OBAT SSP

Autonomic receptors and agents

TARGET TISSUE SYMPATHETIC / PARASYMPATHETIC RECEPTOR
TYPES
EYE Sympathetic: Contracts radial muscle of iris and produces mydriasis
Parasympathetic: Contracts circular muscle of eye and produces constriction
A1 (S)
M3 (P)
LE!"C#LA$ $ESP%SE Sympathetic: $ela&es ciliary muscle' accommodates for near (ision
Parasympathetic: Contracts ciliary muscle for near (ision
) (S)
M3 (P)
A*#E%#S +#M%$ S: ,acilitate secretion of a-ueous humor .y ciliary epithelium/ "ncreased "%P/
P: Contraction of ciliary muscle e&erts pressure on tra.ecular mesh0or1/ %pens its pores2 increases
outflo0 from canal of schlemm/ 3ecreased "%P
)
M3
+EA$! (SA node) S: 4 chronotrope
P: ' chronotrope
)1 5 )6
M6
+EA$! (EC!%P"C
PACEMA7E$S)
S: "ncreased arrythmias
P: o effect
)15)6
+EA$! (C%!$AC!"L"!Y) S: "ncreased force of contraction2 4 inotropy
P: o effect
)15)6
S7"2 SPLAC+"C 8ESSELS S: 8asodilation2 (asocontrsiction at hi9h stimulation2 .eta stimulation usually predominates
P: o effect
)6
E3%!+EL"#M S: o effect
P: 8asodilation mediated .y %2 acti(ates the 9uanylyl cyclase/ "nhi.its CA44 release from E$/
o choliner9ic inner(ation
M3 (P)
)$%C+"AL SM%%!+ M#SCLE S: )ronchodilation
P: )ronchoconstriction
)6
M3
:" SM%%!+ M#SCLE S: $ela&es2 decreased motility and tone2 alpha effect may in(ol(e pre'synaptic inhi.ition of Ach
release
P: Contracts: "ncreased motility and tone
A62 )6 (S)
M3 (P)
SM%%!+ M#SCLE SP+"C!E$S S: Contracts
P: $ela&es
A1
M3
SEC$E!"% S: o effect M3
1
P: "ncreases
MYE!E$"C PLE;#S S: o effect
P: Stimulates
M1
)LA33E$ <ALL S: $ela&es2 less pressure
P: Contracts2 more pressure
)6
M3
:# SP+"C!E$ S: Contracts
P: $ela&es
A1
M3
#!E$#S S: $ela&es
Contracts
P: o effect
)6
A
PE"S2 SEM 8ES"CLES S: E=aculation
P: Erection
A
M
P"L%E$EC!%$ SM%%!+
M#SCLE
S: Contracts
P: o effect
A
!+E$M%$E:#LA!%$Y S<EA! S: "ncreases
P: o effect
M (SYMP)
AP%C$"E (S!$ESS) S<EA!
:LA3S
S: "ncreases
P: o effect
A
L"8E$ S: :luconeo9enesis2 9lyco9enolysis
P: o effect
)62 A
,A! CELLS S: L"P%LYS"S )3
7"3EY S: $E" $ELEASE (8asoconstriction) )1
7"3EY S: 3"LA!"% %, $EAL A$!E$"ES (Maintains perfusion durin9 shoc1 states) 31
Cholinergic Agonists
,i(e types of muscarinic receptors ha(e .een identified/ ,or class purposes2 M1 M6 and M3 are considered
M1 and M3 lin1ed to "P3>3A: cascade
Production of "P3 and 3A: leads to release of intracellular Ca44 0hich can stimulate or inhi.it en?ymes
M1 receptors are found in the myenteric ple&us and 9astric parietal cells
M3 receptors are found in 9lands2 smooth muscle and endothelium
M6 receptors are in heart and smooth muscle
icotinic receptors are lin1ed to a depolari?in9 ion channel
',ound in CS2 autonomic 9an9lia2 adrenal medulla
6
'Ach and nicotinic a9onists stimulate nicotinic receptors
icotinic receptors of autonomic 9an9lia are selecti(ely .loc1ed .y :A:L"%"C .loc1ers (re(ie0ed in choliner9ic anta9onist section)
icotinic receptors at M@ are selecti(ely .loc1ed .y tu.ocurarine and other ndm.As/
DIRECT ACTING CHOLINERGIC AGONISTS
'Consits of esters of choline
'Al1aloids
1/ More resistant to hydrolysis from AC+e than ACh
DRUG/CLASS MECHANISM SPECTRUM/USE KINETICS CLINICAL
General cholner!c
a!on"#"
Stimulation of muscarinic
and nicotinic receptors of (ia
indirect mechanism
:EE$AL %8E$8"E< %, SYS!EMS:
$ESP"$A!%$Y SYS!EM: )ronchoconstriction2 caution 0ith asthmatics
:": "ncreases secretion and motor acti(ity (ia stimulation of muscarinic a9ents/ >82 .elchin92
diarrhea
:#: Promote (oidin9 of urine .y stimulatin9 detrussor muscle and rela&in9 tri9one sphincter
muscles of .ladder
SEC$E!%$Y :LA3S: Stimulate acti(ity of s0eat 9lands2 lacrimal 9lands2 asopharyn9eal
9lands/
Ace#$lcholne% cholner!c
a!on"#
Stim of choliner9ic receptors Miosis2 and contraction of ciliary
muscle/ Produces accommodation
for near (ision/ "ntraocular solution
a(aila.le
3oes not cross )))
*uaternary amine
#sed in intraocular s&
Me#hacholne o nicotinic affinity2
muscarinic stimulation
3ia9nosis of .ronchial
hyperacti(ity/
"nhalation
4 d& .y hyperreacti(ity
of air0ay2 e&cessi(e
.ronchial constriction
Car&achol (Mo"#a#) $esistant to AC+e
hydrolysis2 choliner9ic
a9onist/ 444 Acti(ity at
choliner9ic and nicotinic
receptors
Profound C>8 effects/
L%CAL #SE " EYE
Produce miosis
%cular
3
Be#hanecol $esistant to AC+e
hydrolysis/ "ncreases tone and
intestinal motility/ P#$E
M#SCA$""C A:%"S!/
E&pulsion of urine (ia detrusor
contraction and rela&ation of
tri9one sphincter/ #sed to promote
.ladder emptyin9 in postoperati(e
%%)S!$#C!"8E urinary
retention/
%ral
S*
Contraindicated in:
Asthmatics
+yperthyroidism
Coronary insufficiency
Acid'pepsin disease
Precipitates atrial fi.rillation in
hyperthyroid patients/
SE:
)ronchospasm
S0eatin9
Sali(ation
,lushin9
Parasympathomimetic effects
Plocar'ne Al1aloid that posseses
muscarinic acti(ity/ !ertiary
amine/ Lon9 actin9
Produces rapid miosis/
%pens tra.ecular mesh0or1 to
decrease "%P
Emer9ency "%P lo0erin9 in acute
an9le 9laucoma
Crosses )))
!opical for 9laucoma
%ral for &erostomia
associated 0ith head and
nec1 radiation t&
4Sali(a
SE:
Profuse s0eatin9
Profuse sali(ation
Nco#ne :an9lionic stimulant and
9an9lionic .loc1er/ "nitial
effects are to stimulate
9an9lia/ Prolon9es use
desensiti?es nicotinic receptor
and produces .loc1ade/
Complicated mechanism/
Acute:
4 +$
4 )P
4"ntestinal tone and motility
Smo1inA
INDIRECT ACTING
CHOLINERGIC
AGONISTS
Actions of Ach released from autonomic and somatic ner(e endin9s is terminated (ia en?ymatic destruction/ AC+E hydroly?es
Ach to choline and acetate/ All indirect actin9 choliner9ic a9onists inhi.it AC+e and increase duration of action of endo9enous
AC+/ Produce choliner9ic acti(ity at all choliner9ic receptors (nicotinic and muscarinic) ,e0 therapeutic applications2 used as
insecticides/
Ten"lon (E(or'hon)*) )inds to acti(e site on AC+e
and .loc1s access of
3& of myasthenia 9ra(is/ Short li(ed Patients 0ith M: respond to
dru9 !ensilon 0ithin B minutes/
C
acetylcholine/ )ond is ionic
and short li(es/ 1D'6D minute
effect/
!& of myasthenia 9ra(is
Assess effecti(eness of M:
treatment:
'"f AC+e inhi.itors are e&cessi(ely
administered2 then they can mimic
disease symptoms/ "n this case2
admin of !ensilon 0ill ha(e no
effect or 0orsen 0ea1ness/
"8 in=ection (!hey ha(e anti.odies 0hich
reduce the functional nicotinic
receptors/)
Caution' may pro(o1e
choliner9ic crisis
Ph$"o"#!*ne
(An#lr)*)
,orm co(alent .ond 0ith
AC+e/ $esistant to clea(a9e/
Al1aloid and tertiary amine/
Local application produces
miosis/ 3irect nicotinic
a9onism at M@/
!& 9laucoma
Lo0er "%P
(Pilocarpine more effecti(e)
4 "ntestinal and .ladder motility
,ormerly used to t& o(erdoses of
dru9s 0ith anticholiner9ic effects
li1e atropine/
6 hour duration of action +i9h doses produce
con(ulsions and s1eletal
muscle paralysis/
Also used to anta9oni?e the
neuromuscular .loc1ers2 non
depolari?in9
Neo"#!*ne Synthetic AC+e inhi.itor/
*uaternary amine/
!& myasthenia 9ra(is
!& postoperati(e ileus
!& atony of .ladder
#sed as antidote for competiti(i(e
neuromuscular .loc1ers li1e
tu.ocurarine/
6 hour duration of action SE:
ausea
Sali(ation
,lushin9
+ypotension
May .e useful in anta9oni?in9
effects of non depolari?in9
neuromuscular .loc1ade
IRRE+ERSIBLE ACHe
INHIBITORS
Commonly called or9anophosphates2 these dru9s irre(ersi.ly inhi.it AC+e in t0o steps/ !he %P co(alently phosphoryly?es the
en?ymeAs acti(e site/ +ydrolysis may ta1e 1DDAs of hours/ "n the second step2 1no0n as a9in92 on of the o&y9en'phosphorus .onds
is .ro1en2 further stren9thenin9 the phosphorus'en?yme .ond/ %nce the inhi.itor en?yme comple& has a9ed2 pralido&ime cannot
re9enerate AC+e/ Pralido&ime is used to t& %P poisonin9/
I"o,l)ro'ha#e %P !& of 9laucoma Last for a 0ee1
Mala#hon %P Lipid solu.le2 rapidly
a.sor.ed/ Con(ertd to
B
acti(e compounds in
insects and fish/
Con(erted to inacti(e
compounds in
mammals/
Para#hon %P 3an9eous use' not pu.licly
a(aila.le/
ot deto&ified in
(erte.rates
A -ORD ABOUT
TO.ICITY O/
CHOLINOMIMETICS
3irect actin9 muscarinic a9ents produce predicta.le si9ns of muscarinic e&cess/ S>s include nausea2 (omitin92 diarrhea2 sali(ation2
and s0eatin9/ Symptoms .loc1ed .y atropine/
icotine is the only direct actin9 nicotinic a9ent that causes poisonin9/ "n9estion of lar9e doses causes 4 CS stimulation 0hich
can lead to coma and con(ulsions/ !& 0it (alium/ euromuscular .loc1ade not responsi(e to treatment/
Cholinesterase inhi.itors: %P pesticide o(erdoses must .e treated and reco9ni?ed promptly/ S>S resem.les muscarinic e&cess/
!herapy is a99ressi(e and includes parenteral atropine (lar9e doses sufficient enou9h to produce atropini?ation as e(idenced .y
pupillary dilation and a.atement of parasympathetic symptoms/ Pralido&ime t& used to re9enerate AC+e/
Cholinergic antagonists
DRUG/CLASS MECHANISM SPECTRUM/USE KINETICS CLINICAL
Muscurinic
anta9onists
Competiti(ely anta9oni?es the
effects of choliner9ic a9onists at
muscarinic receptors/ )loc1ade .y a
small dose of atropine can .e
o(ercome .y increasin9 a9onist
concentration/ Selecti(e for
*)"carnc receptors/ #ndetecta.le
actions at nicotinic receptors/
A,,n#$ ,or M0 M1 M2
No a,,n#$ ,or nco#nc
CS: sedati(e efec/
Scopolamine possesses more
cns effects li1e dro0siness
!remor of par1insonAs disease
reduced/ +i9h doses can
cause e&citement2 a9itation2
coma/
EYE: Pupillary constriction is
inhi.ited/ Mydriasis/
(#nopossed of sympathetic
acti(ity)/ Measurement of
accommodation for near
(ision/ May precipitate acute
Cross con=uncti(al mem.ranes
Cross )))
<ell distri.uted
$each le(els in 3D min to 1 hr
E life of 6 hours
ot 0ell a.sor.ed from 9ut
AD+ERSE E//ECTS: #sin9
atropine to treat peptic ulcer disease
0ill produce side effects li1e dry
mouth2 .lurred (ision2 urinary
retentsion/ Side effects are hot flushed
s1in2 delirium2 ele(ated .ody
temperature/ 3ry as a .one2 mad as a
ot all tissues ha(e same
sensiti(ity2 not easy to
titrate
Effects on eye persist
,ree from side effects
:astric acid secretion is
least sensiti(e2 not used
to decrease acid
secretion/
"ndi(idual a9ents for t&
of par1insonAs disease:
Ben3#ro'ne (Co!en#n)
F
9laucoma/ (Measurement of
refracti(e effor 0ithout
interference .y
accommodation/)
C8S: Lo0 doses result in
.radycardia/ Lo0 doses .loc1
presynaptic receptors on
(a9us ner(e/ Ach release
decreased/ C8 response is
not dramatic/ !achycardia/
on inner(ated muscarinic
receptors in endothelial cells
release % and promote
(asodilation/
$ESP: Smooth muscle and
secretory 9lands of air0ay
reci(e muscarinic inner(ation/
)ronchodilation and
reduction of secretion can .e
detected in normal
indi(iduals/ $educe
laryn9ospasm/
:": Mar1ed reduction of
sali(ary secretion/ :astric
secretion reduced less
effecti(ely/ Motility of muscle
is affected from stomach to
colon/ <alls of (iscera are
rela&ed/
:#: $ela& smooth muscle of
ureters and .ladder2 slo0s
(oidin9/ #seful in t& of spasm
reduced .y mild
hatterG/ Effects of %3 may last a
0ee1/ "nfants and 1ids particularly
suscepti.le to hyperthermic effects/ "n
past physosti9mine 0as used2 .ut
currently is considered more
dan9erous than symptomatic
mana9ement/
CONTRAINDICATIONS:
:laucoma2 elderly males 0ith prostatic
hyperplasia
)iperiden
%rphenadrine
Procyclidine
Trhe4$'hen(l
(Ar#ane)
3iphenhydramine
An#*)"c)rnc (r)!"
are *ore e,,ec#5e
a!an"# #re*or #han
a6ne"a or r!(#$/
!a1en in com.ination
0ith dru9s that enhance
dopaminer9ic acti(ity/
!ertiary amines/ Cross
)))/ #sed CS/ 3ru9s
to 1no0 in .old/ Also
treat EPS effects/
Motion sic1ness:
Sco'ola*ne
!a1en .y in=ection or P%/
Most effecti(e ta1en
prior to onset/
!ransdermal patch
0ithdra0n/
Mydriasis and
cyclople9ia:
A#ro'ne
Sco'ola*ne
+omatropine
Cyclopentolate
!ropicamide
Pre(enton of respiratory
secretion and
H
inflammation/ #rinary
retention in men 0ith )P+
S<EA!: Suppresses
thermore9ulatory s0eat
9lands/ Little effect on .ody
temperature/ %rdinary doses
may cause Iatropine fe(erJ
laryn9ospasm from
inhalation anesthetics:
A#ro'ne
Sco'ola*ne
ot irritatin9 to air0ay/
"ncreases chance of post
operati(e urinary
retention and intestinal
hypomo.ility
!reatment of asthma and
C%P3
A#ro5en# (I'a#ro')*)
!ar9et .ronchodilator
tissue locally/
Peptic ulcer t&
Lar9erly replaced .y h6
receptor anta9onists/
:astric acid secretions
are least sen.siti(e/
3oses employed 0ill
.lur (ision2 dry mouth2
and cause urinary
hesitancy/ <ill slo0
9astric emptyin9 time/
Erratically a.or.ed
Me#h"co'ola*ne
#rinary and :"
disorderd/ #sed to t&
o(eracti(e .ladder and
:" disease
,la(o&ate
%&y.utynin
)entyl
K
A#ro'ne #sed to counteract peripheral and central effects of muscarinic e&cess follo0in9 %P to&icity > e&posure/ Push atropine 1'6 m9 - B'1B until
si9ns of effect appear/ As much as 1 9m per day/ $epeat lar9e doses many times/ $esynthesis of receptors is re-uired due to co(alent
.ondin9/ Continue pushin9/
:an9lionic
.loc1ers
Meca*$la*ne
MEC+A"SM>P+YS"%:
Anta9oni?e effects of Ach at
parasympathetic and sympathetic
9an9lia/ Effects are diffuse .ecause
they .loc1 all autonomic outflo0/
Lac1 of selecti(ity/ Pre(ent refle&
ad=ustment of AS/ <hat you see is
0hat you 9et/ "f you ha(e a
choliner9ic2 .eta a9onist2 or
0hate(er2 it 0ill produce its direct
effect <"!+%#! refle& ad=ustment/
icotinic receptor suscepti.le to
.oth depolari?in9 and non
depolari?in9 .loc1ade/ icotine and
e(en Ach at hi9h concentrations can
produce non depolari?in9 .loc1ade/
!oo much a9onist/ o
repolari?ation/ "mpossi.le to control
and ne(er used clinically/ Clincally
effecti(e 9an9lionic .loc1ers are
non depolari?in9 competiti(e
anta9onists at nicotinic receptor/ %
"!$"S"C AC!"8"!Y/
ORGAN SYSTEM E//ETCS7
%r9an system effects dependent upon 3%M"A! inner(ation/ :an9lionic .loc1ade 0ill remo(e
more of the relati(ely dominant AS system/ So2 9an9lionic .loc1er admin effects in (ascular
system 0ill produce parasympathetic effects2 for e&ample/ PL#S2 no refle& compensationLLLLLLL
CNS7 Mecamylamine enters CS and produces sedation2 choreiform mo(ements2 and mental
a.errations/ Anta9oni?e central effects of nicotine/
EYE7
Ciliary muscle is primarily inner(ated .y parasymptathetc/ :an9lionic .loc1ade induces cyclople9ia
0ith loss of accommodation/ Moderate dilation/
C+S7 Parasympathetic tone dominates in the SA node/ :an9lionic .loc1ers 0ill produce moderate
tachycardia/ )lood (essels chiefly inner(ated .y sympathetic fi.ers/ %rthostatic hypotension 0ill
occur/
GI TRACT: Parasympathetic system dominates/ :an9lionic .loc1ers cause mar1ed constipation/
$eduction of secretion is not sufficient to effecti(ely treat peptic ulcer disease/
GENITOURINARY SYSTEM7
:an9lionic .loc1ade causes urinary hesitancy and precipitate urinary retention/ "mpair erection and
e=aculation/
RESPONSE TO AUTONOMIC7
3ru9s that act at post9an9lionic receptors are not .loc1ed .y 9an9lionic .loc1ers/ E 0ould raise
.lood pressure that 0as decreased .y he&amethonium/ $esponses may .e e&a99erated or re(ersed
0ith 9an9lionic .loc1ade/ E ele(ates .lood pressure (ia (asoconstrictor effects/ ormally2 this
0ould elicit refle&i(e (a9al +$ slo0in9/ "n presence of 9an9lionic .loc1ade2 this refle&i(e
.radycardia 0ould %! occur/
M
He4a*e#hon)*7
:an9lionic
.loc1er
"mportant historically as the first clinically utili?ed 9an9lionic .loc1ers/ Effecti(e antihypertensi(e/ "mportant .ecause it allo0s
pharmacolo9ists to 0rite fiendishly difficult test -uestions/
Meca*$la*ne
:an9lionic
.loc1er
Currently the only 9an9lionic .loc1er a(aila.le in the #S/ #sed to control )P in hypertensi(e emer9encies or to produce controlled
hypotension to produce a .loodless sur9ical field in neurosurery/ $apid onset2 short actin9 a9ents such as nitroprusside ha(e 9radually
replaced 9an9lionic .loc1ade/ "nitial control of .lood pressure in patients 0ith acute dissectin9 aortic aneurysm/ )loc1 sympathetic refle&es
and reduce rate of rise of )P at site of tear/
euromuscular
.loc1ers
3epolari?in9 and
non depolari?in9
)loc1 choliner9ic
neurotransmission .et0een motor
ner(e endin9s and nicotinic s1eletal
muscle receptors/ #sed durin9 s& to
induce paralysis/ Achie(ement of
ade-uate muscle rela&ation for s&
re-uirements
ormal function:
Arri(al at action potential
results in influ& of Ca and
release of Ach/ )indin9 of 6
molecules or Ach to receptors
on a6 su.units of the nicotinic
receptor results in ion channel
openin9/ $esultant
mo(ements of a and 7 ions
are associated 0ith
depolari?ation of endplate
mem.rane/ Small
depolari?ation results in
permea.ility and endplate
potential returnin9 to normal
0ithout impulse propa9ation
to rest of muscle/
Lar9e depolari?ation produces
muscle contraction/
AC+esterase remo(es Ach/
,ast response
)loc1ade of normal endplate function:
TUBOCURARINE7
PROTOTYPICAL NON
DEPOLARI8ING NMB% #SE AC+e
"+")"!%$S !% A!A:%"NE/
SUCCYNYLCHOLINE7
PROTOTYPICAL
DEPOLARI8ING MB/ AC!"% "S
3EPE3E! #P% 3",,#S"%
A<AY ,$%M E3PLA!E/ 6 AC+
M%LEC#LES E3 !% E3/
"3#CE P+ASES %, )L%C7A3E
A3 P$E8E! %!+E$ S!"M#L#S
,$%M CA#S":
3EP%LA$"NA!"%/
Competiti(e anta9onism/ Pre(ent
access of Ach to nicotinic receptor and
pre(ent depolari?ation/ $eferred to
non depolari?in9 .loc1ers/
)loc1ade can also occur throu9h
e&cess a9onist induced depolari?ation/
(E&cess nicotine or Ach amplified 0ith
AC+e inhi.ition/) <hoppin9 hi9h
doses of a9onist 0ill cause
depolari?in9 .loc1ade/
1D
All nondepolari?in9 .loc1ers contain 6
Ach molecules concealed 0ithin one
or t0o types of .ul1y and ri9id rin9
structures/ Poorly lipid solu.le and do
not cross )))/ Administered "8/
+i9hly ioni?ed and do not cross
mem.ranes/ Limited (olume
distri.ution/ Competiti(e anta9onist of
nicotinic receptor at M@/ Small doses
compete 0ith Ac+ at nicotinic
receptors/ AC+E inhi.itors can .e
used to anta9oni?e the 3M)s li1e
eosti9mine
Physosti9mine
Endrophonium
At hi9her doses2 some dru9s enter pore
of the ion channel to cause .loc1ade/
DEPOLARI8ING BLOCKADE7
ot an anta9onist/ S)cc$n$lcholne9
!0o AC+ molecules lin1ed end to
end/ :i(en "82 e&hi.its complete
diaphra9matic paralysis/ E&tremely
.rief duration of action/ $apidly
meta.oli?ed .y acetylcholinesterase2
an en?yme of plasma and li(er/ o
plasma cholinesterase at motor/ Su&
.inds at M@ 0ith much 9reater
affinity 0ith AC+/
PHASE 0: 3epolari?in9 .loc1/ Acts
li1e AC+/ Effect is much lon9er/ )inds
to and occupies receptor2
depolari?ation occurs/ $eceptor cannot
11
fire a9ain/
PHASE II7 3esensiti?in9 .loc1/ AC+
.indin9 endplate resultin9 in
depolari?ation/ ,ast e(ent/ !he cell
reploari?es fast due to potassium
current/ <ith S#; on .oard2
repolari?ation does not recur/ At some
point2 processes 0ithin cell 0ill come
into play/ !ime constant is lon9/ After
se(eral minutes2 partial repolari?ation
still occurs 0ith su& still .ound to
receptor/
ADRENERGIC DRUGS
!ypes of receptors and their function2 re(ie0
A1 ,ound in (ascular smooth muscle 0here a9onist .indin9 causes
(asoconstriction/ Stim of A1 receptors causes the : protein to acti(ate the
phospholipase C cascade/ Se-uestered intracellular Ca is released and smooth
muscle contracts/
A6 ,ound primarily on post 9an9lionic sympathetic ner(e terminals 0here a9onist
.indin9 ser(es to .loc1 E release/ ,ound in (ascular smooth muscle 0here
a9onist .indin9 also mediates (asoconstriction/ Stim .y A6 receptors acti(ates
inhi.itory : protein resultin9 in a decrease of CAMP le(els/ %pen 7 channels2
close Ca channels/
)1 )1 primarily found in heart/ 4 Chronotrope and 4 "notropic effects/ ($ate and
contractility as 0ell as C% increased)
)6 Primarily in smooth muscle in lun9s and (asculature/ )6 a9onism causes
.ronchial dilation and (asodilation/
)3 ,ound in fat tissue2 promotes lipolysis
31 ,ound in 1idney/ At normal doses2 31 receptors are acti(ated and maintain
renal perfusion/ +i9her doses cause acti(ation of alpha and .eta li1e effects/
16
A3$EE$:"C A:%"S! 3$#: !A)LE
CLASS>3$#: MEC+A"SM S>S CL""CAL
Adrener9ic A9onist2
catecholamine9ic
effects
C8: 8ascular smooth muscle tone in .lood (essels is dominated
.y sympathetic ner(ous system/ Adrener9ic effects ha(e profound
effects on (ascular tone/31 receptors promote (asodilation of
renal splanchnic and coronary arteries/
+$!: 3irect effects on heart are mediated throu9h )1 receptors
0hose acti(ation results in increased Ca influ&2 .oth in
pacema1er acti(ity and contractility/ Pacema1er acti(ity increased
in pur1in=e fi.ers/ 3irect effects can .e demonstrated in pts 0ith
9an9lionic .loc1ade2 0here (a9al refle& acti(ity is not in play/
<>% (a9al response2 effects on heart rate may .e dominated .y a
refle& response to )P chan9es/
)P: A purse alpha a9onists increased PA$ and decreases (enous
capacitance2 0hich increases )P/ (Phenylephrine)/ C% does not
diminish proportionate to reduction of heart rate due to increased
(enous return increasin9 stro1e (olume/ #se of a pure alpha
a9onist in a hypotensi(e patient pro.a.ly 0ould not e(o1e refle&
slo0in9 of heart .ecause )P is turnin9 to normal/ A purse )E!A
a9onist (isoproterenol) increased +$2 contractility2 and C%/
3ecreased S8$ .y systemic (asodilation/ 3iastolic )P reduced
0hile systolic )P is maintained or sli9htly inceased/
EYE: $adial papillary dilator muscle of iris contains a1 receptors
0hose acti(ation cause mydriasis/ Alpha a9onists increase
outflo0 of a-ueous humor from eye and .eta A!A:%"S!S
decrease production of a-ueous humor/ #seful for treatment of
9laucoma/
$ESP"$A!%$Y !$AC!: )8 in upper resp tract contain a1
receptors/ Acti(ation produces decon9estion/ )ronchial smooth
muscle contains )6 receptors 0hose acti(ation produce .ronchial
dilation/
13
:": $ela&ation of 9astrointestinal smooth muscle mediated .y A6
and )6 a9onists/ Alpha 6 a9onists decrease muscle acti(ity
indirectly .y presynaptically reducin9 AC+ release/ )eta 6
a9onists hyperpolari?e smooth muscle cells and promote
rela&ation/ A6 mediated response is more si9nificant
pharmacolo9ically/ ,ocus on alpha 6/
:#: Pre9nant uterus contracts in response to a1 a9onists and
rela&es in response to )6 a9aonists/ )6 a9onists useful in t& of
premature la.or (ter.utaline)/ )6 receptors of .ladder 0all
mediate rela&ation/ E=aculation depends upon a1 receptor
acti(ation in ductus deferens and prostate/ )ladder .ase2 urethral
sphincte2 and prostate contain a1 receptors 0hich mediate urinary
incontinence/
E;%C$"E: $espond to alpha a9onists 0ith increase s0eat
production/
ME!A)%L"C: )3 receptor .indin9 stims lipolysis/
Sympahomimeti dru9s in li(er stimulate 9lyco9enolysis and
9luconeoenesis primarily throu9h )6 receptors althou9h A
receptors may play a role/
E3%C$"E: Catacholamines stim 9luca9ons release throu9h
)6 acti(ation and .loc1 insulin release throu9h A6 acti(ation/ )1
acti(ates rennin/
CS: 3ependent upon a.ility to cross )))/ Effects ran9e from
ner(ousness to impendin9 disaster/ Catecholamines cross .arrier
e&tremely poorly/ Adrener9ic a9onists may mimic presentation of
an&iety/
1C
Adrener9ic a9onist2
epinephrine
Poseses si9nificant a9onist acti(ity at A12 A62 )12 and )6
receptors/ Stimulates all that is sympathetic/ Potent
(asoconstrictor and cardiac stimulant/
+$ increase
4 inotrope
4 chronotrope
4 C%
4Myocardial o&y9en
demand
4 (asodilation in
s1eletal muscle
(essels
4 systolic )P
4 .ronchodilation
4 9luca9ons release
4 mean .lood
pressure
4 hyper9lycemia
4 increases ,,A ((ia
.eta 3)
4 di(ersion of .lood
from s1eletal muscle
4 $AA system
Meta.oli?ed .y MA%>C%M! and has
short "8 half life
:i(en "M or SC2 epinephrine is lon9er
actin9 due to slo0er a.sorption and local
(asoconstriction
Still utili?d in temporary emer9ency dept
of complete heart .loc1/ Pro'
arrhythmo9enic
Mostly alpha one and .eta 6 a9onists/
Acti(ation of a1 0ill increase peripheral
resistance/ Acti(ation of )6 causes
(asodilation/ et effect is that of
dominant (asodilation/ 3rop in diastolic
)PO
3%C anaphyla&is2 )1 and )6 ma1e it
specific for "9E mediated (asodilation
Most common a9ent for local
(asoconstruction 9i(en durin9 local
anesthesia2 e&ample suturin9 face
Adrener9ic a9onist2
norepinehperine
Possesses acti(ity at all receptors .ut is selecti(e for alpha o(er
.eta/ )1 acti(ity e-ual to or pro.a.ly less than epinephrine/ More
of an alpha a9onist/
4 (asoconstriction <ith norepinepherine2 rise in )P due to
systemic (asocontriction/ o
compensatory (little) ) acti(it
Adrener9ic a9onist2
isproterenol
Synthetic catecholamine/ Stron9 a9onist at )1 and )6 receptors
0ith (irtually no alpha effect/
4 +$
4Chronotrope
4"notrope
)6 (asodilation seems to offset the
constrictor effect and thus produces a
mean .lood pressure decrease/
Mar9inal su.strate for C%M! and
resistant to MA%/ +alf life increased to
appro& 6 hours/
Acute treatment of asthma/ $eplaced .y
selecti(e )6 a9ents/
1B
!emporary emer9ency mana9ement of
complete heart .loc1/
Adrener9ic a9onist2
dopamine
Endo9enous catecholamine/ )inds to 31 and 36/ 36 receptors
are presynaptic in AS' not clinically si9nificant/ 31 are in the
renal (asculature 0here they cause (asodilation/ <hen doses are
increased2 you 9et alpha and .eta receptors/
4 renal .lood flo0 at
normal
concentrations
4 +$
4 ,orce of
contraction
Meta.oli?ed .y MA% and C%M!/
Admin "8
!herapeutic use is t& of shoc1
#se of cardio9enic shoc1 or for renal
perfusion/
Maintain renal perfusion
Adrener9ic a9onist2 )1
3o.utamine
Selecti(e for )1 in the heart/ $elati(ely more inotropic than
chronotropic effects/
4 C%
4 inotrope
:i(en "8
Meta.oli?ed .y MA%
Meta.oli?ed of C%M!
!& of cadiac decompensation or patients
0ith acute C+, or M"
+eart not pumpin92 increase inotropy/
3%ES %! "C$EASEM
MY%CA$3"AL %;Y:E 3EMA3
Alpha a9onists (A1)2
phenylephrine
A1 a9onist 1DD fold less potent than epi/ Sufficient doses produce
a1 acti(ity/
asal decon9estion
Mydriasis
!reat orthostasis
$esistanct to C%M!
o resistance to MA%
Lon9er half life
Penetrates )))
<ill increase )P (no opposed ) stim)
Local anesthesia
Alpha one a9onist2
Metho&amne
A1 selecti(e asal decon9estionP Chronic orthostatic hypotension t&
Elicits refle&i(e .rady C
Past2 use as t& for P/A/!/ (atrial
tachycarda)
Alpha 6 a9onist2
Clonidine
A6 a9onist2 selecti(e/ Presynaptic a9onist effects 0ould decrease
endo9enous release of E/ "t does happen2 .ut mechanism is
.elie(ed to .e the .indin9 of A6 receptors in .rain stem/ Centrally
actin9/ 3ecreases total centeral sympathetic outflo0/
CE!$AL>CL%"3"E/ Effecti(e in decreasin9 .lood pressure
$eduction of )P at
the source of
sympathetic dri(e
3ecrease of side effects durin9 opiate
0ithdra0al/ !herapeutic effect due to
a(aila.ility of catecholamines 0ithin the
CS
Adrener9ic a9onist2 A6 a9onists (Me too)
1F
Alpha 62
:uana.en?
:uanfacne
Adrener9ic a9onist2 )6
Al.uterol
Selecti(e )6 a9onist/ $etain some 0ea1 )1 acti(ity/ 4 +$
4 )ronchodilation
#sed for t& of asthma (ia )6 mediated
dilation of .ronchial smooth muscle/
:i(en .y inhalation route
Adrener9ic a9onist2 )62
!er.utaline
$elati(ely selecti(e )6 a9onism/ Admin oral2 Su.'*2 inhalation 4 !ocolysis (stop
contractions)
4)ronchodilation
Lon9 term t& of C%P3
Patentally in t& of status asthmaticus
Premature la.or
Adrener9ic a9onist2 )62
$itodrine
Selecti(e )6 a9onist/ #sed as tocolytic
Yutopar' uterus on parG
$eduction of
contractions
Control contractions2 delay premature
la.or
Mis/ Adrener9ic a9onist
Ephedrine
atural al1aloid/ Acts primarily .y causin9 the release of stored
catecholamines/ 3irect adrener9ic acti(ity/ +i9h oral
.ioa(aila.ility/ ,irst orally acti(e sympathomimetic/
4+$
4)P
4P8$
"nsomnia
4C%
Cross )))
Lon9 duration of action
Misc adrener9ic a9onist2
Pseudoephedrine
%ne of C ephedrine stereoisomers/ Less potent than ephedrine/
Sudafed/
4)P
43econ9estion
Misc adrener9ic a9onist2
Amphetamine
Phenmetramine
Methylphenidate
Pemoline
CS stimulants .ut all ha(e stron9 sympathomimetic effects
E;CEP! ME!+YLP+E"3A!E ($"!AL")/ ; ))) and are
lon9 actin9/ %ften a.used/ CS stimulated due to release of
dopamine>E/ $italin .loc1s upta1e of dopamine and is sli9htly
more selecti(e/
!hese increase a(aila.ility of EG therapeutic effects can .e
similar to anti'depressants/
4)P
4+$
4$efle&i(e .rady CO
4Appetite
suppression
4 C% is a dose
dependent effect
4 E release
4arrythmia
Contraindicated in MA%"s/ "f MA%" is
inhi.ited in the pre'synaptic terminal2 it
0ill lead to increase in sympathomimetic
effects/ Massi(e cytoplasmic .uildup of
E 0ith concominantly administered
MA%"G hypertensi(e crisis2 etc/
Misc/ adrener9ic
a9onist2
phenylpropanalomine
%rally acti(e2 indirect actin9 sympathomimetic/ $esem.les
ephedrine in spectrum and potency .ut does not seem to produce
the same de9ree of CS stimulation/ A(aila.le %!C/ +as .een
associated 0ith C8A2 hypertensi(e crisis
4decon9estion
4anore&ia
Misc adrener9ic a9onist2
!yramine
!yramine is not a dru9 .ut rather an indirect actin9
sympathomimetic found in (arious fermented foods and
.e(era9es/ Sli9ht sypathomimetic effects under normal
conditions/
<ith MA%"s2 may cause hypertensi(e
crisis/ Massi(e E release
Misc adrener9ic a9onist2
Cocaine
Local anesthetic that produces .oth CS stimulation and
peripheral sympathetic stimulation/ CS stimulation is due to
4)P
4+$
%.(ious
1H
.loc1ade of dopamine reupta1e/ 4CS
Procon(ulsant
Proarrythmo9enic
Misc adrener9ic a9onist2
!CAAs
E&ertion of antidepressant effects throu9h .loc1ade of
norepinepherine and > or serotonin in CS/ )loc1ade of E
upta1e causs indirect sympathomimetic effects
A 0ord a.out ad(erse effects: Sympathomimetic dru9 effects are e&tensions of their receptor affects in the C8 and CS/ Mar1ed ele(ation of )P can cause
cere.ral hemorrha9e and PE/ )1 a9onists can cause dysrhythmias/
ADRENERGIC ANTAGONISTS
THE BIG ALPHA PICTURE
'Alpha receptor anta9onism may .e re(ersi.le or non re(ersi.le
'Some are nonselecti(e
'Ma=or pharmacolo9ical effect is to lo0er .lood pressure thus elicitin9 a refle& tachycardia
'Ateriolar and (enous tone is determined .y A receptors on smooth muscle
'A a9onists lo0er peripheral resistance and .lood pressure
'Epinepherine 0ill L%<E$ .lood pressure in the presence of an a1 anta9onist .ecause )6'mediated (asodilation 0ill cause (asodilation
'Phenomenon called2 epinepherine re(ersal
'Cause %rthostatic hypotention
'Miosis and nasal stuffiness as SE
'<ill decrease resistance to flo0 of urine
'A!A:%"SM %, ALP+A !<% $ECEP!%$S "S <+A! CA#SES !+E $E,LE; !AC+' More norepinepherine is a(aila.le to .ind cardiac )1 receptors
THE PICTURE O/ BETA:ANTAGONISM
'E&tremely important
'#seful in lo0erin9 .lood pressure
'Selecti(e for )1 or )62 or some can .e non selecti(e
'Mechanism of lo0ered )P is due to a decrease in cardiac output
'$educed )P may elicit a refle& alpha'1 mediated increase in (ascular tone
'% P%S!#$AL +YP%!ES"% .ecause alpha ones are not .loc1ed
'$eduction of cardiac 0or1load
'Post M" prophyla&is or therapy
'#sed for an9ina (reduce myocardial o&y9en demand)
1K
')6 .loc1ade in asthmatics may .e dan9erous
'$educe intraocular pressure due to reduced a- humor production
'May .e associated 0ith increases in cholesterol
'+3L and L3L radios reduced/ !he ratio of 9ood to .ad cholesterol is lo0ered/ Clinically2 the ratio is 9i(en as L3L to +3L/ +i9her num.ers are therefore
pro9nostic of increased ris1 for CA3>C+3
'Local anesthetic effects
'Mem.rane sta.ili?in9
GENERAL SUMMARY O/ BETA BLOCKADE E//ECTS7
3ecreased +$
3ecreased C%
3ecreased sympathetic acti(ity
3ecreased cardiac arrythmias
Some ha(e local anesthetic acti(ity
Clinically useful for mana9ement of hypertension
-ARNINGS7
'Made se(eral points a.out .eta .loc1ers an dia.etics/ 3ia.etics ha(in9 an insulin shoc1 crisis depend on sympathetic response to alert themsel(es to a
hypo9lycemic state/ )eta .loc1ers may mas1 tachycardia and therefore e&acer.ate hypo9lycemic episodes
'Contraindicated in patients 0ith se(ere o.structi(e pulmonary diseases (C%P3>asthma)
'Caution 0ith rapid 0ithdra0al/ Persons can .e sensiti?ed to .eta .loc1ers/ $apid 0ithdra0al may cause e&a99erated responses to circulatin9 catecholamines/
E&: Patients 0ith an9ina 0ho are rapidly 0ithdra0n from .eta .loc1er therapy may e&perience 0orsenin9 of symptoms
') .loc1ers can interact 0ith Ca44 channel .loc1ers an cause se(ere hypotension
') .loc1ers can cause cardiac conduction a.normalities
'May mas1 symptoms of de(elopin9 hyperthyroidism
DRUG/CLASS MECHANISM S/S CLINICAL SE
Pheno4$&en3a*ne% al'ha
an#a!on"#% non:"elec#5e
"rre(ersi.le alpha one
anta9onism
Co(alently .inds a1 and a6
receptors/
Lon9 duration of action
Elicits refle&i(e tachycardia
partially au9mented .y
.loc1ade of presynaptic a6
Emer9ence of therapeutic
effects
Pheochromocytoma: !umor
in the adrenal medulla that
releases ;S catecholamines/
Causes hypertension2
tachycardia2 and arrythmias
#sed in preoperati(e period
$aynaudAs:
Postural hypotension
!achycardia (refle&)
asal stuffiness
"nhi.ition of e=aculation
1M
receptors/ ("ncrease in E)
<"LL P$%3#CE EP"
$E8E$SAL
'Causes unopposed )6
mediated (asodilation
Pheno&y.en?amine 0ill
re(erse alpha mediated
(asoconstriction
Autonomic hyperrefle&ia:
May .e used to diminish this
post C8A syndrome
Pra3o"n (Mn're"")
Tera3o"n (H$#rn)
Do4a3o"n (Car()ra)
Selec#5e al'ha one
an#a!on"#"
Selecti(e a1 anta9onism/ <ill
lo(er .lood pressure throu9h
a1 mediated effects/ o refle&
tachycardia/ Lac1 of acti(ity
at presynaptic alpha t0o
receptors/
Lo0ered )P !& hypertension
)P+' prostatic hyperplasia
Postural hypotension' less
li1ely 0ith chronic
administration
<ell tolerated
3i??iness2 lac1 of ener9y
asal con9estion
+eadache
Yoh*&e% "elec#5e a1
an#a!on"#
A6 anta9onism Possi.le au9mentin9 of
se&ual function
o ma=or clinical use
Pro'anolol% Non"elec#5e
&e#a an#a!on"#
)1 and )6 .loc1ade/ +as
local anesthetic acti(ity/ Lo0
oral .ioa(aila.ility and half
life of 3'B hours/
Emer9ence of clinical results
li1e lo0ered )P2 normali?ed
heart rhythm/
!& hypertension
Can .e 9i(en 0ith diuretic
Can .e 9i(en 0ith (asodilator
!& supra(entricular
arrythmias
Chronic an9ina pectoris
"ncreases lon9 term sur(i(al
post'M"
Slo0s (entricular response
rates
May reduce si?e of e(ol(in9
myocardial infarction
SE:
)ronchoconstriction
ot effecti(e 0hen 9i(en
acutely for mi9raines
6D
!& open an9le 9laucoma'
reduces ciliary .ody
production of a- humor .ut
has systemic effects
+yperthyroidism
mana9ement
May reduce systemic
manifestations of an&iety
Na(olol% lon!e"# ac#n! &e#a
&loc6er
onselecti(e .eta .loc1ade/
Lon9 half life/ o anesthetic
acti(ity/
!& +!
!& An9ine
T*olol (TIMOPTIC)%
Non"elec#5e &e#a &loc6er
onselecti(e .eta .loc1ade/
Lac1s local anesthestic
effects/
!& open an9le 9laucoma
May prolon9 post M" sur(i(al
Systemic a.sorption from
topical application may occur/
Caution in asthmatics
Caution 0ith C+,
Pn(olol% non"elec#5e &e#a
&loc6er
onselecti(e .eta .loc1ade/
+as 0ea1 intrinsic
sympathomimetic acti(ity/
+as local anesthetic acti(ity/
$educes +$
$educes C%
May .e preferred in insulin
dependent dia.etics/ ,aster
reco(ery from hypo9lycemic
episodes
Less li1ely to produce plasma
alterations in lipids
Contraindicated in asthmatics
Me#o'rolol (LOPRESSOR)%
a "elec#5e &e#a an#a!on"#
Possesses local anesthetic
effects/ )1 .loc1ade/ +alf life
of three to four hours
$educe +$
$educe C%
Lo0er )P
!& mi9raine
!& hypertension
May impro(e lon9 term M"
sur(i(al
)radycardia
A#enolol (TENORMIN)
Selec#5e &e#a an#a!on"#
o local anesthetic effects/
)1 .loc1ade/
$educe +$
$educe C%
E&tremely hydrophilic
Prolon9s sur(i(al post M"
!& hypertension
!& an9ina
Simular profile of SE to other
.eta .loc1ers
E"*olol (BRE+IBLOCK)
Selec#5e &e#a an#a!on"#
)$E8"'short actin9 .eta (1)
.loc1er/ o local anesthetic
effect/
$educe +$
$educe C%
Admin "8
#sed in critical care settin9s
0hen rapid lo0erin9 of )P is
of (alue/ Meta.oli?ed rapidly
SE profile impro(ed due to
)$E8"2 or short2 half life/
61
.y erythrocytes
Me#$ro"ne )loc1s synthesis or release of
catecholamines/ )loc1s
tyrosine hydro&ylase2 the rate
limitin9 step of E synthesis
!&: Pheochromocytoma'
tumor of adrenal 9lands
Re"er'ne )loc1s reupta1e of E2 EP"2
and serotonin into (esicles/
MA% destroys the
monoamines in the
cytoplasm/ 3ecreased E
release
:radual )P reduction
$educe +$
Slo0 onset
%)S%LE!E +! treatment
e0 E must .e synthesi?ed
G)ane#h(ne )loc1s release of E from
sympathetic ner(e terminal/
3isplaces E from stora9e
(esicles/
:radual +$ reduction
:radual )P reduction
$arely used +! !&
66