A COMPARATIVE STUDY OF riihe LOCAL ANESTHETIC PROPERTIES OF P-AMINO BENZOYL DI-ISO-PROPYL AMINO ETHANOL HYDROCHLORIDE ( ISOCAINE ),

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1 A COMPARATIVE TUDY OF riie LOCAL ANETETIC PROPERTIE OF P-AMINO BENZOYL DI-IO-PROPYL AMINO ETANOL YDROCLORIDE ( IOCAINE ), COCAINE, PROCAINE AND BUTYN L CMITZ AND A LOEVENART From the Pharniacogical Labiratory of the University of Wisconsin Received for publication May 24, 924 While studying the relationship between the chemical constitu#{49} tion and the pharmacological action of two series of procaine derivatives () we became especially interested in the local anesthetic properties of p-amino benoyl di-iso-propyl amino ethanol hydrochloride Einhorn, Fiedler, Ladisch and Uhifelder (2) stated that other alkamine esters of p-amino-benoic acid, including the iso-propyl derivative, had no advantage over procaine Our early experiments, however, showed that this substance is much more active than procaine and practically as efficient as cocaine for anesthetiing the rabbit s cornea and is much less toxic that cocaine for white mice We also found that it had no irritating action on the mucous membranes We, therefore, decided to extend our investigation of this compound to determine whether it would be of clinical value2 As a basis of comparison we used two well known local anesthetics, cocaine and procaine In comparing the different substances cocaine was always assigned a value of Para amino benoyl di-iso-propyl amino ethanol hydrochloride is very closely related to procaine and was first described by Einhorn in 909 (2) We have also investigated the properties of para amino benoyl Downloaded from jpetaspetjournalsorg at APET Journals on April 8, 206 The work here reported is in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology at the University of Wisconsin The authors wish to express their thanks to Dr Roger Adams of the University of Illinois and Dr John chmidt, formerly of the University of Wisconsin, for supplying this compound 67

2 68 L CMITZ AND A LOEVENART di-n-butyl amino propanol, a very closely allied substance first prepared by Kamm, Adams and Volweiler (3) This compound was investigated by Bonar and o!lmann (4) and the soluble sulphate is on the market as Butyn N, COOC,C,N(C,I)2C (Procaine) N2 ( COO C,C,N(C,,(jso))2CL ( Isocaine ) p-amino benoyl di-iso-propyl amino ethanol CI For brevity this compound will be referred to as isocaine N, COO C2C,C2N(C4,<n>)2,04 (Butyn) ANETEIA OF TE RABBIT CORNEA The figures on anesthesia of the rabbit s cornea are taken from our previous article in which is described the technique employed ANETEIA OF TE UMAN CORNEA The technique used in these experiments was similar to that employed in the rabbit experiments but a different instrument was devised to test the reflex Brass pencils were used with the rounded point bent at right angles to the handle These instruments could be sterilied and permitted one to apply a more even pressure on the cornea The subject was placed in a recumbent posture upon a table and three drops of the anesthetic solution were applied to the eye At the end of one minute the subject was told to sit up so that the solution might run out and the excess be wiped off ensitivity was tested every minute, the tests being made with the subject in the recumbent position The results are shown in table 2a The figures in the upper left hand corner (in parentheses) indicate the number of experiments performed with each concentration The other figures (without parentheses) represent the average duration of anesthesia obtained with the particuar concentration Table 2b gives the efficiency ratios based on the data in table 2a Downloaded from jpetaspetjournalsorg at APET Journals on April 8, 206

3 COMPARATIVE TUDY OF LOCAL ANETETIC PROPERTIE 69 TABLE Anesthesia of the rabbit s cornea DURATION OF ANETEIA WIT 2 PER CENT OLUTION APPLIED TO TE CORNEA FOR ONE MINUTE EFPICIENCT RATIO COCAINE!ndividual experiments Avage Cocaine Procaine Isocaine Butyn No anesthesia Duration of anesthesia is expressed in minutes Two per cent procaine applied to the cornea for one minute does not produce anesthesia A two minute application, however does cause anesthesia Cocaine Butyn Isocaine TABLE Average duration of anesthesia of the human cornea 2a Time in minutes TABLE 2b TRENGT OF OLUTION percent 2 percent lperoent (4) 90 (4) 50 (4) 38 (8) 37 (5) 73 (5) 50 (8) 26 (8) 46 (9) 3 Downloaded from jpetaspetjournalsorg at APET Journals on April 8, 206 Efficiency ratio8 based on the average duration of anesthesia of the human cornea (cocaine ) 3 PER CENT 2 PER CENT PEE CENT AVERAGE Cocaine Butyn Isocaine

4 70 L CMITZ AND A LOEVENART ANETEIA OF ENORY NERVE TRUNK Biberfeld and Pototky in 903 (5) tested the action of local anesthetics on the conductivity of the sensory nerve fibers by exposing the sciatic or brachial nerve of the rabbit and sprinkling it with the solid anesthetic substance Then they stimulated at five minute intervals and noted the onset of anesthesia ince that time the principle has been exployed by various investigators Fromher in 94 (6) employed Biberfeld s method but used solutions and determined the minimum concentration required for complete anesthesia ollmann in 98 (7) applied the principle to frogs Our experiments were made on rabbits using the following procedure: The rabbit was anesthetied, the trachea exposed and a tracheal cannula inserted Anesthesia was continued by connecting this cannula with an ether bottle The sciatic nerve on one side was exposed for its entire length, ligated and severed so as to leave the central end as long as possible By severing the nerve, muscle contractions are eliminated during stimulation and the immersion of the nerve trunk in anesthetic solutions is facilitated After the operative part of the procedure was finished, light anesthesia of a constant grade was maintained The respiration was recorded by means of a partly inflated rubber bladder, held in place around the animal s thorax and abdomen by a muslin bandage, and connected with a tambour The minimal current which would produce a change in the respiration was determined For this purpose we employed a Verdin induction coil, using a current of about three volts The position of the secondary coil which produced the minimal current necessary to affect the respiration varied considerably with different animals and even with the two sciatic nerves of the same animal The minimal effective current having been determined, the central end of the severed nerve for a distance of to inch was immersed in a solution of one of the anesthetics for a period of exactly one minute Upon removal from the anesthetic solution the central end of the nerve was covered with gaue saturated with warm physiological salt solution Downloaded from jpetaspetjournalsorg at APET Journals on April 8, 206

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6 72 L CMITZ AND A LOEVENART One minute after the termination of the immersion, the immersed area of the nerve was stimulated to determine whether anesthesia was present or absent If anesthesia was present, that is, if no effect was produced upon the respiration, then the nerve was stimulated above the immersed point in order to prove that an effect upon the respiration was still obtainable In this manner we determined the minimal concentration of each of the anesthetics which would produce blocking of the nerve impulse Between tests the exposed nerve was covered with gaue saturated with normal saline kept at 35 to 40#{76}C After completing a test on one side, the sciatic on the other side was exposed and a test was made with a different anestheticinorder to make a comparison on the same animal The results of this work are shown in table 3 DETERMINATION OF TOXICITY Toxicity was determined for white mice, white rats, rabbits and cats The drugs were injected subcutaneously because this method of administration is the one chiefly used in clinical work The dosage used was on the per kilo basis and the solutions were made up with distilled water The results of these determinations are given in table 4 The toxic symptoms produced by the various drugs were all fairly similar and corresponded very closely to those described for mice in our previous paper Increase in the respiratory rate, paralysis of the hind legs, motor excitement and clonic convulsions appeared in rapid succession Death resulted from respiratory failure Recovery from sublethal doses was very rapid, the convulsions and depression of the respiration disappearing within two or three hours Downloaded from jpetaspetjournalsorg at APET Journals on April 8, 206 DICUION Table 5 is a composite giving the average relative toxicity, the relative efficiency for corneal anesthesia and nerve blocking, and the therapeutic indices The therapeutic indices were calculated individually for each type of anesthesia by dividing the

7 COMPARATIVE TUDY OF LOCAL ANETETIC PROPERTIE 73 Toxicity TABLE 4 table RAT MICE RABBIT CAT Cocaine Procaine Isocaine Butyn Cocaine Procaine Isocaine 5 L ) :E 250, , : #{49} L #{49} :E ; TABLE 5 I I 3 29 RELATIVE, e! :E ANETETIC , Lg h : e! :E : 66 5 ERAPETICINDE h s eo #{76} Downloaded from jpetaspetjournalsorg at APET Journals on April 8, 206 Butyn

8 74 L CMITZ AND A LOEVENART figure representing the relative efficiency by the figure representing the relative toxicity It is obvious that the lower the toxicity of a given anesthetic and the more powerful its action, the better the drug will prove to be clinically We need a single figure which takes into consideration both toxicity and efficiency This figure we designate the therapeutic index We often want to compare two anesthetics in regard to their relative efficiency as anesthetics independently of their toxicity In this case we use the term relative efficiency We wish to emphasie again the importance of specifying the particular type of usage when discussing anesthetic power Therapeutic efficiency for mucous membrane anesthesia is an entirely different proposition from therapeutic efficiency in blocking sensory nerves Thus procaine, by far the safest anesthetic for nerve blocking, is not satisfactory for anesthesia of the intact mucous membrane In order to avoid confusion it is best to speak of membrane anesthesia or corneal anesthesia as distinct from sensory nerve trunk anesthesia The results of the experiments on corneal anesthesia on both rabbits and humans indicate that isocaine has practically the same efficiency as cocaine For rabbits the relative efficiency of isocaine is 90 (cocaine ) while for the human cornea it is 03 For anesthesia of sensory nerve trunks, isocaine is equally as efficient as procaine and six times as active as cocaine The figures for the relative toxicity of isocaine, procaine and cocaine (average of four kinds of animal) are 29, 3 and, respectively Isocaine in other words is approximately twice as toxic as procaine and three tenths as toxic as cocaine The therapeutic indices in table 5 indicate that isocaine has a distinct advantage over cocaine and Butyim for corneal anesthesia Its therapeutic index for this type of anesthesia is three to three and one-half times that of cocaine and Butyn It, therefore, holds out promise of being useful for anesthesia of intact mucous membranes It was found to be less irritating than Butyn or cocaine when applied to the human cornea For paralysis of sensory nerve trunks, however, isocaine is less valuable than procaine because it is twice as toxic and only Downloaded from jpetaspetjournalsorg at APET Journals on April 8, 206

9 COMPARATIVE TUDY OF LOCAL ANETETIC PROPERTIE 75 equally as efficient in blocking sensation Its therapeutic index for this type of anesthesia is about one half that of procaine, twenty times that of cocaine, and ten times that of Butyn Butyn, chiefly because of its high toxicity, probably has no advantage over cocaine for anesthesia of the intact mucous membrane and is much inferior to procaine for paralysis of sensory nerve trunks It is more efficient than cocaine in anesthetiing the cornea but its greater toxicity wipes out this advantage For paralysis of sensory nerve trunks, Butyn is only one-half as efficient as procaine and is about ten times as toxic olhnann in 92 (4) drew practically the same conclusions from his experiments The results of the nerve block experiments with cocaine and procaine were rather surprising Previous investigations of the relative activity of these two compounds indicated that they were about equally efficient in paralying sensory nerves ollmann in 98 (7) came to such a conclusion as the result of experiments performed on the sciatic nerve of the frog and the figures of Bonar and ollmann in 92 (4) give evidence that cocaine is twice as effective as procaine on the frog s sciatic nerve Our results, however, indicate that procaine is six times as efficient as cocaine in paralying the sensory fibres of the sciatic nurve of the rabbit, that is, the effective concentration is one-sixth that of cocaine The results of our toxicity determinations give some valuable suggestions in regard to the differences in susceptibility of various orders and families, a subject of vast importance to pharmacologists The minimum lethal doses we obtained for rats were in all cases a great deal higher than those for mice, rabbits or cats The rat, it seems, is very much less susceptible to local anesthetics than any of the other three kinds of animal studied This same phenomenon has been observed in our department with regard to susceptibility to organic arsenical compounds Gunn (8) points out that the rats also have a very high degree of tolerance to members of the digitalis group of glucosides and to atropine These facts suggest that the rat is in the majority of cases a poor type of animal upon which to base conclusions in regard to toxicity Downloaded from jpetaspetjournalsorg at APET Journals on April 8, 206

10 76 L CMITZ AND A LOEVENART The minimum lethal doses for mice, rabbits and cats also differ from one another but to a much smaller degree Of the three, mice are the least and cats the most susceptible to the local anesthetics studied Rabbits fall about halfway between the two Cats belong to the order Carnivora and have a more highly developed central nervous system than the mice, rats and rabbits, all of which are families of the order Rodentia ince the local anesthetics kill by their action upon the central nervous system, the fact that cats have a more highly developed brain may be a factor in the increased susceptibility which they show owever, there are other differences that must be taken into consideration Cats are carnivorous while rabbits, rats and mice are herbivorous There are, therefore, marked differences in their metabolic processes and consequently there may be differences in the rate of destruction and elimination of the drugs The relative toxicity of the four drugs investigated is approximately the same when determined for mice, rats or rabbits With cats, however, a peculiar fact is noted The toxicity of all the drugs is greater for this animal, as pointed out previously, but the toxicity of cocaine increases beyond that of the others so that the relative toxicity of the other compounds becomes less Nielson and iggins in 923 (9) observed this marked increase in the toxicity of cocaine to the cat and also to the dog They feel that the toxicity of cocaine is more selective and that the higher the development of the brain, the more toxic its action All of these local anesthetics, however, apparently have similar action on the central nervous system and one would expect a similar increase in toxicity to the cat with each one of them The increased development of the brain may account for the increased susceptibility of the cat for the local anesthetic group in general, but in our opinion the increase in toxicity of cocaine beyond that of the other compounds investigated would be more reasonably explained on a basis of difference in fat in the body and difference in rate of excretion The fact that cocaine has an entirely different chemical structure from that of the other three compounds, which all resemble each other, seems to favor such an explanation Downloaded from jpetaspetjournalsorg at APET Journals on April 8, 206

11 COMPARATIVE TUDY OF LOCAL ANETETIC PROPERTIE 77 UMMARY C Isocaine or p-amino benoyl di-iso-propyl amino ethanol hydrochloride promises to be of value for anesthesia of intact mucous membranes It is practically equally as efficient as cocaine in anesthetiing the cornea and is only about threetenths as toxic For paralysis of sensory nerve trunks it is less valuable than procaine because it is twice as toxic and only equally as efficient in blocking sensation Butyn probably has no advantage over cocaine for anesthesia of the intact mucous membrane It is more efficient than cocaine in anesthetiing the cornea but this advantage is overcome by its greater toxicity For paralysis of sensory nerve trunks butyn is only one half as efficient as procaine and is about ten times as toxic Data are presented in regard to the differences in susceptibility of various types of animals to local anesthetics The minimum lethal doses obtained for rats are a great deal higher than those for mice, rabbits and cats Likewise, cats are by far the most susceptible of the four types to all the drugs Mice and rabbits are intermediate between the two, the former being less susceptible than the latter The relative toxicity of the four drugs investigated is approximately the same for mice, rats or rabbits With cats, however, the toxicity of cocaine increases beyond that of the other compounds so that the relative toxicity of the other compounds becomes less REFERENCE () CMITZ AND LOEVENART: Jour Pharm and Exper Therap, 924, xxiii, 59 (2) EINORN, FIEDLER, LADIC AND ULFELDER: Annalen der Chemie, 909, ccclxxi, 42 (3) EINUORN, A: U Patent 82,554 (4) BONAR, M L, AND OLIMANN, T: Jour Pharm and Exper Therap, 92, xviii, 467 (5) POTOTZKY, C: Arch intern de Pharm et Therapie, 903, xii, 29 (6) FROMERZ, K: Arch f Exp Path u Pharm, 94, lxxvi, 257 (7) OLLMANN, T: Jour Pharm and Exper Therap, 98, xi (8) GUNN, J A: Physiological Reviews, 923, iii, 4 (9) NIEIsoN AND IGGIN: Jour Lab and Clin Med, 923, viii, 440 Downloaded from jpetaspetjournalsorg at APET Journals on April 8, ,