Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 263
APPENDIX J
ANTICHOLINBRGIC DRUGS AND THE BEG
by
Hax Fink, Moo.
Thla review examines the effects of anticholinergic compounds
on the human central nervous ayate~, in relation to their eilltery
testing. Such compounds were tester in volunteers to define their
role as incapacitating agents for allitary use. The question
presented is whether, as tested, the chemicals are likely to produce
adverse health effect a or delayed acquelae in the teat subjects, or
whether it is possible even to predict that likelihood This review
focuses on the data derived from electroencephalography.
The data i no lute pro tocola of military experiments teclaasifiet
for this review? reports published in the acientlilc literature on
animals ant man, and my own atutiea. Between 1956 ant 1966,
experimenta were undertaken in my laboratories In New York ant St.
Louis to define the effects of anticholinergic drugs on brain
function and behavior. We sought to tetersine whether any of the
substances had peraIatent behavioral effects that could be useful in
treating the severely mentally ill (1-7).
Atropine and scopolamine (hyoscine) are prototypic
anticholinergic compounds. Their effects are principally
antimuscari nic. Compounds usually classified with these pro totypea
are those used in the treatment of parkinconis~r-auch as
procyclidine (Kematrin), benstropine mesylate (Cogentin), ant
trihexyphenidyl (Artane)--and such ~etlcinala as glycopyrrolate
(Robinol) ant methantheline (Banthlne). Such experimental
anticholinergic compounds as Ditran, JB-329, JB-336, ant WIN 2299
are included in the same class. In some studies, particularly BEG
atudioa in patients, the trlcyclic antidepresasats imipramine and
amitriptyline have been shown to have atropine-like propertlea.
Electroencephalography developed from atutiea published in
1929. In the early aeudiea, changes were assessed by vlanal
inspection of ink~written recorte. These have since been replaced
by electronic and, lately, digital computer methota of quantitative
analysis. These methota provide excellent aseesa~ente of mician1
changes in brain function in man. Unfortunately, the allitarg
reports are limited to lnspectlon.
LITERATURE REVIEW
m e effects of anticholinergic drugs on brain function have
been studied extensively. CNS effects in man are definer
principally on the basis of self-reports, observer evaluations,
*Department of Psychiatry and Behavioral Sciences, School of
Medicine, State Univerafty of New York at Stony Brook, Long 1BlaQd,
New York Ill 94.
J 1
OCR for page 264
neuropsychologic Bests, and physiologic measures. O' these, the
EEG, especially in its present quantitative form, is a sensitive
index of changes in CNS activity, with particular relevance to human
performance and states of vigilance (8,9).
Anticholine Tic drugs have well defined effects on the EEG,
accompanied by measurable behavioral effects. In most drug studies,
EEG patterns correlate well with behavioral changes. Studies of
atropine in animals, however, elicited reports that their EEG showed
increased amplitudes and lowering of frequencies at times when the
animals were apparently restless. Animals examined in halters often
exhibited running movements, but their EEG patterns were similar to
those seen in deep sleep (10). The apparent purposeful movements
associated with "aleep-like" EEG records let some observers to
define an "EEG-behavioral dissociation" with anticholinergic drugs
(1, 11-15). In studisa of pay choactive substances in man' we and
others found a close relationship between the changes in EEG
patterns and the behavioral effects of drug administration (8). The
difference in observations between animals and man led to a
symposium in 1966 that summarizer the data available to that time
(1). The symposium participants concluded that the apparent
"dissociation" in EEG and behavior with antlcholinergic drugs was
limited tO observations in animals and was an artefact of the gross
nature of the measures used in animal trlala, rarely, the inability
tO assess changes in cognition, vigilance, moot, and affect (which
are principal targets of anticholine Tic drugs).
Anticholinergic drugs have a characteristic dose-relatet effect
on brain function, and particularly on the resting, alert
scalp-recorded EEG (3,4,6,7,16-27).
Low doses, such as 1-2 mg of atropine, are sufficient to induce
milt tension, irritability, and anxiety. The subjects are aware of
changes in their perception and mood, and they make errors on
cognitive tests. At these times, the EEG patterns exhibit an
increase in high frequencioa and decreases in the mean alpha
frequency and in the amplitude of the dominant (alpha) frequencies.
These effects may be accompanied by a decrease in heart rate and
some minimal effects on salivation and skin conductance (28, 29).
With higher doses, such as 10-30 ma, or repeated administrations,
the subjects become delirious, showing restlessness, impairment of
motor and sensory functions, cognitive defects, illusory sensations,
and thought disorder, including hallucinations and delusions. Heart
rate is increased, and the peripheral effects of dry mouth and skin,
decreased urination, and difficulty in near vision are prominent.
The EEG shows an increase in slow waves, a decrease in mean
frequency, a decrease in the percent time and amplitudes of alpha
activity, and an increase in the high frequencies, wh.ich can be seen
to be "riding" on the slow wave e. There is a direct association
between the amount of EEG fast waves with behavioral restlessness
and the amount of EEG slow waves with stupor and cognitive defects.
At "toxic" doses, patients are in stupor or coma, with rapid heart
rate and lowered blood pressure. The EEG demonstrates persistent
high-voltage slow waves, with a minimum of alpha and high
frequencies e
J 2
OCR for page 265
In epileptic patients, stable Intramuscular a/ministrations of
atropine at up to 2 mg/kg (30) and 1.2 me of intravenous hyoacine
(24) elicited epileptic spike EEG activity. The changes were
transient, and the records ant behavior of the patients returned to
normal within 24 h.
EEG and behavioral effects may be modifier by the concurrent
administration of other drug e. ~us, atropine (or Ditran) and
chlorpromazine resulted in behavioral stupor that was very deep
(sllowlng surgery without pain reaponaea), accoelpaniet by persistent
EEG high-voltage slow warren and decreases in fast waves. When
Dltran ant yoh$mblne or Ditran and ioIipraoline were given together,
restlessness increased, as tit the ratio of fast waves to slow waves
in the EEG. When patience who e~ibltet a toxic delirium to Ditran
or atroplne were given tetrahydroaminacrin (THA), the stupor wee
relieved ant the EEG shower decreases in both the low ant high
frequencies (1, 7 ~ 31) ~
After acute administration of various compounds, the time for
recovery varies with lose--at low tones, the peak effects on
parenteral administration are seen in 0.5 h and last for up to 6 h;
at high doses, the effects persist for up to 24 h; at toxic doses,
there is a return to baseline values the second day after
administration. Followup EEG data are limited, the principal data
being reports of atropine toxicity. The few statements about EEGs
sugggest that the effects are gone within a few days of the last
exposure (32-37~.
In studies of imipramine, some patients developed an acute
psychotic reaction. These patients were identified as being young
and as exhibiting a "schizophrenic" syndrome--an observation that
led to administration of imiprsmine as a test of "schizophrenia'
(2, 38) .
Although no long-term EEG study of anticholinergic drugs is
available, one study of cholinesterase inhibitors may be cited.
Duf fy en al. (39) reported persistent quantitative differences in
EEG patterns between worker e exposed to the organophosphate compound
sarin and a control group of workers in the same plant not so
exposed .
MII`ITARY DATA
The principal military data on EEG studies are in the Dries
provided in Case Report Summaries - Anticholinergics, and an
addendum provided in a letter by Dr. Frank Marsull! of October 8,
1981. This latter Mary included all the useful EEG records cited
in the formal protocols of the military studies. No EEG records
were found of subjects receiving atropine, scopolamine, EA 3443, or
EA 3167. Of the available records, five were relater to BE, two to
EA 3SBO, and one to EA 3834.
The reports stated that the pretreatment records were within
normal limits and the postexposure records, taken at Parlous times,
were also within normal limits. The records were assessed
visually. The reports did not state the conditions of testing, nor
in it clear how long after exposure the testing was done.
These records were customary for the time and reflected
nonspecific effects that are similar to those reported for many CNS
active compounds. The reports dld provide neuropsychologic-test
J 3
OCR for page 266
data, however, which indicate that the effects of exposures to the
antlcholinergic substances on the military volunteers were
transient, revertlag to baseline values within a few hour a or, in a
few teats repeated at longer intervals, within a few weeks (40-49.
In other studies of the relationship between the changes induced in
EEG and in neuropaychologic teats by CNS-active drugs, there wee a
parallel in the oases and duration of the effects in the different
measures. Argulog by analogy, we would anticipate airily
reversions to nonfat for the EEG changes in these volunteere.
Conclusions
In the experiments in which patient a and normal volunteers were
exposed to single or multiple doses of anticholinergic drugs, a
consistent pattern of EEG ant behavioral change has been described.
In moat volunteer studies, dosea have been low, exposures usually
single, and effects transient. There is no evidence of persistence
of behavioral or EEG effects in these experimental trials (50).
In patients who have been given heroic doses of atropine and
scopolamine (up to 250 ma) and in whom the doses have often been
repeated three timea a week for up no 4 ma, there have been few
signs of persistent toxicity. The patients have been subjected to
periods of coma lasting up to a day. Death has been reported in
only one luatance. In many patlenta, the peralatent effects have
been considered salutary--l.e.; the patients have been conaidered
improved in mental state and discharged to the community' -In the
remainder, they have been reported to be no worse than before
treatment. Conaiderlag the many hundred a of patlenta 90 created and
the continuation of this form of therapy in patients in eastern
Europe today, it is unlikely that there is a behavioral syndrome of
toxicity.
Focusing exclusively on the anticholinergic properties of the
drugs examined in military volunteers, considering the low doses
used and the minimal exposures, ant aware that heroic doses of
ant! cholinergic drug e (inexplicably) fail to stimulate a defined
toxic syndrome, we deduce that the sidle exposures of toses of
anticholinergic drugs used in the volunteers were insufficient to
stimulate a persistent toxic syndrome. The data available are
sufficient to conclude that, as tested, the chemicals are not likely
to produce adverse health effects.
For a more definitive conclusion, a prospective study or a
study similar to that re port et by Duffy et al. (39) in parkinaonta~
patients or Intuatrial workers exposes to anticholinerglcs la
re quired .
J 4
OCR for page 267
REFERENCES
2.
Bradley, P. and Fink, H. (Eta.) 1968: Anticholinergic Druga
and 8rain Functiona in ~imala and Man. Prog. Braln Res. 28, 184
PP ~
Fink, M. Electroencephalographlc and behavioral effecta of
Tofranil. Can. Paych. Aasoc. Jrl. 4:S166-171, 1959a.
3. Fink, M. Effect of an anticholinergic agent, Diethazine, on EEG
and behavior: Slgnificance for theory of convulaive therapy.
Arch. Neurol. Paychiat. 80:380~387, 1959b.
Fink, M. 1960: Effect of anticholinergic. compounda on post
convulalve electroencephalogram and behavior of paychiatric
patients. Elec~eroenceph. clin. Neurophysiol. 12:359-369.
5.
Fink, M. and Itil, T. EEG and human paychophaneacology: IV:
Clinical antidepressants. In: D. Efron, J.0. Cole, J. Levine
and J.R. Wittenborn (Eda.): Paychophaneacology: A Revlew of
Progresa 1957-1967. U.S.G.P.0., Washington, D.C., 671-682,
6 . It il. T.M. 1966 : Quantltative EEG changea induced by
anticholinergic druga and their behavioral correlates in man.
Rec. Adv. Biol. Psychiat. 8:151-173, 1966.
Itil, T. and Fink, M. 1966: Anticholinergic tr~sg-induced
delirium. Experimental modificatiost, quantita~cilre EEG and
behavioral correlations. J. nerv. meet. 1)~. 142: 492-507.
Fink, M. 1969: EEG and human paychopharmacology. Ann. Rev.
Phamacol. 9:241-253.
9. Flnic, M. 1978: EEG and paychophaneacology. In: W.A. Cobb
ant H. van Duidn (Eda): Contemporary Clinlcal Neurophysiology
(Supplement 34), Electroenceph. clin. Neurophysiol. 45:41-56.
10. Wlkler, A. 1952: Phaneacologlc tisaociation of behavior and
EEG "aleeppatterna' in doge: Horphine, n-allyluormorphine
andatropine. Proc. Soc. exp. Blol. 79: 261-264.
11. Wescoe, W.C., Green, R.E., McNamara, B.P. and ECrop, S. 1948:
The influence of atropine and acopolamine on the central
effects of DFE. J. Pharmacol. exp. Therap. 92: 63-72.
Funderburk, W.~. ant Case, T.J. 1951: The effect of atropine
on cortical potentiala. Electroenceph. clin. Neurophyalol.
3:213-233.
13. Rinaldi, F. and Himwich, H.E. 1955: Alerting responaes and
actiona of atropine and cholinergic druga. AMA Arch Neurol
Psychiat. 73: 387-395.
J 5
OCR for page 268
14. Bradley, P. ant Elkes, J. 1957: The effects of some drugs on
the electrical activity of the brain. Brain 80: 77-1170
Longo, Y.G. 1966: Hechanisms of the behavioral and
electroencephalographic effects of atropine and related
compound ~ . Phar~acol Rev . I8: 965-996 .
16. Hi~wich, H. 1954: Effect of large doses of atroplne aulface
on BEG and personality structure. Chem. Corps Med. I.abo.
Contrac t 949.
7 0 hi te, R.P., Rinaldi, F. and lIi~wich, H.E. 1955: Central
andperipheral nervous effects of atropine sufate and Darstlne.
Chem. Corps Med. Labs. Report #66.
18. Ostfeld, A.M., Machine, X. and Unna, K.R. 1960: The effects of
atropine on the electroencephalogram and behavior in man. J.
Pharmacol. exp . Therap . 128: 265-272 .
19. Ostfeld, A.M. and Aruguete, A. 1962: Central nervous system
effective of hyoacine tn man. J. Phamacol. exp. icecap. 1370
13 3-139 . --
200 Banshchikov, Y. M. and Stoliarov, G.1J. 1966: Psychotomimetic
drugs with anticholinergic effects. (Russian) . Zh. nevropatol.
Psi~hiatr. 66: 464-468.
21. Barnes, C.D. 1966: The interaction of amphetamine and eserine
on the BEG. Life Sciences 5 :1897-1902.
Billklewicz, A. and Smoozynski, S . 1970:
Elec troencephalographic changes during atropine-induced coma.
Polish Medical Jrl. 90926-931.
230 Sagales , T., Erill, S . and Domino, E.F. 1975: Effects of
repeated doses of scopolamine on the electroencephalograph)
stages of sleep in nomal volunteers. Clin. Phar~acol. Whelp.
I8: 727-732.
24. Airman, V., Jhamb, Jib. 8~6 ViJayan, G. 1975: Activation of
BEG by hyoacine. Indian J. Hed. Res. 63: 373-377.
25. Commin, P., Bismuth, C., Gaultier, M. and Hellerio, F. 1978:
Apport de la correlation electroencephalographie~clinique
~ 'activi te anticholinergique centrals de la phy sostigmine.
Agressologie 19: 287-292.
26. Mellario, F., Commin, P., Bismuth, C. and Gaultter, M. 1979:
L'electro-encephalographie au cours du ~craitemene par eserine
des intoxications anticholinergiques. Rev. BEG Neurophysiol.
9: 5-~.
27. PichImayr, I. and Lips, U. 1980: Atropin-effkte im
elektroencephalogramm. Studle an 16 pattenten. Anesthesist 29:
249~253.
3 6
OCR for page 269
28. Antrews, P.A., Miller, R.D. and Gordon, A.S. 1955: Evaluation
of atropinization by various routes in Havana. Chemical Corps
Medical Laborat vies Contract Report #59.
29. Wechsler, R. ant Koakoff, Y.D. 1955: Effect on humane of
moderate doses of atropice. Chem. Corps Hed. Labs. Contract
#54.
30. Zsadanyi, 0. ant Molnar, C. 1972: Electroencephalographic
analysis of atropine coma. Acta Physiol. Acad. Sci. Hugger.
41: 63-72.
31. Gershon, S. ant Angriat, B. 1973: Effects of alterations of
cholinergic function on behavior. In: Cole, J., Freedman, A.
and Friedhoff, A. (Eds. ): Psychopathology and
Psychopharmacology. Baltimore, Johns Hopkins Press, 15-36.
32. Forrer, G.R. 1950: Atropine toxicity in the treatment of
schizophrenia. J. Mich. State Het. Soc . 49: IB4-~85.
33. Forrer, G.R. 1956: Symposium on atropine toxicity therapy.
History and future research. J. nerv. sent Dis. 124:256-259.
34. Goldner, R.D. 1956: Symposium on atropine toxicity therapy.
Experience of use in private practice, J. nerv. ment Dis.
124:276-280.
35. Goldner, R.D. 1967: Scopolamine sleep treatment in private
practice. Int . J. Nieuropsychiat . 3: 234-247.
36. Schwarz, H. 1956: Symposium on atropine toxicity therapy.
Statistical evaluation. J. nerv. meet. Dis. 124: 281-286.
37. Wada, T., Horigome, S. and Sakurada, T. 1960: Clinical
experience of the so-called "atropine toxicity therapy"
~ Forrer) . Tohoku J. Exp. Hed. ?2: 398-404.
38. Pollack, M., Klein, D.~., Willner, A., 81umberg, A. and Fink
H. 1965: Imipramine-induced behavioral disorganization in
achizophrecic patients: Physiological and psychological
correlations. Rec Adv. Biol. Paychiat. 7: 53-61.
39. Duffy, Fin., Burchfiel, J.L., Bartela, P.El., Gaon, M. ant Sim
V.~. 1979: Long-term effects of an organophosphate upon the
human electro-encephalogram. Toxicol. Applied. Phamacol.
47 :161-176.
40. Ketchum, J.S. 1963: The human assessment of BZ. CRDL Techn.
Memo. 20-29.
41. Aghajanian, G.K., Kitzes, D.L., Harper, D.G. and Bottlglierl,
N.G. 1965: EA 3580A. Estimate of minimal effective dose in
man. CRDL Techn. Memo. 2-12.
42. Crowell, E.B. EA 3580A: 1965: Estimate of incapacitating Dose
in Man. CRDL Techn. Hemo. 2-20.
J 7
OCR for page 270
43. Hart, J.J. ant Balter, L. 1966: A atuty of posalble realdual
effects of EA 3443 ant EA 3580 on cogultive abilityO EATR 4044.
44. Hayes, A.~. CAR 301,060: 1967.
tose in man. EATM 114-12.
45.
Sidell, F.~., Karger, S. 9 Slmons,
Compound 302,668: ~
Estimate of mintmal effecti~re
C.J. and Weimer, J.T. 1970:
Aeroso1 ad~inistration to man. EATR 4395.
46. Sidell$ FeRe, 1972: Retchuo', J.S., Mselcts, J.E. and Rysor,
K.P. Compount 302,196: Intramnacular ado~inistratlon in man.
EATR 4634.
47. Sitell, FeRe and Braun, B.G. EA 3834A: 1972: Effecta In man
after a single oral dose. EA" AS97.
48. Ketchum, J*S., Kitzes, D. and Copeland, H.
Effects in man. EATR 4713.
EA 3167: 1973:
49. Ketchum, J. S., Sitell, FoRe . Crowell, E.B., AghaJanlan, G.K. ant
Hayes, A. Ho Acropine, acopolaotine ant Di ban: Comparati~re
phaneacology ant antagoniats ln man. PaychopharoIacologia 28:
124-145, 1973 b.
50. Klapper, A.J., McCarroll, J.E. and McColloch, M. 1972: Long
tero~ followup of medical volunteers. Edgewood Arasnal Techulcal
Report #4611, 1972.
J 8
Representative terms from entire chapter:
atropine toxicity
