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Autonomic nervous system 2

Autonomic nervous system 2. - Adrenergic Receptors. They are sub divided into 1. -1 Adrenergic receptors: present on smooth muscle, all blood vessels (causing constriction) and the muscles that cause dilation of pupil of eye. 2. -2 Adrenergic receptors:

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Autonomic nervous system 2

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  1. Autonomic nervous system 2

  2. - Adrenergic Receptors They are sub divided into 1. -1 Adrenergic receptors: present on smooth muscle, all blood vessels (causing constriction) and the muscles that cause dilation of pupil of eye. 2. -2 Adrenergic receptors: They are mainly presynaptic are found at adrenergic and cholinergic nerve terminals. Also, postsynaptic are found in the blood vessels and in the CNS.

  3. -Adrenergic Receptors Divided into: • 1 adrenergic receptors: on heart (some 2 also) increases rate and force of contraction. • 2 adrenergic receptors: present on smooth muscle, some blood vessels (in skeletal muscles), bronchial smooth muscles, skeletal muscles and liver • 3 adrenergic receptors: present in adipose tissue

  4. Subtypes of Adrenergic Receptors Alpha-1 postsynaptic SNS effectors Alpha-2 presynaptic SNS neurons some postsynaptic SNS effectors Beta-1 heart adipocytes Beta-2 smooth muscle most other sites (Beta-3) adipocytes Alpha Adrenoceptors Beta Adrenoceptors

  5. What adrenoceptors “generally” do

  6. Adrenergic Signal Transduction Alpha-1 (similar to M1,M3,M5): Gq PLC IP3 PKC Ca Alpha-2 (similar to M2,M4): Gi inhibit adenylyl cyclase Beta-1 and –2 : Gs stimulate adenylyl cyclase

  7. Catecholamines: Affinity Determines Function Rank order of potency for epinephrine, norepinephrine, and isoproterenol Alpha: EPI > NE >> ISO Beta-1: ISO > EPI = NE Beta-2: ISO > EPI >> NE ISO: an almost pure beta adrenergic agonist NE: is a powerful alpha adrenergic agonist that also stimulates beta-1 adrenoceptors. EPI: relatively high affinity for all adrenoceptors.

  8. If you know the receptor, you can predict the physiology EPI ISO NE ] Heart Rate (bpm) ] Blood Pressure (mmHg) ] Peripheral Resistance

  9. Norepinephrine • NE stimulates alpha-1 adrenoceptors to induce vasoconstriction and hypertension. • The body will respond by reflex bradycardia. • It has direct cardiac stimulation (beta-1). • This is masked by reflex bradycardia due to the hypertensive effect

  10. Epinephrine • EPI stimulates vascular alpha-1 adrenoceptors. It also stimulates beta-2 adrenoceptors (particularly in skeletal muscle vasculature). • So there is minimal change in mean arterial pressure. • Therefore, we see the direct stimulatory effect on heart rate is observed.

  11. If you know the receptor, you can predict the physiology EPI ISO NE ] Heart Rate (bpm) ] Blood Pressure (mmHg) ] Peripheral Resistance

  12. Isoproterenol • ISO stimulates beta-2 adrenoceptors in the vasculature, leading to vasodilation and lowering of blood pressure. • Because ISO does not stimulate alpha-1 adrenoceptors, this vasodilation is greater than that observed with EPI. • This hypotensive effect leads to a reflex lowering of cardiac vagal tone (parasympathetic). • This diminished parasympathetic influence, coupled with direct cardiac stimulation (beta-1), leads to greater tachycardia that observed with EPI.

  13. Autonomic Control of Smooth Muscle Bronchial smooth muscle has beta-2 adrenoceptors Be careful with nonselective beta agonists! “Because the excessive cardiac stimulation produces cardiac arrhythmias and enhanced myocardial oxygen consumption, there is no rationale for using non-beta-2 selective agonists in the treatment of asthma.” Relax G.I. smooth muscle alpha and beta effects reduce motility may contract sphincters Relax uterine smooth muscle beta-2 agonists delay premature labor Relax detrusor muscle (b); contracts sphincter (a) urinary retention Contract radial muscle (a)-- mydriasis

  14. Other Catecholamine Effects Limited effect on CNS Does not cross BBB well Metabolic effects: stress / ”fight or flight” lipolysis glycogenolysis increased metabolic rate decreased insulin secretion

  15. Therapeutic Use of Catecholamines EPI: hypersensitivity reactions additive to local anesthetics EPI / ISO: powerful cardiac stimulant NE: hypotensive crisis / shock

  16. Pharmacokinetics Not effective orally rapid conjugation in G.I. Tract MAO and COMT in the liver Injection: sub-Q or IM are fairly useless IV is preferred method Inhalation: effective, but can cause arrhythmias Metabolites in urine: small amounts pheochromocytoma

  17. Adrenergic Pharmacology NE release + amphetamine + ephedrine • guanethidine • reserpine b-AR + isoproterenol + dobutamine + terbutaline + albuterol - propranolol • metoprolol - cocaine a-AR: +phenylephrine, +methoxamine, +clonidine - phenoxybenzamine, - phentolamine, - prazosin

  18. Adrenergic Agents: a dual strategy 2) Indirect Effect: nerve terminal • Direct Effect: adrenoceptors enhance / inhibit NE release mimic / antagonize effect of NE (Adrenomimetics / blockers)

  19. Adrenomimetic Amines “mimic” the effect of NE Direct selective adrenergic agonists: stimulate alpha or beta adrenoceptors alpha-1: phenylephrine methoxamine alpha-2: clonidine beta-1: dobutamine beta-2: terbutaline albuterol

  20. Alpha-1 Adrenergic Agonists PHENYLEPHRINE • Alpha-1 adrenergic agonist • Weak beta effects • Not a substrate for COMT • Primary use: vasoconstrictor • Treat hypotensive states • shock, spinal anesthesia • Nasal decongestant (Neosynephrine) • rhinitis medicamentosa or rebound • Mydriasis

  21. Alpha-1 Adrenergic Agonists METHOXAMINE • Alpha-1 adrenergic agonist • Does not stimulate beta adrenoceptors • Primary use: vasoconstrictor • Treat hypotensive states • shock, spinal anesthesia • Not metabolized by COMT or MAO

  22. Alpha-2 Adrenergic Agonists CLONIDINE • Alpha-2 adrenergic agonist • Direct vasoconstrictor • Indirect antihypertensive agent • central suppression • Rebound hypertension indirect direct

  23. Beta-1 Adrenergic Agonist DOBUTAMINE • “Beta-1” adrenergic agonist • Stimulates beta-2 and alpha adrenoceptors • Inotropic agent • Vasodilation predominates • preserves renal and G.I. blood flow • heart failure • Tolerance may develop

  24. Beta-2 Adrenergic Agonists TERBUTALINE and ALBUTEROL • Selective beta-2 agonists (normal doses) • Primary use: broncodilator • Reduced risk of cardiac stimulation • May inhibit mast cell secretion • Not metabolized by COMT or MAO • long duration of action • 4 - 8 hours; 0.5 – 2 hours for ISO • Inhalation helps limit side effects

  25. Indirect Adrenergic Agonists AMPHETAMINE • Enhances NE release • Action similar to NE • Powerful CNS stimulant • Less fatigue, increased alertness • Better physical performance • Appetite suppression • Dependency and tolerance

  26. Mixed-Acting Adrenergic Agonist EPHEDRINE • Indirect: induces NE release • Direct: stimulates a and b adrenoceptors • Bronchodilation due to beta effects • replaced by beta-2 agonists • Urinary incontinence • CNS stimulation • Appetite suppression • more effective combined with caffeine • herbal preparation: Ma huang

  27. Mixed-Acting Adrenergic Agonist METARAMINOL • Direct: stimulatesalpha-1 adrenoceptors • weak beta effects (like phenylephrine) • Indirect: replaces NE in storage granules • “false neurotransmitter” • Treat hypotensive states

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