Adrenergic Agonists &    Antagonists Brian J. Piper, Ph.D., M.S.
Objective• Describe the main uses and adverse effects of  selective & non-selective adrenergic agonists• Describe the main...
Sympathetic “Fight or Flight”
Parasympathetic “Rest & Maintain”                  Rest                  Repair                  Renew
** Acetylcholine & muscarinic receptors for sweat glands Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmac...
Jargonsympathomimetic: drug that activatessympathetic nervous systemparasympathomimetic: drug that activatesparasympatheti...
Drugs that affect Autonomic Nervous             System will affect:•   Heart             •   Eyes•   Blood Vessels     •  ...
Where are the adrenergic receptors?Receptor:      α1            α2          β1           β2           β3localization   blo...
Adrenergic Projections (CNS)                                                               brain stem                     ...
Functional Localization                   Descending Projections                     Ascending Projections                ...
Adrenergic Neurotransmission (CNS)                                                Postsynaptic: α1, α2, β1                ...
Pheochromocytoma       • Tumor of chromaffin cells of adrenal medulla         (4:1 NE to Ep)       • Symptoms             ...
“selective” ≈ 50-100 foldGoodman & Gilman (2011). Pharmacological Basis of Therapeutics. p. 278.
Phenylephrine                                                              Epinephrine   • Mechanism: selective α1 agonist...
Clonidine   • Mechanism: neural pre-synaptic α2 agonist (?)   • Uses: mild hypertension                                   ...
Clonidine   • Mechanism: neural pre-synaptic α2 agonist (?)   • Uses: mild hypertension                                   ...
Clonidine• Mechanism: neural pre-synaptic α2 agonist• Uses: mild hypertension, ADHD• Side-Effects: dry mouth & sedation (↓...
β Adrenergic Agonists   Drug                    Mechanism        Use(s)              Adverse Effects   Isoproterenol1     ...
Comparisonof β Agonists for Asthma
Safety of Long-Acting β-agonists for                      Asthma  • A large trial (N=26,000) found a 4-fold elevation    i...
Meta-Analysis of LABA Asthma Related               Hospitalizations                      ->Odds Ratio = 1 means probabilit...
Long Acting B Agonists FDA Warninghttp://www.pdr.net/drugpages/concisemonograph.aspx?concise=1691
Neuroanatomy of Food Intake                                      1      2 Hypothalamus 1) Lateral: hunger center “gas” 2) ...
Norepinephrine & Food IntakeMeyer & Quezner (2005). Psychopharmacology. p. 135.
α1 & β12 Agonists & Arousal                                                       30 Minute Blocks                        ...
Ephedrine    • Ephedra sinica (má huáng) used in traditional      Chinese medicine    • Contains ephedrine and pseudoephed...
Ephedra & Weight Loss: Example              Randomized Controlled Trial• Overweight (BMI > 25) participants were  randomiz...
History of Methamphetamine• 1893: Synthesized by Nagai Nagayoshi in Japan• 1940s- : Popular with military• 1960s- : used f...
History of Methamphetamine    • 1960s- : used for short-term treatment of obesity, narcolepsy,      and, later, ADHD    • ...
True or False:          “the MMP results in Montana have  been more significant than any other drug      prevention progra...
Positron Emission Tomography of the             Dopamine TransporterPD = Parkinson’s Disease
Montana Meth Project                                 • Businessman Thomas                                   Siebel support...
Similarities & Differences of Exposed &          Unexposed Children                                  Unexposed (N=35)     ...
Behavioral Rating Inventory of Executive             Function (BRIEF)•     Please rate whether the following behaviors are...
“Clinically Significant” Behavioral Problems in Children Exposed              Prenatally to Methamphetamine & Other Drugs*...
Common Sympathomimetic Drugs Drug                  Schedule FDA Approved Acute                  High-Dose                 ...
Top Drug Molecules Dispensed to the Pediatric Population From US Retail                   Pharmacies According to Patient ...
Weight, Growth, & Psychostimulants• statistically but clinically  significant?• height ≈ 0.5 cm/year• weight ≈ 2 kg/year• ...
Cocaine   • Mechanism:       – Central: block DAT, NET & SERT       – Peripheral: αβ agonist   • Schedule II (nasal surger...
Why is cocaine reinforcing?                                                                                          C57 m...
Why is cocaine reinforcing?Meyer & Quenzer (2008). Psychopharmacology. p. 283; Rocha (2003). Eur J Pharmacol, 479, 107-115.
Drug Abuse Warning Network  • Tracks number of time drug is                                                     Boston 201...
Reserpine• component of Rauwolfia serpentina (Indian snakeroot)• mechanism: long-term VMAT inhibitor• effects   – ↓ blood ...
Goodman & Gilman (2011). Pharmacological Basis of Therapeutics. p. 304.
Yohimbine•   Content of African tree bark•   Pre-synaptic α2 antagonist•   Inconsistent bioavailability (5 to 80%)•   Purp...
β Blockers Overview•   End in “olol”•   Contraindications: asthma•   Heart, eyes, kidneys (β1 predominate)•   Lungs, smoot...
Controversy Over PhenylephrineHendeles, L. (2006) Oral phenylephrine: An ineffective replacement for pseudoephedrine?J All...
Terminology Refresher  positive ionotropic action (p. 282): increased strength of ventricular contraction  positive chrono...
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Adrenergic agonists & antagonists

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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.

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Adrenergic agonists & antagonists

  1. 1. Adrenergic Agonists & Antagonists Brian J. Piper, Ph.D., M.S.
  2. 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 David Westfall Tom Westfall
  3. 3. Sympathetic “Fight or Flight”
  4. 4. Parasympathetic “Rest & Maintain” Rest Repair Renew
  5. 5. ** Acetylcholine & muscarinic receptors for sweat glands Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmacology, p. 56.
  6. 6. Jargonsympathomimetic: drug that activatessympathetic nervous systemparasympathomimetic: drug that activatesparasympathetic nervous systemsympatholytic: drug that decreases or blockssympathetic responseparasympatholytic: drug that decreases orblocks parasympathetic responseadrenaline = epinephrine
  7. 7. Drugs that affect Autonomic Nervous System will affect:• Heart • Eyes• Blood Vessels • Pupils• Bowels • Lacrimal Gland• Pancreas • Salivary Glands• Ureters • Lung Airways• Bladder • Brain
  8. 8. Where are the adrenergic receptors?Receptor: α1 α2 β1 β2 β3localization blood pancreas heart lungs adipose vessels tissue vas deferens g.i. tract kidney g.i. tract uterus CNS uterus (non- adipose (pregnant) pregnant) tissue ureter stomach salivary glands
  9. 9. Adrenergic Projections (CNS) brain stem spinal cord cerebellum Brodal (2010). Central Nervous System. p. 377. frontal cortex limbic systemPronunciation: http://www.merriam-webster.com/cgi-bin/audio.pl?locusc03.wav=locus+coeruleushttp://dictionary.reference.com/browse/peduncle?s=t
  10. 10. Functional Localization Descending Projections Ascending Projections β1 α1Stahl, S. (2000). Essential Psychopharmacology, p. 165-167.
  11. 11. Adrenergic Neurotransmission (CNS) Postsynaptic: α1, α2, β1 Presynaptic: α2Stahl, S. (2000). Essential Psychopharmacology, p. 160-161.
  12. 12. Pheochromocytoma • Tumor of chromaffin cells of adrenal medulla (4:1 NE to Ep) • Symptoms – ↑ heart rate – ↑ blood pressure/orthostatic blood pressure – ↑ anxiety cortex medulla – ↓ weight – diaphoresishttp://www.learningradiology.com/archives2011/COW%20441-Pheochromocytoma/pheocorrect.htm
  13. 13. “selective” ≈ 50-100 foldGoodman & Gilman (2011). Pharmacological Basis of Therapeutics. p. 278.
  14. 14. Phenylephrine Epinephrine • Mechanism: selective α1 agonist, vasoconstriction • Uses: – decongestant: substitute for pseudoephedrine but controversy (at 10 mg, oral) over effectiveness1 – postural hypotension: ↑blood pressure without cardiac effects, concern: supine hypertension – detumescent (urologist)1Hendeles, L. (2006) Oral phenylephrine: An ineffective replacement for pseudoephedrine?J Allergy Clin Immunology, 118(1), 279-280.
  15. 15. Clonidine • Mechanism: neural pre-synaptic α2 agonist (?) • Uses: mild hypertension 129SV mouse Wild-type α2A Knock-OutZhou et al. (1999). British Journal of Pharmacology, 126, 1522-1530.
  16. 16. Clonidine • Mechanism: neural pre-synaptic α2 agonist (?) • Uses: mild hypertension 129SV mouse Wild-type α2A Knock-OutZhou et al. (1999). British Journal of Pharmacology, 126, 1522-1530.
  17. 17. Clonidine• Mechanism: neural pre-synaptic α2 agonist• Uses: mild hypertension, ADHD• Side-Effects: dry mouth & sedation (↓), sexual
  18. 18. β Adrenergic Agonists Drug Mechanism Use(s) Adverse Effects Isoproterenol1 β1β2 agonist bradycardia palpitations, headaches, (emergency ) tachycardia, flushing Dobutamine β1 agonist congestive heart ↑ size of myocardial infarct α1 agonist/ failure ↑ risk of arrhythmia α1 antagonist (short-term) Albuterol β2 agonist bronchospasm anxiety, headache, (short-term) dry-mouth Salmeterol β2 agonist bronchospasm upper respiratory tract (long-term) inflammation Formoterol β2 agonist bronchospasm nasopharyngitis, headache1Pronunciation: http://dictionary.reference.com/browse/Isoproterenol?s=tsReferences: G & G; Lippincott’s; pdr.net
  19. 19. Comparisonof β Agonists for Asthma
  20. 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 salmeterol1. • 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)1Salmeterol Multi-center Asthma Research Trial (SMART)
  21. 21. Meta-Analysis of LABA Asthma Related Hospitalizations ->Odds Ratio = 1 means probability of event is equal in both groupsOdds Ratio <> 1 means probability of event differs in each groupOR salmeterol = 1.7, OR formoterol = 3.2; OR children = 3.9, OR adults = 2.0Salpeter et al. (2006). Annals of Internal Medicine, 144, 904-912.
  22. 22. Long Acting B Agonists FDA Warninghttp://www.pdr.net/drugpages/concisemonograph.aspx?concise=1691
  23. 23. Neuroanatomy of Food Intake 1 2 Hypothalamus 1) Lateral: hunger center “gas” 2) Ventro-medial: satiety center “brakes”Meyer & Quezner (2005). Psychopharmacology. p. 135.
  24. 24. Norepinephrine & Food IntakeMeyer & Quezner (2005). Psychopharmacology. p. 135.
  25. 25. α1 & β12 Agonists & Arousal 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.Meyer & Quezner (2005). Psychopharmacology. p. 134; from Berridge et al. (2004). Brain Research Review, 42, 33-84.
  26. 26. Ephedrine • Ephedra sinica (má huáng) used in traditional Chinese medicine • Contains ephedrine and pseudoephedrine • Mixed: α1 α2 β1 β2 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. 27. Ephedra & Weight Loss: Example Randomized Controlled Trial• Overweight (BMI > 25) participants were randomized to placebo or ma 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: – placebo response – drop-outBoozer et al. (2002). International J Obesity, 26, 593-604.
  28. 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. 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 demandStarts slow (3 min): http://montana.methproject.org/Our-Work/brain-and-behavior.php
  30. 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. 31. Positron Emission Tomography of the Dopamine TransporterPD = Parkinson’s Disease
  32. 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. 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 17.1% 76.2*Income currently : >35,000 51.4% 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 2.7 (0.3) 1.3 (0.3)**In homep < *.05, **.01, or ***.005 Piper et al. (2011). Pharmacol Biochem Behav, 98, 432-439.
  34. 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. 35. “Clinically Significant” Behavioral Problems in Children Exposed Prenatally to Methamphetamine & Other Drugs*** p < .0005, ** p < .005, * p < .05 Piper et al. (2011). Pharmacol Biochem Behav, 98, 432-439.
  36. 36. Common Sympathomimetic Drugs Drug Schedule FDA Approved Acute High-Dose For Mechanisms methamphetamine II ADHD Per: αβ agonist ↓DAT (Desoxyn) obesity Cen: DA, NE, 5-HT ↓ SERT amphetamine II ADHD Per: αβ agonist ↓DAT (Adderall) narcolepsy Cen: DA, NE, 5-HT Methylphenidate II ADHD Per: αβ agonist (Ritalin) narcolepsy Cen: DA, NE Cen = central nervous system; Per = peripheral nervous system
  37. 37. Top Drug Molecules Dispensed to the Pediatric Population From US Retail Pharmacies According to Patient Age in 2010Chai et al. (2012). Pediatrics, 131(1), 23-31. Grace Chai, PharmD
  38. 38. Weight, Growth, & Psychostimulants• statistically but clinically significant?• height ≈ 0.5 cm/year• weight ≈ 2 kg/year• tolerance• catch-up?Faraone et al. (2008). Journal of the American Academy of Child & Adolesclent Psychiatry, 47(9), 994-1009.
  39. 39. Cocaine • Mechanism: – Central: block DAT, NET & SERT – Peripheral: αβ agonist • Schedule II (nasal surgery)Erythroxylon coca powder crack
  40. 40. Why is cocaine reinforcing? C57 mouseMeyer & Quenzer (2008). Psychopharmacology. p. 283; Rocha (2003). Eur J Pharmacol, 479, 107-115.
  41. 41. Why is cocaine reinforcing?Meyer & Quenzer (2008). Psychopharmacology. p. 283; Rocha (2003). Eur J Pharmacol, 479, 107-115.
  42. 42. Drug Abuse Warning Network • Tracks number of time drug is Boston 2010 implicated in (urban) ER visits Drug N • poly-substance use alcohol 17,796 cocaine 11,431 heroin 10,493 opiates (oxycontin) 8,525 antidepressants 1,875 stimulants (meth, amph) 739 <- Thalamic hemorrhage in crack smoker (CT)http://www.samhsa.gov/data/DAWN.aspx#DAWN%202010%20ED%20Excel%20Files%20%E2%80%93%20Metro%20Tables
  43. 43. Reserpine• component of Rauwolfia serpentina (Indian snakeroot)• mechanism: long-term VMAT inhibitor• effects – ↓ blood pressure – depression – sedation
  44. 44. Goodman & Gilman (2011). Pharmacological Basis of Therapeutics. p. 304.
  45. 45. Yohimbine• Content of African tree bark• Pre-synaptic α2 antagonist• Inconsistent bioavailability (5 to 80%)• Purported male aphrodisiac (ED)Pausinystalia yohimbe
  46. 46. β Blockers Overview• End in “olol”• Contraindications: asthma• Heart, eyes, kidneys (β1 predominate)• Lungs, smooth muscle, uterine muscle (β2 predominate)O to 4:00 (skip add): http://www.youtube.com/watch?v=h2QR8HxxY1I
  47. 47. Controversy Over PhenylephrineHendeles, L. (2006) Oral phenylephrine: An ineffective replacement for pseudoephedrine?J Allergy Clin Immunology, 118(1), 279-280.
  48. 48. Terminology Refresher positive ionotropic action (p. 282): increased strength of ventricular contraction positive chronotropic action (p. 282): increased rate of heart contraction hyperhidrosis (p. 296): excessive sweatingGeneral Refresher 0 to 31:50: http://www.youtube.com/watch?v=bMnz7dgHztg&feature=related

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