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Adrenergic drugs. The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. Some adrenergic drugs act directly on the adrenergic receptor (adrenoceptor) by activating it and are said to be sympathomimetic.
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Theadrenergicdrugsaffectreceptorsthatarestimulatedby norepinephrine orepinephrine. • Some adrenergic drugs act directly on the adrenergic receptor(adrenoceptor)byactivatingitandaresaidtobe sympathomimetic. • Otherswillblocktheactionoftheneurotransmittersatthe receptors(sympatholytics),whereasstillotherdrugsaffect adrenergic function by interrupting the release of norepinephrine fromadrenergic neurons.
Adrenergicneuronsreleasenorepinephrineastheprimary neurotransmitter. Theseneuronsarefoundinthecentralnervoussystem (CNS)andalsoin the sympathetic nervous system, where they serve as links between gangliaandtheeffectororgans. Theadrenergicneuronsandreceptors,locatedeitherpresynapticallyon the neuron or postsynaptically on the effector organ, are the sites of actionoftheadrenergicdrugs.
ADRENOCEPTORS α- RECEPTORS β- RECEPTORS α1-receptor α2-receptor β1-receptor β2-receptor β3-receptor
The α-adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsivetothenaturallyoccurringcatecholamines epinephrine andnorepinephrine. • Forαreceptors,therankorderofpotencyis • epinephrine ≥ norepinephrine >>isoproterenol. • The α-adrenoceptors are subdivided into two subgroups,α1andα2,basedontheiraffinitiesforα agonists and blockingdrugs. • Forexample,theα1receptorshaveahigheraffinityfor phenylephrine than do theα2 receptors.
βReceptorsexhibitasetofresponsesdifferentfromthose ofthe α receptors. • These are characterized by a strong response to isoproterenol,withlesssensitivitytoepinephrineand norepinephrine. • For β receptors, the rank order of potency is isoproterenol > epinephrine >norepinephrine. • The β-adrenoceptors can be subdivided into three major subgroups, β1, β2, and β3, based on their affinities for adrenergicagonistsandantagonists,althoughseveralothers have been identifiedby gene cloning. • β1 Receptors have approximately equal affinities for epinephrine and norepinephrine, whereas β2 receptors havea higheraffinityforepinephrinethanfornorepinephrine.
Mostoftheadrenergicdrugsarederivativesofβ-phenylethylamine. Twoimportantstructuralfeaturesofthesedrugsare: thenumberandlocationofOHsubstitutionsonthebenzenering& thenatureofthesubstituentontheaminonitrogen.
Sympathomimeticaminesthatcontainthe3,4-dihydroxybenzenegroup: (suchas epinephrine,norepinephrine,isoproterenol,anddopamine)are calledcatecholamines. Thesecompoundssharethefollowingpropertie: 2. Rapidinactivation 3. Poor penetrationinto theCNS 1. Highpotency
Compoundslackingthecatecholhydroxylgroups have longer half-lives, because they are not inactivated byCOMT. • Theseinclude: • phenylephrine, • ephedrine,and • amphetamine.
Epinephrineissynthesizedfromtyrosineintheadrenal medulla and released, along with small quantities of norepinephrine, into thebloodstream. • Epinephrineinteractswithbothαandβreceptors. • Atlowdoses,βeffects(vasodilation)onthevascularsystem predominate, whereas at high doses, α effects (vasoconstriction) arestrongest.
PULMONARY EDEMA CNSDISTURBANCE HEMORRHAGE CARDIAC ARRYTHMIAS Includes: anxiety, fear,tension, headache, andtremor.
INHALATION ANESTHETICS HYPERTHYROIDISM COCAINE DIABETES β-BLOCKERS
Becausenorepinephrineistheneuromediatorofadrenergic nerves, it should theoretically stimulate all types of adrenergicreceptors. Inpractice,whenthedrugisgivenintherapeuticdosesto humans,theα-adrenergicreceptorismostaffected.
Isoproterenolisadirect-actingsyntheticcatecholaminethat predominantly stimulates both β1- and β2-adrenergic receptors. • Itsnonselectivityisoneofitsdrawbacksandthereasonwhy itis rarely used therapeutically. • Itsactiononαreceptorsisinsignificant.
Dopamine, the immediate metabolic precursorofnorepinephrine,occursnaturally in the CNS in the basal ganglia, where it functions as a neurotransmitter, as well as in the adrenalmedulla. • Dopaminecanactivateα-andβ-adrenergic receptors.
CARDIOVASCULAR RENAL&VISCERAL Dopamineexerts astimulatoryeffectonthe β1 receptors of the heart, having both inotropic and chronotropiceffects. Dopamine dilates renal and splanchnic arterioles by activating dopaminergic receptors,thusincreasingbloodflowtothe kidneys and otherviscera. Therefore, dopamine is clinically useful in thetreatmentofshock,inwhichsignificant increases in sympathetic activity might compromise renalfunction.
Dobutamineisasynthetic,direct-actingcatecholaminethat is a β1-receptoragonist. • Oneofthestereoisomershasastimulatoryactivity. • Itincreasescardiacrateandoutputwithfewvasculareffects. • Dobutamineisusedtoincreasecardiacoutputincongestive heart failure as well as for inotropic support after cardiac surgery.
Oxymetazolineisadirect-actingsyntheticadrenergic • agonistthatstimulatesbothα1-andα2-adrenergicreceptors. • Itisprimarilyusedlocallyintheeyeorthenoseasa vasoconstrictor. • Oxymetazolineisfoundinmanyover-the-countershort- term nasal spray decongestant products as well as in ophthalmic drops for the relief of redness of the eyes associatedwithswimming,colds,orcontactlens.
Phenylephrineisadirect-acting,syntheticadrenergicdrug that binds primarily to α receptors and favors α1 receptors over α2receptors. • Itisnotacatecholderivativeand,therefore,notasubstrate forCOMT. • Phenylephrineisavasoconstrictorthatraisesbothsystolicand diastolic bloodpressures.
Methoxamine is a direct-acting, synthetic adrenergic drug thatbindsprimarilytoα-receptors,withα1receptorsfavored over α2receptors. • Methoxamineraisesbloodpressurebystimulatingα1 receptorsinthearterioles,causingvasoconstriction. • Thiscausesanincreaseintotalperipheralresistance.
Clonidine is an α2 agonist that is used in essential hypertensiontolowerbloodpressurebecauseofitsactionin theCNS. • Itcanbeusedtominimizethesymptomsthataccompany withdrawalfromopiatesorbenzodiazepines. • Clonidineactscentrallytoproduceinhibitionofsympathetic vasomotor centers, decreasing sympathetic outflow to the periphery.
Metaproterenol, although chemically similar to isoproterenol,isnotacatecholamine,anditisresistantto methylation byCOMT. • Metaproterenolproducesdilationofthebronchiolesand improves airwayfunction. • Thedrugisusefulasabronchodilatorinthetreatmentof asthma and toreverse bronchospasm.
Albuterol,pirbuterol,andterbutalineareshort- acting β2 agonists used primarily as bronchodilators and administered by a metered- doseinhaler.
Salmeterolandformoterolareβ2-adrenergicselective, long-actingbronchodilators. • Salmeterol and formoterol are the agents of choice for treatingnocturnalasthmainsymptomaticpatientstaking other asthmamedications.
Themarkedcentralstimulatoryactionofamphetamineis oftenmistakenbydrugabusers asitsonlyaction. • The CNS stimulant effects of amphetamine and its derivativeshaveledtotheirusefortreatinghyperactivityin children, narcolepsy, and appetitecontrol. • Itsuseinpregnancyshouldbeavoidedbecauseofadverse • effectsondevelopmentofthefetus.
Tyramineisnotaclinicallyusefuldrug,butitisimportant becauseitisfoundinfermentedfoods,suchasripecheese and Chiantiwine. • Itisanormalby-productoftyrosinemetabolism. • Normally,itisoxidizedbyMAOinthegastrointestinaltract, butifthepatientistakingMAOinhibitors,itcanprecipitate serious vasopressorepisodes.
Cocaine is unique among local anesthetics in having the ability to block the Na+/K+-activated ATPase (required for cellularuptakeofnorepinephrine)onthecellmembraneof the adrenergicneuron. • Likeamphetamines,itcanincreasebloodpressurebyα- agonistactionsandβ-stimulatoryeffects.
Ephedrine,andpseudoephedrineareplantalkaloids,that are now madesynthetically. • Thesedrugsaremixed-actionadrenergicagents. • They not only release stored norepinephrine from nerve endingsbutalsodirectlystimulatebothαandβreceptors. • Thus,awidevarietyofadrenergicactionsensuethatare • similartothoseofepinephrine,althoughlesspotent.
Ephedrineenhancescontractilityandimprovesmotor function inmyasthenia gravis. • Ephedrine has been used to treat asthma, as a nasal decongestant(duetoitslocalvasoconstrictoraction),andto raise bloodpressure. • Pseudoephedrineisprimarilyusedtotreatnasalandsinus • congestionorcongestionoftheeustachiantubes.
