Products: Oxytocin products are approved for several species, including horses, dairy cattle, beef cattle, sheep, swine, cats and dogs. There is no milk or meat withdrawal times specified for oxytocin. Oxytocin is a prescription (Rx) drug.

Oxytocin for Injection 20 USP Units/ml in 10 ml, 30 ml, & 100 ml vials; available la­beled generically from several manufacturers.

 

Human-Approved Products:

i.Oxytocin for Injection ;(Human-labeled) 10 Units/ml in 0.5 ml & 1 ml amps, 1 & 10 ml vials; 1 ml Tubex, 1 ml Steri-Dose syringe; Pitocin®  (Parke-Davis); Syntocinon® (Sandoz); Oxytocin® (Wyeth); generic, (Rx)

 

Oxytocin, Synthetic, Nasal Spray  (Human-labeled) 40 Units/ml in 2 and 5 ml squeeze bottles; Syntocinon®  (Sandoz) (Rx)

 

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