Sedatives, analgesics, antidotes, and their interaction a review

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SEDATIVES, ANALGESICS, ANTIDOTES, AND THEIR INTERACTION
A WEIVER
ALLEN BI DOBK N, M D ~
THE TSITEHTSEANA Sl harassed constantly by three needs m his ally work Each
of these contributes to the things that make the d~fference bet~ een an "unevent-
ful anaesthetm' and one charged With ~omphcat!ons They are ~elated m part to
our desire for drugs with specml propqrtms which can producc~ in the pataent a
certain response without any delet~enoUs or other undesirable effect, and can be
hsted as follows
1 Sedataves which produce effectave psychic sedahon dunng the Immediate
preoperatave penod, without provokang rmusea, vonutmg, s~vere respiratory
depressmn, circulatory mstabdaty, histammq.-hke reactions, andl behavmural dis-
turbances ~
2 Potent analKeslcs, with a relahvely short delay m onset and a short durataon
of action, that do not cause s~de-effects~ as noted aigove 3~ Skeletal muscle relaxa-
taon and deep"hypnosis (unconsCaousness) are not necessary features of the
actaon of these agents, since we have statable relaxant drugs, and deep hypnosis
or unconscaousness can be well prowded by mtrous oxide 4
3 Antidotes winch can ensure rapid, smooth recovery to wakefulness and
adequate breathing, wxthout provoking nausea, vomltang~ sngezmg, coughing,
itching, or circulatory &sturbances These drugs should only be used when
clearly mdlcated 5
IHCYSP c NOITADES
The introduction of drugs which ~ra capable of producing tyanqudhty was a
mixed blessing to the anaesthetast Dur ag the past decade, we have reahzed that
analgesms and hypnotacs alone (or lr combination) do not always satasfy the
desire to sedate a patient In the ~aes ch for better sedataves, many new drugs
have been tested to see ff one meets Jt ns real need, but better ones must stall be
sought, and their actions compared ,lth those already m us~ A summary of
these structurally is shown m Table I Selection of the best one among these to
fit our needs has been hampered by the wide dose range of the drugs within
partacular chemical groups, and by w triable side-effects that occur with mdavi-
dual representatives of each group of :d :ugs, as indicated m Tabl~ I
None of the drugs is a "perfect" se datwe m the sense that ~t will invariably
reduce a state of calm mdtfference ~t ) a major stress s~tuataon, even when the
dose is mcreased to the range where to cax effects are seen too frequently ( >~ )%52
Aldous Huxley has stated that
the perfect tranqulhzer should be a drug yvtudh would reheve and console our suffering
specms without domg more harm m the 10ng run than it does good m the short It must
be less hkely to produce undesirable socfal consequences than alcohol or barbiturates,
less lmmlcal to the heart and lungs thafi the tar and mcohne of cigarettes It should
*Professor and Chub-man, Department fo I Anesthesiology, State UmvCrslty of New ,kroY
Upstate Medical Center, Syracuse 13210, New kroY
252
Can Anaes coS J, vol ,11 no ,3 May, 1964
DOBKIN, A B SF.2DATIVES, ANALGESICS 1 AND f ANTIDOTES 253
produce changes in conscmusne~s more pleasant and l more mhmsmally valuable than
mere hypnotic sedation or dreaminess, delusmns of ontmpotence or release from
inhibition
This s~ shll a fantasy, and apphes, of course, to drug, ,i that will be used over a
protracted period of tame
1here are dwergent opinions regarding the use of s~datwe drugs m premedl-
cahon Some feel that none should be used--parhct.larly narcotm analgesm!, ~
and non-barbiturate sedatavesT-whde others hke to use enough to "obtund,
obnubllate and obfuscate-s Beecher has asserted that there sa no place for anal-
gesms m premedmatlon unless the patient has pau~, mainly because a true
sedative actmn sa only evident when pare sa relieved Other~ease nausea, itchiness,
and respiratory depression become thmr most p~oma:~ent effects Many dashke
the barbiturates because they cause confusaonal states, especially na the elderly,
na whom a sensatmn of unreahty accompames the induced half-asleep state,
which increases the alarm caused by an unfamflmr em aronment Psychosedatwes
are feared because they may cause or augment depressmn of circulation dL~a
resplrahon Neurosedatwes are not widely used becmlse most of them must be
gwen over a period of seveIal days before an adequate sedatwe effect becomes
apparent
The use of psycho- and neuro-sedataves in psychmhlm piactace sa rather dafter-
ent from that na anaesthesm because the type of a@aet T that appears m the
psychotac patmnt has no obvious purpose, yet reqmrts long therapy with large
doses to allay the patient's symptoms, whereas the pleoperatave pataent usually
has good reason to be anxaous and even better reasons to be rendered tranqml
in a reatavely short time Thas be accomphshed by ludmlous use of psycho-
can
sedatives and si ample reason for us to continue stud)crag these drugs carefully,
and to persist m our quest for drugs that can consistently allay a patient's fears
after a single m}ectmn
Even more important to the anaesthetist than being able to provide a highly
consistent sedative effect with a drug sa the reqmrement Lof a lack of undestrable
physmlogacal disturbances, such as hypotensmn (especially na the hypertensive
patient), respiratory depressmn (particularly in the patient with emphysema ),
extrapyramadal effects ("twltchmess," restlessness, muscle spasms), and allergic-
type reactions Some of the undesirable responses to evatad~es and analgesm drugs
m the lla pataent are shown in Table II
Nodme and ins assocmtes have d~scussed the human bin-assay of psychosedatave
drugs and have suggested that when the efficacy of these drugs sa studmd, tlhe
percentage of patients showmg moderate to marked amprovement should eb"
plotted against the loganthm of the dose 9 At any low dose level, 30 to 40 per
cent oi pataents may be expected to respond because of a placebo effect As tlhe
dose sa increased, a higher percentage of patmnts should respond untd a maxa-
mum sa reached, leaving only a few patients who do not respond adequately to
the drug The mcldence of toxin effects should be plotted na the same way,
defining a toxin effect as one whxeh sa suflqcmntly eLE~eves na the pataent and alarm-
mg ot" the physician that admlmstratmn of the drug sa discontinued or the dose sa
lowered Figures A1 and B1 show the fypmal response that may be expected
from a satisfactory and an unsatisfactory sedatwe drug
$s ~eli~r~| LarQon oHCI Pacotal HCl Taracta. 3 AHT
u a AH /CH3 AC
OF I CH~ ~
PRACTICE 3 AE AC AE
~;N AS AE AU
T~ES RE$ j CH2fHKp (P) A~ (P) AS = CHCH'CH~'-N\CH OT
H$ AL BG ~$ 8P RES N6 AR NS 8P
BP R F~
THIORIDAZI~E 2 NS 3 P 4 E~ 5 2 PROPRIO~AZINE I 20 2 H$ 3 P EX 5 I-2 MEPAZINE I 75 2 NS $ 0P 4 AL 5 2 CHLORPROTHIXENE 2 HS 3 P 4 9 2
P~RY ANAESTI~IESIA
IN
Dose, Sedotives Tr~iofon CH2CH2ON Troncln Proh~n * 2 HCl CHzCH2OH TIndol (C4H~O4lz CH2CHzOH Prokeloztno CH~ON
CH3 "CN2
EFFICACY
~N 3 Fj"'-'%N CH2
Av~c~ ~ r E 2 CF3 AS AE 0 _ C H 2 0 ,__, - N ~____11t
I ~ THEIR AND Psycho PERPHE ~AZ J CH~CH~CH 2 ~S H$ 3 BF AM AR E){ AL RES 5 | (AI~TIE~ETIC) FLUPHENAZ~JE N ~ 1 C H2CH3CH2-~,~jN 2 HS NS 3 P BP A~ EX AL RES 5 I (ABTIE~ETIC) ACETOPHENAZINE ( S ~j~,C ! CH2CHzCH m gO M6 (P} 3 eP ,i E:~ e~L RES 5 :P 3 CARPHE~AZINE $ i CH3 I 20 W6 ~P) 2 ~$ HS P~ ) - EX 4 .5 2

TABLE S~ow~c & Tern.or=! Phenergon ~ RCl IO 409 To=l Ion P 725 C,~ H<=04 CH$
WIN
CH3 CH~
SIDE-EFFECTS, ~
CH$
~OeF_~S Hypno 3 \CH~ AS AH(A~TIPRURITIC) E N/CH3 I \ CH~ ~H INE I CHCH2-~ I CH 3
CH A~ I CH2CH AS 2 CHzCd2~%..__/N (P)
(P) AH
SF~T~V~ UNDESIRABLE & TRIP~EPRAZINE I 2 HS SD 3 P R ~P 5 I PROI~,ETHAZIN I 50 ~6(P) 2 HS 3 P R ~ ~ES 5 ~-2 ISOPROMETHAZ I 50U6 ~LS 3 P A~ 4 ? PERAZINE N | Cd 50 f~6 ? ? ?
~-~ EFFECTS, $por0ne HCI Thorezme Lo,(oc,,, (cid:12)9 HCI ~HT Ve~prin HC| Ten,one
OF D~ucs ~/~AJOR Neuro CH~ N~ 2 CH3 A~ AE iNE C I /CH~ ~ XCH~ SO AR AS AE CF~ CH~ / z N\ CH~ AM AR AE AHT INE /CH~ CHz -El\
OTEIF_~ I CH2CH2CH ~ 1~) 50 HS ~$ $0 P R ~P~T E:~ AL RE$ 12 ~S~ -~v'- -t~ ~ -',.~- I CH2CH2CHz- 25 E~G (P) HS ~S PS P R BP BTA~ AL ~E RE$ N I CHzCHzCH 15 ~G (P == =r PS P R BP ~T i CH2CHz 30 ~t6 (p) ~S ~P 2
Su~nY PRO~AZI~E 2 3 4 5 CHLORPRO~AAZ I 2 3 TRIFLUOPROMAZINE 2 3, METHOX'YPROM~Z I 2 5
i t
EIo~*l HCl 7~2 0909
~CI Totr~nH ' $u~mo~td RP "'CH 3 Theruhl~hn Andonlol Neurlep|d RP
-CH3 CHz
CH~ \CH~ ~ Lo,~ AH N" \CHs AHT
~
UE sCN AS CH~ CH AC
CH2CH2"I~(CH~ ~U CH2CH ~ AE UETIC)
C~CP~C~2-P (P) RES | CHZ P} ~C RES (P) ~T .{O)-- CH~CHz (P) AM
U~ AL MG ~P ~L P~G 5F eeG (ANTIHISTAMINIC) UG 9P (ANTIE
A~ITRIPTYLi~E e ZO N$ EX 2 IUIPRAUI~E t SO P E~ S TR~EPR~t~E I PO0 2 HS 3 P 5 2 ISOTHIPENDYL I 5 2 H$ 3 AH 4 .E S 2 PROPERICIAZIN I I0 2 NS 3 P 4 - 5 !
TOCOCyl ~!oreed~ne 0 2 ()o~e~l 0 C~t, 2HC' T~n~ovon Dom~ol K ~ RP 9965 NH 2
3 /rH.
CH N...C
"~N N~_C.NH 2 E C~2CH~OC () 2-~ AH 2 N%j,%-C
T
C, CH2CH
I CH u~ (P) U~ZIt~E I CH~CH2CH e~6 IP) (AKTIEUETeC) $~ " t CH2CHzCH HS HOYL CH~CH2CH~ IPJ U6 HS P$ AM R 0P CH 2 UG (P) AM AE (ANTIEMETIC|
UETHDIL~2tNE IO 2 ~S PlP~ I ~ 2 ~45 - S 2 I"HiOPROP~Z~ 2 ~S Pl~OTHIP 1 tO 2 N$ 3 P 4 THIOPIPAMAZINE I IS 2 NS $ OP q 7 5
HCI ~
$ fo~oIH S eelogme o~ Toeer CH3 upsets
INE Ce C~H~O~Sz CH$ N\jN INE ~ N N gH~ H 3 ~ ~, ~E ~x~, 2 Ce,SO~ r0tch,ng,vomzhflg dlsturbonce syndrome joundr Gd d)'suosso6 or endocrine disturbosces hollur properlles i6r u,o
RAZ CI z CH~, dJsordore lessnoss
PROCLORPE CH2 CH I 5 uG (P) 2 r~$ H$ EX AL RES 5 t (A~TIEUETIC) TRiFLUOPERAZ CHzCHzCH i 2 ~G (P) 2 ~S ~$ 2 3 THI( THYLPE~AZNE ~ S~$CH2,C CH2CH2CH2 l0 e~G (P) 2 eaS 3 P A~ AE 5 I" |A~TIs THIOPROPE~Z CH2CHzCH2 4 EX I~ES 5 I 2 (A~JTIEeaETIC) Effe(cid:14)9 4 S,de N( nogsoo neuromusculor EX entropyfomldol 6eezureu AL el|orgy skan UE metobohc RE $ behovmorol rest A0 oddlcting n ~tO/~O 5 ff*cacY 9god I 2 volt 3 poor
723B 8599
~doeo.~el Pieg~c~i Verochl Noz,nen Venice RP RP ~
CH5 -m\ CH~ /CH3-' N\ C~ CH~ / N%. CH~ ICH3 (onhocelylchohnsj |SHT)
C CH~ 2 CH z Ch z ee~ CH~ i ~CH3 S0 l N E ICHCH 2 CHs i CH~ (P)porenfeFol deprl~otlon depr,vohon onesthes,o depression hythmlr
N C~ IP) r~ P~ R ~P ~T ~L ~E$ EPRAZINE PROE~AZNE I CHECH (P) ~G NS PS PRAZ l CH2 (P) AH AHT (O}orel o| Sedohon hypnotic neurosedotivo psychosedohve sensory motor Effe~:l~ prolong P resplrolory hypothormio nnt,emA~,e' onhorr onhsioloooguo oehepmephrmo onhchoi,oorge(cid:14)9 ontihistomm,r osi,serotonln
~CEP~OMAZ@NE 2,5 r~S 3 P EX METHOTRIM (cid:12)9 LEVOUE tO 2 HS AL THIO~E HE I t0~G ? ,~ ? THIOPROMETHAZINE 2 ~S 3 ~ ? 5 MIGRAINE i DOSe 2 T_ypj HS H$ P$ $D UD Other 3 0T ~,H AR AS A AC ~H AHT
Seconol e Nembutol Amyiol CH3 Butlsol
.,CH3
CH C~ 3
3 3
H
0 CHzC 0 CHs P) 0 .CH2CN I,. C\ O CHs p) I CHzCH C~ 0 0 CH2CH I i C I% i CHCHzCH3 0 CH3
~--C (o N--C t I0 l~l~C w N/_/'CH2CH, lOP) N--C m I HN--C (0)
~G ~aO-C MG AD NoO-C MG NaO-C MG HS
SECOBARBiTAL I IOO 2 HS 3 - 4 PENTOSARBITAL i ,_~_n 2 HS 5 o 4 RES 5 I AI~()BARBITAL I 200 2 HS 3 - 4 - I BUTABARBITAL i IO0 2 NS P 4 AD 5 Z
2 Perictor Valmld
~h
4
O
CI3
B~' C~hC 0 H C-OH I OH
CR 0
Sedatives 2 ,,./ C /\ Ci4 z HYDRATE CI I Ci-C~ I C! OH I (CN2OCH-C ~ c O-C-NH (0)
r,} C
CH~CH CH3 (o) MG
CARBROMAL 2 HS =~ - '4 - i 5 I i CHLORAL CM 2 HS 3 - 4 PETRICHLORAL I i GM 2 HS 3 - 4 - 5 - z ETHINAMATE I soo 2 HS 3 - 4 - 5 2
~
Hypnotic Lotion C H CH 2 DEPRESSIOi~) R 1406 O ~= HCl Subllmoze R 42~;3 O ~N C CH2CH 0 RIGIDITY) A Ivodlne 2
H~
C
~
& ~x'y..-- (iv) NARCOTIC \ NE CH2-H/~'~H (P} EX (MUSCLE Q 0 /C-OCH~CH~ 0 (P) CH2CH2CH
OH NS NG
NG EX 2 15 NE MG NS ~D
LEVALLORPHAN I 2 2 SD 3 R 4 RES 5 ,~(REVERSE PHENO~RIOINE 2 SO 3 - 4 R 5 ? FENTANYL ~CH I o 2 SD - 4 R 5 ! PIMINODiNE I ;0 2 SD 3 - 4 R 5 I
2
Nolhne :>0228 H3 2 20 740 CH 2 !H 2
CH2 /CH~
N DEPRESSION) WIN C~'C WiN OH
3
Deprivation CH2C CHzCH-- .N~CH CH3 CH ,c~3 N
CH2CH I CH3 --~ "0"
NARCOTIC
~-'~"
NALORPHINE (~/~N ! ~ IO~G (Iv) 2 s~ 3 R r RES 5 I (REVERSE PENTAZOCINE OH"~ i o~ ~a5 ~P~ 2 SD NS 3 R ? 4 5 I IA~LGESIA) CYCL,~ZOCINE OH I 2 MG (P} 2 SO 3 ? 4 RES 5 ? CODEINE CH30 I 60 MG (P) SO 2 3 - ,~ R NE AD(MILD} 5 2 1
Sensory Cl
Serenose RI625 R 1647 R 4"/ 4749 Inopslne ~ c I ~ H R 1892
N N~-NI
z
R
(P) BT P~ (P)
CH~ 0 (P}
F PS P (SEVERE) 0 ~ PS 3 F 0 CCHzCH2CH MG PS P F P~G PS
HALOPERJDOL o 5MG 2 NS 3 AM 4 EX 5 ANI~OPERIDINE 50 I 2 NS 3 AM 4 EX 5 2 DEHYOROBENZPERIDOL DROPERIDOL O I 5 2 NS 3 AB 4 E(cid:141) 5 I 8UTROPIPAZONE I Ioo 2 NS 3 A~A 4 E(cid:141) 5 2
DIol
Del~lngl Meboral 2 Luminal Veronol MedmoI
CH3 CH 3 MEAN CHART
CHCH-CH, "H
0 CH~CH3 I/ C~ 0 0 C. I ~ 0 0 "H C\ ! CPzCH 0 0 C. 0 CH2CH3 C / 0 DRUG OF
N--C HMI __cI'CH (0) ;--~/CH2CH, ! (0) BITAL N--C I HN~C (0) ~--C/cH2CH ~0 PI N--C HNI_cI'CH2CH3 (0) EACH LEFT
VIN ABARBITAL NoO-C 1 200 Me 2. NS HS - AD 4 5 I-Z MEPHOBARBITAL NoO-C CH3-M~C I mO MS 2 NS MD 3 - 4 - 5 EPILEPSY ALLOBAR HO-C l 1SO MG 2 NS HS 3 - 4 RES AD 5 2 PHENO. MaO-C I00 MG Z HS 3 ~ES AD 4 5 2 NaO.IIC ! SO0 MG 2 H$ $ - eJlr AR 5 3 UNDER BOTTOM
AT
R.I"TAL
raison
Dot Obhvon-C Ptocldyl Dorlden Noludar NUMBERS
0 EXPLAINED
OH C~CH ' .,O~ C~CH /OH C~CH H2CH3 zCH
,,,/ C /\ s z \/ 7\ z %,, 7\ '~,~ u 0 C,=.CH T TCH,CH3 ",N/*O H FORMULA EFF~ACY ARE
PARAFYNOL CHsCHj~ CH MS (0) CH3CH CH~ MG (0) r CH CH .; (o') HS _Me eO~ NS CH 3 M6 (01
METHYL I 50O 2 H$ 3 - 4 - 5 I 'METHYLPENTYNOL' CARBAMATE 3 t zoo Z HS 3 - 4 - 5 I ETHCHLORVYNOL CI f 5oo 2 NS 3 - 4 - 5 I GLUTETHIMIDE ' 500 2 HS 3 5 I METHYPRYLON i 300 Z HS 3 - - 5 I-2 STRUCTURAL 5 ANESTHETIC ABBREVIATIONS
ine
N~lentll Lerit OCH~CH Pnltlum O Oemero! AND
0 s r Oolophlne /C,~
0 CHzCH, ~ %~.~C%~ H ~ "N~...,~ H CHsN\CH3 oc,.c.. NAMES
() N 0 IC C CH~ 0 ~CH2C ~ \c 0
/_~H~o-C E z CH," (P) l;,I TRADE
ALPHAPRODINE CH~-I~I~ ~6 (P) I 60 2 SD NS - 4 R NE AD 5 I AN I L E RIDIN NHt~ C H MS I (P) 50 2 SD AO 4 NE R 5 I IO-IS I M6 2 NS 3 - 4 R NEAD? 5 I METHADONE ~c,/C-CHtCH3 ~ i 10-15 MC 2 SD NS 3 - 4 R NE AD 5 I M'EPERIDINE CHs.N*'--'~C I I00 MS (P) :' SD NS 3 - 4~R PE ~ S I AND EFFECTS SIDE EFFECTS
in GENERIC
MAJOR
rocod Prinodo|
Po OH 2 CH~, Numorphon H Levodromoron Levorphon OH OH SHOWING OTHER UNDESIRABLE
N "0" (el C~zCHz"~ .N--CH ~'CH3 CH3 N (P| CH I CH3 N "0 ~ (P) 3 4
AD(MILD) OH
CH~O MS (P) AD MG AD? |Pl M6 AD PROPERTIES
DIHYDROCODEINE ii 60 ! ~0 2 SD 3 - 4 R NE 5 I-2 PHENAZOCINE |i I 3 M6 2 NS SO BP 3 4 R HE 5 I 'OXYMORPHONE i I-! 5 2 SD NS - 4 R NE 5 ! LEVORPHANOL TARTRATE t 2 IJP= 2 SO NS i3 - 4 R NEAD 5 I I MORPHINE I i 10-15 I 2 SO NS I 3 - ~4.~ NE 5 !
SEDATIVE
R 2t67 (cid:12)9 HC~ R 24'9'8'i r R 5147 R 3345 2 R 4584 ~ :, I WiTH SEDATION
OCH~ 0 .C~NH /x~_J ~ O I OF
_ DRUGS DOSE
-
OF TYPES
HALOANISONE F ~ 25 MS ! (P) 2 NS PS 3 AM 4 EX 5 2 3 ' TRIPERIDOL F 0 C (CH2)3"N~ t MG (P) 2 NS PS AM BT P 4 EX 5 2 i SPiROPERIDOL F ~ o c (CHz~-~ 05 M6 (P) 2 gS PS 5 AM 4 EX 5 2 DIPIPERON F 0 C (CH2)~ 20 MG I P) 2 NS PS 3 P BP AM 4 EX 5 2 8ENZPERIDOL F 9. o 0.5 MG (P) 2 NS PS 3 4 EX 5 ? SUMMARY I AVERAGE 2 MAIN
3
T,~e ! Somo RGIo
0 0 C~ Ueo~os,n U~lto~a 3 O CH~
r z O-CoeJM, 0 5
CM Ox CN,
CN~ CMaCNzCN ! ~ CH~ Cx 3 I ~-CN~-0-CNN-CN-CN CHzCHaCH
(~i CH~ 0 Pl CHz, (0) 2 (OI
0
u TMOBE~ZAMJ0E I $OO~G UEPHEKE$I~ ~ e ~ Gw (0 z e~S uO $ - G ~EPROBAU~TE KH 2 C O I 8O0 e~G ;~ NS MO 3 - 4 AL AO 5 2 3 CA R I $ OPROOOL 0 NH 2 C-OCH I 3SO ~G 2 eJD N$ 3 - AL 4 5 ?
H) H,~ OC~
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"r162 0 f=~.OC c. -~.~oc~,~
cc.
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RPI~E P ~ (0) N~LM~ .~co ~G (0) PS BP EX (TOO
- $ - ~E SE ~$ 3 ~P 3 DESERPIOI.E I t 2 ~S BP 4 - S $ RE $CJ I I 2 ~S 3 P RES 5 $
Sedofives
~*.~
L .~Ci Qeo~c~m Tropn~one
~.O
I 0 O 0
3
iDE ZE PO~IOE O-CH~. CH2CH I C--O~C-~JH2 I CH~
Neuro POX tP) (0) LONE (0) ATL~ 2- (0)
~ ~G ~D ~ uG ~'AL4 CH3CH ~G UD
C NLOROI~ZE ~ETH~e~I~OOIA I00 u P 5 i 0~A~,~IDE I ~00 2 ~S 3 - MEPHENO'~A I 000 2 NS 3 - 5; Euvl I 400 2 ~S 3 - 4
l
.~ger~ ~nodryl CH~ ~ere~ne Or~mom0ne CH 3 I ~H CH~ 0 C14 ~.,"~H,,,C "N L./~'-'- O~
~U CHiCHiS: 2 -
O
AE
H O-CH2CH
~G (P) UP ~tT ~HYDR~IP~E ~C e~G (P) P AS o/ UG (P) AU (~NTiE~ETIC), HC ~G (P) A~
50 P - 50 HS ~H - o 50 HS AH I ~0 HS AH
HYDA'O~YZI~E | 4 DIPHE I 2 3 CYCLIZINE I 2 3 4 5 I 2 4 5
I j
~
Co~lo
Fles~n
(cid:12)9 P~r~f~ HC Robo~le~ : Sycotrol ~
e, JH
0 C-
0 TO~IC 0
zCH~ z
| i ,,,c ~\ CHzCH C~ZCHZ-N
H}
~EBUT~,~ATE e I (O) ~00 MG 3 ~P 4 ? 5 ZOXOZOLAMINE Z UD 3 - r OFF' UAR~ET=TO0 ETHOPROPAZI~E I CH~CH 1 50 e~G (P) 2 uO NS 3 - 4 EX 5 - METHOCARBOMAL ~ OCHzCXzCH vvH~ I I GU (O) Z UD 3 - 4 NE AL 5 t-2 ....... PIPERILATE P|PETHAf~ATE 0,,o ~0 C-r 2 N$ WD 4
o
................
PRN
F~,@n~uel ~onom~ne Lesteco D=ofen
CHs
/CH~
o
E
P
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A~ CH
0 L ~A~IA) O-C~ 0P C~Hs
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C Y C L Oi'~J UG (P) N$ (ACUTE ~ IO) (AI~I"IE~E~IC) ~Y LTOLOX Q MG (0) HS ~O Q/ UG O) A~TIHISTAUIflE
A ,?. 'A I IO 2 P$ 3 AHT 4 - 5 I MECLIZINE I 50 3 A~ 5 Z PHE t 50 2 NS 3 ~H HYDROXYPHENA~ATE I 200 2 NS 3 - 4 - 5 =IPHENYLPYRALI~E I 2 Z 3 AH 5
~
Nostyn z ~r Alcohol
"F,oncopul BH Dime~hylone _H/CH~ " \CH~
6 C
OH I CH~
0 CH~ O~ C~C-CH~ I CH z n
T~A ZA~JO~JE C o, N CH~ (O) r C-C=~H CH |0) (0) CH~ -C--0 H (0) CHsCHzOH (0 P) AD
MG UD ~E CH3CH UG CI L~G UO OU RES
I~0 NS - AL 2 ~o0 NS - - NAGLYCODOL 600 ~S - 3 HO I 6~ ~tS ? 50 EX
CHLORUE I 2 3 4 5 ECTYLUREA I 2 3 4 5 PHE 2 3 5 PROMOXOLANE I 2 3 5 ETHANOL I 4
3 $ ~
3
D~porolene Sof~von CH $uovMII ~c.~c~ CH~CH Suvren 2 '~ \CH3 Trosent~ne /CHzCH ~I\CH2CH
z
CHzCH
c~c~z $
C
II~IE o
CH LORCYCLIZ I 50 ~G (O) 2 HS 3 AS ~H BUCLIZINE ~ lO) ~6 ~00 N8 2 3 P AH 4 NE 5 2-3 BENACTYZINE ~ c c 2 ~6 (0) I 2 t~S UD 3 AS P AC AHT 4 - 5 2 CAPTOOIAUINE 300 UG (0) I UD 2 ~S P e, - 5 2 5 ADIPHENINE 0 HC- C-O-CH~CH I 50 U6 (01 2 N$ (A~TISPASUODIC} AC AS 3 4 - $ 2
Y
~ PHYSICAL DEFECT MENTAL DEFECT DEATH
V1
TISSUEI~
I DEFI OF BLOOD FLOW
k CI
E
N
C
Y
~
DRUGS j
EFFECTS EXCESS RETENTION RETENTION
ANALGESIC METABOLIC DIOXIDE ACiD ACID "~*L "
~
AND I CARBON I 1 LACTIC LPYRUVIC TOXINS
SEDATIVE ENDOCRINE ~ J~ ACIDOSIS ~L EPINEPHRINE ,~ NOREPINEPHRINEJ HYPERKALEMIA ~ HYPOKALEMIA AZOTEMIA HYPERGLYCEMIA ~' HYPOGLYCEMia i' SHOCK
TO EFFECTS
PRESSURE
II ILL PATIENTS RATE VOLUME PRESSURE R-~L VOLUME OUTPUT AURICULAR UPTAKE RESISTANCE
TABLE OF CARDIOPULMONARY BREATHING TIDAL BLOOD PuLsE STROKE CARDIAC RJGHT OXYGEN PERIPHERAL
SIGNS
RESPONSE I CLINIC_AL FEAR APATHY RESTLESSNESS OLIGUR~A VASOSPAS~
PRIMARY FACTORS AFFECTING CAUSESJ INITIATING HEMORRHAGE B PLASMA LQ'mS DEHYDRATION ~ ANESTHET,C DRUGS SEVERE RESPIRATORY DEPRESSION CARDIAC ARRHYTHI~IAS CATECHOLA~INE DEPLETION VASOMOTOR PARALYSIS PROLONGED OPERATION
ACTIVITY
CAUSES
AGE
OF OR HYPOTHER~IA DYSFUNCTION DYSFUNCTION DYSFUNCTION SYUPATHETIC INFECTION ABNOR~ALIflES
IPREDISPOSING EXTREBES HYPER CARDIAC PULBONARY VASO~IOTOR EXCESS SYSTEUlC BIOCHEBICAL
I
V
E
1B2
,TNIKBOD A R SEDATIVES, ,SCISEGLANA AN D SETOVITNAI
NAMUH YASSAOIB FO A DOOG EVITADES GURD NAMUH yA~SAOIB! lO A ROOP EVITADES ~CURD
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57
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2 3 I 2 3 I0 20 30 I00 I Z I 3 ~ , ,I I 2 I 3 I 01I 20 t 03 I 100 I
GURD ESOD STINU DBUG OOSE UNITS
A B
doog drug
Fictm~ 1 Human bloassay of a (A) and a poor (B)I sedatxve Observe that a
drug should be effective m at least 75 per cent of pata-ents (EEho) at a dose level that does not
cause toxic effects m more than 25 per cent of pabents (TD~) Otherwise the drug must be
consldeled unsmtable as a sedative In anaesthebc pracbce, evl~ should use only those drugs
wxth a ve~ wade therapeulae index (TD~ should be three tmae~ greater than 5~DE ).
Since psychosedatwe drugs are seldom used mot, than once m a pataent an
assocaabon with a single anaesthebe, at is reasonable o: expect that the therapeu-
o~t effecbveness should be at least 95 per cent watho at appreciable toxic effects,
and the "best" dose of the drug should be no more than one tinrd of the dose
which causes toxac effects in 25 per cent of pattents II a toxic effect does develop,
there should always be another drug available whl, h, effectwely and promptly
reheves the toxlcaty, and winch itself should be wrb yllaL 100 per cent non-torae
m the therapeutae dose range
Hebb beheves that the nervous system produces ..spontaneous activity and it
reqmres outside sbmulatlon to use up the energy produced He has suggested
that the "cue response" and the intensity of arousal to the central nervous system
are separate funcbons 01 Many of the drugs used in ~ssoclabon with anaesthesm
may be fitted into a bell-shaped curve, the abscissa f~ winch corresponds to the
intensity of arousal acbvlty and represents non-spec e~ nervous stanulabon, and
the ordinate of wlnch corresponds to the cue value of a sbmulus winch represents
well-orgamzed, goal-dtrected behawour (Fig 2)
Most of the avadabe phenotinazme-related psych0sedataves are shown m the
central section of tins figure I have placed them m thss central posltaon because
they tceF~M the psychomotor system m dafferent waysi depending on their chetml-
ca side-chain structure and upon the psychic state 6f th~.~subject They can not
only suppress severe agltabon and reduce a mamc patient to a placid state, but
they can somebmes cause wide mood swings m the relabvely normal individual
--from a state of indifference and drowsiness to one of paine and catatonm On
the other hand, the pabent who is weak and ill from, a physical ailment is easily
put to sleep, and, with excess, may go into coma, for these drugs have a pot~ent
depressant effect on the })ram stem arousal mechamsm 11 I
The usual response m the "normal" subcot to a psyehosedabve may 'be
expected to vary from a mild hypnotic reacbon-wineh merely depresses the
oereblal cortex and raises the threshold of the central nervous system, gm:suac