• α- and β-adrenergic receptor selectivity

  • Adrenergic agonists have been developed which exhibit binding and activation preference for one or another adrenergic receptor type.

    • Some agents bind preferably to α-receptors while others exhibit selectivity for β-receptors.

    • For the case of agonists, binding is associated with receptor activation; therefore, binding selectivity for agonists corresponds to activation selectivity also.

    • For antagonists the singular event is binding, given that antagonists cannot activate receptors (here the references to "pure" antagonists).

    • A drug may exhibit receptor selectivity, a non-absolute preference for a particular receptor type.

      • A drug that is described as "highly specific" will be one that exhibit substantial selectivity for the receptor.

        • Classification of α-and β -adrenergic receptors with respect to receptor affinities is described below.³⁵

  • Brief initial comment about some adrenergic agents.

    • Epinephrine a.k.a. adrenaline activates both α- and β-adrenergic receptors. ³⁵

      • Epinephrine

      • The physiological effects actually observed depend in part on dosage. Because the drug activates both adrenergic receptor types, epinephrine at higher doses can cause significant vasoconstriction.

        • Through cardiac β receptor activation, epinephrine mediates positive inotropic (increased myocardial contractility) and positive chronotropic (increased heart rate) cardiac effects.

      • Hypertensive responses to epinephrine can be explained both by increased cardiac output as a result of enhanced contractility and heart rate as well as by increased vascular resistance due to α receptor activation.

      • In a subset of vessels, β₂ receptor activation causes vasodilatation.

        • Skeletal muscle blood vessels respond in this way. Blood pressure effects, then, following epinephrine depend on a balance between α-adrenergic receptor mediated vasoconstriction and β₂ adrenergic receptor mediated vasodilatation.

        • The response to epinephrine may involve both an increase in the systolic pressure (α-adrenergic receptor mediated) along with a decrease in diastolic pressure (reflecting the β₂-adrenergic receptor activation). The net effect may be an increase in mean blood pressure with a widening pulse pressure.

    • Norepinephrine (Levophed) a.k.a. noradrenaline, levarterenol is a principal agonist of both α₁ and α₂ adrenergic receptors but also activates β₁ adrenergic receptors about to the same extent observed with epinephrine.³⁵  

      • Norepinephrine (Levophed)

      • Following norepinephrine infusion, the blood pressure will rise due to prominent α-receptor activation; however, heart rate is likely to decrease, despite norepinephrine activity at β one receptor sites. The reduction in heart rate is explained by an autonomic reflex mediated by baroreceptors (the increased blood pressure causes a parasympathetic (cholinergic)-mediated decrease in heart rate). The cholinergic, parasympathetic response is sufficient to overcome the norepinephrine direct cardiac β₁ action.

       

    • Some agents are described as direct-acting sympathomimetic drugs-direct activators at the receptors.³⁵

      • For example, phenylephrine (Neo-Synephrine) is classified as a nearly pure α₁ agonist. The absence of the catecholamine structure renders phenylephrine unsuitable as a COMT-substrate (the enzyme catechol-o-methyl transferase thus cannot contribute to phenylephrine inactivation); therefore, phenylephrine exhibits an extended duration of action.

      • Phenylepinephrine (Neo-Synephrine)

         

      • A selective α₁ adrenergic agonist, midodrine (Amatine, ProAmatine)  is classified as a prodrug.

        • This designation indicates that the physiological response noted after midodrine administration is due to a metabolite, in this case desglymidodrine. Desglymidrine differs from methoxamine only by lacking a CH₃ (methyl) group on a side chain. (compared 3D structures below)

      • Midodrine may be used clinically to manage orthostatic hypotension secondary to and autonomic dysfunction which impairs blood pressure homeostasis.

      • Mitrodrine (Amatine, ProAmatine)

       

      •  Desglymidodrine

       

    • Methoxamine (Vasoxyl) is another direct acting α₁ receptor agonist that both increases blood pressure (α₁ mediated vasoconstriction) and bradycardia (reduced heart rate, a parasympathetic-mediated autonomic reflex).

      • Parasympathetic reflexes that reduce heart rate as described above are mediated by the vagus nerve.³⁵

      • Methoxamine (Vasoxyl)

         

    • Other drugs exhibit relative α₂ selectivity and act to reduce blood pressure as a result of central nervous system effects³⁵ , perhaps by reducing sympathetic outflow.

      • Agents of this type useful in hypertension management include:

        • Clonidine (Catapres)

        • Methyldopa (Aldomet)

        • Guanabenz (Wytensin), and

        • Guanfacine (Intuniv, Tenex) .

        • Clonidine (Catapres)

           

        • Methyldopa (Aldomet)

         

        • Guanabenz (Wytensin)

         

        • Guanfacine (Intuniv, Tenex)

        • Another centrally-acting α₂-selective agonist which appears helpful in sedating patients during initial intubation and subsequent mechanical ventilation is dexmedetomidine (Precedex).

          • Dexmedetomidine (Precedex)

    • Xylometazoline (Otrivin) and oxymetazoline (Afrin), both direct-acting α agonists, are effective topical decongestants which act by constriction of nasal mucosa.³⁵

      •  

        Xylometazonline (Otrivin)

         

      • Oxymetazoline (Afrin)

    • Isoproterenol (Isuprel) a.k.a. isoprenaline is principally an agonist at β receptors, causing increased myocardial contractility and increased heart rate.³⁵

      •  

        Isoproterenol (Isuprel, Medihaler-Iso)

      •  In addition, its β-effects promote vasodilation sufficient to reduce both mean arterial and diastolic blood pressure, although systolic pressure might be either slightly decreased or slightly increased.³⁵

       

      • α₁ Receptors^49,46

        Receptor type: α1 (includes α1A, α1B, α1D)

        example agonist:  phenylephrine

        example antagonist:  prazosin

        Signal transduction:  G protein (Gq,Gi/Go  depending on subtype); also depending on subtype, ↑ phospholipase C, D, A2 enzyme activity ↑ IP3, DAG** (true for all α receptor subtypes)

        Receptor type: α1

        Agonist effectiveness:  Epinephrine ≥ Norepinephrine >> Isoproterenol; phenylephrine ("pure" α agonist)

        Tissue Effects following α1-receptor activation Vascular smooth muscle contraction GU* smooth muscle contraction Hepatic:  glycogenolysis, gluconeogenesis Intestinal smooth muscle:  relaxation (membrane hyperpolarization) Cardiac:  positive inotropic (increased contractility); proarrhythmic

        "Transmembrane view of a structural model of the human α1a AR receptor. The α1a AR contains seven transmembrane domains (TM), TM1 to TM7, four intracellular loops (IL) colored individually, and C-terminal domain (C-terminus)." Attribtion: Oganesian A Yarov-Yarovoy V Parks WC Schwinn DA Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway PNAS December 6, 2011 108 (48) 19796-19801. https://www.pnas.org/content/108/49/19796

• *GU--genitourinary; ** IP3: Inositol trisphosphate; DAG:  diacylglycerol

   

  • IP₃:DAG Second Messengers

    IP3	DAG

     

  • α₂ Receptors^49,46

    Receptor type: α2 (includes α2A, α2B, α2D)

    example agonist:  clonidine;  α2Aagonist: oxymetazoline

    example α2: antagonist:  yohimbine; α2A,α2B:  prazosin

    Signal transduction: G protein (Gi ↓ adenylyl cyclase activity); Gi (βγ subunits): ↑K+ channel conductance; Go : ↓Ca2+ channel conductance (L- and N-type) ↓cAMP (true for all α2 receptor subtypes)

  • Receptor type: α2

    Agonist effectiveness:  Epinephrine ≥ Norepinephrine >> Isoproterenol; clonidine (classical α2 agonist)

    Tissue Effects following α2-receptor activation Platelets:  aggregation Pancreatic islet β cells:  reduction in insulin release Synaptic endings:  reduction in norepinephrine release Vascular smooth muscle:  contraction

  •  

    β Receptors^49,46

    Receptor type: β (includes β1, β2, β3)

    example agonist:  isoproterenol;  β1 agonist: dobutamine; β2 agonist : albuterol

    example β: antagonist: propranol;  β1 antagonist: bextaxolol, metaprolol; β2 antagonist: butoxamine

    Signal transduction: G protein (Gs) ↑ cAMP (true for all β receptor subtypes),  ↑adenylyl cyclase,↑ L-type Ca2+ channels

    Receptor type: β1	Agonist effectiveness:  Isoproterenol > Epinephrine = Norepinephrine; dobutamine (antagonist:  CGP 20712A)	Tissue Effects following β1 -receptor activation Renal:  juxtaglomerular cells:  increased renin secretion Cardiac: increased myocardial contractility (positive inotropism) increased rate of contraction increased AV nodal conduction velocity
    Receptor type: β2	Agonist effectiveness:  Isoproterenol > Epinephrine >> Norepinephrine (antagonist ICI 118551); terbutaline (antagonist:  CGP 20712A)	Tissue Effects following β2-receptor activation Smooth muscle (including bronchial, vascular, GI and GU):  relaxation Skeletal muscle:  glycogenolysis and increased K+ uptake. Hepatic effects::  glycogenolysis and gluconeogenesis

    Receptor type: β3

    Agonist effectiveness:  Isoproterenol = Epinephrine > Norepinephrine (antagonist ICI 118551); BRL 37344 (antagonist:  CGP 20712A)

    Tissue Effects following β3-receptor activation Adipose:  lipolysis

  •  

    Dopamine Receptors^49,46

    Receptor type: Dopamine (includes D1, D2,D3, D4,D5 )

    example D1 agonist: fenoldopam; example D2 agonist:  bromocriptine

    example D4: antagonist: clozapine

    Signal transduction: D1:↑ cAMP; D2-D5: ↓cAMP

 

 

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