pseudoefedrin

1. PSEUDO-EPHEDRIN
DRHerni Suprapti dr MKes
Mei 2022
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2. Overview
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◦ Theadrenergicdrugsaffectreceptorsthatarestimulatedbynorepinephrine
(noradrenaline)or epinephrine (adrenaline).
◦ Thesereceptorsareknownasadrenergicreceptorsoradrenoceptors.
◦ Adrenergicdrugsthatactivateadrenergicreceptorsaretermedsympathomimetics,
anddrugsthatblocktheactivationof adrenergicreceptorsaretermedsympatholytic.
◦ Somesympathomimeticsdirectlyactivateadrenergicreceptors(direct-acting
agonists),whileothersactindirectlybyenhancingreleaseorblockingreuptakeof
norepinephrine(indirect-acting agonists).

3. Adrenergicagonists (*):catecholamines.
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DIRECT
-ACTINGAGENTS
◦ Albuterol
◦ Clonidine
◦ Dobutamine*
◦ Dopamine*
◦ Epinephrine*
◦ Fenoldopam
◦ Formoterol
◦ Isoproterenol*
◦ Mirabegron
◦ Norepinephrine*
◦ Phenylephrine
◦ Salmeterol
◦ Terbutaline
INDIRECT
-ACTINGAGENTS
◦ Amphetamine
◦ Cocaine
DIRECTANDINDIRECTACTING(mixedaction)
AGENTS
◦ Ephedrine
◦ Pseudoephedrine

4. Adrenergicreceptors (adrenoceptors)
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◦ Inthesympatheticnervoussystem,severalclassesof adrenoceptorscanbedistinguished
pharmacologically
.
◦ Twomainfamiliesof receptors,designated andβ, areclassifiedonthebasisof theirresponses
to the adrenergicagonistsepinephrine, norepinephrine,and isoproterenol.
◦ Eachof thesemainreceptortypeshasanumberof specificreceptorsubtypesthathavebeen
identified.
◦ Alterationsin the primary structure of thereceptors influence their affinity for various agents.

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6. A.Catecholamines
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Sympathomimeticaminesthatcontainthe3,4-dihydroxybenzenegroup (suchasepinephrine,
norepinephrine,isoproterenol,anddopamine)arecalledcatecholamines.Thesecompoundsshare
thefollowing properties:
1. Highpotency:Catecholamines(with–OH groupsinthe3and4positionsonthebenzenering)
showthehighest potencyin directlyactivating α or β receptors.
2. Rapidinactivation:CatecholaminesaremetabolizedbyCOMTpostsynapticallyandbyMAO
intraneuronally,aswellasbyCOMTandMAO inthegutwall,andbyMAO intheliver.Thus,
catecholamineshaveonlyabrief period of actionwhengivenparenterally
,andtheyare
inactivated(ineffective)whenadministered orally
.
3. PoorpenetrationintotheCNS:Catecholaminesarepolarand,therefore,do notreadily
penetrateintotheCNS.Nevertheless,mostcatecholamineshavesomeclinicaleffects(anxiety
,
tremor,andheadaches)thatareattributabletoactiononthe CNS.

7. B.Non-catecholamines
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◦ Compoundslackingthecatecholhydroxylgroupshavelongerhalf-lives,becausetheyarenot
inactivatedby COMT
.
◦ Theseincludephenylephrine,ephedrine,andamphetamine(Figure6.7).
◦ Theseagentsarepoor substratesfor MAO(animportantrouteof metabolism)and,thus,showa
prolongeddurationof action.
◦ Increasedlipid solubilityof manyof thenon-catecholamines(duetolackof polarhydroxyl
groups)permitsgreateraccesstothe CNS.

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9. D.Mechanismof actionof adrenergic agonists
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1. Direct-actingagonists:Thesedrugsactdirectlyon orβ receptors,producingeffectssimilar to
thosethatoccurfollowingstimulationof sympatheticnervesor releaseof epinephrinefrom the
adrenalmedulla(Figure6.8).Examplesof direct-actingagonistsincludeepinephrine,
norepinephrine,isoproterenol,and phenylephrine.
2. Indirect-actingagonists:Theseagentsmayblockthereuptakeof norepinephrineorcausethe
releaseof norepinephrinefromthecytoplasmicpoolsorvesiclesof theadrenergicneuron
(Figure6.8).Thenorepinephrinethentraversesthesynapseandbindsto or β receptors.
Examplesof reuptakeinhibitorsandagentsthatcausenorepinephrinereleaseincludecocaine
andamphetamines, respectively
.
3. Mixed-actionagonists:Ephedrineanditsstereoisomer,pseudoephedrine,bothstimulate
adrenoceptorsdirectly and releasenorepinephrinefrom the adrenergicneuron (Figure 6.8).

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11. MIXED-ACTIONADRENERGICAGONISTS(1/2)
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◦ Ephedrineandpseudoephedrinearemixed-actionadrenergic agents.
◦ Theynotonlyreleasestorednorepinephrinefromnerveendings(Figure6.8)butalsodirectlystimulateboth  and
β receptors.
◦ Thus,awidevarietyof adrenergicactionsensuethataresimilartothoseof epinephrine, althoughlesspotent.
◦ Ephedrineandpseudoephedrinearenotcatecholsandarepoor substratesfor COMTandMAO.
◦ Therefore,thesedrugshavealongdurationofaction.
◦ EphedrineandpseudoephedrinehaveexcellentabsorptionorallyandpenetrateintotheCNS,but
pseudoephedrine hasfewerCNSeffects.
◦ Ephedrineiseliminatedlargelyunchangedinurine,andpseudoephedrine undergoesincompletehepatic
metabolismbeforeeliminationin urine.
◦ Ephedrineraisessystolicanddiastolicblood pressuresbyvasoconstrictionandcardiacstimulationandcanbeused to
treat hypotension.
◦ Ephedrineproducesbronchodilation,butitislesspotentandsloweractingthanepinephrineor isoproterenol.
◦ Itwaspreviouslyusedtopreventasthmaattacksbuthasbeenreplacedbymoreeffectivemedications.

12. MIXED-ACTIONADRENERGICAGONISTS(2/2)
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◦ Ephedrineproducesamildstimulationof theCNS.
◦ Thisincreasesalertness,decreasesfatigue,andpreventssleep.
◦ Italsoimprovesathleticperformance.
◦ [Note:Theclinicaluseof ephedrineisdecliningbecauseof theavailabilityof better,morepotent
agentsthatcausefeweradverseeffects.Ephedrine-containingherbalsupplements(mainlyephedra-
containingproducts)havebeenbannedbytheU.S.FoodandDrug Administrationbecauseof life-
threateningcardiovascular reactions.]
◦ Pseudoephedrineisprimarilyusedorallytotreatnasalandsinuscongestion.
◦ Pseudoephedrinehasbeenillegallyusedtoproducemethamphetamine.
◦ Therefore,productscontainingpseudoephedrinehavecertainrestrictionsandmustbekeptbehind
thesalescounterintheUnited States.
◦ Importantcharacteristicsof theadrenergicagonistsaresummarizedinFigures 6.15–6.17.

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17. Pharmacology
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◦ Pseudoephedrinecausesvasoconstrictionwhichleadstoadecongestanteffect.
◦ Ithasashortdurationof actionunlessformulatedasanextendedreleaseproduct.
◦ Riskof centralnervoussystemstimulation.
◦ Pseudoephedrineisaphenethylamineandadiastereomerof ephedrinewithsympathomimetic
property.
◦ Pseudoephedrinedisplacesnorepinephrinefromstoragevesiclesinpresynapticneurones,thereby
releasingnorepinephrineintotheneuronalsynapseswhereitstimulatesprimarilyalpha-adrenergic
receptors.
◦ Pseudoephedrineisanalpha-AdrenergicAgonist.
◦ Italsohasweakdirectagonistactivityatalpha-andbeta- adrenergicreceptors.
◦ Receptorstimulationresultsinvasoconstrictionanddecreasesnasalandsinuscongestion.

18. PharmacologicalClassification
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◦ NasalDecongestants
◦ Drugsdesignedtotreatinflammationof thenasalpassages,generallytheresultof aninfection(more
often than not the commoncold) or anallergy related condition, e.g., hayfever.
◦ Theinflammationinvolvesswellingof themucousmembranethatlinesthenasalpassagesandresultsin
inordinatemucusproduction.
◦ Theprimaryclassof nasaldecongestantsarevasoconstrictoragents.
◦ Bronchodilator Agents
◦ Agentsthatcauseanincreasein theexpansionof abronchusor bronchialtubes.

19. WHO AnatomicalTherapeuticChemical(ATC)
Classification
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◦ R- Respiratorysystem
◦ R01- Nasalpreparations
◦ R01B- Nasaldecongestantsfor systemicuse
◦ R01BA- Sympathomimetics
◦ R01BA02- Pseudoephedrine

20. Pharmacokinetic
Absorption,Distributionand Excretion
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◦ Absorption
◦ A240mgoraldoseof pseudoephedrinereachesaCmaxof 246.3±10.5ng/mL fedand272.5±13.4ng/mLfasted,witha
T
maxof 6.60±1.38hfedand11.87±0.72hfasted,withanAUCof 6862.0±334.1ng*h/mL fedand7535.1±333.0ng*h/mL
fasted.
◦ Routeof Elimination
◦ 55-75%of anoraldoseisdetectedintheurineasunchangedpseudoephedrine.
◦ Renal.About55to75%of adoseisexcretedunchange.Therateof excretionisacceleratedinacidicurine.
◦ Drugreleaseappearedtofollowfirstorder kinetics.
◦ Volumeof Distribution
◦ Theapparentvolumeof distributionof pseudoephedrinis2.6-3.3L/kg.
◦ Clearance
◦ A60mgoraldoseof pseudoephedrinehasaclearanceof 5.9±1.7mL/min/kg.

21. ◦ Onlythreedrugsarecommonlyusedasoraldecongestants:phenylpropanolamine(PP
A),
pseudoephedrine(PDE),andphenylephrine (PE).
◦ BothPP
AandPDEarereadilyandcompletelyabsorbed,whereasPE,withabioavailabilityof
onlyapproximately38%,issubjecttogutwallmetabolismandisthoughttobeabsorbed
erratically
.
◦ Peakconcnarereachedbetween0.5and2hrafteradmin.
◦ Allthreedrugsareextensivelydistributedintoextravascularsites(apparentvolumeof
distributionbetween2.6and5.0 L/kg).
◦ No proteinbinding datainhumansare available.
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22. Metabolism/Metabolites
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◦ Pseudoephedrineis<1%N-demethylated toaninactive metabolite.
◦ Themajorityof pseudoephedrineiseliminatedunmetabolizedinthe urine.
◦ Pseudoephedrineisincompletelymetabolized(lessthan1%)intheliverbyN-demethylationtoaninactivemetabolite.
◦ Thedruganditsmetaboliteareexcretedinurine;55-96%of adoseisexcreted unchanged.
◦ WhereasPP
AandPDEarenotsubstantiallymetabolized,PEundergoesextensivebiotransformationinthegutwallandtheliver.
◦ Eliminationof PP
AandPDEispredominantlyrenal,withurinaryexcretionbeingpHdependent.
◦ Elimination of PP
AandPDEmayberapid in children, andthe agentsshould beusedwith cautionin patients with renalimpairment.
◦ Inaddition,PP
Aincrcaffeineplasmalevelsanddecrtheophylline clearance.
◦ Reducedmetabolismof PEoccurswithconcurrentadminof monoamineoxidaseinhibitors.
◦ No directrelationshipbetweennasaldecongestanteffectandplasmaconcentrationhasbeenestablished.

23. Biological Half-Life
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◦ Half-livesarerelativelyshort,approximately2.5hrfor PE,4hrfor PP
A,and6hrforPDE.
◦ UrinarypHcanaffecttheeliminationhalf-life of pseudoephedrine,prolonging itwhenalkaline
(pH8)andreducingitwhenacidic(pH 5).
◦ Theeliminationhalf-life of pseudoephedrinerangesfrom3-6 or 9-16 hourswhenurinarypHis
5or8,respectively
,whilewhenurinarypHis5.8,theeliminationhalf-life of thedrugranges
from5-8 hours.
◦ Inonestudyinchildren6-12 yearsof age,theeliminationhalf-life of pseudoephedrine
averagedabout3hourswhenurinarypHw
as6.5.

24. Mechanismof Action
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◦ Pseudoephedrineactsmainlyasanagonistof alphaadrenergicreceptorsandlessstronglyasan
agonistof betaadrenergic receptors.
◦ Thisagonismof adrenergicreceptorsproducesvasoconstrictionwhichisusedasa
decongestantandasatreatmentof priapism.
◦ Pseudoephedrineisalsoaninhibitorof norepinephrine,dopamine,andserotonin transporters.
◦ Thesympathomimeticeffectsof pseudoephedrineincludeanincreaseinmeanarterialpressure,
heart rate,and chronotropic responseof theright atria.
◦ Pseudoephedrineisalsoapartialagonistof theanococcygeal muscle.
◦ PseudoephedrinealsoinhibitsNF-kappa-B,NF
A
T
,and AP-1.

25. ◦ Thepharmacologicalpropertiesof theephedrinederivativepseudoephedrinewereinvestigatedat
thenuclear level.
◦ Followingintraperitonealinjectionof SpragueDawleyratswithpseudoephedrine,Fosinductionw
as
measuredinvariousbrainareasbyWesternblotsand immunocytochemistry
.
◦ PseudoephedrineinducedFos-likeimmunoreactivityinthenucleusaccumbensandstriatuminatime
andconcentration-dependentmannerwithmaximaleffectat60mg/kg 2hrafter injection.
◦ Immunocytochemicalstudiesconfirmedthatthemajorityof thesignalw
asdetectableinthenucleus
accumbensandstriatum.
◦ Pre-injectionwiththeD1dopaminereceptorantagonistSCH23390partiallyandcompletelyblocked
pseudoephedrine-inducedFos-likeimmunoreactivityinthestriatumandnucleusaccumbens,
respectively
,suggestingthattheactionof pseudoephedrineismediatedviadopaminereleaseand
resultsintheactivationof D1dopamine receptors.
◦ Withtheexceptionof thehigherdosesrequired,theactionsof pseudoephedrineweresimilarto
thosepreviouslydescribedfor thepsychostimulant amphetamine.
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26. ◦ Becausepseudoephedrinehasbeenusedintheclandestinesynthesisof methamphetamineand
methcathinone,bothCNSstimulantswithgreatpotentialfor habituationandphysicaland/or
psychicdependence,theUSenactedtheComprehensiveMethamphetamineControlActof 1996
(USPublicLaw104-237)andlatertheMethamphetamineAnti-ProliferationAct(MAP
A(US Public
Law106-310),titleXXXVIof theChildren'sHealthActof 2000)toreducethepotentialfor misuse
(diversion)of pseudoephedrine.
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