harmaco|ogy Neuromuscu|ar kev|ew

Se|zure Med|cat|on
Selzure Lhe cllnlcal manlfesLaLlon of an abnormal and excesslve exclLaLlon and synchronlzaLlon
of a populaLlon of corLlcal neurons
LpllepLogenesls sequence of evenLs LhaL converLs a normal neuronal neLwork lnLo a
hyperexclLable neLwork
arLlal selzures
4 Slmple focal wlLh mlnlmal spread of abnormal dlscharge normal consclousness and
awareness are malnLalned
4 Complex local onseL and Lhen spreads lmpalred consclousness 1emporal lobe
epllepsy ls mosL common MosL common selzure Lype ln adulLs
4 Secondary Cenerallzed begln focally wlLh or wlLhouL focal neurologlc sympLoms
varlable symmeLry lnLenslLy and duraLlon of Lonlc and clonlc phases osLlcLal
confuslon somnolence wlLh or wlLhouL LranslenL focal deflclL
Cenerallzed selzures
4 Absence (eLlL mal) sudden onseL and abrupL cessaLlon Consclousness ls alLered and
may be assoclaLed wlLh mlld clonlc [erklng of Lhe eyellds or exLremlLles posLural Lone
changes auLonomlc phenomena and auLomaLlsms MosL common Lype ln klds
4 Myoclonlc myoclonlc [erklng ls Lhe ma[or selzure Lype uoesn'L sLarL ouL as a parLlal
4 ALonlc sudden loss of posLural Lone MosL ofLen ln chlldren
4 1onlcClonlc (grand mal) Lonlc rlgldlLy of all exLremlLles followed by Lremor LhaL ls an
lnLerrupLlon of Lhe Lonus by relaxaLlon 8elaxaLlon proceeds Lo clonlc phase wlLh
masslve [erklng of Lhe body buL Lhls slows over Lhe nexL 12 mlnuLes and ls followed by
sLupor
Acqulred Lpllepsy physlcal lnsulL Lo Lhe braln leads Lo changes LhaL cause selzures Lo develop
30 of paLlenLs wlLh severe head ln[urles wlll develop a selzure dlsorder
4 1umors sLroke CnS lnfecLlon febrlle selzure can all lead Lo epllepsy
CeneLlc Lpllepsy muLaLlon causes lncreased exclLablllLy or braln abnormallLy
4 CorLlcal dysplasla dlsplacemenL of corLlcal Llssue LhaL dlsrupLs normal clrculLry
4 8enlgn famlllal neonaLal convulslons
1he cause for mosL cases of epllepsy ls ldlopaLhlc
Cellular Mechanlsms of Selzure CeneraLlon
4 1oo much LxclLaLlon
lonlc lnward na and Ca currenLs
n1 CluLamaLe and AsparLaLe
4 1oo llLLle lnhlblLlon
lonlc lnward Cl ouLward k currenLs
n1 CA8A
AnLlepllepLlc drug LreaLs Lhe sympLoms of selzures noL Lhe underlylng epllepLlc condlLlon
1he goal ls maxlmlze Lhe quallLy of llfe by mlnlmlzlng selzures and adverse drug effecLs
4 AbouL 60 of all people wlLh epllepsy can become selzure free wlLh drug Lherapy
4 ln anoLher 20 Lhe selzures can be drasLlcally reduced
4 Cood oral absorpLlon and bloavallablllLy MosL meLabollzed ln Lhe llver buL some are
excreLed unchanged by Lhe kldney
4 Classlc ALus have more severe CnS sedaLlon Lhan newer drugs
4 8esL drug can be chosen based on mlnlmlzlng slde effecLs ln addlLlon Lo efflcacy
4 Addon Lherapy ls used when a slngle drug does noL compleLely conLrol selzures
1argeLs for ALus Many are pleoLroplc and acL Lhrough mulLlple mechanlsms
4 lncrease lnhlblLory n1 CA8A
4 uecrease exclLaLory n1 CluLamaLe
4 8lock volLage gaLed lnward poslLlve currenLs na and Ca
4 lncrease ouLward poslLlve currenL k
CluLamaLe Lhe braln's ma[or exclLaLory n1
4 2 groups of recepLors
lonoLroplc fasL synapLlc Lransmlsslon
O nMuA AMA kalnaLe
O CaLed Ca and CaLed na channels
MeLaboLroplc slow synapLlc Lransmlsslon
O CulsqualaLe
O 8egulaLlon of 2
nd
messengers (cAM and lnoslLol) modulaLlon of
synapLlc acLlvlLy
4 CluLamaLe recepLors as ALu LargeLs
nMuA recepLor slLes
O keLamlne hencyclldlne dlzoclplne block channel and have
anLlconvulsanL properLles Also block dlssoclaLlve and/or halluclnogenlc
properLles Cpen channel blockers
O lelbamaLe anLagonlzes sLrychnlnelnsenslLlve Clyclne slLe on nMuA
complex
AMA recepLor slLes
O 1oplramaLe anLagonlzes AMA slLe
CA8A ma[or lnhlblLory n1 ln Lhe CnS
4 2 Lypes of recepLors
CA8A
A
posLsynapLlc speclflc recognlLlon slLes llnked Lo Cl channel
CA8A
8
presynapLlc auLorecepLors medlaLed by k currenLs
4 ALus LhaL acL on CA8A
8enzodlazeplne (dlazepam clonazapam) lncrease frequency of CA8A
medlaLed Cl channel openlngs
8arblLuaLes (henobarblLal prlmldone) prolong CA8AmedlaLed Cl channel
openlngs Some blockage of volLagedependenL na channels
CabapenLln may modulaLe amlno acld LransporL lnLo Lhe braln May lnLerfere
wlLh CA8A reupLake
1lagablne lnLerferes wlLh CA8A reupLake
vlgabaLrln elevaLes CA8A levels by lrreverslbly lnhlblLlng lLs maln caLabollc
enzyme CA8ALransamlnase noL currenLly avallable ln Lhe uS
na Channels as ALu 1argeLs
4 neurons flre aL hlgh frequencles durlng selzures A generaLlon ls dependenL on na
channels usedependenL and LlmedependenL na channel blockers reduce hlgh
frequency flrlng wlLhouL affecLlng physlologlcal flrlng
4 ALus LhaL acL on na Channels
henyLoln Carbamazeplne block volLagedependenL na channels aL hlgh flrlng
frequencles usedependenL
Cxycarbazeplne blocks volLagedependenL na channels aL hlgh flrlng
frequencles Also effecLs k channels
Zonlsamlde blocks volLagedependenL na cahnnels and 1Lype Ca channels
Ca Channels as ALu 1argeLs
4 Absence selzures are caused by osclllaLlons beLween Lhalamus and corLex LhaL are
generaLed ln Lhe Lhalamus by 1Lype (LranslenL) Ca currenLs
4 ALus LhaL acL on Ca Channels
LLhosuxlmlde speclflc blocked of 1Lype currenLs and hlghly effecLlve ln
LreaLlng absence selzures
k channels as ALu 1argeLs
4 k channels have lnhlblLory conLrol over neuronal flrlng ln Lhe CnS repolarlze
membrane Lo end A
4 k channel agonlsLs would decrease hyperexclLablllLy ln Lhe braln
valproaLe Lhe only ALu wlLh known acLlons on k channels
8eLlagablne novel ALu ln cllnlcal Lrlals LhaL acLs on a speclflc Lype of volLage
dependenL k channel
leoLroplc ALus
4 lelbamaLe blocks volLagedependenL na channel aL hlgh flrlng frequencles May
modulaLe nMuA recepLor vla sLrychnlnelnsenslLlve Clyclne recepLor
4 LamoLrlglne blocks volLagedependenL na channels aL hlgh flrlng May lnLerfere wlLh
paLhologlc gluLamaLe release May lnhlblL Ca channels
4 1oplramaLe blocks volLagedependenL na channels lncreases frequency aL whlch
CA8A opens Cl channels anLagonlzed gluLamaLe acLlon aL AMA recepLor
4 valproaLe may enhance CA8A Lransmlsslon blocks volLagedependenL na channels
augmenLs k channels
AcuLe Selzure ulsorder LreaLed wlLh Lorazepam or oLher 8enzodlazeplnes
Chronlc Cenerallzed Selzure ulsorder LreaLed wlLh Carbamazeplne
rlnclple enzymes lnvolved wlLh ALu meLabollsm C?2C9 C?2C19 and C?3A
Classlc urugs
4 henyLoln flrsL llne drug for parLlal selzures
lnhlblLls na channels usedependenL
rodrug fosphenyLoln for lM or lv admlnlsLraLlon Plghly bound Lo plasma
proLeln
Palfllfe 2236 hours
Adverse effecLs CnS sedaLlon gum hyperplasla hlrsuLlsm
lnLeracLlons carbamazaplne henobarblLal wlll decrease plasma levels alcohol
dlazepam meLhylphenldaLe wlll lncrease valproaLe can dlsplace from plasma
proLelns SLlmulaLes cLy430 so can lncrease meLabollsm of some drugs
8ecommended ALu durlng pregnancy
4 Carbamazaplne flrsL llne drug for parLlal selzures
lnhlblLs na channels usedependenL
Palf llfe 612 hours
Adverse effecLs CnS sedaLlon AgranulocyLosls and aplasLlc anemla ln elderly
mlld LranslenL leucopenla (10 of paLlenLs) can exacerbaLe some generallzed
selzures
lnLeracLlons sLlmulaLes meLabollsm of oLher drugs by lnduclng mlcrosomal
enzymes sLlmulaLes lLs own meLabollsm May requlre an lncrease ln dose of Lhls
and oLher drugs Lhe paLlenL ls Laklng
4 henobarblLal parLlal selzures effecLlve ln neonaLes
Secondllne drug ln adulLs due Lo more severe CnS sedaLlon
AllosLerlc modulaLor of CA8A
A
recepLor (lncreases open Llme)
8apld absorpLlon
Palfllfe 33118 hours
Adverse effecLs CnS sedaLlon (exclLemenL ln some) skln rashes (allerglc)
Lolerance and physlcal dependence posslble
lnLeracLlons severe CnS depresslon when comblned wlLh alcohol or
benzodlazeplnes SLlmulaLes cyL 430
4 rlmldone parLlal selzures
AllosLerlc modulaLor of CA8A
A
recepLor
noL hlghly bound Lo plasma proLeln AbsorpLlon varles
Palfllfe varlable 313 hrs
ConverLed Lo henobarblLal and phyleLhyl malonamlde 40 excreLed
unchanged
Adverse effecLs CnS sedaLlon
lnLeracLlons enhances CnS depressanLs drug meLabollsm phenyLoln lncreases
converslon Lo henobarblLal
4 8enzodlazaplnes (ulazapam/Clonazapam) sLaLus epllepLlcus (lv)
AllosLerlc modulaLor of CA8A
A
recepLor lncreases frequency
8apld absorpLlon ulazapam comes ln a recLal formulaLlon for Lhe LreaLmenL of
sLaLus epllepLlcus
Palfllfe 2040 hours
Adverse effecLs CnS sedaLlon Lolerance dependence paradoxlcal
hyperexclLablllLy ln chlldren
lnLeracLlons can enhance acLlon of oLher CnS depressanLs
4 valproaLe (valprolc Acld) parLlal selzures flrsLllne for generallzed selzures
Lnhances CA8A Lransmlsslon blocks na channels acLlvaLes k channels
90 bound Lo plasma proLeln
Palfllfe 616 hours
Adverse effecLs CnS depressanL anorexla nausea vomlLlng halr loss welghL
galn elevaLlon of llver enzymes PepaLoLoxlclLy (greaLesL rlsk for klds under 2
yr) May cause blrLh defecLs
lnLeracLlons may poLenLlaLe CnS depressanLs dlsplaces phenyLoln from plasma
proLelns lnhlblLs meLabollsm of henobarblLal phenyLoln carbamazeplne
(430 lnhlblLor)
4 LLhosuxlmlde absence selzures
8locks Ca currenLs ln Lhalamus
Palfllfe 40 hours
Adverse LffecLs gasLrlc dlsLress less CnS effecLs Lhan oLher ALus LranslenL
faLlgue dlzzlness headache
lnLeracLlon admlnlsLraLlon wlLh valproaLe resulLs ln lnhlblLlon of lLs meLabollsm
newer urugs
4 Cxcarbazeplne addon Lherapy monoLherapy ln parLlal selzures LhaL are refracLory Lo
oLher ALus
AcLlvlLydependenL blockade of na channels May augmenL k channels
Palf llfe 12 hours buL converLed Lo 10hydroxycarbazeplne 812 hours
Adverse effecLs CnS sedaLlon slmllar Lo carbamazeplne buL less Loxlc
lnLeracLlons less lnducLlon of llver enzymes buL can slLmulaLe C?3A and
lnhlblL C?2C19
4 CabapenLln addon Lherapy for parLlal selzures MonoLherapy ln newly dlagnoses
parLlal epllepsy
lnLerferes wlLh CA8A upLake
nonllnear absorpLlon SaLurable no proLeln blndlng
LllmlnaLed by renal excreLlon noL meLabollzed
Palfllfe 39 hours admlnlsLered 23 Llmes/day
Adverse effecLs less CnS sedaLlon Lhan classlc ALus
lnLeracLlons none
4 LamoLrlglne addon Lherapy monoLherapy for refracLory parLlal selzures LffecLlve ln
LennoxCasLauL Syndrome and newly dlagnosed epllepsy LffecLlve agalnsL generallzed
selzures
usedependenL lnhlblLlon of na channels gluLamaLe release may lnhlblL Ca
channels
Palfllfe 24 hours
Adverse effecLs less CnS sedaLlon Lhan classlc ALus dermaLlLls (poLenLlally llfe
LhreaLenlng ln 12 pedlaLrlc paLlenLs)
lnLeracLlons levels lncreased by valproaLe decreased by carbamazeplne 8
phenyLoln
4 lelbamaLe 3
rd
llne for refracLory parLlal selzures
lrequencydependenL lnhlblLlon of na channels modulaLlon of nMuA recepLor
Adverse effecLs aplasLlc anemla and severe hepaLlLls resLrlcLs lLs use (black box)
lnLeracLlons lncreases plasma phenyLoln and valproaLe decreases
carbamazaplne SLlmulaLes C?3A and lnhlblLs C?2C19
4 LeveLlraceLam addon Lherapy for parLlal selzures
8lnds Lo synapLlc veslcle proLeln Sv2A may regulaLe n1 release
Palfllfe 68 hours
Adverse effecLs CnS depresslon
lnLeracLlons mlnlmal
4 1lagablne addon Lherapy for parLlal selzures
lnLerferes wlLh CA8A reupLake
Palfllfe 38 hours
Adverse effecLs CnS sedaLlon
lnLeracLlons mlnlmal
4 Zonlsamlde addon Lherapy for parLlal and generallzed selzures
8locks na channels and 1Lype Ca Channels
Palfllfe 13 days
Adverse effecLs CnS sedaLlon
lnLeracLlons mlnlmal
4 1oplmeraLe addon for refracLory parLlal or generallzed selzure MonoLherapy for
parLlal or generallzed selzures LennoxCasLauL syndrome
usedependenL blockade of nA channels lncreases frequency of CA8A
A
channel
openlng may lnLerfere wlLh gluLamaLe blndlng Lo AMA/kA recepLor
Palfllfe 2030 hours
Adverse effecLs CnS sedaLlon
lnLeracLlons sLlmulaLes C?3A and lnhlblLs C?2C19 Can lessen effecLlveness of
blrLh conLrol pllls
4 vlgabaLrln addon Lherapy for parLlal selzures monoLherapy for lnfanLlle spasms (noL
avallable ln uS)
8locks CA8A meLabollsm Lhrough acLlons on CA8ALransamlnase
Palfllfe 68 hours
Adverse effecLs CnS sedaLlve ophLhalmologlc abnormallLles
lnLeracLlons mlnlmal
arLlal CnseL Selzures
4 JlLh secondary generallzaLlon
1
sL
llne carbamazeplne and phenyLoln
valproaLe henobarblLal and prlmldone also usually effecLlve
4 JlLhouL generallzaLlon
henyLoln and carbamazeplne may be used LogeLher
Cenerallzed CnseL Selzures
4 1onlcClonlc Myoclonlc Absence 1
sL
llne ls valproaLe
4 henyLoln and carbamazeplne effecLlne on Lonlcclonlc buL noL oLhers
4 valproaLe and eLhoxysuxlmlde effecLlve ln chlldren wlLh absence selzures buL only
valproaLe proLecLs agalnsL Lonlcclonlc
valproaLe should noL be used ln chlldren under 2 hepaLoLoxlclLy
4 Clonazepam henobarblLal or prlmldone can be useful agalnsL generallzed selzures
buL may have greaLer sedaLlve effecLs Lhan oLher ALus
4 Carbamazeplne may exacerbaLe absence and myoclonlc
4 LamoLrlglne LoplramaLe and zonlsamlde effecLlve agalnsL Lonlcclonlc absence and
Lonlc selzures
SLaLus LpllepLlcus more Lhan 30 mlnuLes of conLlnuous selzure acLlvlLy or 2+ sequenLlal
selzures spannlng Lhls perlod wlLhouL full recovery beLween selzures Medlcal emergency
4 ulazepam lorazepam lv
4 lollowed by phenyLoln fosphenyLoln or henobarblLal when conLrol ls esLabllshed
M|gra|ne 1reatment
Mlgralne
4 3 aLLacks fulfllllng Lhe followlng
4 Peadaches lasLlng 472 hours
4 2 of
unllaLeral
ModeraLe or severe
AggravaLed by rouLlne acLlvlLy
ulsaLlng
4 1 of
nausea and/or vomlLlng
hoLo and phonophobla
4 noL aLLrlbuLed Lo anoLher dlsorder
Chronlc mlgralne headache fulfllllng mlgralne crlLerla for more Lhan 13 days per monLh for
over 3 monLhs noL aLLrlbuLed Lo anoLher dlsorder
aLhophyslology Mlgralnes occur aL Lhe Llme of greaLesL flucLuaLlon ln esLrogen levels
LsLrogenwlLhdrawal mlgralne requlres several days of exposure Lo hlgh levels of esLrogen
4 Changes observed over Llme ln Lhe AC cenLer of Lhe braln's powerful descendlng
analgeslc neuronal neLwork
lron deposlLlon
Secondary Lo free radlcal cell damage durlng mlgralne aLLacks
uegree of AC sLrucLural alLeraLlon depends on duraLlon of headache hlsLory
noL age of Lhe paLlenL
8epeaLed mlgralne aLLacks repeLlLlve damage decreased Lhreshold for furLher
mlgralne aLLacks
4 Mlgralneurs have more M8ldeLecLable whlLe maLLer leslons Lhan conLrols
Leslons lncrease wlLh aLLack frequency posslbly lndlcaLlng progresslon
Lven one headache per monLh could predlspose a person wlLh mlgralnes Lo
subcllnlcal braln leslons
4 CA8A and Mlgralne
lnhlblLlon of corLlcal evenLs
lnhlblLlon of lnpuLs aL level of Lrlgemlnal nuclear complex
lnhlblLlon of lnpuLs of prlmary afferenL flbers
lnhlblLlon of neurogenlc lnflammaLlon
Coals of acuLe mlgralne LreaLmenL LreaL aLLacks rapldly Lo geL Lo a paln free sLaLe resLore
paLlenL's ablllLy Lo funcLlon mlnlmlze use of rescue and backup medlcaLlon opLlmlze selfcare
and reduce uLlllzaLlon be cosLeffecLlve mlnlmlze adverse evenLs
valproaLe (valprolc Acld)
4 CA8A recepLor agonlsL
4 AcLlvaLes gluLamlc acld decarboxylase lncreases CA8A
4 lnhlblLs CA8A amlno Lransferase decreases CA8A breakdown
4 8educLlon of exclLaLory amlno aclds gluLamaLe and asparLaLe
CeneLlcs of Mlgralnes geneLlc facLors are lnvolved ln all Lypes of prlmary headaches
4 lamlllal hemlpleglc mlgralne (lMP) CACnA1A gene lnvolved ln half of Lhe famllles
(requlres 2 oLher muLaLlons) Llkely Lo be lnvolved ln Lhe more common Lypes of
mlgralne (wlLh or wlLhouL aura)
4 lMP muLaLlons render Lhe braln more suscepLlble Lo prolonged corLlcal spreadlng
depresslon caused by excesslve gluLamaLe release or decreased removal of gluLamaLe
and k from Lhe synapLlc clefL
Mlgralne ComorbldlLy
4 3x hlgher rlsk of mlgralne ln paLlenLs wlLh depresslon
4 3x hlgher rlsk of depresslon ln paLlenLs wlLh mlgralnes
4 40 paLlenLs wlLh blpolar have a llfeLlme dlagnosls of mlgralne
4 86 of paLlenLs wlLh mlgralne have a dlagnosls of blpolar dlsorder
4 aLlenLs wlLh mlgralnes have a 24x greaLer rlsk of sLroke
4 6 of people wlLh mlgralnes have epllepsy
4 823 rlsk of mlgralne ln epllepLlcs
4 eople wlLh dlabeLes have a hlgher rlsk for geLLlng mlgralnes
SympLomaLlc 1herapy of Chronlc Mlgralne
4 AnLllnflammaLorles and Analgeslcs (mlld Lo moderaLe)
4 1rlpLans (3P1 agonlsLs) cerebral vasoconsLrlcLor aborLlve drugs for moderaLe Lo
severe mlgralnes AlmoLrlpLan ls Lhe besL
4 narcoLlcs (moderaLe Lo severe)
ark|nson's D|sease
More common ln men CeneLlc llnk AA and Aslans less llkely Lhan Caucaslans
Caffelne and smoklng show some proLecLlve effecLs
Average age of onseL ls around 62
aLhogenesls 4 Lheorles
4 CxldaLlve damage lmpalred proLecLlon
4 LnvlronmenLal Loxlns M1
4 CeneLlc predlsposlLlon muLaLlons ln gene for proLeln alphasynucleln locaLed on ch 4
4 AcceleraLed aglng
aLhophyslology
4 lmbalance of dopamlne and Ach Loss of 8090 of dopamlnerglc producLlon ln Lhe
subsLanLla nlgra
4 Lewy bodles
4 Cardlnal slgns for dlagnosls 18A
4 1remor
4 8lgldlLy
4 Aklnesla and bradyklnesla
4 osLural lnsLablllLy
CharacLerlsLlc problems mlcrographla hypomlmla (decreased faclal anlmaLlon) hypophonla
(sofL speech) dysarLhrla dyspnea fesLlnaLlon (shuffllng galL)
use L1 scan Lo see dopamlne levels ln Lhe subsLanLla nlgra need Lo ellmlnaLe secondary causes
before maklng a dlagnosls
harmacoLherapy
4 Levadopa (Luopa)
Cold sLandard
Crosses Lhe 888 and ls Lurned lnLo dopamlne ln Lhe braln by cenLral dopamlne
decarboxylase
Adverse effecLs nausea vomlLlng posLural hypoLenslon lnvolunLary
movemenLs resLlessness cardlac arrhyLhmlas
Clven wlLh Carbldopa whlch blocks lLs meLabollzaLlon so more dopamlne ls
avallable ln Lhe braln Carbldopa also helps mlnlmlze adverse effecLs
O Carbldopa blocks perlpheral dopamlne decarboxylase so Luopa ls noL
converLed Lo dopamlne ln Lhe perlphery
4 uopamlne agonlsLs (synLheLlc dopamlne) monoLherapy or comblnaLlon
rolong Lhe effecLlve LreaLmenL perlod ln paLlenLs wlLh deLerloraLlng response
uelay onseL of Ldopa Lherapy (especlally ln younger paLlenLs) Cood for LreaLlng
paLlenLs who cannoL LoleraLe hlgh doses of Ldopa
More slde effecLs Lhan Ldopa
Adverse effecLs somnolence dysklneslas nausea vomlLlng orLhosLaLlc
hypoLenLlon nlghLmares halluclnaLlons confuslon dlzzlness
8romocrlpLlne MesylaLe (arlodel)
ergollde MesylaLe (ermax) 13x more poLenL Lhan arlodel
ramlpexol (Mlrapex) urugs LhaL are secreLed by Lhe caLlonlc LransporL sysLem
may decrease Lhe clearance of pramlpexol
8oplnlrole PCL (8equlp) urugs LhaL lnhlblL or lnduce C?1A2 wlll affecL
clearance of roplnlrole
4 CCM1 lnhlblLors lnhlblL breakdown of dopamlne lnLo 3M1 uon'L cross Lhe 888
LnLacapone (ComLan) ad[uncL Lherapy
O Slde effecLs exacerbaLlon of Ldopa slde effecLs dlarrhea urlne
dlscoloraLlon abdomlnal paln
1olcapone (1asmar) ad[uncL Lherapy
O More poLenL and longer acLlng Lhan LnLacapone
O uecrease Luopa by 2330
O Slde effecLs exacerbaLlon of Ldopa slde effecLs dlarrhea urlne
dlscoloraLlon llver LoxlclLy
O MonlLor Ll1s every 2 weeks for 1 year every 4 weeks for 6 monLhs and
Lhen every 8 weeks
4 AmanLadlne (SymmeLrel)
lnhlblLs dopamlne recapLure and blocks Ach and gluLamaLe recepLors
CauLlon ln renal fallure paLlenLs
CurrenLly used Lo reduce chorelc movemenLs
narrow LherapeuLlc range
Adverse effecLs nausea dlzzlness confuslon halluclnaLlons nlghLmares dry
mouLh perlpheral edema ||vedo ret|cu|ar|s (only drug LhaL glves veslcular
brulslng ln Lhe exLremlLles)
4 AnLlchollnerglcs
MonoLherapy or ad[uncL
MosL effecLlve for reduclng Lremor
use ls llmlLed by sldeeffecLs especlally ln Lhe elderly
1rlhexyphenldyl PCL (ArLane)
O Adverse effecLs dry mouLh blurred vlslon somnolence halluclnaLlons
memory lmpalrmenL confuslon urlnary reLenLlon consLlpaLlon
8enzLroplne MesylaLe (CogenLln)
O Adverse effecLs dry mouLh blurred vlslon somnolence halluclnaLlons
memory lmpalrmenL confuslon urlnary reLenLlon consLlpaLlon
4 Seleglllne PCL (Lldepryl)
lnhlblLs monamlne oxldase 8 (MAC8) whlch meLabollzes dopamlne MACA ls
noL effecLed unless Lhe dose ls exLremely hlgh
Jhen used as monoLherapy delays Lhe need of Ldopa by abouL 9 monLhs
Adverse effecLs nausea dlzzlness abdomlnal paln confuslon and exacerbaLlon
of Ldopa slde effecLs
Surglcal opLlons
4 allldoLomy and allldal SLlmulaLlon sLlmulaLe Lhe globus pallldus lmproves Lremor
rlgldlLy and bradyklnesla
4 1halamoLomy and 1halamlc SLlmulaLlon lmproves Lremor and rlgldlLy only
|zhe|mer's D|sease
Au beglns ln Lhe enLorhlnal corLex whlch ls near Lhe hlppocampus and has dlrecL connecLlons Lo
lL lL Lhen moves lnLo Lhe hlppocampus and affecLed reglons begln Lo aLrophy 1he 1
sL
vlslble slgn
ls memory loss (mlld cognlLlve lmpalrmenL)
8lsk facLors ACL female sex ApoL4 head ln[ury famlly hlsLory lower lncome elevaLed
homocysLeln low levels of folaLe and vlLamln 812
Plgher levels of educaLlon moderaLe dally wlne consumpLlons and hlgher levels of flsh ln Lhe
dleL lower Lhe rlsk of Au
A a proLeln LhaL appears Lo be a neuronal survlval facLor May help damaged neurons repalr
Lhemselves and may help parLs of neurons grow afLer braln ln[ury
4 ln Au enzymes cause A Lo be snlpped lnLo fragmenLs one of whlch ls beLa amylold
1he beLa amylold fragmenLs aggregaLe LogeLher lnLo plaques ouLslde Lhe cell 1hey Lhen
[oln oLher molecules and nonnerve cells Lo form lnsoluble plaques
1au makes mlcroLubules sLable
4 ln Au Lau ls chemlcally changed and lL beglns Lo palr wlLh oLher Lau and Lhey become
Langled and nonfuncLlonal As a resulL mlcroLubules dlslnLegraLe collapslng Lhe
neuron's LransporL sysLem 1hls may resulL ln neuronal malfuncLlon and laLer ln deaLh of
Lhe cells
ulagnosLlc crlLerla
4 CognlLlve lmpalrmenL severe enough Lo cause soclal or occupaLlonal dlsablllLy ln aL leasL
2 domalns (memory language calculaLlons orlenLaLlon and [udgmenL)
4 aLhologlc dlagnoses requlres Lhe presence of boLh plaques and Langles ln excess of Lhe
abundance anLlclpaLed for agemaLched healLhy conLrol
1reaLmenL
4 uonepezll AceLylchollnesLerase lnhlblLor
Mlld Lo moderaLe and moderaLe Lo severe Au LreaLmenL
Slde effecLs nausea dlarrhea vomlLlng
lnLeracLlons none (nSAlus should be used wlLh cauLlon due Lo lncreased rlsk of
sLomach ulcers)
AbsorpLlon noL affecLed by food
Long half llfe
Plgh proLeln blndlng
MeLabollzed by C?2u6 and C?3A4
4 8lvasLlgmlne AceLylchollnesLerase lnhlblLor LhaL delays cognlLlve decllne and Llme Lo
lnsLlLuLlonallzaLlon
Mlld Lo moderaLe Au LreaLmenL
Slde effecLs nausea vomlLlng welghL loss upseL sLomach muscle weakness
lnLeracLlons non (cauLlon wlLh nSAlus)
ShorL halfllfe
AbsorpLlon ls affecLed by food Less Lhan 30 bound
MeLabollsm ls nonhepaLlc
4 CalanLamlne AceLylchollnesLerase lnhlblLor LhaL ls effecLlve and well LoleraLed
SlgnlflcanL beneflLs ln cognlLlve and global funcLlon ln 6 monLhs AL 12 monLhs Au
paLlenLs who conLlnues galanLamlne malnLalned Lhelr basellne levels of cognlLlve and
dally funcLlon
Mlld Lo moderaLe Au LreaLmenL
Slde effecLs nausea vomlLlng dlarrhea welghL loss
lnLeracLlons some anLldepressanLs and oLher drugs wlLh anLlchollnerglc acLlon
may cause reLenLlon of excess CalanLamlne ln Lhe body leadlng Lo
compllcaLlons nSAlus should be used wlLh cauLlon
Palf llfe ls shorL
AbsorpLlon ls affecLed by food MosLly unbound Lo proLeln
MeLabollsm ls by C?2u6 and C?3A4
4 MemanLlne nMuA recepLor anLagonlsL
ModeraLe Lo severe Au LreaLmenL
Slde LffecLs dlzzlness headache consLlpaLlon confuslon
lnLeracLlons oLher nMuA anLagonlsLs should be used wlLh cauLlon
Palf llfe ls long
Less Lhan 30 bound absorpLlon noL affecLed by food
MeLabollsm ls nonhepaLlc
4 vlLamln L and Seleglllne have been shown Lo reduce Lhe raLe of decllne of funcLlons
Comblned Lherapy ls noL superlor Lo elLher agenL alone
4 sychoLroplc agenLs helpful for LreaLmenL of neuropsychlaLrlc sympLoms such as
psychosls aglLaLlon anxleLy and depresslon
4 8ulldlng an alllance wlLh famlly careglvers ls crlLlcal Lo success ln Lhe managemenL of
paLlenLs wlLh Au Careglvers are prone Lo depresslon and physlcal lllness as a resulL of
chronlc sLress
4 nun sLudy 8esearchers found LhaL on average Lhe rlsk of developlng Au was 47 lower
ln Lhose who devoLed more Llme ln cognlLlve acLlvlLles Lhan Lhose who dld Lhem leasL
frequenLly Also a hlgher llngulsLlc ablllLy early ln llfe may provlde some proLecLlon
agalnsL Lhe lnfluences LhaL lead Lo Au
mmunopharmaco|ogy
1esLs of lmmunocompeLence
4 Skln LesLs delayed Lype hypersenslLlvlLy
4 Serum lg complemenL Ab LlLers eLc
4 MeasuremenLs of Ab response afLer vacclnaLlon and boosLer
4 C8C clrculaLlng lymphocyLe counL (CLC)
4 LymphocyLe prollferaLlve response assay
1argeLs for lmmune ModulaLlon
4 LffecLors lnvolved ln manlpulaLlng Lhe cells LhaL mounL Lhe lmmune response
erforln
Cranzymes
las Llgand
4 ModulaLors chemlcals LhaL evenLually acL on Lhe LargeL
lln
1nl
1nl
lmmune SLlmulaLlng AgenLs
4 8CC vlable sLraln of M bovls used for lmmunlzaLlon agalnsL 18 used as an
lmmunosLlmlanL agalnsL superflclal bladder cancer
4 1hymosln group of proLeln hormones from eplLhellal cells of Lhe Lhymus used for
ulCeorge's syndrome (Lhymlc aplasla)
4 Levamlsole synLheLlc agenL LhaL sLlmulaLes prollferaLlon and maLuraLlon of 1 cells
Approved ln comblnaLlon wlLh llourouracll for LreaLmenL of uuke's class C colorecLal
cancer
4 Aldesleukln cyLoklne recomblnanL lL2 whlch promoLes producLlon of C1L and
acLlvaLes nk cells used as an ad[uvanL for renal cell carclnoma Causes profound
cardlovascular LoxlclLy and pulmonary edema
4 8oferon A cyLoklne recomblnanL lln2A whlch lnhlblLs cell prollferaLlon and vlral
proLeln synLhesls used ln neoplasms such as kaposl's sarcoma mallgnanL melanoma
Also used ln Pep 8 and C
4 8eLaseron cyLoklne recomblnanL lnl1b used for LreaLmenL of relapslng mulLlple
sclerosls Adverse effecLs flullke sympLoms neuroLoxlclLy renal and cardlovascular
abnormallLles
4 ?ervoy (lplllmumab) used for melanoma 8lnds Lo C1LA4 an lnhlblLory molecule on 1
lymphocyLes and released lnhlblLlon by Cu80 on Lumor cells
4 vecLlblx (anlLlmumab) LargeLs LCl8 and approved for paLlenLs wlLh LCl8expresslng
meLasLaLlc colorecLal cancer
4 under Cllnlcal 1rlals
CM/CSl for colon cancer
uendrlLlc cell Lherapy for sLage lll melanoma
8lovaxlu for nonPodgkln's Lymphoma
Anyara for nonsmall cell lung and renal cancers
Laqulnlmod for relapslng remlLLlng MS
lmmune Suppresslon
4 used for LransplanLaLlon and drug allergles
4 ALgam LymphocyLe lmmune globulln from hyperlmmune serum of large anlmals
made by lmmunlzaLlon wlLh human 1 cells used Lo LreaL allografL re[ecLlon May cause
serum slckness or nephrlLls
4 MuromonabCu3 MAb agalnsL Cu3 Lo prevenL 1hAC lnLeracLlon used for renal
allografL re[ecLlon crlsls AnaphylacLold reacLlon cyLoklne release syndrome
4 8h
o
CAM anLlbodles agalnsL 8ho(u) anLlgen of Lhe 88C used Lo prevenL hemolyLlc
dlsease of newborns 8arely causes anaphylacLlc shock
4 Zenapax (uacllzumab) humanlzed murlne Mab agalnsL Lhe alpha chaln of Lhe lL2
recepLor used for reversal of cardlac allografL re[ecLlon
4 PercepLln (1rasLuzumab) Mab agalnsL Per2/neu growLh facLor used for meLasLaLlc
breasL cancer wlLh overexpresslon of Per2/neu May geL acuLe hypersenslLlvlLy rxns
4 CyclosporlnA and 1acrollmus
Slgnallng vla Lhe 1 cell recepLor lnduces A1 acLlvaLlon and lncreases
lnLracellular Ca elevaLed Ca acLlvaLes Calclneurln a phosphaLe LhaL acLlvaLes
nlA1 AcLlvaLed nlA1 mlgraLes Lo Lhe nucleus and blnds Lo A1 acLlvaLlng
speclflc genes such as lL2
CyclosporlnA blnds Lo cyclophllln
1acrollmus blnds Lo lkblndlng proLeln (lk8)
1he comp|exes b|nd to ca|c|neur|n prevent|ng |ts act|vat|on of Ca and b|ock|ng
act|vat|on of NI1
1reaLmenL of Adverse urug Allergles
4 1ype l Lx anlmal/planL sLlngs polen drugs (Cn) anaphylaxls urLlcarla angloedema
urugs LhaL acL Lhrough cAM LgLheophylllne 8educe release and promoLe
8ronchodllaLlon
rednlsone blocks prollferaLlon of Lhe lgL produclng clones and lnhlblLs lL4
producLlon by 1P cells rolonged LreaLmenL
AnLlhlsLamlne dlrecLly compeLe wlLh hlsLamlnes
LeukoLrlene blockers (Slngulalr)
4 1ype ll Lx druglnduced SLL LhrombocyLopenlc prupura
Subslde wlLhln several monLhs afLer wlLhdrawal of drugs
lmmunosuppresslve Lherapy only when reacLlons are very severe
4 1ype lll Lx serum slckness urLlcarl and eryLhema arLhrlLls lymphadenopaLhy fever
Subslde afLer a few days once Lhe offendlng drug ls wlLhdrawn
CorLlcosLerolds usual LreaLmenL
4 1ype lv Lx Loplcal appllcaLlon conLacL dermaLlLls
knCJ 1A8LL Cn SLluL 33
mmunosuppressant Drugs
CorLlcosLerold rednlsone
4 rophylacLlc Lo prevenL re[ecLlon
4 lnhlblLs acLlvaLlon or acLlon of cells of Lhe lmmune sysLem
4 Slde effecLs Cushlngold reacLlon psychoses glucose lnLolerance lnfecLlons
hypoLenslon caLaracLs skln faglllLy bone dlssoluLlon lmpalred growLh ln chlldren
Cyclosporln (Sandlmmune)
4 used wlLh or wlLhouL rednlsone ln renal hepaLlc pancreaLlc and cardlac LransplanL
4 Speclflc lnhlblLlon of lmmune response blnds Lo cyclophllln lnhlblLs 1 helper cell
acLlvaLlon and producLlon of lL2
4 Absorbed by Lhe Cl meLabollzed ln Lhe llver and ellmlnaLed ln blle
lk306 (1acrollmus) 100x more acLlve Lhan c13yclosporln
4 Same as Cyclosporln used for llver kldney hearL and lung LransplanL
4 Speclflc lnhlblLlon of lmmune response lkblndlng proLeln
4 oorly absorbed afLer oral doslng lL ls exLenslvely dlsLrlbuLed wlLh concenLraLlons
exceedlng plasma levels ln lung spleen hearL and kldney MeLabollzed before
ellmlnaLlon
8apamycln
4 used for Lhe same reasons as lk306
4 Speclflc lnhlblLlon of lmmune response
AzaLhloprlne (lmuran)
4 used for renLal LransplanL rheumaLold arLhrlLls nonspeclflc lnhlblLlon of lmmune
response
4 lL ls a prodrug Suppresses 1 cell acLlvlLy more Lhan 8 cell acLlvlLy
MeLhoLrexaLe (lolex MexaLe)
4 used ln comblnaLlon wlLh cyclosporlne for bone marrow LransplanL or alone for selecLed
auLolmmune dlseases and lnflammaLory dlseases (Lx 8A)
4 lL ls a dyhydrofolaLe reducLase lnhlblLor lnhlblLs repllcaLlon and funcLlon of 1 cells
4 MosL ls excreLed ln Lhe urlne unchanged
4 Slde effecLs hepaLlc flbrosls and clrrhosls 1oxlc effecLs are usually reverslble
Cyclophosphamlde (CyLoxan)
4 Can be used orally for bone marrow LransplanLs
4 nonspeclflc lnhlblLlon of lmmune response suppresses 8 cells more Lhan 1 cells
rodrug so need Lo be acLlvaLed by 430 Lo aldophosphamlde alkylaLlng agenL of uA
lf cyL430 ls blocked Lhen Lhere ls only Lhe Loxlc effecL of Lhe drug
4 Slde effecLs chemlcal lrrlLaLlon
Ck13 (CrLhoclone Ck1)
4 1hls ls a murlne lmmunoglobulln (monoclonal anLlbody)
urlfled lgC
4 used as an ad[uvanL Lo oLher lmmunosuppressanLs ln acLlve re[ecLlon of kldney
4 Complexes wlLh anLlgen and blocks funcLlon of all 1 cells wlLh Lhls recepLor (Cu3)
4 Slde effecLs chllls fever chesL paln Cl dyspnea Lremor
8h
0
(8hogam)
4 Puman anLlbody
4 used for blood Lransfuslon dellvery aborLlon when exposed Lo opposlLe blood
4 8locks Lhe lmmune response agalnsL 88C anLlgens from 8h negaLlve lndlvlduals Lo 8h
poslLlve 88Cs
4 AdmlnlsLered Lhrough lM ln[ecLlon
ALC (AnLllymphocyLlc Clobulln)
4 Comes from anlmal lmmunlzed wlLh human lymphold cells
4 used ln comblnaLlon wlLh Cyclosporln A or cyLoLoxlc drugs ln bone marrow renal and
hearL LransplanLs
4 8lnds Lo 1 cells lnvolved ln anLlgen recognlLlon sLarLs Lo desLroy Lhe 1 cells 8locks
cellular lmmunlLy selecLlvely
4 Slde effecLs PypersenslLlvlLy anaphylaxls paln aL ln[ecLlon slLe
A1CAM (LymphocyLe lmmune Clobulln)
4 Comes from horse
4 used ln comblnaLlon wlLh Cyclosporln A or cyLoLoxlc drugs ln acuLe grafL re[ecLlon
4 8lnds Lo 1 cells lnvolved ln anLlgen recognlLlon and sLarLs Lo desLroy Lhe 1 cells 8locks
cellular lmmunlLy selecLlvely
4 Slde LffecLs hypersenslLlvlLy anaphylaxls paln aL ln[ecLlon slLe
4 AdmlnlsLered Lhrough lv lnfuslon
lmmunosLlmulaLlon
4 CyLoklnes colony sLlmulaLlng facLorys lnLerferons lnLerleuklns 1nls
4 1hymosln proLeln hormone LhaL sLlmulaLes Lhe maLuraLlon of pre1 cells and promoLes
Lhe formaLlon of 1 cells from lymphold sLem cells
4 Levamlsole anLlparaslLlc drug whlch enhances 1 cell medlaLed lmmune responses and
delayed hypersenslLlvlLy
4 8accllle CalmeLLeCuerln used for Lhe lmmunlzaLlon agalnsL 18 and as an
lmmunosLlmulanL ln cancer
NSDs and Drugs Used |n Gout
roperLles of nSAlus
4 AnLlpyreLlc
4 Analgeslc
4 AnLllnflammaLory
rosLaglandlns cause vasodllaLlon and hyperemla Made from AA by Lhe CCx paLhways
nSAlus lnhlblL CCx and Lhus lnhlblL producLlon of Cs
4 Cl
2
and CL
2
produce vasodllaLlon and promoLe edema roduced by endoLhellal cells
4 1xA
2
ls a poLenL vasoconsLrlcLor and ls produced by plaLeleLs
4 Cl
2
and CL
2
senslLlze cuLaneous paln recepLors Lo bradyklnln and hlsLamlne
4 CL
1
and Cl
1
lncrease body LemperaLure when ln[ecLed lnLo Lhe cerebral venLrlcles or
anLerlor hypoLhalamus
4 Cl
2
ls an anLlplaLeleL aggregaLory agenL whlle 1xA
2
ls a very poLenL plaLeleL
aggregaLory agenL
4 CL
1
and CL
2
sLlmulaLe gasLrlc mucus secreLlon and lnhlblL gasLrlc acld secreLlon
(proLecL Lhe sLomach)
4 CL
1
CL
2
and Cl
2
are resplraLory smooLh muscle relaxanLs whlle 1xA
2
and Cl
2a
are
consLrlcLors
4 CL
2
lnhlblLs na and waLer reabsorpLlon ln Lhe kldney lmporLanL when Lhlnklng abouL
adverse effecLs of nSAlus
Asplrln (AceLylysallcyllc acld)
4 Causes lrreverslble aceLylaLlon of CCx enzymes
4 Plgh 1
sL
pass effecL
4 Low dose ASA (81 mg up Lo 300mg/day) has efflcaclous anLlplaLeleL acLlvlLy
8ecause of Lhe hlgh 1
sL
pass effecL lowdose ASA wlll reach plaLeleLs (whlch
release 1xA
2
) buL spare endoLhellal cells (whlch produce prosLaclyclln)
4 lnLermedlaLe dose anLlpyreLlc and analgeslc doses of ASA (3002400 mg/day) noL
anLllnflammaLory
4 Plgh dose anLllnflammaLory (24004000 mg/day) ASA ls noL very poLenL when lL
comes Lo lnhlblLlng CCx2 so need a hlgh dose Lo do so
4 uses
Analgeslc of mlld Lo moderaLe paln of varled orlgln
As anLlpyreLlc for varlous lnfecLlons Should noL be used for vlral lnfecLlon ln
chlldren because of occurrence of 8eyes syndrome
Plgh dose AuA used as anLllnflammaLory agenL ln CA 8A and oLher
lnflammaLory [olnL dlseases
Low dose AuA decreases lncldence of 1lAs unsLable anglna and coronary arLery
Lhrombosls wlLh Ml
4 Adverse effecLs
Cl lrrlLaLlon gasLrlc and duodenal ulcers upper Cl bleedlng mosL common
adverse effecLs due Lo lnhlblLlon of Lhe proLecLlve feaLures of Cs Also due Lo
Lhe facL LhaL ASA ls an acld
lecal blood loss hepaLoLoxlclLy asLhma (due Lo lncreased producLlon of L1s
from Lhe llpoxygenase acLlvlLy) rashes renal LoxlclLy (less frequenL)
Plgh doses may cause sallcyllsm" vomlLlng LlnnlLus decreased hearlng
verLlgo
nephroLoxlclLy may occur aL hlgher doses especlally ln Lhose wlLh preexlsLlng
kldney dlsease
lbuprofen (MoLrln Advll)
4 More poLenL anLllnflammaLory so can work aL lower doses
4 Less Cl dlsLurbances
4 Can counLeracL anLlplaLeleL effecLs of ASA (lf glven LogeLher)
keLoprofen
4 Slmllar effecLs as lbuprofen
4 aLlenLs wlLh lmpalred renal funcLlon wlll ellmlnaLe Lhe drug more slowly
lndomeLhacln
4 used ln acuLe gouL
4 used ln managemenL of paLenL ducLus arLerlosus lnhlblLs Lhe producLlon of CA whlch
keeps Lhe ducLus open
Sullndac rodrug LhaL needs Lo be meLabollzed Lo lLs sulflde derlvaLlve
nabumeLone appears Lo have less Cl adverse effecLs Lhan oLher nSAlus
keLorolac poLenL analgeslc buL only moderaLely effecLlve anLllnflammaLory drug ls used for
posLoperaLlve paln as an alLernaLlve Lo opold agenLs
1olmeLln shorL halfllfe so musL glve more frequenL doses 8arely used now
CCx1 vs CCx2
4 Cox1 ls consLlLuLlve whlle CCx2 ls lnduclble
4 CCx1 ls found ln Lhe endoLhellum plaLeleLs gasLrlc mucosa and small and large bowel
CCx2 ls lnduclble ln lnflammaLory cells and ls consLlLuLlve ln Lhe kldney
Celecoxlb (Celebrex)
4 used for Lhe rellef of slgns and sympLoms of CS and 8A and Lo reduce Lhe number of
adenomaLous colorecLal polypns ln lA (slnce Lhe polyps express a loL of CCx2)
4 Jorks by selecLlve lnhlblLlon of CCx2 uoes noL lnhlblL CCx1 aL LherapeuLlc doses
4 Slde effecLs posslblllLy of edema and waLer reLenLlon Should noL be glven Lo paLlenLs
wlLh overL renal lnsufflclency lncreased rlsk of Lhrombosls ASA lnduced asLhma and
should be avolded ln laLe pregnancy
4 MeLabollzed mosLly by cyL 4302C9 ln Lhe llver CoadmlnlsLraLlon wlLh drugs LhaL are
known Lo lnhlblL 2C9 should be done wlLh cauLlon May reduce Lhe effecLs of ACL
lnhlblLors (mlld dlureLlcs) AdmlnlsLraLlon wlLh fluconazole wlll lncrease Celecoxlb
plasma levels AdmlnlsLraLlon may lncrease LlLhlum plasma levels
All nSAlus carry warnlngs abouL rlsk of cardlovascular evenLs (due Lo lnhlblLlon of proLecLlve
effecLs of prosLacyclln aL hlgh doses and posslblllLy of renal LoxlclLy) nSAlus are conLralndlcaLed
afLer coronary bypass surgery
AceLomlnophen (noL an nSAlu)
4 Analgeslc and anLlpyreLlc
4 Mechanlsm of acLlon ls unclear buL may be due Lo CCx3
4 lew adverse effecLs buL musL be used cauLlously ln paLlenLs wlLh llver dlsease Cverdose
produces hepaLlc necrosls
4 used ln moderaLe paln and ln chlldren wlLh vlral lnfecLlon
ulseaseModlfylng AnLl8heumaLlc urugs
4 Cold preparaLlons are auroLhlomalare and auroLhloglucose Cold salLs are
concenLraLed ln many organs
May have speclal quallLles whlch slow progresslon of bone arLlcular desLrucLlon
uecreases funcLlon of lnflammaLory cells
Slde effecLs dermaLlLls eoslnophllla LhrombocyLopenla leucopenla and
pancyLopenla
lndlcaLed ln 8A paLlenLs who have undergone nSAlu Lherapy 1akes 14 monLhs
Lo have effecL
4 MeLhoLrexaLe an lmmunosuppressanL
lollc acld analog LhaL lnhlblLs amlnolmldazolecarboxamlde and LhymldylaLe
synLheLase and decreases neuLrophlls chemoLaxls and reduces lymphocyLe and
macrophage funcLlon
Slde effecLs can cause nausea and mucosal ulcers Some hepaLoLoxlclLy
ConLralndlcaLed ln pregnancy
used aL low doses ln 8A paLlenLs
4 1nlblocklng agenLs
1nl ls an lnflammaLory cyLoklne whlch lncreases vascular permeablllLy
lncreases leukocyLe lnfllLraLlon and causes fever
lnfllxlmab (8emlcade) anLl1nl anLlbody ofLen glven wlLh meLhoLrexaLe
O Slde effecLs resplraLory LracL lnfecLlon nausea headache slnuslLls rash
and caugh 8eacLlvaLlon of laLenL 18
O used ln 8A as well as Crohn's dlsease and ankyloslng spondyllLls
LLanercepL (Lnbrel)
O 8ecomblnanL fuslon proLeln whlch blnds 1nl molecules
O Slde effecLs local paln and swelllng (glven subC)
CouL lnflammaLory dlsorder caused by crysLalllzaLlon of urlc acld ln [olnLs 1hls Lhen causes
severe lnflammaLlon
4 Cs are produced when uraLe crysLals appear ln Lhe [olnLs neuLrophlls are recrulLed
and Lhese produce more Cs as well as chemoLacLlc agenLs Mns phagocyLlze crysLals
and produce lnflammaLory agenLs
urugs used ln CCu1
4 Colchlclne
8lnds Lo Lubulln of leukocyLes lnhlblLlng mlgraLlon and phagocyLosls
Slde effecLs dlarrhea nausea vomlLlng 8arely causes halr loss and bone
marrow depresslon
rlmarlly used ln LreaLmenL of acuLe gouLy arLhrlLls nod used Loo much slnce
Lhe adverse effecLs are acuLe and Lerrlble
4 nSAlus
uecrease lnflammaLlon buL also lnhlblL uraLe crysLal phagocyLosls
lndomeLhacln ls used more ofLen
used ln acuLe gouL now because colchlclnes ofLen cannoL be LoleraLed All oLher
nSAlus have been used successfully excepL for ASA and LolmeLln
O Analgeslc doses of ASA cause neL reabsorpLlon of urlc acld 8Au!
4 urlcosurlc agenLs (robenlcld and Sulflnpyrazone)
Jork by lncreaslng urlc acld secreLlon from Lhe proxlmal Lubules
Slde effecLs can cause Cl lrrlLaLlon and allerglc dermaLlLls robenecld has been
reporLed Lo cause nephrlLlc syndrome
used only lf several bouLs of gouL have occurred Should noL be used lf paLlenL ls
excreLlng large amounLs of urlc acld
4 Allopurlnol ma[or drug used ln gouL LreaLmenL
CompeLes wlLh xanLhlne for use of xanLhlne oxldase enzyme whlch reduces urlc
acld producLlon AlloxanLhlne (converLed from Allopurlnol) dlrecLly lnhlblLs
xanLhlne oxldase
Slde effecLs may cause Cl dlsLurbances nausea vomlLlng dlarrhea hepaLlc
LoxlclLy Allerglc skln reacLlon may occur
used ln chronlc gouL when probenecld and sulflnpyrazone cannoL be used
when urlnary uraLe ls grossly elevaLed for recurrenL renal sLones ln paLlenLs
wlLh renal lmpalrmenL and when serum ls grossly elevaLed
Also used Lo prevenL hyperurlcemla from desLrucLlon of cancer cells by chemo
agenLs ln LreaLmenLs of lymphoma and leukemla lncreases effecLlveness of 6
mercapLopurlne because lL prevenLs oxldaLlon of Lhe drug
1hyro|d harmaco|ogy
LevoLhyroxlne (L1
4
) drug of cholce for long Lerm managemenL of hypoLhyroldlsm
4 AfLer lngesLlon plasma 14 levels rlse 1013 buL plasma 13 levels do noL age because
of Lhe slow converslon of 14 Lo 13
4 L14 provldes a sLeady source of 13 slmllar Lo whaL ls seen afLer endogenous 14
secreLlon
4 Pas less Lhan opLlmal absorpLlon so need Lo Lake a hlgh dose PlghesL absorpLlon occurs
when glven on an empLy sLomach AbsorpLlon decreases sllghLly wlLh age
4 lacLors effecLlng L14 absorpLlon and meLabollsm
lncrease L14 requlremenL
O lnLesLlnal dlseases Cellac Crohn's shorLbowel syndrome
O urugs LhaL acceleraLe 14 meLabollsm by llver (phenyLoln
carbamazeplne rlfampln seLrallne)
O urugs LhaL lnhlblL 14 converslon Lo 13 (amlodarone)
O lncrease ln 18C (ex exogenous esLrogen pregnancy)
uecrease L14 requlremenL
O uecrease ln 18C (ex exogenous androgens)
4 uose of Lhyrold replacemenL Lherapy ls lower ln elderly and hlgher ln lnfanLs and
chlldren
ulsLrlbuLlon of plasma 1SP levels are noL Causslan buL skewed Lo Lhe lefL lL ls
reasonable Lo sLrlve for a plasma 1SP ln Lhe lower Z of normal
ln Lhe average healLhy person full replacemenL can be glven aL onseL and Lhere
ls no need Lo bulld up Lhe dosage slowly
JlLh exLreme obeslLy dose should be based on lean body mass
4 1SP levels need Lo be checked aL 46 weeks because plasma 1SP levels fall very slowly
so lL would Lake a whlle Lo come back Lo normal afLer Lherapy ls sLarLed
14 has a half llfe of 6 days and 3 halfllves are requlred for any drug Lo reach
sLeady sLaLe levels ln Lhe blood
lf 1SP levels are elevaLed afLer 812 weeks of Lherapy Lhen Lhe 14 dosage needs
Lo be lncreased and 1SP should be reassess afLer anoLher 68 weeks
4 Jhen normallzlng 1SP free 14 ls ofLen ln Lhe upper end of normal or sllghLly above
normal
need hlgher 14 Lo generaLe adequaLe 13 ln Lhe absence of Lhe Lhyrold gland
slnce normally Lhe Lhyrold would produce abouL 20 13
4 lf dose seems lnapproprlaLely large conslder noncompllance
4 lf free 14 levels are hlgh normal or elevaLed and 1SP ls elevaLed conslder LhaL Lhe
paLlenL ls Laklng Lhe meds sporadlcally especlally ln anLlclpaLlon of a docLor's vlslL
4 CverreplacemenL wlLh 14 leads Lo suppressed 1SP and should be avolded especlally ln
older paLlenLs
osLmenopausal women wlLh suppresslve doses of 14 are aL rlsk for lower bone
mlneral denslLy (sLlmulaLes osLeoclasLs acLlvlLy)
aLlenLs wlLh suppresslve doses are aL a 3x lncreased rlsk of aLrlal flbrlllaLlon
(sympaLhomlmeLlc feaLures of 14)
4 1here ls no evldence of beneflL from L14 Lherapy ln paLlenLs who have normal Lhyrold
funcLlon
4 1oxlclLles reverslble hyperLhyroldlsm (lf glven Loo much) hearL palplLaLlons
osLeoporosls
LloLhyronlne (L1
3
) synLheLlc 13
4 More acLlve Lhan 14 buL noL recommended because lL has a shorLer half llfe ls more
cosLly and has hlgher hormonal acLlvlLy whlch can enhance cardloLoxlclLy
(sympaLhomlmeLlc)
4 used for shorL Lerm 1SP suppresslon
PyperLhyroldlsm 1SP levels wlll be very low
4 Causes
Craves' dlsease body produces anLlbodles whlch sLlmulaLe Lhe 1SP recepLor
Cccurs ln younger paLlenLs A brulL ls paLhognomonlc of Craves' Causes ocular
dlsLurbances such as exophLhalmos lld lag and propLosls
1oxlc nodular golLer dlsease of Lhe elderly Lnlarged Lhyrold gland LhaL
conLalns a small rounded mass or masses whlch produce Loo much Lhyrold
hormone
SubacuLe LhyroldlLls usually preceded by a vlral lnfecLlon (u8l) and
lnflammaLlon LhaL lead Lo desLrucLlve release of preformed Lhyrold hormone
AbrupL onseL and onseL of paln ln Lhe Lhyrold gland
lodlne or amlodaronelnduced hyperLhyroldlsm
SelfadmlnlsLered Lhyrold hormone would have no golLer due Lo Lhe facL LhaL
Lhe gland ls noL belng sLlmulaLed
4 1he maln concern of unLreaLed hyperLhyroldlsm ls cardlac compllcaLlons due Lo Lhe
lncrease ln Lhe number of recepLors assoclaLed wlLh hyperLhyroldlsm 8eLa blockers
should be sLarLed lmmedlaLely unLll Lhyrold hormone levels are conLrolled
4 ulagnosls
1SP screenlng more senslLlve and speclflc Lhan free 14 alone
lasma l14 can Lell abouL dlsease severlLy and serve as a basellne for Lherapy
8adloacLlve lodlne upLake LesL lf unclear
O 8ule ouL pregnancy
O Craves' dlsease hlgh 8Al LhaL ls dlffuse
O nodular golLer hlgh 8Al LhaL ls nodular
O 1hyrold scan hlgh homogenous 8Al
1reaLmenL of PyperLhyroldlsm
4 AnLlLhyrold medlcaLlon used for paLlenLs under 40 wlLh small glands and mlld dlsease
ropylLhlouracll (1u) and MeLhlmazole (1apazole) 1hloamldes
O lnhlblL mulLlple sLeps ln Lhe synLhesls of 14 and 13 and leads Lo gradual
decrease ln Lhyrold hormone levels over 28 weeks lnhlblLs oxldaLlon of
lodlde lodlnaLlon of Lyroslne and coupllng of lodlnaLed Lyroslne
4 1u also lnhlblLs Lhe converslon of 14 Lo 13 leadlng Lo a qulck
reducLlon ln 13
O urug dose needs Lo be LlLraLed sLarL low and LlLraLe upward Lo lowesL
effecLlve dose
O Some paLlenLs wlLh Craves dlsease go lnLo remlsslon afLer 1218 monLhs
and Lhe drug can be dlsconLlnued 8uL half Lhe paLlenLs who go lnLo
remlsslon have anoLher recurrence wlLhln Lhe year
O MeLhlmazole ls Lhe drug of cholce slnce lL cosLs less
4 Pas a long halfllfe (only need Lo Lake Lwlce a day) so paLlenL
compllance ls beLLer 1u ls glven 34 Llmes a day
4 lewer adverse effecLs
4 Shouldn'L be glven ln pregnancy can cause aplasLla cuLls
(congenlLal defecL of Lhe scalp)
O 1u ofLen Lhe drug of cholce ln pregnancy and severe LhyroLoxlcosls
because of Lhe addlLlonal beneflL of lnhlblLlon of 14 Lo 13 converslon
O Adverse effecLs allerglc reacLlon (mosL common) AgranulocyLosls (rare
buL llfeLhreaLenlng decrease ln J8C counL) Severe llver ln[urles and
acuLe llver fallure wlLh 1u
O 1oxlclLles reverslble hypoLhyroldlsm (from a dose LhaL ls Loo hlgh)
agranulocyLosls llver ln[urles
oLasslum lodlde (kl) rarely used as sole Lherapy
O 8locks release of Lhyrold hormones by lnhlblLlon of Lhyroglobulln
proLeolysls
O use afLer Lhloamldes slnce kl may lncrease lodlne sLores
4 od8asedow lodlnelnduced hyperLhyroldlsm
O uecreases Lhyrold slze and vascularlLy (can be glven before surgery)
O May be useful ln shorL Lerm managemenL of Lhyrold sLorm and may be
helpful ln preoperaLlve prep for surgery Cland escapes Lhe block ln 28
weeks
O ulsadvanLages lncreases lnLraglandular lodlne concenLraLlon crosses
Lhe placenLa and may cause feLal golLer
4 8adloacLlve lodlne used when Lhere ls fallure or lnLolerance of anLlLhyrold
medlcaLlon noncompllance hlsLory of LhyroLoxlc crlsls or severe compllcaLlons of
hyperLhyroldlsm (cardlac)
8apldly absorbed and concenLraLed ln Lhe Lhyrold 8eLa emlsslons cause
parenchymal desLrucLlon wlLhln a few weeks
AdvanLages effecLlve easy Lo admlnlsLer low expenslve no paln
1oxlclLy permanenL hypoLhyroldlsm (easy Lo LreaL)
ConLralndlcaLed durlng pregnancy and breasLfeedlng excreLed ln breasL mllk
and can cross Lhe placenLa
recauLlons posLpone pregnancy afLer Lherapy avold close conLacL for 3 days
permanenL hypoLhyroldlsm ls lnevlLable
4 Surgery noL common ln Lhe uS and reserved for severe cases such as pregnanL
women wlLh severe dlsease who are allerglc or noL respondlng Lo anLlLhyrold meds
D|abetes harmaco|ogy
2 camps on phllosophy of glucose conLrol
4 1lghL conLrol reduces Lhe lncldence and progresslon of reLlnopaLhy nephropaLhy
neuropaLhy and macrovascular ln[ury JlnnL8!
4 Loose conLrol prevenL hypoglycemla
lnsulln absorpLlon ln soluLlon human lnsulln forms hexamers 1o be absorbed Lhe hexamer
musL dlssoclaLe Lo a dlmer and Lhen Lo a monomer 1he monomerlc form ls absorbed lnLo Lhe
caplllary beds surroundlng Lhe subcuLaneous reservolr
4 1he raLe llmlLlng sLep ls Lhe dlssoclaLlon Lo Lhe monomerlc form
lnsulln Analogues
4 8apldacLlng (prandlal) less zlnc allows lL Lo acL fasLer and have a shorL duraLlon A loL
llke physlologlc lnsulln
Llspro (Pumalog) amlno acld composlLlon ls ldenLlcal Lo human lnsulln excepL
828 and 829 are reversed 1hls conflguraLlon decreases Lhe Lendency for self
assoclaLlon and favors formaLlon of monomers
AsparL (novolog) asparLlc acld makes lnsulln negaLlvely charged and lncreases
dlssoluLlon
Clullslne (Apldra) lyslne for asparaglnes and gluLamlc acld for lyslne Same
effecLs as AsparL
Anlmal lnsullns have lncreased anLlgenlc properLles an cause a loL of reacLlons
4 ShorLacLlng (prandlal) 8egular lnsulln Pas some zlnc whlch forms hexamer complexes
wlLh lnsulln AL Lhe slLe of ln[ecLlon hexamers dlssoclaLe lnLo dlmers and Lhen
monomers whlch rapldly dlffuse lnLo clrculaLlon
eaks afLer 23 hours so noL good for regulaLlng mealLlme lnsulln
U1 |t |s |ess expens|ve!!!
4 lnLermedlaLeacLlng (basal)
neuLral roLamlne Pagedorn (nP Pumulln) lnsulln proLamlne and zlnc form
a complex wlLh low solublllLy
O Slower dlssoluLlon from slLe of ln[ecLlon
O Mlxed wlLh regular llspro or asparL for rapld and delayed effecLs
LenLe dlsconLlnued
4 LongacLlng (basal) more zlnc allows slower onseL and long duraLlon
ulLralenLe dlsconLlnued
Clarglne peakless" so less llkely Lo cause hypoglycemla
O CannoL mlx wlLh oLher lnsullns
ueLemlr (Levemlr) dlffers from human lnsulln because 1 amlno acld ls omlLLed
from Lhe end of Lhe 8 chaln and a faLLy acld has been aLLached Lo Lhe spoL
lnsLead
O eakless doesn'L lasL as long as glarglne
O May have less dayLoday varlablllLy good resulLs ln paLlenLs who eaL
Lhe same meals day Lo day buL have varlable blood glucose levels
(brlLLle dlabeLlcs)
4 lnsulln Mlx
remlxed shorL acLlng and lnLermedlaLe acLlng lnsulln
ClycosylaLed Pemoglobln (PbA1c) a 3 monLh average of blood glucose levels lL provldes good
lndlcaLlon of long Lerm glycemla lormed slowly and nonenzymaLlcally from hemoglobln and
glucose
4 88Cs are freely permeable Lo glucose so Lhe raLe of glycosylaLlon ls dlrecLly
proporLlonal Lo amblenL glucose concenLraLlon
4 normal ls 46
4 7 170 mg/dl
Lach 1 above or below 33 mg/dl
Slldlng scale lnsulln ls admlnlsLered based on a slngle polnL ln Llme blood glucose before
meals or bed
4 1hese blood glucose levels only reflecL Lhe lasL lnsulln admlnlsLraLlon noL currenL needs
lL ls posslble Lo compound a prlor mlsLake leadlng Lo drops or splke reacLlve oxldaLlve
sLress and vascular damage
urugs for Lhe ManagemenL of 1ype 2 uM
4 lnsulln SecreLagogues
Sulfonylureas (Su)
O used Lo be Lhe 1
sL
llne drug 2
nd
generaLlon drugs are more poLenL
O Jorks Lhrough dlrecL sLlmulaLlon of lnsulln release Mlmlcs lncreased
blood glucose
O LffecLlveness depends on adequaLe cell funcLlon newly dlagnosed
paLlenLs have Lhe besL response 8esulLs ln a decrease of l8C and
PbA1c
O Long Lerm use resulLs ln a decrease ln Lhe number of beLa cells and Lhe
drug becomes less effecLlve (secondary fallure raLe of 310/year)
O 8elaLlvely few sldeeffecLs hypoglycemla (sLlmulaLes lnsulln secreLlon
and decreases hepaLlc clearance of lnsulln and decreases glucagon vla
SS) Mlld welghL galn
O ConLralndlcaLlons elderly paLlenLs wlLh lmpalred renal or hepaLlc
funcLlon noL approved ln Lhe uS for pregnancy or dlalysls
MegllLlnldes newer class
O 8epagllnlde naLegllnlde
O lnhlblL A1 senslLlve k channels leadlng Lo lnsulln secreLlon (blnd Lo Su8
aL a slLe dlsLlncL from Su)
O More selecLlve for pancreaLlc beLa cells
O 310x more poLenL Lhan Su lasLer onseL Lhan Su ShorLer duraLlon no
hyperlnsullnemla (lnsulln release ls glucose dependenL) expenslve!!!
O uose ls glven before each meal buL meals can be delayed or sklpped
wlLh no rlsk of hypoglycemla slnce lL ls glucose dependenL
O urugs noL cleared by Lhe kldneys and can be used ln renal and moderaLe
hepaLlc lnsufflclency
O Adverse effecLs welghL galn and hypoglycemla (less Lhan Su)
4 lnsulln SenslLlzers enhance lnsulln acLlon wlLhouL affecLlng lnsulln secreLlon
no hypoglycemla slnce Lhey don'L sLlmulaLe lnsulln secreLlon
8lguanldes (MeLformln)
O uecreases hepaLlc glucose producLlon lncreases lnsulln senslLlvlLy
decreases blood Lrlglycerldes and free faLLy aclds welghL loss
O Cne of Lhe mosL useful and safesL compounds Lo LreaL Lype 2 uM
O AlmosL always a 1
sL
llne drug (only agenL approved ln chlldren)
O Slde effecLs Cl dlsLurbances (use smaller doses and Lake wlLh dlnner)
O ConLralndlcaLlon renal lnsufflclency slnce lL ls cleared by kldneys
O ClumeLza new form of meLformln LxLended release form and fewer
Cl slde effecLs
1hlazolldlnedlones (1Zus)
O SenslLlze end organs Lo lnsulln vla blndlng Lo Lhe peroxlsome
prollferaLlonacLlvaLed recepLor gamma (A8)
4 A8 sysLem nuclear recepLors LhaL acL as LranscrlpLlon
facLors for genes ln glucose and llpld meLabollsm and lnsulln
slgnallng
O logllLazone (AcLos) and 8oslgllLazone (Avandla)
O AcL on muscle faL llver and bone (lncrease glucose upLake Lhrough
CLu11 and CLu14) uecreases hepaLlc glucose ouLpuL (noL as much as
MeLformln) and regulaLes llplds (lncreases PuL decreases 1g and
llpolysls)
O CnseL of acLlon ls slow because Lhey are 1ls
O use plogllLazone aL Lhe beglnnlng of Lherapy or wlLh lmpalred glucose
Lolerance Lo preserve cell funcLlon
O Slde effecLs fluld reLenLlon mlld anemla and perlpheral edema welghL
galn fracLure
O ConLralndlcaLlons CPl and hepaLlc dlsease
4 glucosldase lnhlblLors (Acarbose)
lnhlblL lnLesLlnal hydrolysls of complex CPCs leadlng Lo decreased dlgesLlon and
absorpLlon of sLarch and dlsaccharldes
Cnly modeslLy effecLlve ln lowerlng glucose as a monoLherapy
Slde effecLs flaLulence dlarrhea abdomlnal paln
4 LxenaLlde (8yeLLa) lncreLln mlmeLlc LhaL exLends Lhe Llme of lnsulln
CL1 and Cl are naLurally occurrlng hormones LhaL are released from cells ln
Lhe guL ln response Lo food
O AccounL for Lhe dlfference ln lnsulln concenLraLlons ellclLed by oral vs
lv glucose
CL1 lmproves glycemlc conLrol
O lncreases glucosedependenL lnsulln secreLlon (when glucose reLurns Lo
normal Lhls sLops)
O uecreases glucagon secreLlon (unLll glucose reLurns Lo normal)
O Slows gasLrlc empLylng (welghL loss)
O uecreases food lnLake welghL loss
O Palfllfe ls very shorL slnce lL ls degraded by ulv
LxenaLlde ls reslsLanL Lo ulv lnacLlvaLlon (longer halfllfe)
Adverse effecLs Cl dlsLurbances hypoglycemla wlLh Su
ln[ecLed subC 8lu wlLh breakfasL and dlnner
4 SlLagllpLln (anuvla) lncreLln enhancer
lnhlblLs ulv
Cleared by Lhe kldney long halfllfe only need a slngle dose plll
Adverse effecLs u8l headache abdomlnal paln nausea dlarrhea
uoes noL lncrease Lhe occurrence of hypoglycemla when admlnlsLered alone
wlLh meLformln or wlLh plogllLazone
4 Amylln (ramllnLlde Symlln) anLlhyperglycemlc effecLs
arL of Lhe complex sysLem of glucose regulaLlon
AcLlons complemenL lnsulln's acLlons
O uecreases posLprandlal glucagon secreLlon
O CasLrlc empLylng
O Suppress food lnLake
naLlve amylln mlsslng ln Lype 1 uM and lower posLprandlal ln Lype 2 uM
ShorL halfllfe
Analog also a shorL halfllfe used ln dlabeLlcs currenLly uslng lnsulln Clven
before meals Lo help lower posLprandlal glucose leadlng Lo less flucLuaLlon
durlng Lhe day Clven subC before every meal
Adverse effecLs Cl dlsLurbances lnsullnlnduced hypoglycemla (Lype 1)
SLL SLDLS 48 and 49