1. THE PHARMACOLOGY OF ADRENERGIC RECEPTORS M.T. Piascik PHA 824 December 11 & 16, 2008

2. Learning Objectives The student should be able to explain or describe; The pharmacodynamic principles that aid in the understanding of adrenergic receptors and the actions of drugs on these receptors. The criteria upon which alpha and beta receptors are defined. The second messenger systems utilized by alpha and beta receptors and how activation of these receptors leads to a change in physiologic function.

3. Learning Objectives (cont.) The student should be able to explain or describe; The effects of alpha and beta receptor activation on the heart and blood vessels. The effects of isoproterenol, epinephrine and norepinephrine on the cardiovascular system. The clinical uses and potential toxicities of epinephrine, norepinephrine and isoproterenol with emphasis on epinephrine.

4. The Adrenergic Receptors

5. Beta Adrenergic Receptors DRUGK D BETA 1 RECEPTORK D BETA 2 RECEPTOR Epinephrine800 nM800 nM Norepinephrine1000 nM10,000 nM Isoproterenol80 nM80 nM

6. Which of the dose-response curves represents activation of the beta1 receptor and which represents activation of the beta2 receptor?

7. Beta Adrenergic Receptor Systems TissueReceptor Subtype Heartbeta1 Adipose tissuebeta1 Vascular smooth musclebeta2 Airway smooth musclebeta2 Kidney-renin release from JG cellsbeta1

8. Cellular Signaling Activated by the Beta1 Receptor in the Heart

9. Physiologic Consequences of Beta1 Receptor Activation Rhythm disturbances are a major concern with drugs that activate the beta1 receptor.

10. The BETA1-Adrenergic Receptor as a Therapeutic Target 1)Agonists- congestive heart failure 2) Antagonists- hypertension, ischemic heart disease, congestive heart failure, supraventricular tachyarrhythmias.

11. Cellular Signaling Activated by the Beta2 Receptor in Smooth Muscle

12. Physiologic Consequences of Beta2 Receptor Activation

13. The Beta2-Adrenergic Receptor as a Therapeutic Target Agonists- Airways dysfunction (asthma, chronic bronchitis emphysema), tocolytics Antagonists- No therapeutic uses.

14. The BETA2-Adrenergic Receptor as a Therapeutic Target 1)Agonists- congestive heart failure 2) Antagonists- hypertension, ischemic heart disease, congestive heart failure, supraventricular tachyarrhythmias.

15. Alpha Adrenergic Receptors K D K D K D BETA 1 RECEPTOR BETA 1 RECEPTOR ALPHA RECEPTOR Epinephrine 800 nM800 nM5000 nM Norepinephrine 1000 nM10,000 nM* 6000 nM Isoproterenol 80 nM80 nM 10,000 nM** * At doses used in therapeutics, Norepinephrine is void of Beta2 activity ** At doses used in therapeutics, Isoproterenol is void of Alpha1 activity

16. Presynaptic Alpha2 Receptors

17. Postsynaptic Alpha1 Receptors

18. Physiologic Consequences of Alpha1 Receptor Activation

19. Interaction Between Vascular Alpha1 and Beta2 Receptors

20. Integrated Cardiovascular Responses

21. Integrated Cardiovascular Response to Isoproterenol and Norepinephrine

22. Integrated Cardiovascular Response to Epinephrine

23. Therapeutic Uses of Epinephrine Oral dosing of epinephrine, norepinephrine or isoproterenol is not possible due to its rapid metabolism in the gut by MAO. Epinephrine can be given topically, by injection (s.c., i.m. i.v) or inhalation

24. Therapeutic Uses of Epinephrine (cont.) Actions at the Beta2 Receptor The treatment of respiratory distress or bronchspasm caused for example by asthma (i.e. status asthmaticus) or anaphylaxis as a result of allergic responses. Actions at the Beta1 Receptor Epinephrine is also used to provide rapid inotropic support in cardiopulmonary resuscitation

25. Therapeutic Uses of Epinephrine (cont.) Actions at the Beta2 Receptor The treatment of respiratory distress or bronchspasm caused for example by asthma (i.e. status asthmaticus) or anaphylaxis as a result of allergic responses. Actions at the Beta1 Receptor Epinephrine is also used to provide rapid inotropic support in cardiopulmonary resuscitation

26. Therapeutic Uses of Epinephrine (cont.) Actions at the Alpha1 Receptor Epinephrine is often used in combination with local anesthetic agents (such as articaine, bupivacaine or lidocaine) to prolong the duration of anesthetic action. Epinephrine is used in surgery to reduce bleed.

27. Epinephrine Toxicities Arrhythmias Hypertension Toxicity can occur following systemic administration or systemic absorption following oral administration.

28. Epinephrine Toxicities Arrhythmias Hypertension Toxicity can occur following systemic administration or systemic absorption following oral administration.

29. Epinephrine Toxicities Toxicity can be potentiated in patients taking tricyclic antidepressants, nonselective beta blockers, cocaine and amphetamine-like drugs and those under general anesthesia.

35. Beta2-AR Beta1-AR