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.
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 uses and adverse effects of adrenergic antagonists David Westfall Tom Westfall
** Acetylcholine & muscarinic receptors for sweat glands Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmacology, p. 56.
Jargonsympathomimetic: drug that activatessympathetic nervous systemparasympathomimetic: drug that activatesparasympathetic nervous systemsympatholytic: drug that decreases or blockssympathetic responseparasympatholytic: drug that decreases orblocks parasympathetic responseadrenaline = epinephrine
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)
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.
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) Ventro-medial: satiety center “brakes”Meyer & Quezner (2005). Psychopharmacology. p. 135.
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.
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.
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.
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
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
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.
Positron Emission Tomography of the Dopamine TransporterPD = Parkinson’s Disease
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
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.
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.
“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.
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
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
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.
Cocaine • Mechanism: – Central: block DAT, NET & SERT – Peripheral: αβ agonist • Schedule II (nasal surgery)Erythroxylon coca powder crack
Why is cocaine reinforcing? C57 mouseMeyer & Quenzer (2008). Psychopharmacology. p. 283; Rocha (2003). Eur J Pharmacol, 479, 107-115.
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 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