Adrenergic agonists & antagonists

This presentation was delivered over two days to second year pharmacy students enrolled in a course in pharmacology & toxicology. This lecture is designed to accompany Goodman & Gilman's (12e) chapter 11.

1. Adrenergic Agonists & Antagonists Brian J. Piper, Ph.D., M.S.

2. Objective Describe the main uses and adverse effects of selective & non-selective adrenergic agonists Describe the main uses and adverse effects of adrenergic antagonists Tom Westfall David Westfall

3. Sympathetic “Fight or Flight”

4. Parasympathetic “Rest & Maintain” Rest Repair Renew

5. * * Acetylcholine & muscarinic receptors for sweat glands Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmacology , p. 56.

6. Jargon s ympathomimetic : drug that activates sympathetic nervous system p arasympathomimetic : drug that activates parasympathetic nervous system s ympatholytic : drug that decreases or blocks sympathetic response p arasympatholytic : drug that decreases or blocks parasympathetic response a drenaline = epinephrine

7. Drugs that affect Autonomic Nervous System will affect: Heart Blood Vessels Bowels Pancreas Ureters Bladder Eyes Pupils Lacrimal Gland Salivary Glands Lung Airways Brain

8. Where are the adrenergic receptors? Receptor: α 1 α 2 β 1 β 2 β 3 localization blood vessels pancreas heart lungs adipose tissue vas deferens g.i . tract kidney g.i . tract uterus (pregnant) CNS uterus (non-pregnant) adipose tissue ureter stomach salivary glands

9. Adrenergic Projections (CNS) Pronunciation : http:// www.merriam-webster.com/cgi-bin/audio.pl?locusc03.wav=locus+coeruleus http://dictionary.reference.com/browse/peduncle?s=t b rain s tem s pinal cord c erebellum f rontal c ortex l imbic s ystem Brodal (2010). Central Nervous System . p. 377.

10. Functional Localization Descending Projections Ascending Projections β 1 α 1 Stahl, S. (2000). Essential Psychopharmacology , p. 165-167.

11. Adrenergic Neurotransmission (CNS) Postsynaptic: α 1, α 2, β 1 Presynaptic: α 2 Stahl, S. (2000). Essential Psychopharmacology , p. 160-161.

12. Pheochromocytoma Tumor of chromaffin cells of adrenal medulla (4:1 NE to Ep ) Symptoms ↑ heart rate ↑ blood pressure/orthostatic blood pressure ↑ anxiety ↓ weight diaphoresis cortex medulla http://www.learningradiology.com/archives2011/COW%20441-Pheochromocytoma/pheocorrect.htm

13. “selective” ≈ 50-100 fold Goodman & Gilman (2011). Pharmacological Basis of Therapeutics . p. 278.

14. Phenylephrine Mechanism: selective α 1 agonist, vasoconstriction Uses: decongestant: substitute for pseudoephedrine but controversy (at 10 mg, oral) over effectiveness 1 postural hypotension: ↑blood pressure without cardiac effects, concern: supine hypertension detumescent (urologist) 1 Hendeles, L. (2006) Oral phenylephrine: An ineffective replacement for pseudoephedrine? J Allergy Clin Immunology, 118(1), 279-280. Epinephrine

15. Clonidine Mechanism: neural pre-synaptic α 2 agonist (?) Uses: mild hypertension Zhou et al. (1999). British Journal of Pharmacology, 126 , 1522-1530. 129SV mouse Wild-type α 2A Knock-Out

16. Clonidine Mechanism: neural pre-synaptic α 2 agonist (?) Uses: mild hypertension Zhou et al. (1999). British Journal of Pharmacology, 126 , 1522-1530. 129SV mouse Wild-type α 2A Knock-Out

17. Clonidine Mechanism: neural pre-synaptic α 2 agonist Uses: mild hypertension , ADHD Side-Effects: dry mouth & sedation (↓), sexual

18. β Adrenergic Agonists Drug Mechanism Use(s) Adverse Effects Isoproterenol 1 β 1 β 2 agonist bradycardia (e mergency ) palpitations, headaches, tachycardia, flushing Dobutamine β 1 agonist α 1 agonist/ α 1 antagonist congestive heart failure (short-term) ↑ size of myocardial infarct ↑ risk of arrhythmia Albuterol β 2 agonist bronchospasm (short-term) anxiety, headache, dry-mouth Salmeterol β 2 agonist bronchospasm (long-term) upper respiratory tract inflammation Formoterol β 2 agonist bronchospasm nasopharyngitis , headache 1 Pronunciation : http://dictionary.reference.com/browse/Isoproterenol?s=ts References: G & G; Lippincott’s; pdr.net

19. Comparison of β Agonists for Asthma

20. Safety of Long-Acting β -agonists for Asthma A large trial (N=26,000) found a 4-fold elevation in asthma related deaths with salmeterol 1 . Deaths are uncommon (2/1000 patient-years) Prior research on more frequent outcomes has been revealed inconsistent results What to do? Tally studies (worst) Authority (ok) 1 Salmeterol Multi-center Asthma Research Trial ( SMART )

21. Meta-Analysis of LABA Asthma Related Hospitalizations Odds Ratio = 1 means probability of event is equal in both groups Odds Ratio <> 1 means probability of event differs in each group OR s almeterol = 1.7, OR formoterol = 3.2; OR children = 3.9, OR adults = 2.0 Salpeter et al. (2006). Annals of Internal Medicine, 144 , 904-912. ->

22. Long Acting B Agonists FDA Warning http://www.pdr.net/drugpages/concisemonograph.aspx?concise=1691

23. Neuroanatomy of Food Intake Meyer & Quezner (2005). Psychopharmacology . p. 135. Hypothalamus 1 ) Lateral: hunger center “gas” 2 ) Ventro -medial: satiety center “brakes” 1 2

24. Norepinephrine & Food Intake Meyer & Quezner (2005). Psychopharmacology . p. 135.

25. α 1 & β 12 Agonists & Arousal Meyer & Quezner (2005). Psychopharmacology . p. 134; from Berridge et al. (2004). Brain Research Review, 42 , 33-84. 30 Minute Blocks Phenylephrine (10 x 10 -9 mol ), isoproterenol (4 x 10 -9 mol ) or both injected into the medial septum. Behavior based on EEG/EMG.

26. Ephedrine Ephedra sinica ( má huáng ) used in traditional Chinese medicine Contains ephedrine and pseudoephedrine Mixed: α 1 α 2 β 1 β 2 agonist, NE releaser 2002: FDA withdrawal from OTC diet agents over concerns of strokes & arrhythmias (but gone?) Kaplan (2011). Gastroenterology Clinics North America, 39(1), 69-79.

27. Ephedra & Weight Loss: Example Randomized Controlled Trial Overweight (BMI > 25) participants were randomized to placebo or m a huang /kola pills ( tid ) Analytical chemistry revealed 33 mg ephedrine & 14 mg caffeine Ambulatory monitoring revealed slight changes (BP: Placebo -3; Herbal +4) Adverse effects: insomnia & anxiety Weight loss but: p lacebo response drop-out Boozer et al. (2002). International J Obesity, 26 , 593-604.

28. History of Methamphetamine 1893: Synthesized by Nagai Nagayoshi in Japan 1940s- : Popular with military 1960s- : used for short-term treatment of obesity, narcolepsy, and, later, ADHD 1983-2005 : state and federal laws attempt to reduce use by decreasing availability of ephedrine and pseudoephedrine 2000s- : several aggressive (factually correct?) advertising campaigns are aimed at reducing demand

29. History of Methamphetamine 1960s- : used for short-term treatment of obesity, narcolepsy, and, later, ADHD 1983-2005 : state and federal laws attempt to reduce use by decreasing availability of ephedrine and pseudoephedrine 2000s- : several aggressive (factually correct?) advertising campaigns are aimed at reducing demand Starts slow (3 min): http://montana.methproject.org/Our-Work/brain-and-behavior.php

30. True or False : “the MMP results in Montana have been more significant than any other drug prevention program in history”? Youth Risk Behavior Survey High School students were asked about lifetime methamphetamine use before and after the Montana Methamphetamine Project. Anderson (2010) J Health Econ, 29 , 732-742 .

31. Positron Emission Tomography of the Dopamine Transporter PD = Parkinson’s Disease

32. Montana Meth Project Businessman Thomas Siebel supported graphic advertising in 2005 Goal was to reach each teenager 3+ times/week (TV, radio, print). To View Ads: http://www.montanameth.org/View_Ads/index.php

33. Similarities & Differences of Exposed & Unexposed Children Unexposed (N=35) Exposed (N=31) Trimesters of Methamphetamine 0 (0) 2.5 (0.3)*** Income while pregnant : <15,000 Income currently : >35,000 17.1% 51.4% 76.2* 60.0% Maternal Age at Birth (years) 26.9 (1.1) 29.8 (1.5) Nicotine 17.1% 76.2*** Alcohol 11.4% 71.4%*** Marijuana 11.4% 58.8%* Biological father involved 85.7% 44.8%*** Number of other children In home 2.7 (0.3) 1.3 (0.3)** Piper et al. (2011). Pharmacol Biochem Behav , 98 , 432-439. p < *.05, **.01, or ***.005

34. Behavioral Rating Inventory of Executive Function (BRIEF) Please rate whether the following behaviors are never, sometimes, or often a problem (1-3 points): Emotional Control (EC) : overreacts to small problems Inhibit (INH): interrupts others Shift (SHI): becomes upset with new situations Working Memory (WM): when given three things to do, remembers only the first or last Initiate (INI): has trouble coming up with ideas for what to do in play time Plan/Organize (PO): gets caught up in details and misses the big picture Organization of Materials (OM): cannot find things in room Monitor (MON): does not check work for mistakes Behavioral Regulation Index + Metacognition Index = Global Executive Composite (Mean= 50.0, SD = 10) Gioia GA, Isquith PK, Guy SC, et al. (2000). Behavioral Rating Inventory of Executive Function: Professional Manual. Psychological Assessment Resources: Lutz.

35. *** p < .0005, ** p < .005, * p < .05 “Clinically Significant” Behavioral Problems in Children Exposed Prenatally to Methamphetamine & Other Drugs Piper et al. (2011). Pharmacol Biochem Behav , 98 , 432-439.

36. Common Sympathomimetic Drugs Drug Schedule FDA Approved For Acute Mechanisms High-Dose methamphetamine ( Desoxyn ) II ADHD obesity Per: αβ agonist Cen: DA, NE, 5-HT ↓DAT ↓ SERT amphetamine (Adderall) II ADHD narcolepsy Per: αβ agonist Cen: DA, NE, 5-HT ↓DAT Methylphenidate (Ritalin) II ADHD narcolepsy Per: αβ agonist Cen: DA, NE Cen = central nervous system; Per = peripheral nervous system

37. Top Drug Molecules Dispensed to the Pediatric Population From US Retail Pharmacies According to Patient Age in 2010 Chai et al. (2012). Pediatrics, 131(1) , 23-31. Grace Chai, PharmD

38. Weight, Growth, & Psychostimulants s tatistically but clinically significant? h eight ≈ 0.5 cm/year w eight ≈ 2 kg/year t olerance c atch-up? Faraone et al. (2008). Journal of the American Academy of Child & Adolesclent Psychiatry, 47(9 ), 994-1009.

39. Cocaine Mechanism: Central: block DAT, NET & SERT Peripheral: αβ agonist Schedule II (nasal surgery) Erythroxylon coca powder crack

40. Why is cocaine reinforcing? Meyer & Quenzer (2008). Psychopharmacology . p. 283; Rocha (2003). Eur J Pharmacol , 479 , 107-115 . C57 mouse

41. Why is cocaine reinforcing? Meyer & Quenzer (2008). Psychopharmacology . p. 283; Rocha (2003). Eur J Pharmacol , 479 , 107-115 .

42. Drug Abuse Warning Network Tracks number of time drug is implicated in (urban) ER visits p oly-substance use Drug N alcohol 17,796 cocaine 11,431 heroin 10,493 opiates ( oxycontin ) 8,525 antidepressants 1,875 stimulants (meth, amph ) 739 Boston 2010 http://www.samhsa.gov/data/DAWN.aspx#DAWN%202010%20ED%20Excel%20Files%20%E2%80%93%20Metro%20Tables <- Thalamic hemorrhage in crack smoker (CT)

43. Reserpine c omponent of Rauwolfia serpentina (Indian snakeroot ) m echanism: long-term VMAT inhibitor e ffects ↓ blood pressure d epression sedation

44. Goodman & Gilman (2011). Pharmacological Basis of Therapeutics . p. 304.

45. Yohimbine Content of African tree bark Pre-synaptic α 2 antagonist Inconsistent bioavailability (5 to 80%) Purported male aphrodisiac (ED) Pausinystalia yohimbe

46. β Blockers Overview End in “ olol ” Contraindications: asthma Heart, eyes, kidneys ( β 1 predominate) Lungs, smooth muscle, uterine muscle ( β 2 predominate) O to 4:00 (skip add): http://www.youtube.com/watch?v=h2QR8HxxY1I

47. Controversy Over Phenylephrine Hendeles , L. (2006) Oral phenylephrine: An ineffective replacement for pseudoephedrine? J Allergy Clin Immunology, 118(1), 279-280.

48. Terminology Refresher p ositive ionotropic action (p. 282): increased strength of ventricular contraction p ositive chronotropic action (p. 282): increased rate of heart contraction h yperhidrosis (p. 296): excessive sweating General Refresher 0 to 31:50: http://www.youtube.com/watch?v=bMnz7dgHztg&feature=related