CNS DRUGS

BOARD EXAM REVIEW -2012

INTRODUCTION
Major developments in the study of CNS drugs:
!ll drugs "#CNS e$e%ts a%t on spe%i&%
Rs that modulate synapti% transmission'
( )*T: +!s , !l%ohol - nonsp a.ns
( Clini%al trials : /ven non0Rs0mediated
a%tions demonstrate alterations in
synapti% transmission'

Drugs 0 most impt tool in the study of
CNS physiology1 espe%ially !gonist
, !ntagonist e$e%ts
Dis%overy of a%tions of e$e%tive drugs : led
to valua2le hypotheses a2out dse me%hs'
/.' !ntipsy%hos on D! Rs 0 provide 2asis
for impt %on%epts on pathophysio of
s%hi3o1 OR4 a.ns of !gs#antags on
+!5! pathophysio of dses as
an.iety#epilepsy1 *ar6inson7s1 et al'


OR+!NI8!TION!9 *RINCI*9/S of the CNS
5rain 0 %p. pattern of intera%ting nu%lei
, neurons : regulate ea%h other7s
a%tivities 1 generally thru %hemi%al
neurotransmission'
Ma%roanatomy : *ls read ++
Cellular Organi3ation:
Neurons ; essential to 2rain f.ns <
%ommuni%ates thru synapses1 "#vesi%les
as %entral synapses for NT storage'

Support %ells 0 other %ells in CNS ; outnum2er neurons:
0 In%ludes: glial %ells1 vas%ular %ells1
CS=0forming %ells '
> Ma%roglia ; most a2undant support %ells
> !stro%ytes 0 meta2oli% support 0 provide
energy intermediates , supplementary
removal of NT $ release'
> Oligodendroglia 0 myelin0produ%ing %ells
> Mi%roglia ; asso "#in?amm#inf.n d#t
ma%rophage # mono%yte lineage'





*rin%ipal =un%tion of the CNS:
Integrates info fr a variety of e.ternal#
internal sour%es , %oordinates 2ody
f.ns a%%dg to environmental demands'
> Involves transmitter systems and
neuronal a%tivity'
Role of drugs : to enhan%e#2lunt e@%a%y
of A or a %om2inatn of spe%i&% NTs ,
ion %hannels to a%hieve desired e$e%t'
Identi&ed targets for %entrally
a%ting drugs:
Ion %hannels B mediate %hange in
e.%ita2ility indu%ed 2y NTs
NT Rs to "#% drugs 2ind C 2iologi%al
responses
Transport proteins ; rea%%umulate the
released NT



> Mem2rane transporters:
0 a%%umulate released NT B pa%6age
for reuse
0 Inhi2itn of reupta6e C D %on% ,
stay of NT in synapti% spa%e
E/.' SSRI F
0 Inhi2tn of vesi%ular storage
E/.' storage of N/ 2y ReserpineF
C depletion of releasa2le NT'
Categories of CNS neuronal systems
GI/R!RCGIC!9
> dire%t involvement of sensory per%eption
, motor %ontrolH %omposed of "ell
delineated path"ays of large myelinated
&2ers "#large %ell 2odies , long a.ons
relay info in a seIuential pattern'
* Lesion at any in! in"a#a"itates t$e
%$oe syste&
* J types of hierar%hi%al neurons:
Relay #proje%tion neurons K long distan%e
signals - transmit e.%itatory neurons'
> NT: glutamate
> Spe%i&% NTs are limited 1 TGUS1 major
pharma interventn K profound e$e%t
CNS e.%itation'
9o%al %ir%uit neurons ; smaller than relay
neurons "#a.ons ar2ori3ing in vi%inity of
%ell 2ody C mainly inhi2itory
> NTs: +!5!1 gly%ine
NONS*/CI=IC or DI==US/
Neuronal Systems
Contain monoamines EN/1 D!1 L GTF
or other path"ays emanating from
the reti%ular formation and possi2ly
peptide0%ontaining path"ays'
%onsist of &ne unmyelinated &2ers
transmit very slo"ly at M'L m#s
divergent a.ons 2ran%h out rptedly1
di$use innervatn of f.nal sites
sleep#a"a6e attn1 appetite1 emotions




SIGNI'ICAN( )RO)ER(IES o* CNS
+,-.s/
Spe%i&%ity#Nonsp of !.ns
Spe%i&% drug - a$e%ts an identi&a2le
me%hanism uniIue to target %ells that
2ear Rs for the drug
Nonsp drug - "hen drug produ%es its
e$e%ts on various target %ells 2earing
Rs for the drug'
Spe%i&% drug 2e%omes nonspe%i&% "ith
large doses , route of adm'


The more potent a drug is at its target site1 the lo"er the possi2ility that it 2e%omes nonspe%i&%'
! drug "ith 2road spe%trum of a%tvty may not %ause identi%al e$e%ts at all levels of the CNS'
0 /.' Sed#hypnoti%s1 +!s C limited use as
CNS neurons %ontrolling RT#CNS
are sensitive to their a.ns
Opioids C %onsider RT depression ,
%onstipation as side e$e%ts'
E0e"ts o* CNS +,-. Co&1inations/
O R.ti% additive e$e%ts 0
0 anti%holinergi% , levodopa for
*ar6inson7s disease
O =atal additive e$e%ts
0 /thanol P Dia3epam -Q Rdepression
0 Morphine P CNS depressant -Q
R resp depression

!ntagonism 2et"een depressants and stimulants is varia2le
0 TRU/ pharma antagonism - Morphine
, Nalo.one
0 *hysio antagonism - e.hi2ited 2y J CNS
drugs : pt depressed 2y an opioid %ant 2e
returned to N 2y %a$eine'
Sele%tivity of drugs for a spe%i&% NT is a %ause for potential drug intera.ns 2e%ause the total e$e%t
may 2e additive or %ompetitive'

Consider drug intera%tion "#%on%urrent administration of J drugs'
> Need for a drug0free interval period
2et"een R. to minimi3e this e$e%t'
Transient e.%itation after inta6e
of small initial doses of some CNS
depressant drugs'
E23 Initial stimulant e$e%t of al%ohol
gregariousness at onset of
drin6ing1 OR1 stage of e.%itement
of +!s

R.: *re0inta6e of a depressant drug that
is devoid of e.%itatory a%tvty
/.' Dia3epam as preanesth med
Uni*o,& +e#,ession
0 follo"s repeated inta6e of depressants
Wit$+,a%a sy&#to&s ; upon a2rupt
d#% of a %hroni%ally ta6en depressant
R2/ s-1stit-tion t$e,a#y in a++i"tion
)osti%tal depression
0 follo"s a%ute inta6e of 4 doses of CNS
stimulants1 5UT1 as a rule1 e.%itation
doesn7t follo" a%ute 2s inta6e of CNS
depressant drugs'
0 %aused 2y fatigue , e.haustion of NT
stores
0 *osti%tal depression ; additive "ith
depressant drugs

BBB - impt 2oundary 2et"een CNS
and periphery permea2ility 2arrier
to di$usion of su2sts from 2lood to
2rain
0 EPF 555 : ma%romole%ules1 polar NTs1
pre%ursors , meta2olites
0 R permea2ility : lipophili% su2sts 1
%ere2ral in?ammation
, is%hemia'
Res#onse to Da&a.e
0 CNS neurons ; terminally
di$erentiated %ells thus E0F
proliferative response to damage
( Re%ent studies: use of neural stem
%ell proliferation for repla%ement of
neurons , R.ti% repair'
0 Other physio adaptive me%hanisms
of neurons ; maintain f.n $ injury
ION CG!NN/9S , NT re%eptors
Modi&%ation of ion %hannels in neuronal plasma mem2ranes C neuron ele%tri%al e.%ita2ilityH
Involves major %ationsE NaP1 SP1 CaPP and anionE Cl0F
N: Re.tra%ell NaP than intra%ell thus in%reases in permea2ility to NaP C depolari3ation
N: SP intra%ell %on% is greater than e.tra%ell1 thus In%reased permea2ility to SP C hyperpolari3ation
Chs in intra%ell CaPP %on% C a$e%ts multiple pro%esses in %ell C %riti%al to release of NTs
!%tivation of Cl0 %hannels I*S* "hile ina%tivation %an lead to hypere.%ita2ility'
Nerve %ells 0 J types of %hannels 2ased on the me%hs %ontrolling their gating:
T voltage0gated ; respond to %hs in
mem2r potential of the %ell < fast !*
T ligand0gated ; respond to 2inding of NTs
on Rs'
NTs e.ert e$e%ts 2y 2inding to J %lasses of Rs:
- Ionotropi% Rs ; a$e%ts ligand0gated %hannelsH 2inding of ligand opens the %hannel "ea6 or
insensitive to mem2rane potential
!%tivatn C 2riefEmillise%sF opening of
%hannels ; responsi2le for fast synapti%
transmission1 typi%al of hierar%hi%hal
path"ays
- Meta2otropi% Rs 0 +0protein %oupled Rs ; 2inding of NT to this Rs C doesn7t result in dire%t gating of
%hannel 2ut engages a +0protein prd.n of J
nd
messengers that modulate voltage0gated %hannels'
> CaPP %hannels , SP %hannels ; targets
of +0protein in the voltage0gated
%hannels
> !%tivation C duration of e$e%t lasts tens
of se%s ; minutes
* Meta1ot,o#i" Rs 5 #,e+o& in t$e +i0-se
ne-,ona syste&s in CNS
6 J types of path"ays:
7E2"itato,y
P stimulation U small depolari3ation or
/*S* - R in NaP , SP permea2ility
8 8 "#su@%ient a%tvtn of e.%itatory
&2ers 8 8 8 /*S* depolari3es
postsynapti% mem2rane to
threshold 8 .ene,ation o* /
9a o, none A)9
Inhi2itory
P stimulation U sele%tive opening of Cl0
%hannels U hyperpolari3ation of
postsynapti% mem2r I*S*
N/UROGORMON/S : su2sts released
from neurons of hypothalami% ;
hypophyseal %ir%uits to 2lood
/.' O.yto%in1 arginine0vasopressin
N/UROM/DI!TORS: su2sts involved
in postsynapti% responses to NTs
/.' %!M*1 %+M*1 inositol phosphate
N/UROTR!NSMITT/R ; su2st se%reted
2y a neuron to target %ells NT e$e%ts
Me%hanisms :
0 /.%itation depolari3ation
0 Inhi2ition hyperpolari3atn
0 VConditionalW or modulatory
N/UROMODU9!TORS : arise from non0
synapti% sites1 yet in?uen%e e.%ita2ility
of nerve %ells /.' COJ1 ammonia1
neurosteroids1 NO1 purines1 adenosine1
nitri% o.ide1 ei%osanoids'
N/UROTRO*GIC =!CTORS: su2sts
produ%ed "#in CNS 2y neurons1 glial
%ells1 astro%ytes1 transient in?ammation
or immune %ells that assist neurons in
damage repair'
/.'Neurotrophins1 neuropoeiti% fa%tors1
gro"th fa%tors1 &2ro2last +=s1
insulin0li6e +=1 platelet0derived +=1
a.on guidan%e mole%ules
CEN(RAL NEURO(RANSMI((ERS
!mino a%ids ; a2undant in CNS , are potent modi&ers of neuronal e.%ita2ility
u2iIuitous distri2ution in CNS
X Di%ar2o.yli% amino a%ids: +lutamate , aspartate - WfastW1 po"erful1 reversi2le /)CIT!TORY e$e%ts on
neurons
X Mono%ar2o.yli% amino a%ids: +!5!1
gly%ine1 Z0alanine1 taurine 0 INGI5ITORY
X GABA 0 major inhi2itory NT
[ main types of Rs: !1 51 C
T +!5! ! ; most prominent , a2undant
> ligand0gated Cl
0
ion %hannel or
ionotropi% Rs 0 inhi2ition is asso "# R
Cl0 %ondu%tan%e
> site of a.n of most neuroa%tive drugs
/.' 5en3os1 2ar2is1 ethanol1 anestheti%
steroids1 +!s
> Gas [ su2unit sE \1 Z1 gammaF '


main Rs types: +!5!! , +!5!5 Rs
+!5!! Rs ; more a2undant site of
a%tion of most neuroa%tive drugs
/.' 2en3os1 2ar2is1 al%ohol1 +!s
[ major su2units: \1 ], gamma
Inhi2ition 0 asso "# R Cl
0
%ondu%tan%e
T +!5! 5 ; meta2otropi% Rs 0 intera%ts
"ith +0proteins Binhi2it adenylyl
%y%lase B a%tivate SP %hannels B
redu%e CaPP %ondu%tan%e
T +!5! C ; less "idely distri2uted than
! , C , not "ell intera%ted 2y 2en3os
, 2ar2is

X +ly%ine
inhi2itory NT a2undant in 2rainstem
and spinal %ord
other inhi2itory NTs: Z0alanine1 Taurine
X +lutamate , !spartate 0 very ^ 2rain
%on%entration , po"erful VfastW
e.%itatory e$e%t on neurons
> +lutamate e.%itoto.i%ity neuron %ell
death "ith R NT %on%entration'
X A"$ -
A
st
%pd identi&ed as NT in CNS
Cholinergi% path"ay ; impt role in %ognitive
f.ns1 esp memory
> /.' _ amts of !Ch K !l3heimer7s dse'
Intera%tion "#mus%arini% , ni%otini% Rs C
!Ch e$e%ts
!Ch a%tivatn C rapid R in?u. of NaP # CaPP
su2sseIuent depolari3ation
R/NI/` :
Mus%arini% Rs E!NSF , Rd Chap AA for N Rs'



X MONO!MIN/S - %ate%holamines
ED!1N/F and L0GT EserotoninF
*resent in minimal amts in CNS
*ath"ays - sites of a.n of many drugs
X DO*!MIN/
orig regarded as pre%ursor of N/
L D! Rs :
7 DA0li6e EDA , DL RsF
7 DJ0li6e Rs EDJ1 D[1 DaF




QLMb CNS %ate%holamine %ontent - D!
Nery large amts of D! 0 in 2asal ganglia
[ Major D!0%ontg path"ays:
0 nigrostriatal ; degenerates in *ar6inson
0 meso%orti%al
0 tu2ero0infundi2ular
*ath"ays , Rs 0 impli%ated in s%hi3o ,
*ar6inson7s dse and in adverse e$e%ts $
pharma%oR. of said dsrdrs'


X NE ; most are lo%ated in lo%us %eruleus
%an hyperpolari3e neurons ,
in%reases SP %ondu%tan%e1 mediated
2y \0J Rs , enhan%es e.%itatory
inputs'
0 esta2lished NT in synapses
o /pinephrine 0 vague physio properties

X L0GT ESerotoninF a%ts on many Rs
!ll LGT Rs e.ert inhi2itory ,
e.%itatory a%tions
L0GT path"ays may2e involved "ith
hallu%inations indu%ed 2y 9SD
Other regulatory f.ns of L0GT:
sleep1 temperature1 appetite1
neuroendo%rine %ontrol'
X Gistamine 0 thought to a$e%t arousal1
2ody tempt1 vas%ular dynami%s
0 GA and GJ
0 no R.ti% appli%atn1 only antags
X *eptides: opioids1 neurotensin1
su2stan%e *1 somatostatin1 NI*1
%hole%ysto6inin1 neuropeptide Y1
thyrotropin0releasing fa%tor : asso%iatd
"ith sensory unmyelinated &2ers that
transmit no.ious stimuli'
X NI(RIC OXIDE
e.ist in su2stantial amts in CNS as
NOSEnitri% o.ide synthaseF
/n3yme a%tivated 2y Ca %almodulin ,
a%tivatn of NMD! Rs K ^ intra%ell Ca
K generation of NO
*hysio role of NO: in vas% smooth mm
Role in synapti% transmission : %ontroversial
* Beie*/ st,on.est ,oe o* NO : *o, on.te,&
+e#,essn o* syna#ti" t,ans&issn in "e,e1e-&



Classi&%ation:
+eneral CNS depressants:
anestheti%s1 al%ohols1
sedative0 hypnoti%s
c Depress e.%ita2le CNS tissues
; release NTs P general
depression of postsynapti%
response , ion movt'
+eneral CNS stimulants:
0 po"erful stimulants
/.' *entylenetetra3ol
0 "ea6 stimulants
/.' Methyl.anthines
c 5lo%6 inhi2itory %enters <
dire%t neuronal e.%itation'
Drugs that sele%tively
modify CNS f.n:
0 anti%onvulsants1 NS!IDs
0 opioids1 anti*ar6inson7s1
0 appetite suppressants1 ethanol1
0 antiemeti%s1 antipsy%hoti%s1
0 some stimulants , sedative0
hypnoti%s1 antidepressants
c Cause depression or e.%itation
/nd of CNS Intro
GENERAL ANES(=E(ICS
Boa,+ E2a& Re>ie%- 200?
I+ea GA "$a,a"te,isti"s/
- In+-"e oss o* "ons"io-sness s&oot$y @ ,a#i+y3
- ),o&#t ,e"o>e,y o* "o.niti>e *2ns a*te, +,-. is +A"
- Wi+e &a,.in o* sa*ety
- De>oi+ o* a+>e,se e0e"ts
NO sin.e anest$eti" is "a#a1e o* a"$ie>in. +esi,a1e e0e"ts %Ao a+>e,se ,ea"tions3
Baan"e+ anest$esia : i&#,o>e+ GA t$at -ses a "o&1ination o*/ IV B*o, in+-"tionCD
in$aation B*o, &aintainan"e o* anest$esiaCD &-s"e ,ea2antsBto *a"iitate t,a"$ea
int-1ation @ o#ti&iEe s-,.e,yC AND #,eo# &e+s to #,e>ent si+e e0e"ts3
Types of +!:
- IN : 1a,1it-,ates B($io#entaD Met$o$e2itaC1 1enEo+iaEe#inesBMi+aEoa&D DiaEe#a&CD
),o#o*oD Feta&ineD o#ioi+ ana.esi"s EMorphine =entanyl1 Sufentanil1 !lfentanil1
RemifentanilF1et al'
- Inhalation : Nolatile liIuids EIso?urane1 Des?urane1 Sevo?uraneF1 gaseous ENOF
C-,,ent anest$esia #,a"ti"e/ Use of %om2ined drugs in minimal e$e%tive doses "hile minimi3ing
adverse rea%tions'
Stages of !nesthesia E+udel7s signF:
St of analgesia Eat later phase1 amnesiaF
St of e.%itement
St o* s-,.i"a anest$esia ; loss of responsiveness to no.ious stimuliE/.' Trape3ius mus%le sIuee3e
, reesta2lishment of regular RRF - ,eia1e in+i"ation t$at s-,.i"a anest$esia $as 1een
a"$ie>e+ a+eG-ate *o, s-,.i"a in"ision3
St of medullary depression
),eo# &e+s ; a &-st to give to prevent V2adW rea%tions to anesthesia
NS monitoring ; most %ommon method of assessing depth of anesthesia
> Others: //+02ased automated methods: 5ISE2ispe%tral inde.1 *SI Ephy state inde.F1 CSI E%ere2ral state
inde.F more rapid re%overy from anesthesia'

ING!9/D !N/STG/TICS
Nitrous o.ide1 Galothane1 /n?urane1 Metho.y?urane1 Iso?urane1 Des?urane1 Sevo?urane
=a%tors that in?luen%e the upta6e of a therapeuti% %on% of an anestheti% to the 2rain in%lude:
solu2ility of the anestheti%1 its %on% in the inspired air1 volume of pulmonary ventilation1 pulmonary
2ld ?o" and partial pressure gradient 2et"een arterial and mi.ed venous 2ld anestheti%
%on%entration'
1+/.as #a,tition "oeH"ient 5 in+e2 o* so-1iity the relative a@nity of an anestheti% for the
2lood %ompared "ith that of the inspired air'
Relation of anestheti% solu2ility to *C to partial pressure to M!C ddd
/.' Nitrous o.ide , des?urane ; insolu2le
in 2ld
/.' NO#des?urane ; insolu2le
halothane#iso?urane solu2le
!netheti% %on% in the inspired air ; dire%tly proportional to the partial pressure or tension in alveoli ,
in 2lood'
e M!C ; anesth %on% that produ%es
immo2ility in LMb of pts e.posed to
no.ious stimulus'
e M!C ; inversely proportional to the 5:+
partition %oe@%ient


LOCAL ANES(=E(ICS
Boa,+ E2a& Re>ie% -200?
Lo"a anest$eti"s
- Cause reversi2le 2lo%6 of impulse %ondu%tion along nerve a.ons , other e.%ita2le mem2ranes B
2lo%6 pain sense from sympatheti% vaso%onstri%tor impulses to spe%i&% areas of the 2ody'
- Utili3e Na "$annes as t$e &aIo, &eans o* A) .ene,ation3
- Co%aine ; A
st
9! introdu%ed in mar6et
- 2 #,ototy#a LAs: ),o"aine este, @ Li+o"aine a&i+e
- Site: dermis , soft tissues lo%ated in the
area of nerves ' /ster 9!s ; prone to hydrolysis
thus have shorter DO!
- 9ess e$e%tive "hen inje%ted into infe%ted tissues
- Syste&i" a1s,#tn o* inIe"te+ LA +e#en+s on/ dosage1 site of inje%tion1 drug0tissue 2inding 1 lo%al
2ld ?o"1 use of vaso%onstri%tors1 and physi%o%hem props of the drug itself'
!ppli%ation of 9! to a highly vas%ular area more rapid a2sorption than that of poorly perfused
tissues as tendon1 fats1 dermis'
BeneJts o* Vaso"onst,i"to, Be#ine#$,ineC -se in LA/
Q Redu%es a2srptn of 9! from the inj.n site
2y de%r 2lood ?o" in this area this is
impt for 9!s "ith short DO!'
/.' ),o"aineD Li+o"aineD Me#i>a"aine

Q lo"er lo%al 2ld levels 2y [Mb 0 lead
to enhan%ed neuronal upta6e Jndary to
higher lo%al tissue %on% in the area of
drug adm "ith redu%ed systemi% e$e%ts'
K S)INAL ANES(=ESIA/ E#ine#$,ine
a%ts on s' %ord at the \0adreno%eptors
f inhi2it release of su2stan%e * ,
redu%e sensory neuron &ring led to
use of Clonidine , De.medetomidine
augment 9! e$e%t in su2ara%hnoid
spa%e , on periph nerves'

Q Naso%onstri%tors 0 _a%tive in prolonging
9! e$e%t "hen anestheti%s are more
lipid solu2le , long a%ting sin%e their
mole%ules are highly tissue 2ound'
/.' 5upiva%aine1 Ropiva%aine
- *rimary MO! of 9!s:
5lo%6 voltage0gated Na %hannels

Types of 9!:
Topi%al: nasal mu%osa1 "ound margins
Inje%tion : in vi%inity of peripheral nerve endingsEin&ltrationF
Inje%tion at major nerve trun6s E2lo%6sF
/pidural , su2ara%hnoidal inje%tion surrounding the spinal %ord
IN regional anesthesia0 5ier 2lo%6 ; for short surgi%al pro%edures of U/#9/
ALCO=OLS
Boa,+ E2a& Re>ie% 200?
so%ially a%%epted re%reational drin6
9o"0moderate amts
an.iolyti%
euphori%
improves appetite
*ro2lem: al%ohol a2use#al%oholism1 VDUIW
=orms: /thanol#Methanol#ethylene gly%ol

E(=ANOL
=20-so-1e L a1so,1e+ ,a#i+y *,o& GI( ;
M #ea! 1+ "on" in N0 &in L ,a#i+ tiss-e +ist,i1-tion
'oo+ +eays a1so,#tion 1y so%in. .ast,i"
e&#tyin. ti&e
CNS/ A"$ie>es *aste, 1,ain a"o$o "on" sin"e
it ,e"ei>es a,.e >o o* 1+ Oo% < easy
#assa.e t$,- BBB
(y#i"a a+-t "an &eta1oiEe P-10 .&s a"o$o #e, = 1 9+,in!Q o* 1R oE 1ee,D N-SoE
%ineD
1 oE +istie+ R0 #,oo* s#i,its3
K ?0T a"o$o : o2i+iEe+ in i>e,D t$e ,est e2",ete+ in -,ine @ t$,- t$e -n.s
9 B,eat$Q test - se,>e as 1asis *o, e.aity o* DUI
2 &ain #at$%ays o* a"o$o &eta1ois&/ AD= Ba"o$o +e$y+,o.enaseC @
MEOSB &i",oso&a et$ano o2i+iEin. syste&C3
ME(ABOLISM o* ALCO=OL /
Et$ano >ia AD= @ MEOS U "on>e,te+ to a"eta+e$y+e U >ia ALD= a"etate
AD= : "atayEes "on>e,sion o* a"o$o to a"eta+e$y+e in i>e, : ?0T i>e, o2i+ation
6 AD= : #,esent in i>e, 1-t aso #,esent in 1,ain
in 1,ain @ sto&a"$ B K .ast,i" &eta1
in 1-t ess in +At Ve>e o* .ast,i"
AD= in C "ont,i1-tes to se2-
,eate+ 1+ a"o$o "on" +i0e,en"es3
D. et$ano o2i+ationD =< is t,ans*e,,e+ *, a"o$o
to ni"otina&i+e a+enine +in-"eoti+eBNAD<C to
*o,& NAD= .ene,ation o* an 2"s o* NAD=
in i>e, %A *,eG a"o$o U "ont,i1-te to &eta1oi"
+iso,+e,s in "$,oni" a"o$ois&
MEOS &i2e+-*2n o2i+ase syste& : "onsists
1o o* "yto"$,o&e )WS0 enEy&es -ses NAD)=
as "o*a"to, in et$ano &eta1ois& in+-"e+ 1y
"$,oni" a"o$o "ons-&#tion ,es-ts in si.ni*
in",eases not ony in et$ano &eta1os&D 1-t aso
in "ea,an"e o* ot$e, +,-.s ei&inat+ 1y "y)WS0
Bto2insD *,ee ,a+i"asD =2O2C
)=ARMACODXNAMICS
CNS/ CNS +e#,essant >a,ia1e e0e"ts *,o& se+ationD 9$i.$QD so%e, ,2n ti&es BS0-
100&.A+LCY i&#ai,e+ &oto, *2nD s-,,e+ s#ee"$D ata2ia B100-200 &.A+LCY e&esisD
st-#o,B200-S00CY "o&aBN00-W00CY ,es#i,ato,y +e#,essionD +eat$ B KS00&.A+LC
* asso %A .-ta&ate @ GABA N(s
Mo+e,ate a&tsB K100&.A+LC 5 +e#,essant 5 "a,+io&yo#at$yD $ea,t *ai-,eD
a,,$yt$&iasD =)N
S&oot$ &-s"es : >aso+iato, 2o to VMC +e#,ession @ +i,e"t s&oot$ &-s"e ,ea2ation 1y
a"eta+e$y+e a2n < >aso+iation-in+-"e+ $y#ot$e,&ia
Li>e, @ GI( : &ost "o&&on &e+i"a "#2 : *atty i>e,D $e#atitisD "i,,$osis *ai-,eD "$,oni"
#an",eatitisD .ast,itisD 1ee+in.D &an-t,ition
Ne,>o-s syste& : toe,an"eA#$y +e#en+en"eY +ei,i-& t,e&ensD We,ni"!e Fo,sa!o0
syn+Y ne-,o#at$ies
'e +e* ane&ia : &ost "o&&on
V i&&-ne syste&
Z CA ,is! : &o-t$D GI(D i>e, : a"eta+e$y+e "an
+a&a.e t$e DNA < t$e *,ee ,a+i"as
C$,oni" "ons-&#tion o* a,.e a&ts o* a"o$o 5K Z,is! o* +eat$s
A"o$o-+,-. inte,a2ns/ +At its e0e"t on "yto )WS0
(=ERA)X
ACU(E IN(OXICA(ION/
- Goa/ #,e>ent se>e,e ,es# +e#,ession @ as#i,ation o* >o&it-s
'ata BAC - KW00&.A+L
- R2 e2istin. $y#o.y"e&ia @ !etosis : a+& .-"ose
- ($ia&ine : to #,ote"t *,o& W-F syn+,o&e
- '-i+s : *o, +e$y+,ation
- F< as on. as N !i+neys : *o, se>e,e >o&itin.
* Be%a,e o* Vse,-& )OW : a..,a>ate+ 1y .-"ose
ALCO=OL WI(=DRAWAL SXNDROME
A1,-#t %it$+,a%a o* a"o$o -se
Main .oa/ ),e>ent seiE-,esD +ei,i-& D a,,$yt$&ias
- Mi+ %+,% &ay not nee+ +,-. inte,>ention
- Resto,e i&&e+iate ee"t 1aan"e %A F<D M.<<D )OW ,a#i+yD "onsistent %A ,ena *2n3
- ($ia&ine : in a "ases o* a"o$o to2i"ity
- S#e"iJ" R2/ s-1stit-tion R2 %A a on.e, a"tin. S-= a.t3 E23 BenEo+iaEe#ine : DOC +At
%i+e &a,.in o* sa*ety
B+iaEe#a&D "$o,+iaEe#o2i+eD "o,aEe#ateC
- Co&#ete +eto2iJ"ation : &ay ,eG-i,e se>e,a &os to ass-,e no,&aiEation o* NS *2nD es#
see#3
ALCO=OL DE)ENDENCE
- )sy"$oso"ia R2 @ Re$a1 #,o.,a&s 5 1o R2
- 'DA-a##,o>e+ +,-.s/ Dis-J,a&D Nat,e2oneD A"a&#,osate
- Dis-J,a&
MOA/ in$i1its ALD= no o2i+ation o* a"eta+e$y+e a"eta+e$y+e a""-&-ates3
In t$e #,esen"e o* +is-J,a&D ALD= is in$i1ite+ a"eta+e$y+e is not o2i+iEe+
a""-&-ates -n#easant sensationB sa&e as a"o$o into2i"ationC3
DRUGS O' ABUSE
5oard /.am Revie" ; JMMg

Dr' hudith 5' Song%o
=a%ulty1 Dept of *harma%ology
Mem2er: *S/C*1 *O+S
DeJnition
Drugs that are not medi%ally approved
2ut used 2e%ause they %reate strong
feelings of euphoria or alter per%eptive
sense e$e%t of all addi%tive drugs'
Repetitive e.posure to said drug
indu%es adaptive %hanges in 2rain <
toleran%e U d#% U "ithdra"al syndr
E0e"t/ "o&#-si>e -se 5 9 $a&a,!
o* a++i"tion Q
DE)ENDENCE >s ADDIC(ION
De#en+en"e refers to Vphysi%al
dependen%eW --Q repetitive e.posure
to a drug -Qindu%e adaptive %hanges
--Q toleran%e , "dr"l S. upon d#%
of a2used drug'
Dependen%e %an also o%%ur "th non0psy%ho
a"ti>e +,-.s B E23 Nit,ate >aso+iato,sD
1,on"$o+iato,sC


A++i"tion 0 %ompulsive relapsing
drug use triggered 2y V%ravingsW1
despite E0F %onseIuen%es [ [
D#C inta6e -Q EPF "ithdra"al
syndrome
De#en+en"e ; invaria2ly o%%ur "ith
%hroni% e.posure 2ut only a fra%tion
"ill develop a ha2it1 lose %ontrol ,
2e%ome addi%ted'
Reati>e ,is! *o, A++i"tion/
0 Co%aine ; L
- !mphetamine 0L
- Opioids ; a
- Ni%otine 0a
- !l%ohol ; [
- 5en3odia3epines ; [
- Canna2inoids ; J
- LSDD Mes"aineD )sio"y1in : 1
- )$en"y"i+ineD Feta&ine -1
(=EORX/
13Mesolim2i% D! system ; Ao target of addi%tive drugs a%tivated dire%tly 2y addi%ting drugs RD!
%on%entration'
J' D! ; 2elieved to 2e the neuro%hemi%al %orrelate of pleasure , re"ard' RD! levels is the origin of adaptive
%hs underlying dependen%e and addi%tion'
As a general rule, all addictive drugs activate the mesolimbic DA system.

CassiJ"ation o* A1-se+ D,-.s
o 1
st
G,o-# : a"ti>ate Gio-"o-#e+ Rs/
7 In"-+e/ o#ioi+sD "anna1inoi+sD
G=BB.a&&a $y+,o2y 1-ty,i" a"i+CD
$a-"ino.ens
A3 O)IOIDS
7 Most "o&&ony a1-se+ o#ioi+s/ Mo,#$ineD =e,oinD Co+eineD O2y"o+oneD
Me#e,i+ineD


7 Indu%e toleran%e and dependen%e
`ithdra"al syndr may 2e very severe
)*T for Codeine - nausea , N1
intense dysphoria1 mus%le a%hes1
la%rimation1 rhinorrhea1 mydriasis1
piloere%tion1 s"eating1 diarrhea1
ya"ning , fever <lasts for fe" days
Opioids as analgesi% rare dev
of addi%tion , "ithdra"al synd
5UT if used for re%reational aims <
highly addi%ting

R2 *o, a"-te O#ioi+ to2i"ity/
> Nalo.one ; opioid antag 0 life0saver -Q
reverses e$e%ts of a%ute opioid
overdose "#n minutes
> Opioid addi%ts: Nalo.one -Q triggers
a%ute "dr"l or pre%ipitated S.' 5/`!R/ i
7 R2 *o, o#ioi+ a++i"tion/ Su2stitution
therapy ; *rin%iple d
> Methadone 0DOC

CANNABINOIDS
J0ara%hidonyl gly%erolEJ0!+F and
!nandamide endogenous %anna2inoids
that a%t as NTs < Vretrograde
messengersW released at postsynapses
< di$use thru e.tra%ellular spa%es to
2ind "ith presynapti% C5A Rs K inhi2it
the release of glutamate or +!5!
e.ogenous %anna2inoids - marijuana j
stimulant e$e%t in minutes j ma.imum
e$e%t in A0JG - euphoria#rela.ation
Marijuana 0high doses -Q visual hallu%ination1 depersonali3ation1 psy%hoti% spells1 Rappetite1 nausea
relief1 _IO*1 analgesia'
Chroni% use -Q dependen%e "#mild1
2rief "dr"l syndr' !ddi%tn potential EJF
DRON!5INO9 #N!5I9ON/ 0the only
approved syntheti% %anna2inoid
agonists

G=BB.a&&a O= 1-ty,i" a"i+C : meta2olite of +!5! ; V.W f.n ; "as utili3ed in AklM as gen anestheti%
2ut restri%ted d#t its narro" margin of safety P addi%tive potential
( a sedative1 euphori%1 enhan%er of
sensory per%eptions1 feeling of
so%ial %loseness1 amnesia 0%alled
iG-i+ e"sta"y

SYNO: W%lu2 drugW1 Vgrievous 2ody
harmW1 Vdate rape drugWEsin%e
odorless1 %an 2e readily a2sor2ed
in 2everages' *ea6 plasma %on%
in JM0[M min $ inta6e of a AM0JM
mg#6g dose
elimination t m in [M
minutes'

LSDD MESCALINED )SXLOCIBIN
7 %alled hallu%inogens nalter %ons%iousness1 pt senses things that are
not prsent1 sees them distorted1 li6e shape , %olors
syno: psy%hotomimeti%s d#t psy%hosis0li6e S.Edepersonali3ation1 hallu%ination1 ?ash2a%6sF
produ%e somati% S.: di33iness1 paresthesia1 2lurred vision
Di$eren%e 2et hallu%inogens , other drugs:
Do not indu%e dependen%e nor addi%tion 2ut freIuent e.posure leads to toleran%e
Mole%ular target: LGT0J! Rs
o J
nd
+ROU* 0 Drugs that mediate e$e%ts thru ionotropi% Rs
In%ludes: Ni%otine1 5en3odia3epines1 !l%ohol1 Setamine1 *hen%y%lidineE*C*F1 Inhalants

NICO(INE
more than LMb addi%tion in%iden%e
%ommon in to2a%%o smo6ers1 %he"ers , snu$ers
agonist at Ni%otini% !Ch Rs -Q improves %ognitive performan%e may 2e of value in !l3heimer7s
dementia
"ithdr"al milder %ompared to that of opioids
7 R2/
Su2stitute %he"ed1 inhaled1 or transdermally delivered ni%otine for that %ontained in %igarettes
Other alternatives: smo6e0free areas -Q prevents J
nd
hand smo6e
5upropion 0 antidepressant
BEN\ODIA\E)INESABARBI(URA(ES
%ommonly used as an.iolyti%s , sleep indu%ers
5en3os 0 a2used 2y some for their
euphoriant e$e%t
5ar2is ; most %ommonly a2used S0G ne.t to ethanol 5UT rarely pres%ri2ed
2oth asso%iated "ith +!5! Rs
ALCO=OL BE(=ANOLC
7 regularly used 2y many
Only a fe" 2e%ome dependent , addi%ted to it 5UT a2use is a very serious health pro2lem1 d#t diseases
asso%iated "ith al%oholism'
!lters f.n of many Rs ; %omple. pharma%ology
Dependen%e ; apparent in l0AJG after d#% of heavy drin6ing as "dr"l S.
Delirium tremens ; L0ALb mortality
7 R2/
!l%ohol "dr"l S. ;supportive ; use of 2en3os Eo.a3epam1 lora3epamF
Chroni% a2users ; psy%hoso%ial approa%h
Drug R.: di$erent goals
] Dis-J,a& %reates aversion to"ard
al%ohol dg inta6e 2y: inhi2iting
a%etaldehyde dehydrogenase
] Nat,e2one !ntag#partial !g of mu
opioid Rs < o%raving for al%ohol "ith fe"
relapses ; enhan%ed R. "#2ehavioral R.


( TopiramateEantiepilepti%F fa%ilitates
+!5! f.n P antagoni3es glutamate Rs
P may o meso%orti%al0lim2i% D!
release after al%ohol j o %ravings
( E!%amprosateF 0 NMD! Rs antag ; less
e$e%tive than Naltre.one
FE(AMINE @ )C) B)$en"y"i+ineC
7 developed as +en anestheti%s
7 %alled V%lu2 drugsW1 Vangel dustW1 VhogW1
Vspe%ial SW
7 their e$e%ts 2e%ame apparent "hen pts in surgery reported unpleasant vivid dreams , hallu%inations after
anesthesia
7 sold as po"der1 liIuids1 %aps1 pills snorted1 ingested1 smo6ed1 inje%ted --Q
psy%hedeli% e$e%ts . AG1 R5*1 impaired memory , visual a2n
7 high doses -Q out of 2ody , near0death e.perien%e
7 E0F dependen%e , addi%tion
%hroni% use -Q long0lasting psy%hosis
IN=ALAN(S
a2use ; re%reational e.posure to vapors of: nitrates1 nitrous o.ide1 amyl nitrite EVpoppersWF1 6etones1
aliphati% , aromati% hydro%ar2ons ; fd in household and industrial produ%ts
inhaled via sni@ng p hu@ng p as
a++i"tion +e>eo#s ^ 1a..in. 3
prevalent in %hildren , young adults
MO!: V .W
( V*oppersW < Ao %ause smooth m rela.atn
P Rere%tion1 non0addi%ting
( Chroni% < to.i%ity e$e%ts on organs

o N
,+
GROU) : D,-.s t$at 1in+ to t,ans#o,te,s o* 1io.eni" a&ines3
COCAINE
major "orl"ide pro2lem
highly addi%tive ; relative ris6: L
al6aloid in leaves of Erythroxylan coca
%lini%al use: 9! , ophthalmi% mydriati%
V%ra%6 %o%aineW Esmo6edF instantaneous VrushW parenteral or a2sor2ed thru mu%ous mem2ranes
Enasal snortingF
5lo%6s reupta6e of D!1 LGT1 N/ transporters'
D!T 2lo%6 -Q responsi2le for re"arding e$e%ts of %o%aine'
N/T 2lo%6 -Q a%tvtd SNS -Q G*N1 ta%hy1 vent arrhythmias1 anore.ia1 insomnia1 hypera%tvty1 Rris6 for
stro6e1 IC hge1 MI1 sei3ures'
Sus%ept pts dependent , addi%ted after fe" e.posures to %o%aine -Q very strong %ravings1 high
addi%tion lia2ility
NO S)ECI'IC AN(IDO(E3 R2 s-##o,ti>e3
AM)=E(AMINES
Meta&#$eta&ine
7 dire%t a%ting sympathomimeti% agts release of 2iogeni% amines EN/1D!F
Together "#+G5 , e%sta%y - V%lu2 drugsW
Di$er from e%sta%y in the %onte.t of use ; %alled Vhard %oreW addi%tives d#t IN route
7 In general1 amphetamines-QR%ate%hols -Q Rarousal , _sleep
7 ZDA -Q euphoria1 a2n movts1 psy%hoti% episodes
7 ZS-=( 5K $a-"ino.eni" @ ano,e2i.eni"D $y#e,t$e,&ia
Unli6e other a2used drugs !mphetamines are neuroto.i% ; V.W me%h ; 2elieved to 2e d#t NMD! Rs
a$e%ting mainly L0GT , D!'
Can 2e ta6en as pills1 inje%ted or smo6ed
/$e%ts: e.%itation1 euphoria1 agitation1 2ru.ismEtooth grindingF1 ?ushed s6in1 ta%hy1 arrhythmias1 G*N %risis
ECS(ACX BMDMAC
7 name of a %lass of drugs that are dvts of amphetamine0related %pd: MDM!
E methylenedio.ymethamphetamine F
7 originally used in psy%hoR. 2ut "#o useful e$e%ts
M!IN /==/CT: *O to foster feelings of intima%y , empathy "#o impairing intelle%tual %apa%ity
7 CURR/NT: produ%ed in small Iuantities distri2uted as VravesW in small parties
the prototypal popular designer drug
9i6e amphetamine %auses release of 2iogeni% amines 2y reversing the a.n of their transpoters
preferential a@nity to S/RTELGT transporterF thus1 in%reasing e.tra%ellular %on% of LGT
qq
%ause a profound release of LGT that
there is mar6ed intra%ell LGT depletion
for JaG $ a single dose < %hroni% use
K neuroto.i%ity'
Ot$e, e0e"ts o* MDMA/
( hyperthermia P dehydration =!T!9
> D#t fear of a2ove S. pt often drin6
GJO .%essive amts GJO
into.i%ation
( serotonin syndrome: !N hypera%tivity1 %hange in mental status1 NM a2n1 sei3ures
( EPF "ithdra"al syndrome : depression up to several "6s or R aggression
CLINICAL )=ARMACOLOGX
No sin.e +,-. R2 "an eH"ienty ei&inate a++i"tion
In massive overdose1 antidote drug may 2e life0saving ho"ever1 =D!0approved antags are only
availa2le for 2en3os
, opioids
Clonidine ; \0adr agonist ; %entrally a%ting used "#su%%ess in attenuating "ithdra"al S.
Su2stitution R. 0 long a%ting agonist in pla%e of the addi%ting drug 0 approved for opioids , ni%otine
2ene&ts: _asso health ris6s1 _ drug0asso %rime1 , 2etter so%ial integration' Control of persisting
dependen%e is motivated 2y 2ehavioral approa%h to motivate addi%ts to gradually redu%e the dose
and 2e%ome a2stinent'
5iggest %hallenge: R. of addi%tion itselfiii
Naltre.one ; mi.ed !g0!ntag drug modest e$e%t ; for opioid , al%ohol a2use
5a%lofen ; high0a@nity +!5!02 Rs !g inhi2its D! neurons signif _ %ravings'
Rimona2ant ; %anna2inoid !ntag developed for ni%otine1 al%ohol1 %o%aine1 heroin'
end
O)IOID
ANALGESICS
Morphine ; prototypal opioid agonist
MOR)=EUSD +ree6 god of dreams
Sour%e: Opium poppyE*apaver somniferumF
al6aloid fr poppy seeds U opium U many
al6aloids U AMb Mo,#$ine "ontent
Ot$e, +>ts/ =e,oinD "o+eineD Nao2one
/ndogenous opioid peptides: endorphins1 en6ephalins1 dynorphin arise fr' *OMC1 preen6ephalin !1
, preprodynorphin Eproen6ephalin 5F
O#ioi+s a"t on en+o.eno-s #e#ti+es %Ao#ioi+-i!e #$a,&a #,o#e,ties3

Ran! o* EH"a"y o* "o&&on O#ioi+s/
Mo,#$ine Gydro , o.ymorphone
Methadone Meperidine =entanyl
9evorphanol Nal2uphine
5uprenorphine 5utorphanol Q O.y%odone
and Gydro%odone Q O.y%odone and
Gydro%odone *enta3o%ine Q Codeine
Q *ropo.yphene
CassiJ"ation/
'- a.onistsE M1 heroin1 hydromorphone1 o.ymorphone1 Methadone1 =entanyl1 Sulfentanil1
Meperidine1 9evorphanolF
&i+-&o+e,ate A.sE%odeine , dvts1 *ropo.yphene1 Dipheno.ylate1 Difeno.in1 9operamideF
O#ioi+s %it$ &i2e+ a"tions:!g0!ntags ENal2uphine1 *enta3o%ine1 5uprenorphine1 5utorphanolF
Mis%ellaneousETramadolF
SIGNI'ICAN( )=ARMA )RO)ER(IES/
A
ST
pass liver meta2olism ; lo"ers 2ioavaila2ility need for a higher *O dose than parenteral
Co+eine @ O2y"o+one ; e$e%tive orally d#t redu%ed A
st
pass meta2olism
Nasal inhalation rapid R.ti% 2ld levels
Other routes: transdermal1 parenteral
Dist,i1-tion/ Rapidly leave 2lood B highly perfused tissues , less to adipose t' 2ut tends to
a%%umulate 2e"are of freIuent or q dose1 %ontinuous adm sin%e opioids are very lipophili%' E23
'entany


Morphine has a neuroe.%itatory meta2oliteEM[+F responsi2le for sei3ures'
> M[+ EM0[0glu%uronide ; not mediated 2y mu Rs 2ut 2y +!5!#gly%inergi% systemF'
AMb of M ; meta2 to Ml+ a%tive analgesi% a0l. more than parent M'
Meperidine U normeperidine meta2olite in q doses -Q e.%itatory Esei3uresF
=entanyl no a%tive meta2olites reported
Codeine ; its %onversion to M is of greater impt sin%e "o+eine #e, se $as o% aHnity *o, o#ioi+
Rs3
ORGAN E''EC(S
CNS :a@nity to mu Rs -Q euphoria1 analgesia1 sedation1 respiratory depression1 %ough
suppression1 miosis Evalua2le in overdose as E0F toleran%e1 trun%al rigidity1 n , v1 tempEmu0Rtempt1
6appa0_temptF
D>ts o* #$enant$,ene : &o,e se+ation , less freI "# syntheti% preps
Resp depression ; a$e%ts all opioids ; ho"ever less in opioids intera%ting "ith 6appa Rs EMeperidineF
!s %ough suppressants: doses 2elo" that reIuired for analgesia1 , devoid of addi%tion potential
%ommonly used antitussives: Codeine1 De.tromethorphan1 levopropo.yphene1 Nos%apine
* (,a&a+o : %entrally a%ting analgesi%1 independent of mu Rs a%tivityH predom MO! is 2lo%6ade of LGT
reupta6e' Can also inhi2it N/ reupta6e' 5elieved to 2e a "ea6 mu R agonist' To.i%ity: sei3ures' No
reported resp , depression'
Miosis no dev of toleran%e - measure of
opioid overdose ; mediated 2y p0sympath
path"ay R.: Nalo.one , !tropine
Trun%al rigidity 0 R tone of large trun6 mm B
_thora%i% %omplian%e -Q interferes v#ventilation'
> =entanyl ; highly lipid solu2le ; IN adm ;
R.: opioid antags , NM5s
n , v 0 opioids a%tivate the CT8
Temperature ; mu Rs !gs EMorphineF -Q R tempt
00 6appa Rs -Q _tempt

*eripheral e$e%ts ; Most opioids has no signi&%ant e$e%ts on other than 2rady1 )*T1 Me#e,i+ine 5
ta"$y +At anti&-s"a,ini" a2n3
K &ini&a on "e,e1,a "i,"-D 2#t +. ,es# +e#,ession Z)CO2 "e,e1,a >aso+iat R%er2ral
2ld ?o" , IC*
+IT ; slo"ed -Q %onstipationEdessi%ated stoolsF
5iliary tra%t ; 2iliary %oli% "#Ramylase#lipase
Renal 0 _f.n1 antidiureti% e$e%t1 ureteral %oli%
Uterus ; may prolong la2or1 ho"ever studies sho" enhan%ement of %ervi%al dilat "#Meperidine
),-,it-s ; ?ushed1 "arm1 it%hy s6in prola%tin1 somatotropin 2ut inhi2it release
of 9G
Remar6a2le relief of dyspnea of *ulmonary edema d#t 9N= -Q _ an.iety1 _ preload Evenous
toneF1 _ afterload E*NRF
R. of diarrhea
Redu%es shivering ; Meperidine ; most pronoun%ed via its a.n on su2types of \0J adrenergi% Rs
!s preop meds ; an.iolyti%1 analgesi%1 sedative properties
Opiods in utero 0 fetus 2e%omes dependent in utero -Q "dr"l syndrome postpartum
R.: Dia3epam1 *aregori%1 Methadone
DONT US/ in pts "#impaired pulmonary f.n to avoid !Resp=ailure
5e %autious in pts "# liver malfun%tion sin%e opioids are meta2oli3ed in the liver
!drenal insu$ and hypothyroidism ; e.hi2it e.aggerated , prolonged responses to opioids'
(o2i"ity/
E2tensions o* t$ei, #$a,&a e0e"ts
R2/ A"-te o>e,+ose
o#ioi+ a++i"tion
)-,e A. < %ea! #a,tia A. 5KVana.esia < %+,% ,ea"tion
=ea+ inI-,ies < o#ioi+ 5K ,es# +e#,ession 5K "e,e1,a >aso+iat : et$a in #ts %AZIC)3
)=ARMACOLOGIC M2
O' MOVEMEN( DISORDERS

Boa,+ E2a& Re>ie% -200?
)ARFINSONISMB)a,aysis A.itansC
! progressive disa2ility %hara%t 2y rigidity1 2rady6inesia1 tremor1 , postural insta2ility
N: 2asal ganglia has R D! %on%entration
A1n/ _D! in *ar6insonism'
Drug R. "ith 9evodopa , other D! agonists has 2een su%%essful in alleviating %lini%al features of this
dse'
!lternative 2ut %omplementary approa%h aims to restore the N 2alan%e of %holinergi% , dopaminergi%
in?uen%es on the 2asal ganglia "ith antimus%arini%s'
D!minergi% therapy at an early stage may 2e most e$e%tive in alleviating S. of *ar6insonism'
S.ti% R. of mild *ar6inson7s is pro2a2ly 2est avoided until there is some degree of disa2ility or S.
2egin to have a signi&%ant impa%t on the patient7s lifestyle'
! trial of amantadine or antimus%arini% drug may 2e started "hen drug intervention is really
ne%essary'
D!nergi% R. 0 prn for progressive dse1 either alone or in %om2ination'
*T 0 for improvement of mo2ility
Severe *ar6insonism P longterm %p.s of levodopa R. E/.' on0o$ phenomenonF 0 trial R. "ith COMT
inhi2itor
Deep02rain stimulation ; may 2e helpful in pts "ho fail to respond to other measures
Young pts "ith mild *ar6inson7s ; Selegiline or Rasagiline
)a,!insonis& may 2e indu%ed 2y drugs'
Q Reserpine , Tetra2ena3ine K deplete
2iogeni% amines from storage sites
Q Galoperidol , *henothia3ines K 2lo%6
D! Rs
Q *ar6insonism ; also o%%urred in healthy
meperidine users attempting to support
opioid ha2it "# M*T*EA0methyl0a0phenyl0
A1J1[1l tetrahydropyridine - proto.inF ,
su2seIuently developed severe form of
*ar6insonism
LEVODO)A
N: D! do not enter 555 TGUS1 if given into the peripheral %ir%ulation NO R.ti% value
9/NODO*! 0 immediate meta2oli% pre%ursor of D! enters 2rain via 9!T de%ar2o.ylated to D!
5ene&ts of dopaminergi% anti*ar6inson drugs appear to depend mostly on intera%tion "ith DJ
RsE lo%ated in striatal neurons , a.ons in su2stantia nigra F1 5UT DA Rs stimulatn may also 2e
reIuired for ma.imal 2ene&t'
9evodopa ; a2sor2ed rapidly 2ut delayed 2y food1 esp amino a%id %ontent U J#[ of the dose as urine
meta2olitesE GN! , DO*!C F
Unfortunately only A0[b enters the 2rain un%hanged d#t predominant peripheral de%ar2o.ylation to
D!E "hi%h doesn7t penetrate the 555F j TGUS1 9evodopa must 2e given in large doses if used singly
'
Usually adm in %om2ination "ith a dopa de%ar2o.ylase inhi2itorE "#%h does not enter the 555 F K o
periph meta2olism of levodopa1 Rplasma levodopa levels more dopa enters the CNS'
Car2idopa ; peripheral dopa de%ar2o.ylase inhi2itor redu%es daily dose of 9evodopa 2y rLb'
C9INIC!9 US/
9evodopa 0 ameliorates all %lini%al features of *ar6insonism 5UT is parti%ularly e$e%tive in relieving
2rady6inesia'
5est results a%hieved in the A
st
fe" yrs of R.'
Daily dose must 2e redu%ed over time to avoid side e$e%ts
Clini%al trials sho" diminished e@%a%y post [0a yrs R.' It does not stop the progression of
*ar6insonism 1 2ut its early initiation lo"ers the MR'
Responsiveness ; may ultimately 2e lost that previously e$e%tive doses fail to eli%it R.ti% e$e%t'
*rep: Com2ined 9evo , Car2idopa ; !dvised to give at lo" dose P in%rease D!nergi% R. via D!
agonist drug1 if needed1 to redu%e the ris6 of development of responnse ?u%tuations'
ADVERSE E''EC(S/
+IT upset ; gMb 0 R.: divided doses or immediate p% or anta%id [M in ahead of drug
> !void *henothia3ines or any neurolepti% as antiemeti% redu%e anti*ar6 of 90dopa
> `#Car2idopa lesser +IT e$e%ts ; JMb 0 pts %an tolerate higher doses'
CNS 0 irregularities d#t q %ate%holamine formatn peripherally 0 _in%iden%e even "# dse , esp
"hen %om2ined "#Car2idopa'
( *ostural G*OT ;%ommon ; aS. 0 o "# %ont R.
Dys6inesias 0 gMb "ith %hroni% R. ; %ommonly presented as %horeoathetosis of fa%e , distal
e.tremities
5ehavioral e$e%ts ; insomnia1 agitation1 depression1an.iety1 delirium1 hallu%inations1 euphoria1et%' 0
more %ommon in levo0%ar2i E"hydF R.: atypi%al antipsy%hoti%s
Response =lu%tuations - Von0o$ phenomW ; in pts "ho responded "ell to initial R. ; V.W
Mis% e$e%ts: mydriasis1 2ld dys%ra%ias1 hot ?ushes1 gout1 a2n in smell#taste1 2ro"nish
saliva#urine#vagina1 priapism
DRUG =OLIDAX
d#% of drug for [0JAdays -Q transient improvement in response # alleviate adverse e$e%ts'
Carries ris6 of aspiration pneumonia1 venous throm2osis1 pulmonary em2olism1 depression Jndary to
immo2ility of *ar6inson7s TGUS1 drug holidays are NO longer re%ommended
DRUG IN(ERAC(ION
5l -Q Rmeta2 of 90dopa -Q _ R.ti% e$e%t
M!OI -Q G*N %risis
CON(RAINDICA(IONS : shdnt 2e given to psy%hoti% pts1 angle %losure glau%oma1 h. of melanomaE
sin%e 90dopa is a pre%ursor of melanin , may a%tivate malign melanoma
DO)AMINE Rs AGONIS(S
Dire%tly a%t on D! Rs 1 do not reIuire en3ymati% %onversion to an a%tive meta2olite1 no potential
meta2olite to.i%ities1 don7t %ompete "#other su2st for a%tive transport into the 2ld , a%ross 555
A)OMOR)=INE - #otent DA A. : -se+ &ainy as ,es"-e +,-. *o, #ts %A+isa1in. ,es#onse
O-"t-ations to e>o+o#a3
* DA A.s - A
st
line R. *or *ar6inson7s
BROMOCRI)(INE -Q DJ !g ergot dvt
!lso for endo%rinopathies1esp hyperprola%tinemia1 2ut in lo"er doses than for *ar6inson7s'
)ERGOLIDE
/rgot dvt dire%tly stimulates 2oth DA#DJ Rs
Clini%al trials -Q more e$e%tive than 5romo%riptine 2ut nonergot drugs are preferred sin%e its
asso%iation "ith valvular heart dse'
)RAMI)EXOLE
non-e,.ot +,-. %A#,e*e,entia aHnity *o, DN Rs
E0e"ti>e *o, &onoR2 o* &i+ )a,!inson_s
Aso $e#*- *o, a+>an"e+ +se - ao%s ,+2n o* Le>o+o#a +ose 5K ` ,es#onse O-"t-ations
< R2 o* a0e"ti>e 1e$a>io,
)ossess ne-,o#,ote"ti>e a"t>ty j s"a>en.e $y+,o.en #e,o2i+e in DA "e "-t-,es3
RO)INIROLE
nonergot al6aloid 0 same I. as *ramipe.ole
ADVERSE E''EC(S/
+IT a2n
Dys6inesias ; irreversi2le "#lo"ered doses
*sy%hiatri% rea%tions ; more %ommon than "ith 90dopa
CNS ; post G*OT at start of R.1 painless digital vasospasm1 arrythmias Ed#% R.F1 peripheral edema
Mis%ellaneous: heada%he1 nasal %ongestion1 Rarousal1 pulmonary in&ltrates1 erythromelalgia1
un%ontrolla2le urge to fall asleep
ContraI.: *ts "#G. of *SYCGOSIS1 a%tive *UD1 re%ent MI1 periph vas% dse
MAOI
Re"a/ > M!O0! meta2oli3es N/ , LGT
> M!O05 meta2oli3es D!

Selegiline ; irreversi2le inhi2itor of M!O05 at R.ti% doses , M!O051 as "ell "ith q doses'
Shd not 2e ta6en "ith Meperidine1 TC!s1 SSRIs serotonin synd S.' May also enhan%e adverse
e$e%ts of levodopa
Resa.iine ; M!O05 inhi2itor ; more potent than Selegiline
Cate"$o-O- Met$yt,ans*e,ase In$i1ito,s
* DO)A in$i1ition 8 "o&#ensato,y a"t>tn o* ot$e, #at$%ays o* L-+o#a &eta1ois&D es# COM(
a bNOMDB N-O-&et$y+o#aC e>es a #oo, R2ti" ,es#onse to Le>o+o#a
> _ R.ti% response to 90dopa ; sin%e [OMD %ompetes "#90dopa for an a%tive %arrier me%hanism that governs
its transport a%ross intestinal mu%osa , the 555'
(o"a#one @ Enta"a#one a prolong the a.n of 90dopa 2y _ its periph meta2olism via
%ompetition "ith the %arrier transport'
Tol%apone ; in%reases liver en3yme levels TGUS a need for patient7s %onsent 2efore start of R.'
Enta"a#one ; preferred sin%e E0F hepatoto.i%ity
A)OMOR)=INE ; dvt of Morphine -Q potent D! agonist ; e$e%tive for temp relief of o$0prds of a6inesia in
pts on dopaminergi% R.
AMAN(ADINE - antiviral1 anti0In?uen3a ! drug "ith anti0*ar6insonian a.n ; also a dopaminergi% agonist
-Q in?uen%es the synthesis of D!
Q less potent than 90dopa
Q overdosage -Q a%ute to.i% psy%hosis to %onvulsions
Q livido reti%ularis Q periph edema not asso
Q anti%holinergi% e$e%ts "#s or renal dse

!Ch02lo%6ing drugs 0 1enEt,o#ine &esyateD 1i#e,i+enD o,#$ena+ineD #,o"y"i+ineD
t,i$e2y#$eni+y improve tremor , ridity of *ar6insonism 2ut have minimal e$e%ts on
2rady6inesia'
SURGERX 0 for advan%ed stages
Thalamotomy or *osteroventral pallidotomy
Gigh0freIuen%y deep 2rain stimulation 0 _MR
Transplantation of D!nergi% tissueEsu2st nigra fr fetus
Ne-,o#,ote"ti>e ($e,apy 0 utili3es several agents su%h as: antio.idants1 antiapoptoti% agts1
glutamate antags1 glial0derived neurotrophi% fa%tor1 %oen3yme tAM1 %reatine1 antiin?ammatory
drugs'
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