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HuBio 543 September 26, 2007

HuBio 543 September 26, 2007. Neil M. Nathanson K-536A, HSB 3-9457 nathanso@u.washington.edu Adrenergic Agonists &Other Sympathomimetics. CLASSES OF SYMPATHOMIMETICS. Indirect-acting. Direct-acting. Mixed-acting. Amphetamine Tyramine. Albuterol Dobutamine Dopamine Epinephrine

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HuBio 543 September 26, 2007

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  1. HuBio 543September 26, 2007 Neil M. Nathanson K-536A, HSB 3-9457 nathanso@u.washington.edu Adrenergic Agonists &Other Sympathomimetics

  2. CLASSES OF SYMPATHOMIMETICS Indirect-acting Direct-acting Mixed-acting Amphetamine Tyramine Albuterol Dobutamine Dopamine Epinephrine Fendolopam Isoproterenol Norepinephrine Phenylephrine Ritodrine Salmeterol Terbutaline Ephedrine

  3. Reminder: Subtypes of Adrenergic Receptors a: EPI > NOR >>ISO ß: ISO > EPI > NE a1: contraction of smooth muscle (incl. VSM) a2: presynaptic receptors ( decrease NE release) ß1: in heart and juxtaglomerular cells (and some fat cells) ß2: relaxation of smooth muscle ß3: some fat cells NOTE ON ß2: (1) mediate relaxation of skeletal muscle vasculature (2) P’cologically administered NE is not effective

  4. The Ugly Truth About Epinephrine EPINEPHRINE: MORE POTENT AT ß2 THAN AT a1 Therefore: you would predict that low doses of EPI preferentially activate ß2 receptors over a1 receptors Low doses of EPI: preferentially activate ß2 receptors in skeletal muscle vasculature: cause vasodilation, leading to a decrease in total peripheral resistance (TPR) High doses of EPI: activate both ß2 and a1 receptors: a1 response predominates, resulting in vasoconstriction, which causes an increase in total peripheral resistance (TPR)

  5. Effects of Epinephrine on the Cardiovascular System Drug Direct Reflex Action Effect Effect Result Cardiac output, HR, Systolic pressure Increase rate and force Stimulate ß-AdR ----- Stimulate ß2-AdR (preferentially over a1-AdR) Vaso- dilation Diastolic pressure ----- TPR

  6. DA NE EPI ISO (0.5 µg/min) (10 µg/min) (10 µg/min) (10 µg/min) 100 Pulse rate 50 180 BP (mm. Hg) 120 60 Peripheral Resistance 15 min 15 min 15 min 15 min Slow IV administration in humans

  7. NE EPI ISO DA PHEN. TPR BP HR Effects of agonists on cardiovascular function (slow IV administration)

  8. “In the Corner With the Gladiators: Trying Out the Life of the Cut Man” by Harry Hurt, III NYT, 8/26/07

  9. Necrosis Following Extravasation of Epinephrine

  10. Effects of Norepinephrine on the Cardiovascular System Drug Direct Reflex Action Effect Effect Result Cardiac output, HR, (Increase rate and force) Strongly stimulate ß-AdR HR Diastolic pressure Stimulate a1-AdR Vaso- constriction Systolic pressure TPR

  11. DA NE EPI ISO (0.5 µg/min) (10 µg/min) (10 µg/min) (10 µg/min) 100 Pulse rate 50 180 BP (mm. Hg) 120 60 Peripheral Resistance 15 min 15 min 15 min 15 min Slow IV administration in humans

  12. NE EPI ISO DA PHEN. TPR BP HR Effects of agonists on cardiovascular function (slow IV administration)

  13. Effects of Isoproterenol on the Cardiovascular System Drug Direct Reflex Action Effect Effect Result Cardiac output, HR, Systolic pressure HR, Force Increase rate and force Stimulate ß-AdR Stimulate ß2-AdR Much vaso- dilation Diastolic pressure ----- TPR

  14. DA NE EPI ISO (0.5 µg/min) (10 µg/min) (10 µg/min) (10 µg/min) 100 Pulse rate 50 180 BP (mm. Hg) 120 60 Peripheral Resistance 15 min 15 min 15 min 15 min Slow IV administration in humans

  15. NE EPI ISO DA PHEN. TPR BP HR Effects of agonists on cardiovascular function (slow IV administration)

  16. DOPAMINE D1 > ß > a1 Can activate: (1) vasodilatory dopamine (D1) receptors in renal, mesenteric, and coronary vascular beds (2) beta receptors in heart (greater effect on contractile force that rate) (3) stimulates NE release from nerve terminals (contributes to cardiac effects) (4) high doses can activate vascular a1 receptors

  17. DA NE EPI ISO (0.5 µg/min) (10 µg/min) (10 µg/min) (10 µg/min) 100 Pulse rate 50 180 BP (mm. Hg) 120 60 Peripheral Resistance 15 min 15 min 15 min 15 min

  18. NE EPI ISO DA PHEN. TPR BP HR Effects of agonists on cardiovascular function (slow IV administration)

  19. Effects of Phenylephrine on the Cardiovascular System Drug Direct Reflex Action Effect Effect Result (No Effect) ------- (No Effect) HR HR Diastolic pressure Stimulate a1-AdR Vaso- constriction Systolic pressure TPR

  20. NE EPI ISO DA PHEN. TPR BP HR Effects of agonists on cardiovascular function (slow IV administration)

  21. + phenylephrine 200 BP mm Hg. 50 Symp. Nerve act. Vagus Nerve act 100 HR bpm 40 0 1.0 Time (min)

  22. Sec after phenylephrine 30 10 20 200 BP, mm Hg. 100 0 1200 Pulse Interval (msec.) 1000 800 130 140 120 110 Systolic Pressure (mm Hg.)

  23. ß2- Adrenergic Agonists Albuterol Ritodrine Terbutaline Salmeterol

  24. 100 ISO Tracheal Muscle % reduction of intraluminal pressure 50 ALB 0 100 Cardiac Muscle (Rate) ISO % increase in rate ALB 50 0 100 Cardiac Muscle (Force) % increase in force of contraction ISO 50 ALB 0 0.0001 0.001 0. 01 0. 1 1 10 Concentration (µg/ml)

  25. Time Course of Bronchodilation Produced by Albuterol and Salmeterol SALMETEROL FEV1 ALBUTEROL PLACEBO FIRST DOSE SECOND DOSE 12 6 0 3 9 Time (Hours)

  26. EFFECTS OF ISOPROTERENOL & ALBUTEROL IN HUMANS ISOPROTERENOL 90 Pulse Rate 60 FEV1.0 30 % Increase Over Basal Value 10 ALBUTEROL 50 FEV1.0 30 Pulse Rate 10 DOSE (IV)

  27. “ß1- Adrenergic Agonists” Dobutamine One isomer is ß1 agonist and a1 agonist Other isomer is ß1 agonist (and apparently weak a1 antagonist) Increases contractile force, little effect on heart rate or TPR Used to increase cardiac output (e.g., CHF) Why does dobutamine have little effect on HR and TPR? 1. Human atria: 40- 50% ß1; human ventricle: 70- 85%ß1 2. Little or no ß2- mediated vasodilation, so no reflex tachycardia 3. a1 agonist activity may also contribute to direct stimulation of ventricles and lack of vasodilation

  28. Fenoldopam • Dopamine D1 receptor agonist • IV administration causes rapid vasodilation • Used for emergency management of severe hypertension

  29. 0 100 200 300 400 IV Administration of Fenoldopam Patients with Postcardiac Surgery Hypertension 190 Systolic BP 140 Heart Rate (bpm) Pressure (mm Hg) 90 Heart Rate Diastolic BP 40 Time (minutes)

  30. NE NE NE NE NE NE NE Indirect-acting sympathomimetics NE Re-Up TYRAMINE AMPHETAMINE

  31. Cocaine blocks vasopressor response to tyramine and potentiates response to norepinephrine BP + Tyramine + Norepinephrine Pretreat with Cocaine: BP + Tyramine + Norepinephrine

  32. Cocaine potentiates sympathetic transmission (and effects of NE administration) NE NE NE NE NE NE X NE NE Re-Up Re-Up NE NE NE NE NE NE NE uptake blocked by cocaine Normal uptake of NE

  33. Effects of epinephrine and ephedrine on blood pressure in dog 160 80 BP (mm. Hg) EPINEPHRINE 0 240 160 BP (mm. Hg) 80 EPHEDRINE 0

  34. EPHEDRINE TACHYPHYLAXIS IN THE DOG BP 1 min. Ephedrine (3 mg/kg) administered, every 10 min

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