Adrenergic Agonists ANS Lect 14_2010BbF

Adrenergic Agonists ANS Lect 14_2010BbF - Adrenergic...

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Adrenergic Agonists Sympathomimetics
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Lecture Objectives I. Review sympathetic system II. Examine differences between Adr R affinities and catecholamine structures III. Review Adrenergic R system IV. Examine NE/EPI effects upon a & b receptor activation V. Therapeutic Use/Adverse Effects: a1, a2, b1, b2 Adr Agonists Selective and Non-selective Direct acting Indirect acting Mixed acting Mechanism of action
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I. Review Sympathetic Nervous System Input from. .. Neurotransmitters include. .. Receptors include. .. Sympathomimetics are drugs that are designed to stimulate SNS Bind directly to adrenergic Rs to initiate signalling cascade Indirectly altering endogenous []s at particular site of action
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Substitution at aromatic ring, a or b carbon or terminal amino group yields wide variety of sympathomimetics (KNOW TABLE 13-1) What happens with: a carbon substitution: b carbon substitution: amino substitution: C3/C5 substitution : C3/4 hydroxyl group: a b
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OH OH CH3 CH2(CH3)2 OH CH3 OH CH3 OH CH3 DA NE EPI IPE Ephedrine Phenylephrine
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R subtypes based on different affinities to various compounds R subtype homology ~ 30-40% between a and b subunits Glycosylation regulates expression From previous lecture: R Relative Affinity Ag ANT a 1 EPI ≥ NE> IPE Phenylephrine Prazosin a 1A, a 1B, a 1D a 2 EPI ≥ NE > IPE Clonidine Rauwolscine a 2A/ a 2C, a 2B b 1 IPE > EPI = NE Dobutamine Metoprolol b 2 IPE > Epi>>NE Salbuterol ICI11855 b 3 IPE = NE > Epi
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III. Review: Adrenergic Receptors (GPCR) * Creates binding pocket x involved in ANT binding
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Relative Affinities: EPI>NE> IPE Relative Affinities: EPI > NE> IPE a 1 signalling cascade VSM:↑ depolarization & SMC contraction (MLCK) GI : Hyperpolarization- smc relaxation (Ca -KCh) a 2 signalling cascade Hyperpolarization/Inhibit cellular activity Indirectly + NO SMC contraction via PLC to ↑ [Ca]i G bg K+ ch + Figure 12.8a
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Germann and Stanfield Figure 12.8b Relative Affinities: b 1 IPE > NE = Epi b 2 IPE > Epi>>NE b 3 IPE > NE > Epi b 1/2 signalling cascade via G a s b 1 linked to ↑Ca ++ (AC) activates MLCK b 2 ↑ cAMP inactivates MLCK →SMC relaxation Activates G bg and K+Ch hyperpolarization b 3 via G a ? Negative ionotopic Lipolysis, thermogenesis Peripheral vasodilation via NOS
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IV. Effects of Adrenergic Receptor Activation: NE/EPI
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