THE BARBITURATES

Brit. J. Anaesth. (1962), 34, 240

THE BARBITURATES BY JOHN W. DUNDEE AND D A V I D W.

BARRON

Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland (In addition to these methylated compounds, other radicals such as ethyl (C,H5) have been substituted in the 1 position but none of the resulting compounds are being used in man.) Although one is inclined to consider changes in the 5 position as being of prime importance in determining the action of different compounds, it must be stressed that each of the four groups possesses a distinctive action by which it can be recognized clinically. These are as follows: (a) Barbiturates. Sleep cannot be produced in 0 H 0 one arm-brain circulation time after the intra1 I 1C — N . H venous injection of an effective narcotic dose of 6 \ / '\ /' '\ CS IC-OH any of the members of this group. /V 3/ (b) Methylated barbiturates. These frequently, H C—N I 1 | I but not invariably, cause sleep in one arm-brain 0 H 0 H circulation time. The methyl radical confers conKETO form. ENOL form. vulsive activity, of which tremors and involuntary FIG. 1 muscle movements are manifestations. The barbituric nucleus. (c) Thiobarbiturates. Sleep occurs in one armbrain circulation time after intravenous injection Lloyd (1957) has pointed out that it is more of an effective dose, and return of consciousness correct to regard barbituric acid as a pyrimidine is more rapid than after the same dose of the comderivative, but throughout this paper the malonyl parable oxybarbiturates. urea terminology is used. (d) Methylated thiobarbiturates. These combine a similar rapidity of onset which is accompanied CHEMICAL GROUPING by convulsive activity. Although barbituric acid itself is devoid of hypIt has been shown by Cope and Hancock (1939) notic activity, compounds in clinical use are all and Knoefel (1945) that the conversion of a barderived from the parent nucleus by alterations in biturate to a thiobarbiturate frequently introduces the 1, 2 and 5,5' positions. Varying substitutions stimulant properties; a hypnotic drug being conin the 5 position determine the degree and dura- verted into a convulsant. Richards (1951) has tion of narcosis, but apart from these the drugs observed a marked species difference in this resfall into four distinct chemical groups as follows: ponse and it has not been substantiated in man. It is worth while at this stage considering some (a) Barbiturates (or oxybarbiturates) 1=H, 2 = 0 of the group properties of the methylated compounds, since this will avoid unnecessary repeti(b) Methylated oxybarbiturates 1 = CHS, 2 = 0 tion. Work from this centre has demonstrated that (c) Thiobarbiturates 1=H, 2 = S the frequency and severity of convulsive activity (excitatory phenomena) worsens with increasing (d) Methylated thiobarbiturates 1=CH 3 , 2 = S dosage. With any given dose there is a relationship 240

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Classically, barbituric acid is regarded as the cyclic ureidc of malonic acid, i.e. malonyl urea. The acid and its derivatives possibly exist in two forms as shown in figure 1. The acidity of this compound is due to the hydrogen atom which migrates from the nitrogen atom in the 1 position. In aqueous solution it dissociates into hydrogen ion and barbiturate ion. The sodium salts (in the 3 position) are water soluble and can be administered intravenously.

THE BARBITURATES between this incidence and the analgesic (or antanalgesic) action of the premedication. Another possible group property which is as yet inadequately studied is the lack of extravenous irritation of the non-sulphurated compounds. This may also apply to the deleterious effects of intra-arterial injection. RECOGNIZED CLASSIFICATION

PRINCIPLES OF 5,5' SIDE CHAIN SUBSTITUTION

As stated previously, the relative intensity and duration of action of the many possible compounds

in each of the four chemical groups already discussed depends on the radicles in the 5 and 5' position. The parent compound, barbituric acid, has no hypnotic properties and much study has been devoted to the 5-H substituents. It is proposed first to discuss these in general terms and then illustrate the effects produced with reference to the well-known drugs. Both the hydrogens on the carbon must be replaced by alkyl or aryl groups in order to confer hypnotic properties on the barbiturates. Alkyl is a general term for an aliphatic radical, i.e. those derived from the parent substance methane (CHJ, while aryl is the general term for an aromatic radicle whose parent substance is benzene (C,H 6 ). By virtue of these definitions the aryl compounds are fully unsaturated while alkyl derivatives may be totally or partially saturated. The alkyl side chain can be of the following varieties: H H (a) straight, e.g.

- AI -

H—C

I

(ethyl; saturated)

H H H =C-

(allyl; unsaturated)

AA A H3C (b) branched, e.g. H3C

\ /

H H

I I I I

C—C—C— (3' methyl butyl) H H H2 H

(c) cyclical, e.g.

H2 C/ \


X

(cyclohexenyl)

C—C

I I

H2 H2

Adriani (1946) also mentions the possibility of acyl substitution (R-CO-: where R represents any radical), but there are no examples of this in common use. Within certain limits an increase in the length of the side chains is accompanied by an enhancement of narcotic potency and shortening of duration of action. Adams (1944) attributes this to the resulting increase in atomic weight, but this can-

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Most pharmacology textbooks divide the barbiturates into either three or four groups according to their duration of action. Two of these are invariably termed "long acting" and "ultra-short acting", and the remainder are either divided into "intermediate acting" and "short acting" or grouped together as "medium acting". This classification is based on the effects of average therapeutic doses of these drugs and, within certain limits, bears a relationship to the length of the 5 and 5' side chains. However, in clinical practice some barbiturates are most commonly given by mouth; others can be given orally, by intramuscular injection, and occasionally intravenously; those most commonly employed by the anaesthetist are almost invariably given by intrvenous injection. While it is feasible to apply this classification to those drugs which are normally given by mouth, it is erroneous and even misleading to group the intravenous anaesthetics in the same scheme. These compounds can be given by single or intermittent injection because of the rapid onset of sleep which they produce, and the controllability of the depth of narcosis which results from this rapid action. The duration of narcosis with these depends on a number of faaors, such as total dosage, physical condition of the patient, technique of administration (single injection or intermittently over a period of time) and on the degree of sensory stimulation to which the patient is subjected. It would seem much more logical to employ the term "rapidly acting" for the thiobarbiturates and some of the common methylated barbiturates and consider these separately from the sedatives and basal narcotics which are used in general medical practice or occasionally as premedication.

241

242

BRITISH JOURNAL OF ANAESTHESIA

LONG ACTING BARBITURATES

It is not proposed to discuss these in detail, except in so far as they illustrate some of the relationships between chemical structure and clinical action which have already been reviewed. These compounds are all oxybarbiturates with short side chains. 5 H H CH, CH, C,H,

5' H CH, CH, C,H, C,H,

Phenobarbitone: in clinical use as a long acting hypnotic.

C,H, C,H,

No hypnotic properties. Weak hypnotic: no clinical use. Weak hypnotic: no clinical use. Weak hypnotic: no clinical use. Barbitone: in clinical use as a long acting hypnotic.

CH,

Diallybarbituric acid: a potent hypnotic sometimes classed as being "intermediate acting".

There is a delay before the onset of maximum narcotic effect of these compounds, even after intravenous injection. MEDIUM ACTING BARBITURATES

Discussion will be limited to the three compounds of which the thio-analogues are in use as intravenous anaesthetics. The 5, 5' side chains common to both groups are shown in table I. There is a great chemical similarity between these compounds, in spite of which each barbiturate has a distinct clinical action which can be related to the side chains as follows. (a) Replacement of the saturated ethyl (C^Hj) by the unsaturated allyl (C,H,) results in quinalbarbitone being slightly more potent and having a slightly shorter duration of action than pentobarbitone. (fc) Moving the methyl (CH3) radical from the 1 to 3 position in the butyl side chain results in amylobarbitone having half the potency of pentobarbitone. There is no reliable data on the comparable duration of action of these two drugs. RAPIDLY ACTING BARBITURATES

(a) Thiobarbiturates. The same relationship exists between the three thiobarbiturates listed in table I as has been described for their oxygen analogues. It is generally agreed that thiamylal is slightly more potent than thiopentone although opinions differ as to rapidity of recovery from equivalent doses of the two drugs. Thioethamyl has half the potency of thiopentone. Despite the differences in potency, the quality of anaesthesia produced by all three compounds is similar. Another closely related compound is the German drug Inactin which differs chemically from thiopentone in the 5' side chain only. The 1methyl-butyl radical of thiopentone is replaced by the shorter 1-methyl-propyl group of Inactin: CHS—CH,—CH— CHS This compound has about two-thirds the potency of thiopentone but otherwise the action of the two drugs is similar. A further related compound is thialbarbitone (Kemithal) which differs from thiamylal only in the 5' side chain where, in this instance, there is a cyclohexenyl ring (CGH,). Thialbarbitone has

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not be the sole answer, as clinical practice has shown that one of the 5 side chains must be kept relatively simple. A marked degree of dissimilarity is often found between the two side chains. Compounds with two simple similar side chains have low hypnotic potency and prolonged action. Double bonds in alkyl substituent groups produce compounds that are more vulnerable to tissue oxidation and are, therefore, shorter acting. As long ago as 1925, Dox stated that the 5, 5' side chains must contain not less than four and not more than eight carbon atoms. This applies to all compounds in current use, with the exceptions of thialbarbitone and methohexitone which each have a total of nine carbons in the two side chains. If the side chains are too long there is a loss of hypnotic potency, and convulsant and other toxic properties may appear. Halogenation of the alkyl substituents also increases the potency and intensity of action of the barbiturates. Bromine is the only halogen in clinical use for this purpose. The only other substitution of interest is the inclusion of a sulphur atom (in methitural) which will be discussed later. Clinical impressions suggest that these factors which increase the narcotic potency of the barbiturates may also hasten the onset of their action. The group of compounds to which this applies are usually given orally and no precise data is available.

243

THE BARBITURATES TABLE I

Side chains of three commonly used barbiturates together with their thio analogues. Side chains

Chemical name 5

Ethyl-1 -methyl-butyl

Allyl-1-methyl-butyl

CH3—CH2—

CH2=CH—CH2—

Barbiturate

Thiobarbiturate

Pentobarbitone

Thiopentone

Quinalbarbitone

Thiamylal

Amylobarbitone

Thioethamyl

5'

CH3—CH2—CH2—CH— CH3 CHj—CH2—CH2—CH— CH 3

CH3—CH2

C H3—CH—CH2—CH2— CH3

approximately half the potency of thiamylal (or thiopentone). Buthalitone (Transithal) is usually described as 5 allyl 5' isobutyl thiobarbiturate but in the terminology adopted in this paper the 5' side chain is described as 2 methyl-propyl: CH,—CH—CH3—

I

CH, This side chain is more closely related to that of Inactin (1-methyl-propyl) than to any other compound. Since attention has already been drawn to the effect of altering the position of the methyl group (of thiopentone and thioethamyl) it is not surprising to find that buthalitone is less potent than Inactin. In practice this means that thiopentone has twice the potency of buthalitone. Claims for more rapid recovery from the latter drug have not been substantiated and this is not unexpected in view of its chemical composition. In contradistinction to the five thiobarbiturates already mentioned, the induction of anaesthesia with buthalitone is frequently accompanied by hiccough and coughing but there is no obvious relationship between these side effects and the chemical structure of the drug. Another thiobarbiturate which produces induction complications similar to buthalitone is methitural (Methothiurate, Neraval, Thiogenal). It is interesting chemically in that the 5 side chain contains a sulphur atom in the methyl-thio-ethyl group: CH,—S—CH 3 —CH, This radical is also found in the essential amino

acid, methionine and it was hoped that this would protect the liver from the toxic effects of the thiobarbiturate. The 5' side chain is the same for that of thiopentone and thiamylal and this complicated linkage results in more rapid recovery than from thiopentone. The fact that this compound is no longer available commercially is because the severity of the respiratory complications more than outweighs any possible advantages from rapid recovery. Study of the chemical structure of the latter two compounds with regard to the number of carbon atoms, manner of linkage, atomic weights, etc., has failed to reveal any common causative factor for respiratory upset. (b) Methylated oxybarbiturates. These drugs all possess certain characteristics which can be attributed to the CH 3 radical in the 1 position. Hexobarbitone has a methyl group in the 5 position and a cyclohexenyl ring in the 5' position. The potency is about one-half that of thiopentone and is thus about equipotent with thialbarbitone which also possesses a cyclohexenyl ring. Methohexitone has an allyl grouping in the 5 position and a methyl pentenyl chain in the 5' position. This latter which does not appear in any other compound in clinical use is represented thus: H5G,—C = C—CH—

I CH, (l-methyl-2-pentenyl). It would appear that this side chain confers three distinct properties: (a) enhanced potency; (b)

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Ethyl-3-methyl-butyl

BRITISH JOURNAL OF ANAESTHESIA

244

anaesthesia is accompanied by a prohibitively high incidence of tremor and muscle movements. B.82 is the methylated form of buthalitone, again having the same potency and sharing the undesirable side effects (respiratory upset) of the parent compound and, in addition, exhibiting the complications conferred by 1-methylation. COMMENT

From this survey it has been possible to demonstrate certain clear-cut relationships between chemical structure and clinical action of the barbiturates. The most important of these are illustrated in figure 2, which is based on observations carried out by the authors. From the clinical point of view the most important relationships are as follows: (1) Sulphuration results in a compound which, in adequate dosage, produces sleep in one arm-brain circulation time. (2) 1-methylation of either a barbiturate or thiobarbiturate confers convulsant properties which are manifested as abnormal skeletal muscle activities.

O H

O H CH3 • CH 2

\

/ C

/

\

C H 3 • C H 2 • CH 2 • CH

C—N

\

/ C—N

i l3 l CH

SULPHURATION

0=0

CH 3 • CH 2

>•

Accelerated induction and recovery

0 Na

JL I

\

C—N \

\

CH3 • CH2 • CH2 • CH

c=s

C—N C Na

I

CH 3 Thiopentone

Pentobarbitone

LOSS OF Loss of potency CH 2 O H

O CH 3 CH 3 • CH 2

CH 3 • CH 2

C—N

c /

c=s -< \

/

CH 3 • CH2 • CH

C—N

CH 3

O Na

METHYLATION Marked excitatory phenomena

JL I

\ (/ C—N \c=s

CH 3 • CH 2 • CH

CH 3

\

C—N

Na

Inactin

B.137 FIG. 2 Chemical relationship between four compounds and the effects produced by various structural alterations.

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rapidity of recovery; and (c) high incidence of cough and hiccough following injection. Narconumal and Narcodorm (Narkotal) each Tiave a 1-methyl-ethyl (iso propyl) radical in the 5 position: CH, }CH CH/ They differ only in the 5' side chain which is an allyl group in Narconumal and a brom-allyl group in Narcodorm. These simple side chains produce compounds which are much longer acting than the thiobarbiturates (hence their almost complete eclipse in clinical anaesthesia), but the halogenated form is slightly more potent than Narconumal. (c) Methylated thiobarbiturates. The properties conveyed by 1-methylation also apply to this group of drugs. Although none of these compounds are in clinical use, they are included because they illustrate some fundamental relationships between chemical structure and clinical action. B.I37 is the methylated form of Inactin, having a similar potency to the parent compound, but

Group

Approved name

Trade names

Long-acting

Barbitone

Medinal, Veronal

Phenobarbitone

Luminal, Gardenal

1 H

H

2 O

0

Side chains 5 CH3—CH2—

CH3—CH2—

5' CH3—CH2— H

„\ / i\ / c c i I / X / H H

C

H Medium-acting

Pentobarbitone

Nembutal

H

O

CH3—CH2—

CH3—CH2—CH2—CH—

Amylobarbitone

Amytal

H

O

CH3—CH2—

CH3 CH3—CH—CH2—CH2—

Quinalbarbitone

Seconal

H

O

CH 2 =CH—CH 2 —

CH3—CH2—CH2—CH—

Thiopentone

Pentothal, lntraval

H

S

CH3—CH2—

CH3—CH2—CH2—CH—

AH 3

CH3

Rapid-acting

H2 H

CH 3

Thialbarbitone

Kemithal

H

s

CH 2 =CH—CH 2 —

H 2 C(™)C-

Buthalitone

Transithal

H

s

CH 2 =CH—CH 2 —

H2H2 CH3—CH—CH2— CH3 H2 H

Hexobarbitone

Cyclonal

CH3

0

CH3—

Methohexitone

Brietal

CH3

0

CH2=CH—CH2—

H 2 C

/^~^\C_ \ ^ Q/

C2 H5 CsC

CH— CH3

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TABLE II

Barbiturates in common clinical use.

Comment

More potent than barbitone

Half potency of pentobarbitone Approx. equipotent with pentobarbitone

Half potency of thiopentone

Ditto. High incidence of respiratory upset

Half potency of thiopentone; high incidence of muscle movement Two to three times potency of thiopentone; high incidence of muscle movement and respiratory upset

246

BRITISH JOURNAL OF ANAESTHESIA

(3)

REFERENCES

Adams, R. C. (1944). Intravenous Anesthesia, 1st ed. New York and London: Hoeber. Adriani, J. (1946). Chemistry of Anaesthesia, 1st ed. Oxford: Black well. Cope, A. C , and Hancock, E. M. (1939). Substituted vinyl barbituric acids. 1: Isopropinyl derivatives. J. Amer. chem. Soc, 61, 96. Dox, A. W. (1925). Barbitursauren und die Pikrinsaureaktion. Zeschr. f. physiol. Chem. (Berl. u. Leipz.), 118. Knoefel, P. K. (1945). Stimulation and depression of the central nervous system by derivatives of barbituric acid. J. Pharmacol, exp. Ther., 84, 26 Lloyd, J. B. (1957). The barbiturates: chemical constitution and nomenclature. Brit. J. Anaesth., 29, 473. Richards, R. K. (1951). Studies on convulsive thiobarbiturates. Curr. Res. Anesth., 30, 348.

BOOK REVIEW Appraisal of Current Concepts in Anesthesiology. Edited by John Adriani. Published by the C. V. Mosby Company, St Louis, U.S.A. Pp. 279. Price 58s. Wine tasting is a delightful experience. It educates and refines taste, opening up for the novice the possibilities of new horizons of beauty and for the cultivated it may recapture old glories and warm memories. One might, with justification, approach a book with this tide in much the same spirit and expect a titillation of the appetite and an expansion of the vision.' Alas such will not be the case, for disappointment lies heavily between the covers of this little volume: the wine is rather stale and in some cases would have been better left corked—in the literal rather than the "taster's" sense. Many teaching departments have found the "abstract and discussion group" the finest way of reviewing progress in a subject and the papers reviewed lead often to a wide discussion and general clarification of the subject under review. The material here is gathered together from the "multigraphed" proceedings of such a group. The authorship of the contributions is therefore varied and the standard of them perhaps inevitably very uneven. This method of compflation also accounts for the probable unfamiliarity of readers on this side of the Atlantic with the names in the list of contributors, with the exception, of course, of the distinguished Director of the Department of Anesthesiology of the Charity Hospital, New Orleans, Louisiana. Surprisingly the material is often dated and sometimes shows misleading bias. There are other pump oxygenators besides the "sigmamotor-bubble-oxygenator combination", now surely in most centres

abandoned. Likewise the terminology used in the chapter on "Pulmonary Function Tests" is not in line with current thought and usage. Other chapters are too superficial to be of real assistance, such as those, for example, on "Surgery of the Aorta", "Hypothermia", and "Hyperventilation". Sometimes information given is incorrect Presumably the case quoted as exemplifying the damage which may follow the sterilization of ampoules of anaesthetic in liquids is that of Roe and Wooley. If so, in this instance judgment was not for the plaintiff as reported here, but for the defendant. Incidentally the quoted "Mclntosh" reported here as advocating the heat sterilization of ampoules in 1941 is presumably Sir Robert Macintosh. Sometimes the conclusions reached will be quite unacceptable, such as that, for example, at the end of the chapter on "compliance", where it is said that "Only one definite conclusion may be drawn from the results obtained, however. The patient is able to ventilate more adequately when breathing spontaneously than when being ventilated artificially." A commendable tendency these days is for the editors to insist that when authorities are quoted the references be given as fully as possible and to use approved names rather than proprietary names for drugs. Neither of these desirable editorial functions has been exercised. There are on the other hand some good chapters; in particular that on "The Treatment of Shock by Induced Hypotension", a subject crying out for review and assessment Those on "The Radford Nomogram" and "Arachnoiditis" are also very useful reviews. In summary, regretfully the reviewer prefers wine tasting. Cecil Gray

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The relative potencies of the compounds are determined by the constituents of the 5, 5' side chains. It would appear that the complexity of the two side chains is the dominant factor influencing potency. (4) Certain side chains appear to produce a high incidence of cough and hiccough but the exact causative factor of this has not been established. Of necessity, some of the drugs referred to are not in current clinical use in this country. This may lead to some confusion. Table II gives details of the chemical composition of the compounds which anaesthetists are most likely to encounter, together with some of the actions related to their chemical structure.