Direct, Indirect and mixed acting Sympathomimetic agents

Sympathomimetic agents are drugs that stimulate the sympathetic nervous system, increasing heart rate, blood pressure, and the force of cardiac contraction. They can be used therapeutically or abused.

1. By-
Dr. Prerana B. Jadhav
M. Pharm, Ph.D.
Pharmaceutical Chemistry
Assistant Professor,
SanjivaniCollege of Pharmaceutical Education and
Research, Kopargaon.
SympathomimeticAgents

2. Norepinephrine
•Mechanismofaction:
•Itperformsitsactionbybeingreleasedintothe
synapticcleft,whereitactsonadrenergicreceptors
predominantlyonthealphaadrenoreceptors.
•Metabolism:
•NorepinephrinerapidlymetabolizedbybothCOMT
andMAO,resultinginpoororalbioavailabilityand
shortdurationofaction

3. •Therapeutic uses:
•Itisusedtocounteractvarioushypotensive
crises,becauseit'saactivityraisesbloodpressure
andasanadjuncttreatmentincardiacarrest
becauseitsBeta-activitystimulatestheheart.It
haslimitedclinicalapplicationcausedbynon-
selectivenatureofitsactivities.
•Adversereactions:dizzinessorweakness,upset
stomachandfeelingsofnervousnesscanoccur.

4. Epinephrine
•Mechanismofaction:
•Itbindswithadrenergicreceptorswhichresultsinmetabolic
changeswhenitbindstoalphaadrenergicreceptors.
•TherapeuticUses:
•bronchialasthma,hypersensitivityreactions,heartblockcardiac
arrest,controlofbleedingfrequentlyaddedtolocalanaestheticlike
lignocaine
•Adversereactions:
•anxiety,totachycardia,palpitation,tremorsrestlessness,headache,
acutepulmonaryoedemaetc.

5. Phenylephrine
•Phenylephrinediffersfromepinephrineonlyinlackingap-OHgroup.
•Mechanismofaction:
•Itispotentvasoconstrictorbutlesspotentthanepinephrine.
•Metabolism:MetabolizedbyMAO(Monoamino-oxidose)anditlacks
catecholmoietyhencenotmetabolizedbyCOMT
•Therapeuticuses:
•treatmentofseverehypotension,nasaldecongestant,usedtotreat
openangleglaucoma
•Adversereactions:Hypertensionandprostatichyperplasia

6. Dopamine
•Differs from NE in lacking of 1-OH group.
•It is the immediate precursor of NE
•DA is rapidly metabolized by COMT and MAO and has a short DOA
with no oral activity.
•It is used intravenously in treatment of shock.
•In contrast with the NE and E, DA increases blood flow to the kidney
in doses that have no chronotropiceffect on the heart or that cause
no increase in blood pressure. The increased blood flow to the
kidneys enhances glomerularfiltration rate, Na excretion, and, in
turn, urinary output.

7. Methyldopa
•DiffersstructurallyfromL-DOPAonlyinthepresenceofaalpha-methylgroup.
•Mechanismofaction:
•ItisoriginallysynthesizedasanL-AromaticAminoAcidDecarboxylase(AADC)inhibitor.
Howeverit'smechanismofactionisnotcausedbyinhibitionofAADCbutratherbyits
metabolisminCNStoitsactivemetabolitea-methylnorepinephrine.
•Metabolism:
•Methyldopaconvertedtoa-methyldopaminebytheenzymeAADCwhichfurther
convertedtoa-methylnorepinephrinebytheenzymedopamineBhydroxylase.
•TherapeuticUses:
•Itisusedinclinicaltreatmentofhypertensionpre-eclampsia.
•AdverseReactions:
•Dizziness,agitation,drymouth,migraineandsedation.

8. Dobutamine
•Abeta-1agonistcatecholaminethathascardiacstimulantaction
withoutevokingvasoconstrictionortachycardia.Itisproposedas
acardiotonicaftermyocardialinfarctionoropenheartsurgery.
•Dobutamineactsprimarilyonbeta-1adrenergicreceptors,with
negligibleeffectsonbeta-2oralphareceptors.Itdoesnotcause
thereleaseofendogenousnorepinephrine,asdoesdopamine.
•Mechanismofaction:Dobutaminedirectlystimulatesbeta-1
receptorsofthehearttoincreasemyocardialcontractilityand
strokevolume,resultinginincreasedcardiacoutput.

9. Isoproterenol
•Isoproterenol,alsoknownasisoprenaline,actsasanon-selectivebeta-
adrenergicreceptoragonist,meaningitstimulatesbothbeta-1andbeta-2
receptors,leadingtoincreasedheartrate,forceofcardiaccontraction,
andbronchialsmoothmusclerelaxation;itisprimarilyusedtotreat
severebradycardia(slowheartrate)andacutebronchospasm,although
itsuseisoftenlimitedduetopotentialsideeffectslikearrhythmias;
•Itismetabolizedprimarilyintheliverandlungsthroughconjugation
reactions.Catechol-O-methyltransferase(COMT)playsasignificantrolein
themetabolismofisoproterenol.

10. Terbutaline
•Terbutalineisabeta-2adrenergicagonistusedasa
bronchodilatorandtopreventprematurelabor.
•Terbutalineisindicatedforpreventionandreversalof
bronchospasminpatientsatleast12yearsold,with
asthmaandreversiblebronchospasmassociatedwith
bronchitis.
•Terbutalineissulphatedorglucuronidatedpriorto
elimination.

11. Salbutamol
•Salbutamol,alsoknownasalbuterol,isashort-actingbeta-2adrenergic
receptoragonistthatworksbyrelaxingthesmoothmusclesintheairways,
leadingtobronchodilation;itisprimarilyusedtotreatasthmasymptomslike
wheezingandbreathlessnessbyfacilitatingeasierbreathingthroughthe
relaxedairways.
•Metabolism:
•The majority of salbutamolmetabolism occurs in the liver through the
enzyme sulfotransferase, where it is converted into inactive metabolites.
•Therapeutic Uses: Asthma management, COPD

12. Bitolterol
•ItdiffersfromisoprenalinbyreplacingtheN-isopropyltobeta2directing
N-ter-butylgroup.
•Mechanismofaction:BitolteralisatypeofBeta2adrenergicagonist.
WhenBetaadrenergicreceptorareactivateditsactivationresultsin
relaxationofsmoothmuscleinthelunganddilationandopeningofthe
airwayswhichmakeairfloweasythroughthetubes.
•Metabolism:ItismetabolisedbyCOMT
•Therapeuticuses:Itisusedforthereliefofbronchospasminconditionlike
COPDandasthmas.

13. Bitolterol
•Adverse reactions: Cough, dry Mouth, high
Blood Pressure, irritation of the larger a
passages of the lungs, mouth irritation,, taste
problems

14. Xylometazoline, oxymetazoline, and
naphazoline
•Allselectivealpha1agonistshavetherapeuticactivityas
vasoconstrictors.
•Structurallytheyinclude2-arylimidazolinesEx.
xylometazoline,oxymetazoline,andnaphazoline.
•Theseagentsareusedfortheirvasoconstrictiveeffectsas
nasaldecongestants.
•All2arylimidazolalpha1-agonistcontainonecarbonbridge
betweenC-2ofimidazolineringandaphenylring,andthusa
phenylethylaminestructurefeatureisthere.

15. Xylometazoline, oxymetazoline, and
naphazoline
•Ortho-lipophilicgroupsonthephenylringare
impotantforalpha-activity.However,Metaorpara-
bulkylipophilicsubstituentsonthephenylringmaybe
importantforthealpha1-selectivity.
•Xylometazolineandoxymetazolinehavebeenusedas
topicalnasaldecongestantsbecauseoftheirabilityto
promoteconstrictionofnasalmucosa.Whentakenin
largedoses,oxymetazolinemaycausehypertension

16. Structures of Xylometazoline, oxymetazoline, and naphazoline

17. Indirect acting agents: Hydroxyamphetamine
•Hydroxyamphetamine:
•It is an effective indirect acting sympathomimeticdrug. The
presence of alpha-methyl group increases effectiveness of
indirect acting agents.

18. •Mechanism of action:
•Hydroxyl -amphetamines in periphery causes the release of noradrenaline
when it acts on the adrenergic nerve terminals, alpha and B receptors.
•Metabolism: 4-Hydroxyamphetamine is the metabolized by dopamine
beta-hydroxylaseinto 4-hydroxynorephedrine or eliminated in the urine
•Therapeutic uses:
It is used to dilate the pupil for diagnostic eye examinations and for
surgical procedures on the eye.
•Adverse reactions:
It may induce dryness of mouth, restlessness, insomnia, anorexia. With
higher dose there may be hypertension, tachycardia, angina pain and
cardiac arrhythmia.

19. Pseudoephedrine
•Itisthe(S,S)diastereoisomerofephedrine.
•Itindirectlystimulatesalpha-adrenergicreceptors,causingthe
releaseofendogenousnorepinephrine(NE),whileitdirectly
stimulatesbeta-adrenergicreceptors
•Usedtotreatnasalandsinuscongestion,aswellasallergicrhinitis.
•MetabolisedinliverbyN-demethylationtoinactivecompound.
•AdverseReactions:Insomnia,nervousness,excitability,dizziness
andanxiety.hallucinations,arrhythmias,hypertension,seizures

20. Propylhexedrine
•Itisanotheranalogofamphetamineinwhichthearomaticringhasbeenreplaced
withcyclohexanering
•Mechanismofaction:Thisdrugproducesvasoconstrictionandadecongestant
effectonthenasalmembranes.
•Therapeuticuses:It'smajoruseisforlocalvasoconstrictiveonnasalmucosain
thesymptomaticreliefofnasalcongestioncausedbythecommoncold,allergic
rhinitisorsinusitis

21. AGENTS WITH MIXED MECHANISM
•Ephedrineisoneoftheexample
ofphenylethylamineconsidered
tohavemixedmechanismof
actionusuallyhavenohydroxylon
aromaticringbutdohaveaß-
hydroxylgroup.
•Mechanismofaction:
•Thedrugactsonbothalphaand
Betareceptors.

22. •Ephedrinehastwoasymmetriccarbonatoms,thustherearefouroptically
activeforms.Theerythroracemateiscalledephedrineandthreoracemate
knownaspseudoephedrine.
•LackingH-bondingphenolicOHgroup,ephedrineislesspolarandthus
crossestheBBB
•Ephedrinedoesnothaveanyphenolicsubstituentsonthephenylringgivingit
amixedactingresponse
•Metabolism:ItisP-hydroxylatedandN-demethylatedbycytochrome,P450
mixedfunctionoxidases.
•TherapeuticUses:allergicdisorderscold,hypotensiveconditions.
•Adversereactions:Arrhythmia,anxiety,tachycardia,headache,hypertension,
acutepulmonaryedema,panicattack.