Medicinal chemistry, sympathomimetic agents, unit-2 ,4th sem

Medicinal chemistry, sympathomimetic agents

1. TOPIC-SYMPATHOMIMETIC AGENTS
B.PHARMACY, 4
th
SEM
MsSnigdhaRaniBehera
AssociateProfessor
SchoolofPharmacy,ARKAJAINUniversity
Jamshedpur,Jharkhand.

2. SYMPATHOMIMETIC AGENTS
Sympathomimeticsaresubstancesthatmimicormodifytheactionsofendogenous
catecholaminesofthesympatheticnervoussystem.
Directagonistsdirectlyactivateadrenergicreceptorswhileindirectagonists
enhancetheactionofendogenouscatecholamines.
Sympathomimeticsstimulatealpha-1adrenergicreceptors,beta-adrenergic
receptors,anddopamine(D)receptorsinvarioustargettissues,i.etheeyes,heart,
andvascularsmoothmuscle.
Theseagentsordrugsactonadrenergicreceptordirectlyorindirectlybyblocking
thebreakdownorneuronaluptakeofcatecholamines.{Sympathomimeticdrugs
increaseheartrateandbloodpressure}

3. SAR OF SYMPATHOMIMETIC AGENTS
SAR-Structureactivityrelationship
SAR:Itisdefineastherelationshipbetweenthechemicalstructureofa
moleculeanditsbiologicalactivity.
Thisallowsmodificationoftheeffectorthepotencyofabioactive
compound(typicallyadrug)bychangingitschemicalstructure.
Manyofthesympathomimeticdrugscontainβ-phenyl
ethylamineasparentstructure.

4. Structurally,substitutionormodificationisoccureon:
Catecholoraromaticring
β-Carbon
α-Carbon
Aminogroup
β–Hydroxylgroup
•I.Phenylringsubstitution-
•Themodificationofβ-phenylethylamineinfluencenotonlythemechanismof
action,thereceptorselectivitybutalsotheirabsorption,oralactivity,
metabolismandthusdurationofaction(DOA)

5. 1.Naturallyoccurringcatecholamineisactiveatbothαandβreceptorbuthavea
poororalactivityasitisrapidlymetabolizedbyCOMT.Thusthechangein
positionofhydroxylgroupfrommetaandParapositiongivesadrugwith
goodmetabolicactivity.
2.Whenhydroxygroupisadjacentwithmetapositionthenα2agonistactivityof
thedrugincrease.

6. 3.Whenhydroxygroupisreplacedbymethoxygroupthentheβ2activityof
theringwillincrease.
4.Whenweincreasethechainlengthofthehydroxygroupthentheα2activity
increaseandβ2activitydecrease.
5.Whenbothhydroxygroupwillremovefromthearomaticring,thenthey
willeasilycrossBBBandhavemoreCNSactivity.
e.g.Amphetamine.

7. β-Hydroxyl Group
Theβcarboncontainonehydroxygroupandβcarbonistheasymmetric
carbonthatmeansitisachiralcompound.
Whenthischiralcompoundexistis‘R’formitsactivityis100%or
activityincrease.
Whenthischiralcompoundexistis‘S’formitsactivityisdecrease.

8. α-Carbon
Whenintheα-carbon,thehydrogenisreplacedbymethylgroupandthe
chainlengththenthebulkinessofthecompoundisincreasethentheactivity
ofthecompoundisdecreased.

9. Amine Group
Aminegroupisthedecidingfactorfortheactivityofcatecholamine.
WhenaminegroupisPrimaryandsecondaryinnaturethentheα-activityis
increaseandβ-activityisdecrease.i.e.Epinephrine(Adrenaline)
WhenaminegroupisTertiaryandquaternaryinnaturethentheα-activity
isdecreaseandβ-activityisincrease.
.Morethesizeofalkylsubstituent,
higherwillbeβ-activityandlower
Theα-activity.i.e.Isoprenaline,
Solbutamole.

10. Classification of Sympathomimetic Agents / Drugs
Direct Acting Indirect Acting Mixed Acting
Nor-epinephrine
Epinephrine
Phenylephrine
Dopamine
Methyl dopa
Clonidine
Dobutamine
Isoproterenol
Terbutaline
Salbutamol
Bitosterol
Naphazoline
Oxymetazoline
Xylometazoline
Hydroxy
Amphetamine
Pseudoephedrine
Propylhexedrine
Ephedrine
Metanominol

11. 1.DirectactingDrugs-
ThesearethosedrugsandAgentswhichdirectlybindwithadrenergic
Receptors(Bothαandβ)andgivesitsPharmacologicalaction.
Theactionproducedareofrapidonsetandofshortduration.
Nor-epinephrine:Itisanaturalcatecholaminephenethylaminederivative.
Properties:Itisawhiteorbrownish-White,crystallinepowder,slightly
solubleinethanolandsolubleinwater.

12. Mechanismofaction:
Potentatα-receptor.(Lesspotentadrenalins).
Alsoeffectonβ1-receptorbutnoeffectonβ2-receptor.
Uses:
StrongVasoconstrictionproperties.Soitisusedinlocal
anaestheticsolutionsfordentaluse.
Reducedtheabsorptionandtolocalizetheeffectsof
localanastetics.
Intravenousinfusionforthetreatmentofhypotension.
Itsprincipleuseistosupportbloodinvariousacutehypotensive
states,especiallyinmyocardialshock.
Storage:
Itbecomescoloredonexposuretoairandlight.Itshouldbestoredin
well-closedairtightcontainers,underaninertgasandprotectedfromlight.

13. Epinephrine-
Adrenalineisacatecholamineandbelongstothefamily
ofbiogenicamines.
Properties:Itisawhiteorcreamywhite,sphaero-crystallinepowder.
Itdissolvesinsolutionsofmineralacids,potassiumhydroxide,
andofsodiumhydroxide,butsparinglysolubleinwater,insolubleinethanoland
ether.
Mechanismofaction:
Itdirectlybindwithα1andβ1andβ2receptor.(Potentforall)
Itgivenbyoralrouteintheformofpro-drug(Pivalicacid)topreventfirstpass
metabolism.
Uses:
Itisusedasasympathomimetic,broncholytic,andanti-asthmatic.
Itisusedtopreventbleedingduringsurgeryorincaseofinnerorganbleeding.
Because
adrenalineleadstoconstrictionofbloodvessel.
Itisadministeredincombinationwithlocalanesthetics.

14. Inthiscombination,anestheticshavelong-lastingeffectandcanbeadministered
insmallerdoses.
Itisusedinthetreatmentofheartblockorcirculatorycollapseandopen-angle
glaucoma.
Itisusuallythedrugofchoiceinacuteallergicdisordersandhistaminereactions.
Inemergencytreatmentofanaphylaxisandanaphylacticshockinthecardio
pulmonarydisease.
Storage:
Epinephrineislightsensitiveandeasilyoxidizedonexposuretoairbecauseofthe
catecholringsystem.
Thedevelopmentofapinktobrowncolourindicatesoxidativebreakdown.
Tominimizeoxidation,solutionsofthedrugarestabilizedbytheadditionofa
reducingagent.Ex-sodiumbisulphite.
Adrenalineshouldbestoredinwell-closedairtightcontainers,whichispreferably
filledwithnitrogen,andprotectedfromlight.

15. Phenylephrine*-
Phenylephrineisavailableashydrochloridesalt.
Properties:
Itisawhite,odorless,bittertaste,crystallinepowder.
Itissolubleinwater,alcohol,andglycerol.
Mechanismofaction:
Bindatα1receptor.
Noactiononβreceptor
Storage:
Itshouldbestoredinairtightcontainertoprotectfromlight.

16. Synthesis:
Phenolwith2-chloroacetylchloridegives2-chloro-1[3-hydroxy
phenyl]ethanone.(M-Chloroacetylphenol)
2-chloro-1[3-hydroxyphenyl]ethanonereactwithNH2CH3itgives1-(3-
hydroxyphenyl)2-(methylamino)ethanone.
1-(3-hydroxyphenyl)2-(methylamino)ethanoneundergoreduction
reactions(additionofhydrogen)toformPhenylephrine.

17. Uses:
Phenylephrineisaselectiveα1-receptoragonist.Oralabsorptionisnotreliable
andsoitisgivenparenterallyortopicallyaseyeornasaldrops.
Phenylephrinepredominantlyactsonperipheralarteriolesresultsinarisein
systolicanddiastolicpressuresaccompaniedbyamarkedreflexbradycardia.
Phenylephrineisusedasanasaldecongestant,mydriatricandasavaso-pressor
agent.
Vasoconstrictionofarterioes,IrisandconstrictionofUterus.
Increasebloodpressureinacutehypotension.

18. Dopamine-
Itisaneurotransmitterthathelpstoregulatemovement
Andemotionalresponse.
Properties:
Itisawhiteoralmostwhitecrystallinepowder,
solubleinalcohol,sparinglysolubleinacetoneandmethylenechloride,butfreely
solubleinwater.
Mechanismofaction:
Itisdirectlystimulateβ1andα1receptor.(DualactingDrug)
Storage:
Itshouldbestoredinwell-closedairtightcontainers,protectedfromlight.
Uses:
Itisusedinthetreatmentofshock.
ItincreasesbloodflowtotheKidneys

19. DopamineexertstheCVSeffectsbyinteractingwithD1-dopaminergicreceptors
especiallyintherenal,mesenteric,andcoronarybeds.
Itisalsousedinheartattack,trauma,surgeryandotherseriousmedical
condition.
Methyldopa-
Properties:
Methyldopaisawhitetoyellowishwhite,odorlessfinepowder,andissolublein
water.
Mechanismofaction:
Methyldopaisconvertedintoα-methylnor-epinephrinebyenzymedopamine
betahydroxylaseandbindwithα2.

20. Uses:
Thismedicationisusedaloneorwithothermedicationstotreathighblood
pressure.(Hypertension)
Loweringbloodpressurehelpstopreventstrokes,heartattacksandkidney
problems.
Storage:Itshouldbestoredinwell-closedairtightcontainers,protectedfrom
light.

21. Clonidine-
Properties:
Clonidineisanimidazolederivatethatactsasanagonistofalpha-2adrenorceptors.
Mechanismofaction:
Itiscentrallyactingonα2receptor.
Uses:
Itisusedinthetreatmentofhypertension,nasaldecongestant,openeyeglaucoma.
Itisapotentsedative-hypnoticdrugandcanpreventpost-operativeshivering.

22. Dobutamine-
Itisasyntheticcatecholamine.
Properties:
Itisawhiteoralmostwhitecrystallinepowder,sparinglysolubleinwaterand
alcoholandsolubleinmethanol.
Mechanismofaction:
Itdirectlystimulateβ1aswellasα1receptor.(Dualactingdrug)
Uses:
ItisusedinICUforthetreatmentofcongestiveHeartfailure,Cardiogenicshock,
pulmonaryoedemaandtoincreasecardiacoutput.
Storage: It should be stored in well-closed airtight containers, protected from light.

23. Isoproterenol-(Isoprenaline)
Isoproterenolhydroclorideisarecentcompound.Itisanonselectiveandsynthetic
catecholamine.
Properties:
Itisawhiteoralmostwhitecrystallinepowder,freelysolubleinwater,sparingly
solubleinalcohol,practicallyinsolubleinmethylenechloride.
Mechanismofaction:
Itisanonselectiveβagonistandhasstrongβ1andβ2agonistactivity.
β1-Increasecardiacoutput
β2-Increasebronchodialation

24. Uses:
Itsprimaryuseisinthetreatmentofbronchialasthma.
Itisusedasanantiarrhythmicagentandinthetreatmentofshocktoincrease
heartrate.
ItisaCNSstimulantandperipheralvasodilator.
Storage:
Itshouldbestoredinwell-closedairtightcontainers,protectedfromlight.
Terbutaline-

25. Terbutaline-
Terbutalineisanon-catecholaminethereforeisresistanttoCOMT.
Properties:
Itexistsasagray-whitecrystalline
powder,odorlessandwithabittertaste,soluble
inwaterandalcohol.
Mechanismofaction:
Itbindwithβ2receptor.
ItisbetterthanIsoprenalinedrug.
Uses:
Terbutalineisabrochodialatormedicinethatisusedtotreatsymptomssuchas
Wheezing,shortnessofbreath,chesttightness,breathingdifficulties,coughing
etc.associatedwithasthma.
Itisusedtotreatanacuteattackofasthmaaswellasforpreventionoffuther
asthmaattacks.

26. Storage:
Itshouldbestoredinwell-closedairtightcontainers,protectedfromlight.
Salbutamol*-
Properties:
Itisawhiteoralmostwhitecrystallinepowder,sparinglysolubleinwater,but
freelysolubleinethanol.

27. SynthesisofSalbutamol:
2-Hydroxybenzylalcoholisreactwithchloroacetylalcoholbyremovalof
oneHCLitforma1
st
intermediate.
1
st
intermediatethenreactwith2-methylpropan-2-amineitwillform2
nd
intermediatebyremovingoneHCL.Thenitwillundergoreduction(additionof
hydrogen)toformSalbutamol.

28. Mechanism of action:
Directlybindwithβ2receptor.(Selectiveβ2agonist)
Uses:
Itisusefulinthetreatmentofacutemyocardialinfarction,severeleftventricular
failure.
Ithasbeenusedtoarrestprematurelaborandiseffectiveinocularhypotension
bytopicalapplication.
Itisusedonlyasabronchodilatorandisthedrugofchoiceinthetreatment
ofbronchialasthma.
Itisalsousedtotreatemphysema.(Aconditionthatinvolvesdamagetothewalls
oftheairsacsi.ealveolioflungs)
Storage:
Itshouldbestoredinwell-closedairtightcontainers,protectedfromlight.
Dose:
Byoralinhalationtheadultdoseis100microgram,followedbyaseconddose
after5min,ifrequired.

29. Bitolterol–
Itisanewβ2adrenergicagonist.
Properties:
Bitolterolisconsiderasaprodrugforcolterol.
Mechanismofaction:
Directlybindwithβ2receptor.(Selectiveβ2agonist)
Uses:
Bitolterolisusedasitsmethanesulfonatesaltforreliefofbronchospasmin
conditionssuchasasthma,chronicbronchitisandemphysema.
Storage:
Itshouldbestoredinwell-closedairtightcontainers,protectedfromlight.

30. Naphazoline–
Itisarapidanddirectactingsympathomimeticdrugandexistinanionisedform.
Chemicallyitis2-(1-naphthylmethyl)-2-imidazolineandanimidazoline
derivatives.
Properties:
Itisawhitecrystalline,odourless,andbittercompound.
Thesaltissolubleinwaterandinalcohol.
TheyessentiallyexistinanionizedformatphysiologicalpHbecauseofthevery
basicnatureoftheimidazolinering(pKa9to10).
Mechanismofaction:
Itisapowerfulα–receptorstimulant.(Bothα1andα2)

31. Uses:
Mostlyusedasalocalvaso-constrictorforthereliefofnasalcongestiondueto
allergicorinfarctionmanifestations.
Itisalsoemployedasanophthalmicsolutionforthereliefofocular
congestion(swolleneyelidsandeyessensitivetobrightlight)and
blepharospasm(Eyetwitching).
Storage:
Itshouldbestoredinwell-closedairtightcontainers,protectedfromlight.
Dose:
Fornasalmucosa,2dropsof0.05%solution;forconjunctivitis,1to2dropsofa
0.1%solutionafterevery3to4hours.

32. Oxymethazoline–
Itisadirectactingsympathomimeticdrug.
Chemicallyitis3-(4,5-dihydroxy-1H-imidazol-2-ylmethyl)-
2,4-Dimethyl-6-tert-butylPhenol.
Mechanismofaction:
Itisbindwithbothα1andselectiveα2Receptor.(Itstimulatesthebloodvesselsof
nose)
Uses:
Itactasadecongestantduringtheallergyorinfectionofthenasalpassage.
Dose:Byintranasal,1dropofa0.1%solutioninadult;orasprayof0.05%
solution.

33. Xylomethazoline–
Itisadirectactingsympathomimeticdrug.
Chemicallyitis2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]-4,5
dihydro-lH-imidazole.
Mechanismofaction:
Itispartiallyagonistatα2andselectiveagonistatα1Receptor.
Uses:
Itisfoundtoactasavasoconstrictor,whenappliedtopicallytomucousmembranes
particularly.
Itisfrequentlyemployedasalocalvaso-constrictorfornasalcongestioncausedby
sinusitisorrhinitis.(Otrivin)
Dose:Byintranasal,1dropofa0.1%solutioninadult;orasprayof0.05%solution.

34. Indirect Acting
Indirectactingsympathomimeticdrugsarethosethatactindirectlytoincreasethe
concentrationofendogenousneurotransmitterbyreleaseofendogenousNE.
ThesedrugsenterthenerveendingbyactiveuptakeanddisplaceNEfromits
storagegranules.
1.Hydroxyamphetamine-
Hydroxyamphetamineisindirectactingsympathomimeticagentsandderivatives
ofAmphetamines.
Itischemically4-(2-aminopropyl)Phenol.
Properties:
Itisawhitepowderfreelysolubleinwater.
Mechanismofaction:
Indirectlyactingsympathomimeticsagentwhichcausesthereleaseofnor
epinephrinefromadrenergicnerveterminals.

35. Uses:
Itisasympathomimeticandanticholinergiccombinationandrelaxesmusclesof
theeyebydilatingthepupil(mydriasis).
Innarcolepsy(suddenattackofsleepincompletelyinappropriatesituations).
Itisusedinchildrenwithhyperkineticsyndrome.
Itactananorexiant(Drugthatactonthebraintosuppressappetite)inthe
treatmentofobesity.
2.Pseudoephedrine–
ItisanopticallyactiveisomerofEphidrine.
Mechanismofaction:
Itisstimulatesbothαandβreceptors.
ItstimulatesCNS.

36. Uses:
Itisusedasvasoconstrictortotreatnasalandsinuscongestionoftubesthatdrain
fluidfromyourinnerears.
Itincreasesthebloodpressure(Hypertension)byincreasingcardiacoutputandby
causingvasoconstrictor.
3.Propylhexedrine–
Itischemically(±)-1-cyclohexyl-N-methypropan-2-amine.
Mechanismofaction:
Itisstimulatesα-receptorsinthemucosaofrespiratorytract.
Sameactionshownasepinephrineandnor-epinephrine.
Uses:
Itisusedforthereliefofcongestionduetocold,allergiesandallergic
rhinitis(Inflammationofmucousmembraneofnose)anditseuphoriceffects.

37. Mixed Acting Drug-
Mixedactingsympathomimeticdrugsarethosecausesactivationof
adrenergicreceptorsbybothdirectbindingaswellasendogenouslystored
nor-epinephrinefrompre-synapticterminals.
1.Ephedrine –
It is chemically 4-(2-amino propyl)Phenol.
It occurs naturally. It has two asymmetric carbon atoms, so it has four isomers.
Mechanism of action:
It act both directly and Indirectly.
It stimulates both αand βreceptor.

38. Uses:
Itisusedasbronchodialator,nasaldecongestant,orthostatic
hypotension(conditioninwhichyourbloodquicklydropswhenyoustandup
fromasittingorlyingposition)ormystheniagravis(aneuromusculardisorder
thatcausesweaknessintheskeletalmuscles).
Itusedinvariousallergicdiseaselikehayfever(anallergicreactiontopollen)
andurticaria(Askinrashtriggeredbyareactiontofood,medicineorother
irritants)
2.Metaraminol-
Chemicallyitis3-(-2-amino-1-hydroxy-propyl)phenol.
Properties:
ItisawhitecrystallinepowderandfreelySolubleinwater.
Mechanismofaction:
Itactonbothαandβreceptorstimulatesnoradrenaline.
Uses:
Itcanbeusedparenterallyasvasopressorinpreventionofacutehypertension
stateoccurringwithspinalanaesthesia.

39. THANK YOU
STAY SAFE
AND
STAY HEALTHY