Dopram-V

Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Oral toxicity studies were carried out in nine dogs and sixty rats for 30 days. Dogs were given doxapram orally by capsule at doses of 20, 50 and 125 mg/kg/day, and one group received the drug intravenously at 20 mg/kg/day. Rats received the drug by stomach tube at 40, 80 and 160 mg/kg/day, with one group receiving 20 mg/kg intravenously daily. Four dogs died, three while receiving the high dose of 125 mg/kg and one at 50 mg/kg. At each dosage level signs of tremor, lacrimation, excessive salivation, occasional vomiting, diarrhea, stiffness of the extremities and respiratory stimulation were observed in all dogs. The hemogram, urinalysis and blood chemistry showed no changes which were considered attributable to the drug.

Histologically, the central nervous system in both species showed congestion, perivascular hemorrhages and petechial hemorrhages. These changes were interpreted as resembling hypoxic changes. The experiments were repeated in dogs at 2.5, 5, 10 and 20 mg/kg/day and no such lesions were seen.

The acute LD50 of doxapram appears to be in the same dose range for various species of animals including mice, rats, adult dogs, newborn dogs and cats. The intravenous LD50 was approximately 75 mg/kg while the oral and subcutaneous LD50’s were three to four times greater and the intraperitoneal LD50 about twice as great.

No significant irritation was produced when a saline solution of doxapram at a pH of 4.3 was administered intramuscularly to rabbits at concentrations of 1, 2 and 4%. On the other hand, aqueous solutions of the same concentrations caused tissue irritation in rabbits when given subcutaneously.

Safety Margin for the Various Species2,9

The acute LD50 of doxapram HCl in unanesthetized animals appears to be in the same dose range for various species of animals including mice, rats, adult and neonatal dogs and cats. Intravenously, the LD50 was determined to be approximately 75 mg/kg. The oral and subcutaneous LD50 was three to four times the intravenous LD50 whereas the intraperitoneal LD50 was about twice as great.2,9

The maximum tolerated dose (MTD) of doxapram HCl in unanesthetized animals appears to be in the same dose range for various species of animals including mice, rats, adult and neonatal dogs and cats. Intravenously, the highest MTD tested was determined to be approximately 40 mg/kg. The oral and subcutaneous MTD was three or four times the intravenous MTD whereas the intraperitoneal MTD was about twice as great.

The highest dose given intravenously to horses was 66 mg per 100 lbs with chloral hydrate anesthesia, and 60 mg per 100 lbs with gas anesthesia. All animals responded normally and no toxic symptoms were observed.

The clinical use of doxapram in lightly and deeply anesthetized animals has confirmed the respiratory stimulant and arousal effects previously demonstrated in the laboratory. In one study with 48 dogs and 18 cats subjected to various surgical procedures using pentobarbital sodium as the anesthetic, marked increases in ventilation occurred within one minute following a single intravenous injection of 5 mg doxapram per kg of body weight (2.5 mg/lb). The most dramatic improvement occurred in lightly anesthetized dogs pretreated with either promazine or fentanyl-droperidol and atropine. Doxapram accelerated the return of pedal reflexes in all animals.

Doxapram consistently sustained an increased heart rate beginning one minute after injection. A second injection generally failed to further increase heart rate. EKG disturbances of T-wave polarity and magnitude occurred with the use of doxapram but tended to abate with time. Second injections of doxapram generally did not aggravate the EKG distortions.

Ten animals had pre-existing EKG signs of cardiac damage and tolerated doxapram well.

In another study with 73 dogs subjected to various surgical procedures using methoxy-flurane or halothane as the anesthetic, the arousal time was materially shortened, and respiratory minute volume and rate were increased following a single intravenous injection ranging from 0.08 to 1.95 mg/lb with an average dose of 0.44 mg/lb.

Doxapram was effective in intravenous dosages of 1 mg/kg or less in increasing ventilation and reducing arousal time, especially following methoxyflurane. Tidal volume and respiratory rates were increased; the response normally occurred in 10–20 seconds following injection. No side effects were observed. There were 35 dogs under halothane and 33 dogs under methoxyflurane anesthesia in this study.

In 20 horses subjected to various surgical procedures using intravenous injections of chloral hydrate, chloral hydrate and magnesium sulfate, or pentobarbital as the anesthetic, marked increases in ventilation occurred within 30 seconds following intravenous injection of doxapram in doses ranging from 0.20 to 0.66 mg/lb with an average of 0.28 mg/lb for chloral hydrate and 0.20 to 0.25 mg/lb for the barbiturate. The arousal time was materially shortened, and respiratory minute volume and rate were increased.

In another study involving 34 horses anesthetized with halothane or methoxyflurane, marked increases in ventilation occurred within 30 seconds following intravenous injection of doxapram in doses ranging from 0.08 to 0.50 mg/lb, with an average dose of 0.21 mg/lb. The average recovery time was shortened by one-third or more.

In a series of clinical studies involving 80 neonatal canine patients, suffering respiratory crisis following dystocia or caesarean section, doxapram administered either subcutaneously, sublingually or via umbilical vein in doses from 1–5 drops (1–5 mg) resulted in a marked increase in ventilation and survival of all patients.

In a series of clinical studies involving 16 neonatal feline patients, suffering respiratory crisis following caesarean section or dystocia, doxapram administered either subcutaneously or sublingually (topically) in doses of 1 to 2 drops (1–2 mg) resulted in a marked increase in ventilation and survival of all patients.

The action of Dopram-V (doxapram hydrochloride) is rapid, usually beginning in a few seconds. The duration and intensity of response depends upon the dose, the condition of the animal at the time the drug is administered, and depth of anesthesia. Repeated doses should not be given until the effects of the first dose have passed and the condition of the patient requires it.

Dosage should be adjusted for depth of anesthesia, respiratory volume and rate. Dosage can be repeated in 15 to 20 minutes, if necessary.

Note: Vial should be discarded after a maximum of 50 entries.

1. Lunsford, C.; Cale, Jr., A. D.; Ward, J. W.; Franko, B. V. and Jenkins, H.: 4-(b-substituted ethyl)-3, 3-diphenyl-2-pyrrolidinones. A new series of CNS stimulants. J. Med. Chem. 7:302 (1964).

2. Ward, J. W. and Franko, B. V.: A New Centrally Acting Agent (AHR-619) with Marked Respiratory Stimulating, Pressor, and “Awakening’’ Effects; Fed. Proc. 27:(2):325 (1962).

3. Funderburk, W. H.; Oliver, K. L. and Ward, J. W.: Electrophysiologic Analysis of the Site of Action of Doxapram Hydrochloride. J. Pharmacol. Exp. Ther. 151:3 (1966).

4. Funderburk, W. H.; Oliver, K. L.; Ward, J. W.: Cerebral Blood Flow Changes Due to Doxapram Hydrochloride (AHR-619); Fed. Proc. 22:(2):482 (Abstract) (1963).

5. Reports on File. Pharmacology Department, A. H. Robins Company.

6. Alphin, R. S. and Franko, B. V.: Inhibition and Stimulation of Gastric Secretions by Doxapram Hydrochloride (AHR-619); Fed. Proc. 22(2):662 (Abstract) (1963).

7. Kato, H. and Buckley, J. P.: Possible Sites of Action of the Respiratory Stimulant Effects of Doxapram Hydrochloride. J. Pharmacol. Exp. Ther. 144:260 (1964).

8. Bruce, R. B.; Pitts, J. E.; Pinchbeck, F. and Newman, J.: Excretion, Distribution, and Metabolism of Doxapram Hydrochloride. J. of Med. Chem. 8:157 (1965).

9. Woodard, G.; Ward, J. W. and Mann, G. T.: Safety Evaluation of the Respiratory Stimulant Doxapram Hydrochloride by Oral and Parenteral Administration to Laboratory Animals. Tox. and Appl. Pharmacol. 6:364 (1964).

10. Klemm, W. R.: Physiologic Responses to Equivalent Doses of Doxapram and Various Analeptic Combinations in Acute Barbiturate Narcosis in Dogs. Tox. and Appl. Pharmacol. 8:505 (1966).

11. Klemm, W. R.: Evaluation of Effectiveness of Doxapram and Various Analeptic Combinations in Dogs. J. Am. Vet. Med. Assoc. 148:894 (1966).

12. Jensen, E. C. and Klemm, W. R.: Clinical Evaluation of an Analeptic, Doxapram, in Dogs and Cats. J. Am. Vet. Med. Assoc. 150(5):516–525 (1967).

13. Polak, A. and Plum, F.: Comparison of New Analeptics in Barbiturate-Poisoned Animals. J. Pharmacol. Exp. Ther. 145:27 (1964).

14. Short, C. E.: Proc. American Animal Hospital Association, Washington, D. C., 1969.

Dopram is a registered trademark of Baxter Healthcare Corporation and is used under license.

© 2010 Boehringer Ingelheim Vetmedica, Inc. All Rights Reserved.

Manufactured for:
Boehringer Ingelheim Vetmedica, Inc.
St. Joseph, MO 64506 U.S.A.

11960 Rev. July 2010 5020H P688-298USA/01-10