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1. Drugs Acting on
Autonomic Nervous System (ANS)
Objectives:
After studying this unit, you should be able to –
Main drug acting on the cholinergic and sympathetic system, the
prototype drug is described in detail and other drug of same group is
described in short;
Differentiate between the actions of the cholinergic and sympathetic
nervous system on different organs;
Enumerate the uses of different agonist and antagonists acting on the
autonomic nervous system; and
The side effects and overdose of these agents.

2. Theautonomicnervoussystem(ANS),isadivisionoftheperipheralnervous
systemthatactslargelyunconsciously/involuntarilyandregulatesbodily
functionssuchas
heartrate
digestion
respiratoryrate,
pupillaryresponse,
urination,and
sexualarousal.
Autonomic nervous system
Theautonomicnervoussystemhasthreebranches:
1.thesympatheticnervoussystem,
2.theparasympatheticnervoussystem,
3.theentericnervoussystem.
Thesympatheticnervoussystemisoftenconsideredthe"fightorflight"system,while
theparasympatheticnervoussystemisoftenconsideredthe"restanddigest"or"feed
andbreed"system.

4. I. THE PERIPHERAL EFFERENT NERVOUS SYSTEM
A.Theautonomicnervoussystem(ANS)controlsinvoluntaryactivity(Fig./Table).
1.Parasympatheticnervoussystem(PNS)
a.Longpreganglionicaxonsoriginatefromneuronsinthecranialandsacralareasofthespinal
cordand,(withfewexceptions,synapseonneuronsinganglialocatedclosetoorwithinthe
innervatedorgan).
b.Shortpostganglionicaxonsinnervatecardiacmuscle,bronchialsmoothmuscle,andexocrine
glands.
c.Parasympatheticinnervationpredominatesoversympatheticinnervationofsalivaryglands,
lacrimalglands,anderectiletissue.
2.Sympatheticnervoussystem(SNS)
a.Shortpreganglionicaxonsoriginatefromneuronsinthethoracicandlumbarareasofthe
spinalcordand(synapseonneuronsinganglialocatedoutsideof,butcloseto,thespinal
cord.Theadrenalmedulla,anatomicallyconsideredamodifiedganglion,isinnervatedby
sympatheticpreganglionicaxons.)
b.LongpostganglionicaxonsinnervatemanyofthesametissuesandorgansasthePNS.
c.Innervationofthermoregulatorysweatglandsisanatomicallysympathetic,butthepost-
ganglionicnervefibersarecholinergicandreleaseacetylcholineastheneurotransmitter.
B.Thesomaticnervoussystem(Fig.)controlsvoluntaryactivity.Thissystemcontainslongaxons
thatoriginateinthespinalcordanddirectlyinnervateskeletalstriatedmuscle.

5. Autonomic Nervous System
•The motor limb of the ANS is anatomically divided into sympathetic and
parasympathetic.

6. C. Neurotransmitters of the autonomic and somatic nervous systems
1.Acetylcholine(ACh):
a.AChisreleasedbyexocytosisfromnerveterminals.
b.AChistheneurotransmitteracrosssynapsesatthegangliaoftheSNSandPNSand
acrosssynapsesintissuesinnervatedbythePNSandthesomaticnervoussystem.
c.AChissynthesizedinnerveterminalsbythecytoplasmicenzyme choline
acetyltransferase(ChAT),whichcatalyzesthetransferofanacetategroupfromacetyl
coenzymeA(acetylCoA)tocholinethathasbeentransportedinto‘‘cholinergic’’
neuronsbyaNa
+
-dependentmembranecarrier.SynthesizedAChistransportedfrom
cytoplasmtovesicle-associatedtransporters(VAT).
d.AChisstoredinnerveterminalvesicles that,throughCa
+2
calcium-dependent
exocytosis,arereleasedbynerveactionpotentials.Onrelease,AChisrapidly
hydrolyzedandinactivatedbytissueacetylcholinesterase(AChE)andalsobynon-
specificbutyrylcholinesterasetocholineandacetate(hydrolysisblockedbybotulinum
toxin).
e.AChisnotadministeredparenterallyfortherapeuticpurposesbecauseitis
hydrolyzednearlyinstantlybybutyrylcholinesterase.

7. 2. Norepinephrine and epinephrineare catecholamines, possessing a
catechol nucleus and an ethylamine side chain.
a.Storageandrelease
(1)Norepinephrineisstoredinvesiclesthat,throughacalcium-dependent
process,releasetheircontentsbyexocytosisfromnerveterminalsat
postganglionicnerveendingsoftheSNS(exceptatthermoregulatorysweat
glands,whereAChistheneurotransmitter).
(2)Norepinephrinereleasecanbeblockedbysuchdrugsasbretyliumand
guanethidine.
(3)Norepinephrinealsoexistsinanon-vesicularcytoplasmicpoolthatis
releasedbyindirectlyactingsympathomimeticamines(e.g.,tyramine,
amphetamine,ephedrine)byaprocessthatisnotcalciumdependent.
(4)Norepinephrineandsomeepinephrinearereleasedfromadrenergicnerve
endingsinthebrain.Intheperiphery,epinephrine,alongwithsome
norepinephrine,isthemajorcatecholaminereleasedfromadrenalmedulla
(chromaffincells)intothegeneralcirculation,wheretheyfunctionas
hormones

9. b.Biosynthesisofcatecholamines(Fig.)
(1)Inpre-junctionalnerveendings,tyrosineishydroxylatedby
tyrosinehydroxylase,therate-limitingenzymeinthe
synthesisofcatecholamines,toformdihydroxyphenylalanine
(dopa);dopaisthendecarboxylatedbydopadecarboxylase
toformdopamine.
(2)Dopamineistransportedintovesicles,(astepblockedby
reserpine),whereitishydroxylatedonthesidechainby
dopamineβ-hydroxylasetoformnorepinephrine.
(3)Incertainareasofthebrainandintheadrenalmedulla,
norepinephrineismethylatedontheaminegroupoftheside
chainbyphenylethanolamine-N-methyltransferase(PNMT)
toformepinephrine

10. c.Termination
(1)Theactionofnorepinephrineisterminatedprimarilybyactivetransport
fromthecytoplasmintothenerveterminal(uptake1),(aprocessthatis
inhibitedbycocaineandtri-cyclicantidepressantagentssuchasimipramine).
(2)Norepinephrineisthentransportedbyasecondcarriersystemintostorage
vesicles,asisdopamineandserotonin,aprocessalsoblockedbyreserpine.
(3)Anotheractivetransportsystem(uptake2)islocatedongliaandsmooth
musclecells.Thereisalsosomesimplediffusionawayfromthesynapse.
(4)Norepinephrineandepinephrinealsoareoxidativelydeaminated by
mitochondrialmonoamineoxidase(MAO)innerveterminalsandeffector
cells,notablyintheliverandintestine.IsoformsofMAO(AandB)havebeen
identified.DopamineismetabolizedprimarilybyMAO-B.
(5)Nervecellsandeffectorcellscontaincatechol-O-methyltransferase(COMT),
whichmetabolizescatecholamines.Metabolites,including3-methoxy-4-
hydroxymandelicacid(VMA),provideameasureofcatecholamineturnover
inthebody.

11. Autonomic Receptors
Cholinoceptor(acetylcholine):
i.Nicotinic –ionotropic(n, m)
ii.Muscarinic –G-protein coupled (M1-5)
Adrenoceptor (epinephrine, norepinephrine)
i.Alpha (α1
ABD
, α2
ABC
): G-protein coupled
ii.Beta (β1-3): G-protein coupled
iii.Dopaminergic receptors (D1-5): G-protein coupled

12. 12
Cholinergic Neurotransmission
•Synthesis
Choline Acetyl Transferase
•Storage
Vesicles
•Release –Na
+
/ Ca
2+
•Receptor Activation
Musc/ Nic
•Termination of Action
Acetyl cholinesterase

13. D. Receptors of the nervous system
1.Cholinoceptors:
Twotypes
a)Nicotinicb)Muscarinic
a.Nicotinicreceptors:
Cholinoceptorsthatareactivatedbythealkaloidnicotine
(1)Nicotinicreceptorsarelocalizedatmyoneuraljunctionsofsomaticnerves
andskeletalmuscle(NM),autonomicganglia(NG),includingtheadrenal
medulla,andcertainareasinthebrain.
(2)Nicotinicreceptorsconsistofapentameroffourproteinsubunitsinskeletal
muscleandtwoproteinsubunitsinneuronsthatformligand-gatedion
channelporesinthecellmembranes
(3)Inskeletalmuscle,AChinteractswithnicotinicreceptorstoopenchannels
thatpermitpassageofions,mostlyNa+.TheNa+currentproduces
membranedepolarizationandapropagatedactionpotentialthroughthe
transversetubulesofskeletalmuscle,resultinginthereleaseofCa2+from
thesarcoplasmicreticulum(SR)and,throughafurtherseriesofchemicaland
mechanicalevents,musclecontraction.
(4)HydrolysisofAChbyAChEresultsinmusclecellrepolarization.
Example:Nicotineagonist,likesuccinylcholine,b.Nicotinicreceptorantagoniststubocurarineand
trimethaphancanblocktheeffectofAChatskeletalmuscleandautonomicganglia,respectively

14. Nicotinic Receptors: ion channels

15. b. Muscarinic receptors:
Cholinoceptorsthat are activated by the
alkaloid muscarine
(1)Muscarinicreceptorsarelocalizedonnumerousautonomic
effectorcells,includingcardiacatrialmuscle,cellsoftheSAandAV
nodes,smoothmuscle,exocrineglands,andvascularendothelium
(mostlyarterioles)
(2)Muscarinicreceptorsconsistofatleastthreefunctionalreceptor
subtypes(M1–M3).
–MuscarinicM1-receptorsarefoundinsympatheticpostganglionic
neuronsandinCNSneurons;
–M2-receptorsarefoundincardiacandsmoothmuscle;and
–M3-receptorsarefoundinglandularcells(e.g.,gastricparietalcells),
andthevascularendotheliumandvascularsmoothmuscle.
–M2-andM3-receptorspredominateintheurinarybladder.Allthree
subtypesarefoundintheCNS.

16. (3)AChinteractswithM1andM3muscariniccholinoceptorstoincrease
phosphatidylinositol(PI)turnoverandCa2+mobilization-
(a)
ByactivationofGprotein(Gq),theinteractionofAChwithM1andM3muscarinic
cholinoceptorsstimulatesphospholipaseC(polyphosphatidylinositol
phosphodiesterase),whichhydrolyzesPItoinositoltrisphosphate(IP3)and
diacylglycerol(DAG).
(b)IP3mobilizesintracellularCa
2+
fromtheendoplasmicandsarcoplasmicreticula,
andactivatesCa
2+
-regulatedenzymesandcellprocesses.
(c)Diacylglycerol(DAG)activatesproteinkinaseC,whichresultsinphosphorylationof
cellularenzymesandotherproteinsubstratesandtheinfluxofextracellular
calciumthatresultsinactivationofcontractileelementsinsmoothmuscle.
(4)AChalsointeractswithM2muscariniccholinoceptorstoactivateG
proteins(G1),whichleadstoinhibitionofadenylylcyclaseactivitywith
decreasedlevelsofcyclicAMPandtoincreasedK+conductancewitheffector
cellhyperpolarization.
(5)CholinergicagonistsactonM3muscarinicreceptorsofendothelialcellsto
promotethereleaseofnitricoxide(NO),whichdiffusestothevascular
smoothmuscletoactivateguanylylcyclaseandincreasecyclicGMP(cGMP)
andtoproducerelaxation

17. 17
Adrenergic Neurotransmission
•Synthesis
Tyrosine Hydroxylase**
Dopa-decarboxylase•
Storage
Dopamine-hydroxylase
•
Release–Na
+
/Ca
2+
•
Receptor Activation:

1

1
•
AutoreceptorActivation

2
•
Termination of Action:
Diffusion / COMT / MAO

18. 2.Adrenoceptors
a.α-Adrenoceptors:
(1)α-Adrenoceptorsareclassifiedintotwomajorreceptor
subgroups(therearesubtypesofeachgroup).
•α1-Receptorsarelocatedinpost-junctionaleffectorcells,notablyvascular
smoothmuscle,whereresponsesaremainlyexcitatory
•α2-receptorsarelocatedprimarilyinpre-junctionaladrenergicnerve
terminals,andalsoinfatcellsandinβ-cellsofthepancreas.
(2)Functions:
•α-Adrenoceptorsmediatevasoconstriction(α1)
•GIrelaxation(α1)
•Mydriasis(α1)
•Inhibitionofreleaseofnorepinephrineandotherneurotransmitters(α2)
•Inhibitionofinsulinrelease(α2)&
•Inhibitionoflipolysis(α2).

19. 3)α-Adrenoceptorsaredistinguishedfromβ-adrenoceptorsbytheir
interaction(indescendingorderofpotency),withtheadrenergicagonists
epinephrine>norepinephrine>isoproterenol,andbytheirinteraction
withrelativelyselectiveantagonistssuchasphentolamine.
4)α1-Receptors,likemuscarinicM1andM3cholinoceptors,activateguanine
nucleotidebindingproteins(Gq)inmanycells,whichresultsinactivation
ofphospholipaseCandstimulationofphosphoinositide(PI)hydrolysisthat
leadstoincreasedformationofinositoltrisphosphate(IP3)and
mobilizationofintracellularstoresofCa2+andtoincreaseddiacylglycerol
(DAG)andactivationofproteinkinaseC.
5)α2-Receptors,likemuscarinicM2-cholinoceptors,activateinhibitory
guaninenucleotide-bindingproteins(Gi),inhibitadenylylcyclaseactivity,
anddecreaseintracellularcyclicAMP(cAMP)levelsandtheactivityof
cAMP-dependentproteinkinases.

20. b.β-Adrenoceptors
(1)β-Adrenoceptors:Itislocatedmostlyinpostjunctionaleffectorcells,areclassified
intotwomajorreceptorsubtypes,β1-receptors(primarilyexcitatory)andβ2-
receptors(primarilyinhibitory).
(a)β1-Receptorsubtype
(i)β1-Receptorsmediateincreasedcontractilityandconductionvelocity,andrenin
secretioninthekidney(β3-receptorsmediateactivationoffatcelllipolysis).
(ii)Theβ1-receptorsubtypeisdefinedbyitsinteraction(indescendingorderof
potency)withtheadrenergicagonists isoproterenol>epinephrine=
norepinephrineandbyitsinteractionwithrelativelyselectiveantagonistssuchas
atenolol.
(b)β2-Receptorsubtype
(i)β2-Receptorsmediatevasodilationandintestinal,bronchial,anduterinesmooth
musclerelaxation.
(ii)Theβ2-receptorsubtypeisdefinedbyitsinteraction(indescendingorderof
potency)withtheadrenergicagonists isoproterenol=epinephrine>>
norepinephrine.

21. (2)β-Receptoractivation:
(a)β-Receptorsactivateguaninenucleotide-bindingproteins(Gs)
(b)Activationstimulatesadenylatecyclase(AC)activityand
increasesintracellularcAMPlevels;theactivityofcAMP-
dependentproteinkinases.
Adrenoceptor-mediatedchangesintheactivityofprotein
kinases(intracellularCa
2+
)bringaboutchangesintheactivityof
specificenzymes;structuralandregulatoryproteins,resultingin
modificationofcellandorganactivity.

22. Adrenergic Neurotransmitters
Rank Order of Potency
Isoproterenol: β
1
=β
2
= β
3
>>>>α
1
= α
2
Norepinephrine : α
1
= α
2
= β
1
= β
3
>>>>β
2
Epinephrine: α
1
= α
2
= β
1
=β
2
= β
3
Dopamine: DA
1
>β
1
> α
1
22

24. II. PARASYMPATHOMIMETIC DRUGS
A.Direct-actingmuscariniccholinoceptoragonists
1.Actionandchemicalstructure
a.Direct-actingparasympathomimeticdrugsactatmuscarinic
cholinoceptorstomimicmanyofthephysiologiceffectsthatresult
fromstimulationoftheparasympatheticdivisionoftheANS
b.Bethanechol(Urecholine)andcarbacholarecholineesterswitha
quaternaryammoniumgroupthatarestructurallysimilarto
acetylcholinebutmoreresistanttohydrolysisby
acetylcholinesterase.Theβ-methylgroupofbethanechol
substantiallyreducesitsactivityatnicotinicreceptors.
c.Pilocarpineisatertiaryaminealkaloid.

25. 2. Pharmacologic effects
a.Eye:
(1)Direct-actingmuscariniccholinoceptoragonistscontractthecircularsmooth
musclefibersoftheciliarymuscleandiristoproduce,respectively,aspasmof
accommodationandanincreasedoutflowofaqueoushumorintothecanalof
Schlemm,resultinginareductioninintraocularpressure(IOP).
(2)Drugscontractthesmoothmuscleoftheirissphinctertocausemiosis.
b.Cardiovascularsystem
(1)Direct-actingmuscariniccholinoceptoragonistsproduceanegativechronotropic
effect(reducedSAnodeactivity).
(2)DecreaseconductionvelocitythroughtheAVnode.
(3)Drugshavenoeffectonforceofcontractionbecausetherearenomuscarinic
receptorson,orparasympatheticinnervationof,ventricles.
(4)Direct-actingmuscariniccholinoceptoragonistsproducevasodilationthatresults
primarilyfromtheiractiononendothelialcellstopromotethereleaseofNOand
producesrelaxationofvascularsmoothmuscle.[Vascularsmoothmusclehas
muscarinicreceptorsbutnoparasympatheticinnervation].

26. c.GItract:
(1)Direct-actingmuscariniccholinoceptoragonistsincreasesmoothmuscle
contractionsandtone,withincreasedperistalticactivityandmotility.
(2)Drugsincreasesalivationandacidsecretion.
d.Urinarytract:
(1)Direct-actingmuscariniccholinoceptoragonistsincreasecontractionofthe
ureterandbladdersmoothmuscle.
(2)Thesedrugsincreasesphincterrelaxation.
e.Respiratorysystem:
Effectsofdirect-actingmuscariniccholinoceptoragonistsinclude
bronchoconstrictionwithincreasedresistanceandincreasedbronchial
secretions.
f.Othereffects:
(1)Thesedrugsincreasethesecretionoftearsfromlacrimalglandsand
increasesweatglandsecretion.
(2)Thesedrugsproducetremorandataxia.

27. 3. Specific drugs and their therapeutic uses.
These drugs are used primarily for diseases of the eye, GI tract, urinary tract, the
neuromuscular junction, and the heart.
a.Bethanechol(Urecholine):
(1)It is used to stimulate smooth muscle motor activity of the urinary tract to
prevent urine retention.
(2)It is used occasionally to stimulate GI smooth muscle motor activity for
postoperative abdominal distention and for gastric atonyfollowing bilateral
vagotomy(in the absence of obstruction).
(3)It is administered PO or SC, not by IV or IM route, because parenteral
administration may cause cardiac arrest.
(4)It has low lipid solubility and is poorly absorbed from the GI tract. When
given orally, GI effects predominate, and there are relatively minor
cardiovascular effects.
(5)Bethanecholhas limited distribution to the CNS.
(6)It is resistant to hydrolysis by AChEand plasma cholinesterase and thus has
a longer duration of action than ACh(2–3 hours)

28. b. Methacholine(Mecholyl)is occasionally used to diagnose bronchial hypersensitivity.
Patients with no clinically apparent asthma are more sensitive to methacholine-induced
bronchoconstriction than normal patients.
c. Pilocarpine
(1)Pilocarpineis occasionally used topically for open-angle glaucoma, either as eye
drops or ocular insert (Ocusert). b-Adrenergic receptor antagonists such as timolol
and betaxololand prostaglandin analogues such as latanoprostare the drugs of
choice to treat open-angle glaucoma. Other drug classes used include a-adrenergic
receptor agonists such as epinephrine and diuretics such as acetazolamide.
(2)When used before surgery to treat acute narrow-angle glaucoma (a medical
emergency), pilocarpineis often given in combination with an indirectly acting
muscarinic agonist such as physostigmine.
(3)Pilocarpineand cevimeline(Evoxac), a newer muscarinic receptor agonist, increase
salivary secretion. They are used to treat Sjogren’ssyndrome.
(4)Pilocarpineis a tertiary amine that is well absorbed from the GI tract and enters the
CNS.
d. Carbacholis rarely used except if pilocarpineis ineffective as a treatment for open-angle
glaucoma.
e. Cevimelene(Evoxac)is used to treat Sjogrensyndrome–associated dry mouth.
f. Varenicline(Chantix), a direct-acting nicotinic receptor agonist, is approved for use in
smoking cessation.

29. 4. Adverse effects and contraindications
a. The adverse effects associated with direct-acting muscarinic cholinoceptor
agonists are extensions of their pharmacologic activity.
Themostseriousinclude nausea,vomiting,sweating,salivation,
bronchoconstriction,decreasedbloodpressure,anddiarrhea,allofwhich
canbeblockedorreversedbyatropine.Systemiceffectsareminimalfor
drugsappliedtopicallytotheeye.
b.Thesedrugsarecontraindicatedinthepresenceofpepticulcer(because
theyincreaseacidsecretion),asthma,cardiacdisease,andParkinson
disease.
Theyarenotrecommendedinhyperthyroidismbecausetheypredisposeto
arrhythmia;theyarealsonotrecommendedwhenthereismechanical
obstructionoftheGIorurinarytract.

30. B. Indirect-acting parasympathomimeticagents
1.Chemicalstructure
a.Edrophoniumisanalcoholwithaquaternaryammoniumgroup .
b.Neostigmineandphysostigmineareexamplesofcarbamicacidestersofalcohols
(carbamates)witheitherquaternaryortertiaryammoniumgroups.
2.Mechanismofaction
a.Indirect-actingparasympathomimeticagentsinhibitAChEandincreaseAChlevelsat
bothmuscarinicandnicotiniccholinoceptorstomimicmanyofthephysiologiceffects
thatresultfromincreasedAChinthesynapticjunctionandstimulationofcholinoceptors
oftheparasympatheticdivisionoftheANS.
b.AChinteractswithAChEattwosites:TheN+ofcholine(ionicbond)bindstothe
anionicsite,andtheacetylesterbindstotheesteraticsite(serineresidue).AsAChis
hydrolyzed,theserine-OHsidechainisacetylatedandfreecholineisreleased.Acetyl-
serineishydrolyzedtoserineandacetate.Thehalf-life(t
1/2
)ofacetylserinehydrolysisis
100–150microseconds.
c.Edrophonium(Tensilon)actsatthesamesitesofAChEtocompetitivelyinhibitACh
hydrolysisbythefollowingprocesses:
1)N+ofedrophoniumbindstheanionicsite.
2)PhenolichydroxylofedrophoniuminteractswithhistidineimidazoliumN+ofthe
esteraticsite.
3)Edrophoniumhasashortdurationofaction(5–15min).

31. d.Neostigmine(Prostigmin),physostigmine(Eserine,Antilirium),anddemecarium
(Humorsol),likeACh,interactwithAChEandundergoatwo-stephydrolysis.However,the
serineresidueoftheenzymeiscovalentlycarbamylatedratherthanacetylated.Hydrolysis
ofthecarbamylserineresidueismuchslowerthanthatofacetylserine(30min–6h).
(1)Neostigmine,physostigmine,anddemecariumalsohavedirectagonistactionat
skeletalmusclenicotiniccholinoceptors.
(a)Becauseofitsquaternaryammoniumstructure,neostigmineispoorlyabsorbedfrom
theGItractandhasnegligibledistributionintotheCNS.
(b)Physostigmineiswellabsorbedafteroraladministration,anditenterstheCNS.
e.Pralidoxime(Protopam)
(1)PralidoximeisanAChEreactivatorthatmustbeadministeredIVwithinminutesof
exposuretoanAChEinhibitorbecauseitiseffectiveonlypriorto‘‘aging.’’
(2)Pralidoximeactsasanantidotefororganophosphorusinsecticideandnervegas
poisoning.[tbindstheanionicsiteandundergoesanucleophilicreactionwithPO
4
groupofalkylphosphorylatedserinetocausehydrolysisofthephosphoserinebond
thatisatleast106timesfasterthanthatoccurringinwater.]
(3)Thisdrugismosteffectiveattheneuromuscularjunction.ItisineffectiveintheCNS
andagainstcarbamylatedAChE.
(4)Pralidoximeproducesfewadverseeffectsinnormaldoses

32. 3. Pharmacologic effects
a.Withthemajorexceptionofarterioletoneandbloodpressure,wheretheireffects
arelesspronounced,thepharmacologiceffectsofindirect-actingparasympathomimetic
agentsaresimilartothoseofdirect-actingmuscariniccholinoceptoragonists
4.Therapeuticuses
a.Glaucoma
(1)Physostigmineisoftenusedconcurrentlywithpilocarpineformaximumeffectin
thetreatmentofacuteangle-closureglaucoma,amedicalemergency.
(2)Physostigmine,demecarium,echothiophate,andothercholinesteraseinhibitors
havebeenlargelyreplacedforthetreatmentofchronicopen-angleglaucomaby
topicalb-adrenergicreceptorantagonistssuchastimololandbetaxolol,andby
prostaglandinanaloguessuchaslatanoprost.Theyareusedwhenotherdrugsare
ineffective.Prolongedusemayincreasethepossibilityofcataracts.
b.GIandurinarytractatonycanbetreatedwithneostigmine,whichisusedmuchlike
bethanechol.

33. 3. Pharmacologic effects
c. Myasthenia gravis
(1)Myastheniagravisisanautoimmunediseaseinwhichantibodiescomplex withnicotinic
receptorsattheneuromuscularjunctiontocauseskeletalmuscleweaknessandfatigue.
Neostigmine,ortherelatedAChEinhibitorspyridostigmine(Mestinon,Regonol)or
ambenonium(Mytelase),isusedtoincreaseAChlevelsattheneuromuscularjunctionto
activatefullytheremainingreceptors.
(2)MyastheniagraviscanbediagnosedusingtheTensilontest,whichcanalsoassesstheadequacy
oftreatmentwithAChEinhibitors.Smalldosesofedrophoniumimprovemusclestrengthin
untreatedpatientswithmyastheniaorintreatedpatientsinwhomAChEinhibitionis
inadequate.Ifthereisnoeffect,orifmuscleweaknessincreases,thedoseoftheAChEinhibitor
istoohigh(excessiveAChstimulationattheneuromuscularjunctionresultsinadepolarizing
blockade).
(3)AtropinecanbeusedtocontrolexcessivemuscarinicstimulationbyAChEinhibitors.
(4)Tolerancemaydeveloptolong-termuseoftheAChEinhibitors.
d.Alzheimerdisease:Donepezil
(Aricept),galantamine(Reminyl),rivastigmine(Exelon),and
tacrine(Cognex)areAChEinhibitorsusedtoamelioratethecognitivedeficitassociatedwith
Alzheimerdisease
e.Neostigmineoredrophoniumcanbeusedfollowingsurgerytoreverseneuromuscularblockade
andparalysisresultingfromadjunctuseofnon-depolarizingagents.
f.Atropineandscopolaminepoisoningcanbetreatedwithphysostigmine,whichreversesthe
centraland(tosomeextent)theperipheraleffectsofcompetitivemuscarinicantagonists.

34. 5. Adverse effects and toxicity
a.Theadverseeffectsassociatedwithindirect-actingsympathomimeticagents
areanextensionofpharmacologicactivityandarisefromexcessive
cholinergicstimulation.
b.Adverseeffectsincludemuscariniceffectssimilartothoseofdirect-acting
cholinergicdrugsandnicotiniceffectssuchasmuscleweakness,crampsand
fasciculations,excessivebronchialsecretions,convulsions,coma,
cardiovascularcollapse,andrespiratoryfailure.
c.Manylipid-solubleorganophosphatesareusedasinsecticides (e.g.,
malathion)ornervegases(e.g.sarin)andmaybeabsorbedinsufficient
quantitiesfromtheskinorlungstocausecholinergicintoxication.
d.Treatmentincludesthefollowingsteps:(1)Maintainrespirationand
decontaminatetopreventfurtherabsorption.(2)Administeratropine
parenterallytoinhibitmuscariniceffects.(3)Administerpralidoximewithin
minutesofexposure.

35. Drugsactingonadrenergicreceptors
a)Sympathomimeticdrugs- Alsoknownas adrenergic
agonists
b)Sympatholyticdrugs-Adrenergicantagonists
Sympatheticdivision
Thoracicnervesandlumbernerves.
Thoracolumbaroutflow(T1-L2)
Adrenergic receptors are α
1
-α
2
and β
1
-β
3

36. A.Sympathomimeticdrugs-
Thesearestimulantcompoundswhichmimictheeffects
ofendogenousagonistsofthesympatheticnervous
system.Theprimaryendogenousagonistsofthe
sympatheticnervoussystemarethecatecholamines
(adrenaline,noradrenaline,anddopamine ),which
functionasbothneurotransmittersandhormones.
Sympathomimeticdrugsareusedtotreatcardiacarrest
andlowbloodpressure,orevendelayprematurelabor,
amongotherthings.

37. Adrenaline
Nor adrenaline
Dopamine
Phenylephrine
Isoprenaline
Dobutamine
Sympathomimetic agonists/drugs
Salbutamol

38. Classifications of sympathomimetic drugs
A. According to mode of action
1. Directly acting-
Adrenaline
Noradrenaline
Isoprenaline
Dopamine
2. Indirectly acting-
Tyramine
Amphetamine
Methamphetamine
3. By both mechanism-
Ephedrine

39. Classifications of sympathomimetic drugs
B. According to receptor selectivity
α
1
agonist
phenylephrine
Methoxamine
α
2
agonist
Clonidine
Both α
1
and α
2
agonist
Adrenaline
Noradrenaline
β
1
agonist
Dobutamine
β
2
agonist
Salbutamol
Both β
1
and β
2
agonist
Adrenaline
Isoproterenol
Both α-β agonist
Adrenaline
Ephedrine
C. According to Chemical Nature
Catecholamines
Adrenaline
Noradrenaline
Isoprenaline
Dopamine
Non-catecholamines
Ephedrine
Amphetamine
Phenylephrine

40. D.Accordingtotherapeuticutility
1.Vasoconstrictors
Adrenaline
Noradrenaline
Metaraminol
2.Vasodilators
Isoprenaline
Dopamine
3.Bronchodilators
Salbutamol
Terbutaline
4.CNSstimulants
Amphetamine
Methamphetamine
5.Cardiacstimulants
Adrenaline
Isoprenaline
Ephedrine
6.Nasaldecongestants
Ephedrine
Oxymethazoline
Dopamine
7.Uterinerelaxants
Salbutamol
Nylidrin

41. Mechanismsofaction
Themechanismsofsympathomimeticdrugscanbe
direct-acting(directinteractionbetweendrugand
receptor),suchasα-adrenergicagonists,β-adrenergic
agonists,anddopaminergicagonists;orindirect-acting
(interactionnotbetweendrugandreceptor),suchas
MAOIs,COMTinhibitors,releasestimulants,and
reuptakeinhibitorsthatincreasethelevelsof
endogenouscatecholamines.
COMT: Catechol-O-methyl transferase

42. Adrenergicreceptoragonists-Directacting
Directstimulationofthe α-andβ-adrenergicreceptorscanproduce
sympathomimeticeffects.Salbutamolisawidelyuseddirect-acting β
2
-
agonist.Otherexamplesinclude phenylephrine,isoproterenol,and
dobutamine.
Indirect-acting
Dopaminergicstimulantssuchas amphetamine,ephedrine,and
propylhexedrineworkbycausingthereleaseofdopamineand
norepinephrine,alongwith(insomecases)blockingthereuptakeof
theseneurotransmitters.
Dopaminergicagonists
StimulationoftheD1receptorbydopaminergicagonistssuchas fenoldopamis
usedintravenouslytotreathypertensivecrisis.

44. Distribution of adrenergic receptors
Receptor and signalingSite Effects on activationα
1
Activation causes
increase Ca
+2
Blood vessels
Salivary glands
GIT
Male sex organ
Radial Muscle (pupil)
Liver
Pregnant uterus
Pancreas
Vasoconstriction
Salivation
Relaxation of GIT
Sphincter contraction
Contraction of radial
muscle
Glycogenolysis
Contractionof uterus
Decrease pancreatic
secretion
α
2
Activation decreases
cAMP
CNS
Pre-synaptic nerve
terminals
Blood vessels
platelets
Inhibition of
neurotransmitters
release from nerve
ending
vasoconstriction
Platelet aggregation

45. β
1
Activation increases cAMP
Heart (dominant)
Fat cells
Juxtaglomerularcells
(Kidney cells)
Increase heartrate
Increase force of contraction
Lipolysis
Increase renin secretionβ
2
Activation increases cAMP
Bronchial smooth muscle
Blood vessels of small
coronary artery, liver, skeletal
muscle
Betacells of pancreas
Broncho dilation
vasodilationβ
3
Activation increases cAMP
Adipose tissue, CNS Lipolysis
D
1
Smooth muscle Dilate renal blood vessels
D
2
Nerve endings Modulate transmitter release

47. Clinical uses of sympathomimetic drugs
Norepinephrine,phenylephrine,metaraminol,mephenteramine
andmethoxaminemaybeusedtomaintainbloodpressurein
severehypotension.
Theuseoftheseagentsmaybeindicatedifthehypotensivestateisdueto
sympatheticfailure,suchaspossiblyoccurringfollowingspinalanesthesiaorinjury.
Inshockduetoothercauses,reflexvasoconstrictionistypicallyintense;adding
alphaagonistsmaybeharmfulbyfurthercompromisingorgan(e.g.renal)perfusion.
α
agonist

48. Dopamine,(Intropin),atlowconcentrations,actsatD
1
receptors
andimprovemyocardialcontractility(positiveinotropism).
Centrally-actingsympathomimetics,suchasclonidineor
methyldopa,areeffectiveantihypertensivedrugs.
ß
adrenergicreceptoragonistshavehadlimiteduseinchronic
managementofcongestiveheartfailure.
Epinephrine,avasoconstrictor,isusedinnoseandthroatsurgical
procedures.Vasoconstriction-reducedbleedinginsurgical
procedures.
aadrenergicagonistsmaybeusedforthetreatmentofpriapism
(persistenterectionprobleminmale)

49. ß
adrenergicreceptoragonistshaveaprominentroleinchronic
andacutemanagementofasthma.
ß
2
selectiveadrenergic
receptoragonists(salbutamol),mediatingbronchodilation,are
preferable.
Epinephrineistheagentofchoiceinemergencymanagementof
acutehypersensitivityreactions(reactiontofood,insectbites,
drugallergy)
Subcutaneousepinephrineadministrationalleviatesymptoms
rapidlyandmaybelifesavingwhenairwayiscompromisedorin
hypotensiveshock.
Mechanism:
ß
adrenergicreceptoractivationmaysuppressmast
cellreleaseofhistamineandleukotrienemediators.

50. Organ Effect
Eye Dilates
Heart Increasesrateandforceofcontraction
Lungs Dilates bronchiolesviacirculatingadrenaline
Blood
vessels
Dilateinskeletalmuscle(inanimals).
Constrictsingastrointestinalorgans
Sweat
glands
Activatessweatsecretion
Digestive
tract
Inhibitsperistalsis
Kidney Increases reninsecretion
Penis Inhibits Tumescence
Ductus
deferens
Promotesemissionpriortoejaculation
Functionsofsympatheticnervoussystem

52. B.sympatholyticdrugs-Antiadrenergicdrugs
isamedicationthatopposesthedownstreameffects
ofpostganglionicnervefiringineffectororgans
innervatedbythesympatheticnervoussystem(SNS).
Theyareindicatedforvariousfunctions;forexample,
theymaybeusedasantihypertensives.Theyarealso
usedtotreatanxiety,suchasgeneralizedanxiety
disorder,panicdisorderandPTSD.
Antiadrenergicdrugs-
1.Adrenergicreceptorblockers
2.Adrenergicneuronblockers

53. •α
1
blockers –
•prazosin
•terazocin •βblockers-
•Non-selective beta blockers
–Alprenolol
–Bucindolol
–Carteolol
–Carvedilol(has additional α-blocking activity)
–Labetalol(has additional α-blocking activity)
–Nadolol
–Penbutolol
–Pindolol
–Propranolol
–Sotalol
–Timolol
1.Adrenergicreceptorblockers

54. β1-selective agents
Acebutolol
Atenolol
Betaxolol
Bisoprolol
Celiprolol
Esmolol
Metoprolol
Nebivolol
β2-selective agents
Butaxamine
ICI-118,551

55. 2. Adrenergic neuron blockers
synthesis blocker: α-methyl dopa
Depletion of stores-Reserpine
Release blocker: Guanethidine, Bretylium

56. Mechanism of action of sympatholytic drugs
Adrenergicreceptorantagonist-Directacting
Directinhibitionofthe α-andβ-adrenergicreceptors cancelthe
receptor-mediatedsympathomimeticeffects.
Indirect-acting
Adrenergicneuronblockersdepletecatecholaminesorprevent their
releaseatadrenergicneuronsandthusabolishthecatecholamine -
inducedreceptor-mediatedsympathomimeticeffect.

57. Organ Effect
Eye Dilates
Heart Increasesrateandforceofcontraction
Lungs Dilates bronchiolesviacirculatingadrenaline
Blood
vessels
Dilateinskeletalmuscle(inanimals).
Constrictsingastrointestinalorgans
Sweat
glands
Activatessweatsecretion
Digestive
tract
Inhibitsperistalsis
Kidney Increases reninsecretion
Penis Inhibits Tumescence
Ductus
deferens
Promotesemissionpriortoejaculation
Functionsofsympatheticnervoussystem