During the last decade, a new group of drugs, known as the barbiturates, has come into prominence in veterinary medicine as hypnotics and anesthetics. Today we find that these derivatives of barbituric acid are used quite extensively in human medicine and in the small animal field of veterinary medicine. The therapeutic action of the derivatives of this parent barbituric acid molecule, which is weakly acid but has no sedative or hypnotic effect, has been made possible because one or both of the hydrogens on the side chains are replaceable. Thus, barbital or diethyl barbituric acid was obtained by replacing each hydrogen with an ethyl radical, forming a derivative which did possess hypnotic and sedative action

Peterson, I. E.

English

During the last decade, a new group of drugs, known as the barbiturates, has come into prominence in veterinary medicine as hypnotics and anesthetics. Today we find that these derivatives of barbituric acid are used quite extensively in human medicine and in the small animal field of veterinary medicine. The therapeutic action of the derivatives of this parent barbituric acid molecule, which is weakly acid but has no sedative or hypnotic effect, has been made possible because one or both of the hydrogens on the side chains are replaceable. Thus, barbital or diethyl barbituric acid was obtained by replacing each hydrogen with an ethyl radical, forming a derivative which did possess hypnotic and sedative action.</p

Peterson, I.

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Barbiturates Their applicatiolls to veterinary therapeutics I. E. Peterson, '44 D URING the last decade, a new group of drugs, known as the barbiturates, has come into prominence in veterinary medicine as hypnotics and anesthetics. Today we find that these derivatives of barbituric acid are used quite extensively in human medicine and in the small ani-mal field of veterinary medicine. The therapeutic action of the derivatives of this parent barbituric acid molecule, which is weakly acid but has no sedative or hypnotic effect, has been made possible because one or both of the hydrogens on the side chains are replaceable. Thus, barbital or diethyl barbituric acid was obtained by replacing each hydrogen with an ethyl radical, forming a derivative which did possess hypnotic and sedative action. Similarly, by replacing one hydro-gen with an ethyl radical and the other with a phenyl radical, phenyl ethyl bar-bituric acid or phenobarbital, was ob-tained. This had twice the potency of bar-bital, yet possessed no greater toxicity. Further chemical research with barbituric acid produced pentobarbital or nembutal, by substituting an ethyl radical for one hydrogen and a methyl-butyl group for the other. This drug was not used phar-macologically or clinically for many years after it was first synthesized. An isomer of pentobarbital called amy tal, which had greater hypnotic effect, more rapid action, and faster elimination than pentobarbital, was produced by Shonle in 1920. The so-dium salts of these barbituric acid deriva-tives were later shown to be more soluble and more adapted to intravenous and in-tramuscular injection, thus giving quicker and deeper, but shorter, effects. 198 The barbiturates may be generally clas-sified as long or short acting, and the two groups should not be used interchange-ably. The choice of drug to be used de-pends on the type of patient, length of time and rapidity of action desired, con-dition of the patient, and history of pre-vious medication. The barbiturates are destroyed mostly in the liver and are ex-creted to a certain extent by the kidneys. In toxic doses, the respiratory system is affected more quickly than is the cardiac system, but in animals which have a cir-culatory disturbance, the barbiturates af-fect the heart and blood pressure even in light doses before the respiratory system shows any effects of overdosage. In gen-eral, the contra indications of the barbitu-rates are hepatic disease, renal impair-ment, circulatory disturbances, acidosis, anemia, respiratory distress from any cause, toxemia, shocks, and previous ad-ministration of other sedatives, hypnotics, or anesthetics in large doses. Especially those patients showing toxemia or shock should be watched very closely during administration of the barbiturates for any idiosyncrasy to the drug. The barbiturates are not usually considered to be habit forming in humans, but a few cases of this occurrence have been reported. Advantages The advantages of barbiturates are enumerated as follows: 1. The degrees of action may be easily graded from very slightly sedative to com-plete anesthesia. 2. The effect is very prompt, within a The Veterinary Student few minutes after oral doses and imme-diately after intravenous. 3. Full doses cause little effect on other functions. 4. The respiratory system, circulation, metabolism, and smooth muscle remain almost normal until full toxic doses are reached. 5. Most of them have no serious after-effects. 6. They produce no serious local ef-fects so they may be administered by all channels. The disadvantages of the barbiturates are the following: 1. The response to the drug is not al-ways the same. 2. The hypnotic action is sometimes preceded by excitement, which is the rea-son for using a small dose of morphine in dogs before administering the barbitu-rates. 3. As anesthetics they are administered at a single dose, thus making for error in the concentration in the body, and they require much safer handling when used for general anesthesia than when used as basal narcotics. 4. They require too large dosage and are therefore too expensive in large ani-mal practice. Indications The barbiturates in general are indi-cated for the following conditions: 1. As a sedative in nervous conditions, 2. As an analgesic in neuritis and pru-ritis, 3. To control nausea and vomiting, 4. As a motor depressant in convulsive states as in epilepsy, Glclampsia, and strych-nine poisoning, 5. Preliminary to local anesthetics to prevent accidents with cocaine and pro-caine, 6. As preanesthetic narcotic, and 7. As anesthetics. In poisoning with these drugs, respira-tory stimulants are used. The following drugs have been used as antidotes: picro-toxin or metrazol with ephedrine, picro-toxin, metrazol, ephedrine, coramine, icoral, strychnine, caffeine, dinitrophenol, Spring, 1944 and benezdrine sulfate. Picrotoxin seems to be quite superior due to its lasting ef-fect but all of them must be given in re-peated dosage since they are eliminated from the body more quickly than the bar-biturates. These should be supplemented by injections of hypertonic dextrose solu-tion and artificial respiration. The bar-biturates have been used for euthanasia in large doses to small animals and the younger large animals. The use for this purpose has been limited due to the cost compared to that of saturated magnesium sulfate solution. The barbiturates produce death without violent struggling as is seen in many other products used for this purpose and thus are quite humane. Classification The barbiturate drugs fall into two general classifications, the short acting group and slow acting group. The short acting group includes pentothal sodium, seconal sodium, pentobarbital sodium, amy tal, and sodium amy tal. This group produces anesthesia very rapidly but is short acting due to the rapid elimination of the drug from the body. Pentothal sodium, or sodium ethyl thio-barbituric acid, is one of a series of new thiobarbiturates. It is rapidly destroyed in the body, and although it is rapid in effect the duration of this effect is rela-tively short. It is an excellent anesthetic for minor operations in small animals for the effect may be gone in 20 to 30 minutes. The solution should be freshly made and slowly administered, a careful check be-ing kept on the dose as injection proceeds. When anesthesia is sufficiently advanced, injection must cease; when the patient is unconscious and respiration is shallow, anesthesia is usually present. The onset of anesthesia is usually so rapid that the normal stages of anesthesia cannot be 0 b-served during the administration of this drug. The dosage varies in different ani-mals; 7.0 to 11.0 mg. per pound body weight injected intravenously with a standard dose of 10.0 mg. per pound of body weight as an average is recom-mended. The anesthesia will persist for 25 to 30 minutes when an average dose of 199 pentothal sodium is injected following the administration of 8 to 32 mg. of morphine and 0.4 to 0.6 mg. of atropine to dogs. Seconal sodium has been used in human medicine much more extensively than in veterinary medicine. However, it is of some value as a hypnotic when given in small repeated doses to small animals for the period of recovery is much shorter than that of the longer acting barbiturates. This drug causes less renal disturbance than other members of the short acting group, thus being indicated in those pa-tients in which pentobarbital sodium would have a detrimental effect on the renal system. There are no after effects following the administration of this drug. It has a large margin of safety in dosage but larger doses seem to produce restless-ness rather than the desired hypnosis. This drug is recommended for preanes-thetic medication in small animals. The dosage is usually 48 mg. to cats and small dogs. Large doses followed by toxic re-actions of the drug may be counteracted by injection of hypertonic dextrose with caffeine and ephedrine. Nembutal Pentobarbital sodium or nembutal is a more slowly acting member of the short acting group. This is prepared in the forms of pentobarbital sodium and pentobarbital calcium. The sodium salt is more readily soluble and, thus, probably acts more quickly than the calcium salt. There is no pharmacological difference in their re-action, and they may be used interchange-ably. The sodium salt is hygroscopic and cannot be prepared in the tablet form. The calcium salt of pentobarbital is not hygroscopic and is prepared in the tablet form for oral or rectal administration only. Pentobarbital sodium is the only salt of the two which is prepared in the ampoule form for intravenous or intramuscular in-jection. Solutions to be used for this pur-pose should only be prepared from the sterile anhydrous form which is supplied in sterile ampoules. Under no circum-stances should the pentobarbital sodium which is prepared in pulvule form for oral administration be used for intravenous or 200 intramuscular inejction. The 5 percent weight-volume solution is prepared with sterile water in the ampoule for this pur-pose. Discard any solution of this drug which exhibits slight opalescence or hazi-ness. Pentobarbital sodium in preanesthetic medication has many advantages similar to those of sodium amy tal in which it re-lieves preoperative apprehension by the patient, affords more quiet induction of anesthesia, reduces the amount of general anesthetic required, and diminishes the postoperative nausea and vomiting in small animals. In comparison to sodium amy tal in preanesthetic medication, only one-half the dose need be used to produce the same effect and the period of postoperative re-covery is only about one-half as long as that following the use of sodium amy tal. Overdosage of either drug will produce respiratory distress and postoperative rest-lessness, so one must caution against use of barbiturates in doses sufficient to pro-duce a deep preanesthetic effect for such doses predispose to respiratory embarrass-ment especially when they are supple-mented with ether to the point of full anesthesia. Respiratory distress may also be more often noticed in those cases in which morphine and pentobarbital sodium were used in conjunction in preanesthetic medication, followed by complete ether anesthesia. So morphine is commonly used alone as a preanesthetic medicament in dogs. Applications Pentobarbital sodium is used in doses of 50 to 100 mg. orally for preanesthetic medication in cats since morphine is ex-citing to this animal. If the patient will not take the drug by way of the mouth, it may be given in the form of an enema when mixed with a little water and in-serted into the rectum. Suppositories of pentobarbital calcium in cacao butter base seem to give good results in controlling the convulsions of chorea and in control-ling the nausea and vomiting complicat-ing roentgen therapy. These are most successful when administered per rectum immediately following x-ray treatment. The Veterinary Student Pentobarbital sodium is not used to any great extent in obstetrics since there are limiting factors to the use of barbiturates in these cases regardless of the route of administration. When used in dosage large enough to produce complete analgesia or complete anesthesia, this drug is quite apt to produce respiratory and vascular de-pression in the pregnant female and en-tails great risk of producing narcosis in the newborn and intensive resuscitation efforts are often necessary with close supervision for the first 12 hours after administration to the dam. This drug has been used to good advantage in the con-trol of strychnine convulsions. It has shown good results in the control of other nervous symptoms especially those shown in chorea of dogs following canine distem-per complications of the nervous system. Pentobarbital sodium should not be used in cases of cardiac pr respiratory disturb-ance, in case of generalized arteriosclero-sis or in cases of impaired liver or renal function. During the postoperative period the patient should be observed closely for tendency towards choking. This drug should not be used following heavy mor-phine sulfate medication since both of these drugs may produce undesirable re-spiratory depression. Morphine sulfate is used hypodermically in low dosage to con-trol the postoperative restlessness due to pain only. Some patients are much more susceptible to the toxic reactions of pento-barbital sodium than others, and these should be observed closely following medi-cation for toxic symptoms of an idiosyn-crasy or hypersensitivity to the drug. Administration Nembutal can be administered by a va-riety of methods. Under ordinary circum-stances the therapeutic effects of this drug can be obtained by oral administration, but there are certain advantages to paren-teral administration. Nausea, vomiting, diarrhea or other factors interfering with absorption of the orally administered drug may make it desirable to give it by the parenteral route. Intramuscular injection shows a slower onset and lowered inten-sity of action of the drug than does intra-Spring, 1944 venous injection but the circulatory and respiratory depression are less marked. Local reaction is usually slight or absent. The intravenous route of administration of pentobarbital sodium offers the imme-diate placing of the patient under the in-fluence of the hypnotic and is the method of choice in emergency conditions. The intravenous injection of this drug must be made carefully and slowly. The rate of injection should not exceed 1 cc. per min-ute. The patient should be observed closely during the injection to make cer-tain that respiratory or circulatory dis-turbances do not appear before the char-acteristic sleep of general anesthesia. Three to 5 minutes should elapse during the administration of the solution, for too rapid injection has been the cause of many of the hazards of this drug which surgeons complain about. Pupillary Reflex The pupillary reflex should guide the anesthetist in the administration of the drug. Dilatation of the pupil occurs first, followed by contraction. When the pupil reaches one-fourth the size of the normal pupil, a sufficient dose has been given. The onset of narcosis may be immediate or may take up to 30 minutes by the intra-venous route. The intravenous method is now recognized as the best method and if done properly, anesthesia with pentobar-bital sodium may be accomplished in all types of patients without danger. When administered per os, its action is some-what uncertain and the dosage cannot be regulated as efficiently. The onset of nar-cosis may be delayed if the stomach is full. As a general rule the animal recovers in 12 hours, but narcosis may last from 24 to 48 hours. The dosage rate is from 8 to 12 mg. per pound body weight when administered intravenously in small ani-mals. The animal should be weighed to get the exact dosage. It must be increased or repeated in larger dogs with a higher metabolic rate with faster elimination of the drug from the body. The use of nembutal in large animal practice has been limited due to the cost and to the undesirable postoperative ef-201 fects of the drug, in which there is a long period of recovery from its effects. It has been used with success for general anes-thesia in foals in doses of 5 to 25 cc., de-pending upon the size of the foal. In calves and small cattle nembutal has been used intravenously for general anesthesia in doses of 50 to 125 cc. with good results. In mature horses excellent results have been obtained in using pentobarbital so-dium as a sedative. Fifteen cc. per 1,000 pounds body weight in large horses will facilitate the easy handling of the indi-vidual in a few minutes. The amount may be increased for very large and nervous horses. The sedative dose for a horse suf-fering from pain in the digestive tract is usually 15 to 25 cc. administered intra-venously. The high cost of this drug com-pared to choral hydrate has limited its usefulness in the large animal field of veterinary medicine. Amy tal and sodium amy tal are quite similar to nembutal in action but require greater dosage. Thus, their use in vet-erinary medicine has been limited to only a few cases in the small animal field. Slow Acting Group The slow acting group includes barbital and phenobarbital, or luminal, and their sodium salts. These members of the bar-biturates are indicated where a very slow and long-acting agent is desired. Barbital and barbital sodium may be used where prolonged effects are not a disadvantage. Their action is very pro-longed and extends well into the post-operative period, thus complicating post-operative medication. For that reason they are not as extensively used for preanes-thetic medication in surgery as the shorter acting members of the barbituric acid series. As the effects wear off, there may be disturbing mental complications. In addition, they may place undue strain on the heart and kidneys and so are contra-indicated in any cardiac or renal disturb-ance. Their use in obstetrics has not been very extensive probably due to their ef-fect on the renal system already over-burdened by pregnancy. The sodium salt of barbital has been used as an intra-202 muscular injection in nervous and mental disorders. These slower acting barbitu-rates have a definite value in convulsive conditions, but the shorter acting members have been used in the treatment of strych-nine convulsions and the toxemia of tet-anus infection due to their advantage of immediate action. Barbital or barbital sodium have been used in dosages of 0.3 to 0.6 Gm. prior to the use of either pro-caine or cocaine in local anesthesia. The average dose of either of these drugs is 0.16 to 1.0 Gm. for dogs and 0.1 to 0.25 Gm. in cats. They have not been used in large animals due to their cost and the prolonged postoperative effects. Phenobarbital and phenobarbital sodium or luminal are also members of the slower acting barbiturates. Their action is even more prolonged than that of barbital. Their suggested dosage is 0.03 to 0.2 Gm. Pheno-barbital is especially useful in small re-peated doses of 0.03 to 0.1 Gm. through-out the day in preventing the occurrence of attacks of epilepsy. They have the same objections for use as preanesthetic agents as barbital and barbital sodium. If used for that purpose the average dose is 0.06 to 0.2 Gm. Large doses of phenobarbital in surgical cases have resulted in collapse and pneumonia, due to abolition of the cough reflex. A failing heart, bronchitis, renal disease, or tuberculosis contraindi-cate the use of phenobarbital in anesthetic doses. Because of these contraindications which are similar to those of barbital, it is seldom used in obstetrics. Tolerance to the drug has been noticed on repeated small doses. In dogs, not more than 0.4 Gm. of phenobarbital should be given daily, and that only in divided doses of 0.05 to 0.1 Gm. each. The dosage for cats is usually 0.02 to 0.015 Gm. at a single administration. The dosage is increased 10 percent when the sodium salt is used. As with barbital, phenobarbital is seldom used in large animal patients for similar objections to cost and postoperative effects. REFERENCES 1. E. R. Frank. 1942. Veterinary Surgery noies. Bur-gess Publishing Co .• Minneapolis. Minn. 2. H. J. Milks. 1943. Veterinary pharmacology. ma-teria medica. and therapeutics. Alexander Eger and Co. Chicago. Ill. 3. Eli Lilly and Co. 1943. Therapy with the Barbiturates. The Veterinary Student 

Barbiturates

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Barbiturates

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