Central Depressive Effect (Pentobarbital and Carbromal) : Carbrital
Central Depressive Effect (Pentobarbital and Carbromal) : Carbrital
Central Depressive Effect (Pentobarbital and Carbromal) : Carbrital
EDITION 05
REFERENCES
( I ? Hurtner, R. P,arid Ciisic. J. W., J . Am. Clzcm. Soc., (9) Knorr, I,,, Ber., 22, 2092(188Y).
6 5 , 262(1!)43); ibid , 65, IS%?( 194.7). (10) Gardner, J. H., and Stevens, J . R . . .I. ,4777. l’hrm.
(21 Tilford. C €1.. Van Camoen.. M. C . . and Shelton. R .
I ~I ~~ ~ Soc.. 71.1859119491.
S..;bid.. 69,2Y62~1!447). ~ (11) krit. pat. GOF,181, August 10, 1948; through Chem.
(3) Scholz, C. R . , Ahstr. First Nat. Med. Chem. Sym- Abstr.,43,3472c(1949).
posiuni of the A m . Chetn. Soc.. Ann Arbor, Mich., June, (12) Schulemann, W., Schonhofer, F.. and Wingler, A.,
1948, pp. 10, 1I . 1J. S. pat. 1,752,617,April 1.1930.
(4) Roherts, R . C . , and Johnson, ’l‘. B . , J . A m . Chem. (13) I.eonard, F., and Solmssen, IT. V., J. A m . Chem. Soc.,
So(., 47,1396(1925) 70,2064(1948).
( 5 ) Case. H. F.. and Koft, E . , ibid., 63, 508(1941): (14) Tilford, C. H.. Shelton, R. S., and Van Campen.
(6) Atkinson, E. R . , and Lawler, H. J . , “Organic Syn- M . G . , Jr.,ibrd.,70,4001(1048).
theses,” Coll. Vul. I , John Wiley 8- Sons, Inc., New York, (15) Wegerhoff, P . ,Ann.,
1941, p. 222. (16) Huttrer, C. P . , Dje
(7) Underwood, H . W.,and Kochmann, E. I,., J. A m . R. L., aiidScholz, C. R., J.
Chcm. Sol., 46,2072(1924). (17) Slotta, K. H . , and Behnisch, K.,Ber., 68,768(1936).
(8) Cortene, F.. “Organic Syntheses.” COIL Val. 11, (18) Dlicke, F. P.. and Zienty. F. B..J. A m . Chem. Soc.,
John Wiley & Sous, Inc., N e w York, 1943, p. 91. 61,776(1939).
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DOSE OF DEPRESSANT, MGM/KG. TIME, H O U R S
Pig. l.-Thc anti-Metrazol effects of pentobarbital Fig. 3.-The joint central dcprcssive effect of pen-
and carbron~al. tobarbital and carbromal (Carbrital).
The intersects of the lines shown by arrows give (1) 0 Pentobarbital alone; (2) x carbrotnal alone;
on the abscissa the minimal hypnotic and anesthc-
tic doses. Slope of line A represents the scdative
( 3 ) 0 pentobarbital plus carbrotnal; ( 4 ) +
summa-
tion of (1) and ( 2 ) as experimentally determined;
potency of each drug. The distance on the ordi- (5) A calculated from the values on the individual
nate between solid line B and the dotted line A ' shows curves for an additive effect of pentobarbital and
the depth of hypnosis. carbromal, including a joint hypnotic action [see
reference 3 for details in calculation).
the first lowcr line signifies a sedative potency while
the ordinate a t the minimal hypnotic level repre-
sents the extent of prehypnotic sedation. The dif- bits1 on the abscissa, a value of 1.2, which indicates
ference in values on the ordinate between the sccond the sedative potency of pentobarbital. The differ-
solid line B and the dotted line A' shows the depth ence on the ordinates between the solid line B and
of hypnosis and this divided by the amount of the thc dotted line A' a t 30 rng./Kg. of pentobarbital
deprcssant required above the minimal hypnotic is 48 mg./Kg. of Metrazol, and this divided by the
dose in producing such a stage of hypnosis gives the difference between 30 mg./Kg. and its minimal
hypnotic potency. For example, the slope of line hypnotic dosc (1.5 mg./Kg.), viz., a ratio of 48/15
A for pentobarbital is the ratio of 17 mg./Kg. of or 3.2, is taken as its hypnotic potency. The seda-
Metrazol 011 the ordinatc to 15 mg./Kg. of pentobar- tive and hypnotic potencies of pentobarbital and
carbromal so calculated, expressed in terms of their
anticonvulsant activities, are thus 1.2 and 3.2 mg.
of Metrazol per mg. of pentobarbital, 1.3 and 0.6
trig. of Mctrazol per mg. of carbrornal. The mini-
mal hypnotic doses for pentobarbital and carbrotnal
arc 15 and 40 mg./Kg., respectively. Thc maximal
prehypnotic sedation is shown by their anticon-
vulsant action (at their minimal hypnotic dose levels)
equivalent to 18mg.jKg. of Metrazol for pentoharbi-
tal and 70 mg./Kg. for carbrornal. As calculated
from the slopes of the lines for hypnosis, pentobdr-
bital is about five times more potent than carbromal
as a hypnotic agent. Although their sedative po-
I tencies are nearly equal, a greater degree of sedation
1 I - - - -1 may he induced with larger doses of carbromal
1 2 3 4 5 6 7 8 9 10 than with pentobarbital without producing hyp-
TIME POURS
nosis. Generlil anesthesia occurs with 30 mg./Kg.
Fig. 2 -The ouset and duration of central ner- of pentobarbital. It was JlOt possible t o produce
vous depression induccd by pentobarbital-Na and general anesthesia with carbromal at 2.0 Gni./Kg..
carbrotnal as indicated by their anti-Metrazol ac- a minimal lethal dose.
tivity.
In equivalent hypnotic doses, the effect of pen- The rate of onset and the duration of central dc-
tobarbital is quicker, while that of carbromal is more pressive action of pentobarbital and carbrornal are
prolonged. shown in Figs. 2 and 3. I n Fig. 2. two times their
minimal hypnotic dose of each. Their joint anti-
Metrazol effect is seen to be grentcr than that due to
a summation of their individual effects, either hy
adding the values on the indiviclual curves or as
calculated from thcse values for an additive effect
of pentobarbital and carbrornal, including a joint
tic
I hypnotic action ( 3 ) . This is evident a t the fourth
hour after ingestion when the effect of pentobarbital
had vanished when it IVIS given alone. At that time
the effect of thc combindtiorl was approximately
three times greater than the individual effect of
carbromal. The eriharicecl anti-Metrazol activity
of the combhlation may be explained by a synergism
of the two in central nervous depression.
The synergistic effect of pentobarbital and car-
broinal is further shown in Fig. 4 by data which were
obtained with equivalent sedative doses of the com-
bination of the two in various proportions. Thc
experimcntal curve shows their synergistic effect; its
L
15
- 11.25 7.5 3 75 O
curvature represents the intensity of synergism (4).
The dottcd straight line is for an additive joint ac-
PENTOBARBITAL, MGM/KG tion.
0 10 20 30 40
CARBROMAL, MGM/KG.
Pig. 4.-The synergistic effect of pentobarbital and CONCLUSION
carbromal,
The synergistic effect is shown by the experimen- As determined b y t h e anti-Metrazol activity in
tal curve; an additive effect is indicated by the rats, Carbrital (1.5 parts of pentobarbital plus 4
dotted straight line.
parts of carbromal) was shown t o produce a
niinirnal hypnotic doses were used. I t is seen that a rapid and prolonged ccntral depression. The
maximal aiiti-Metrazol effect was reached with early hypnotic effect is primarily due t o pentobar-
pentobarbital about fiftcen minutes after ingestion;
bital, while the prolonged sedation is maintained
about one hour with carbromal. Since carbromal
is given in a suspension, the difference in onset may by carbrornal. T h e two also produce their seda-
be due to a difference in the rate of absorption of thc tive etTert synergistically.
two drugs from the gastrointestinal tract. After
having reached a maximum, the effect of carbromal
receded at a much slower rate than that of pento- REFERENCES
harbital. The duration of effect was five hours for (1) Chen, G., and Portman, R., “The Determination of
pentobarbital; approximately ten hours for car- Central Nervous Uepression, to he puhlished.
hromsl. (2) Miller, L. C., aud Tainter, M. I,., P m r . SOC.E x p f l .
B i d . M e d . . 57,261 (1944).
Similar results are shown in Fig. 3, obtained froin (3) Chcn, G., and Portman, R., “The Joint Effect of
an experiment in which the joint effect of pentobar- Central Nervous Depressants,” t o be published.
(4) Loewe, S., and Muisechnek, F.. Arch. exgil. Path.
bital and carbrornal was also determined with oue Phavmakol.. 114,313(1926).