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

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

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

4. EPINEPHRINE: MORE POTENT AT ß2 THAN AT  1 The Ugly Truth About Epinephrine Therefore: you would predict that low doses of EPI preferentially activate ß2 receptors over  1 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  1 receptors:  1 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 Stimulate ß-AdR Increase rate and force ----- Cardiac output, HR, Systolic pressure Stimulate ß 2 -AdR (preferentially over  1 -AdR) Vaso- dilation ----- TPR Diastolic pressure

6. Slow IV administration in humans

7. NE EPIISO DA PHEN. HR BP TPR 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 Strongly stimulate ß-AdR (Increase rate and force) HR Cardiac output, HR, Stimulate  1 -AdR Vaso- constriction TPR Diastolic pressure Systolic pressure

11. Slow IV administration in humans

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

13. Effects of Isoproterenol on the Cardiovascular System Drug Direct Reflex Action Effect Effect Result Stimulate ß-AdR Increase rate and force Cardiac output, HR, Systolic pressure Stimulate ß 2 -AdR Much vaso- dilation ----- TPR Diastolic pressure HR, Force

14. Slow IV administration in humans

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

16. DOPAMINE D1 > ß >  1 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  1 receptors

19. NE EPIISO DA PHEN. HR BP TPR Effects of agonists on cardiovascular function (slow IV administration)

20. Effects of Phenylephrine on the Cardiovascular System Drug Direct Reflex Action Effect Effect Result ------- (No Effect) HR Stimulate  1 -AdR Vaso- constriction TPR Diastolic pressure Systolic pressure

21. NE EPIISO DA PHEN. HR BP TPR Effects of agonists on cardiovascular function (slow IV administration)

22. 200 50 BP mm Hg. Symp. Nerve act. Vagus Nerve act HR bpm 100 40 01.0 Time (min) + phenylephrine

23. 200 100 0 1200 1000 800 BP, mm Hg. Pulse Interval (msec.) 30 2010 Sec after phenylephrine 120 110 130140 Systolic Pressure (mm Hg.)

24. ß 2 - Adrenergic Agonists Albuterol Ritodrine Terbutaline Salmeterol

25. 100 50 0 % reduction of intraluminal pressure % increase in rate % increase in force of contraction Tracheal Muscle Cardiac Muscle (Rate) Cardiac Muscle (Force) 0.00010. 10. 01100.0011 Concentration (µg/ml) 100 50 0 100 50 0 ISO ALB

26. SALMETEROL ALBUTEROL PLACEBO FIRST DOSE SECOND DOSE 0 3 6 9 12 FEV 1 Time (Hours) Time Course of Bronchodilation Produced by Albuterol and Salmeterol

27. 90 60 30 % Increase Over Basal Value 10 50 30 10 ISOPROTERENOL ALBUTEROL Pulse Rate FEV 1.0 Pulse Rate FEV 1.0 DOSE (IV) EFFECTS OF ISOPROTERENOL & ALBUTEROL IN HUMANS

28. “ß 1 - Adrenergic Agonists” One isomer is ß1 agonist and  1 agonist Other isomer is ß1 agonist (and apparently weak  1 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.  1 agonist activity may also contribute to direct stimulation of ventricles and lack of vasodilation Dobutamine

29. Dopamine D 1 receptor agonist IV administration causes rapid vasodilation Used for emergency management of severe hypertension Fenoldopam

30. 4003002001000 40 90 140 190 IV Administration of Fenoldopam Patients with Postcardiac Surgery Hypertension Time (minutes) Pressure (mm Hg) Heart Rate (bpm) Diastolic BP Heart Rate Systolic BP

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

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

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

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

35. 1 min. EPHEDRINE TACHYPHYLAXIS IN THE DOG Ephedrine (3 mg/kg) administered, every 10 min BP