Adrenergic agonists & antagonists

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

Tom WestfallDavid Westfall

Sympathetic “Fight or Flight”

Parasympathetic “Rest & Maintain”

RestRepairRenew

*

* Acetylcholine & muscarinic receptors for sweat glands

Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmacology, p. 56.

Jargon

sympathomimetic: drug that activates sympathetic nervous systemparasympathomimetic: drug that activates parasympathetic nervous systemsympatholytic: drug that decreases or blocks sympathetic responseparasympatholytic: drug that decreases or blocks parasympathetic responseadrenaline = epinephrine

Drugs that affect Autonomic Nervous System will affect:

• Heart• Blood Vessels• Bowels• Pancreas• Ureters• Bladder

• Eyes• Pupils• Lacrimal Gland• Salivary Glands• Lung Airways• Brain

Where are the adrenergic receptors?

Receptor: α1 α2 β1 β2 β3

localization blood vessels

pancreas heart lungs adiposetissue

vas deferens g.i. tract kidney g.i. tract

uterus (pregnant)

CNS uterus (non-pregnant)

adipose tissue

ureter stomach salivary glands

Adrenergic Projections (CNS)

Pronunciation: http://www.merriam-webster.com/cgi-bin/audio.pl?locusc03.wav=locus+coeruleushttp://dictionary.reference.com/browse/peduncle?s=t

brain stemspinal cordcerebellumfrontal cortexlimbic system

Brodal (2010). Central Nervous System. p. 377.

Functional Localization

Descending Projections Ascending Projections

β1

α1

Stahl, S. (2000). Essential Psychopharmacology, p. 165-167.

Adrenergic Neurotransmission (CNS)

Postsynaptic: α1, α2, β1Presynaptic: α2

Stahl, S. (2000). Essential Psychopharmacology, p. 160-161.

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

“selective” ≈ 50-100 fold

Goodman & Gilman (2011). Pharmacological Basis of Therapeutics. p. 278.

Phenylephrine• 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.

Epinephrine

Clonidine• Mechanism: neural pre-synaptic α2 agonist (?) • Uses: mild hypertension

Zhou et al. (1999). British Journal of Pharmacology, 126, 1522-1530.

129SV mouse

Wild-type α2A Knock-Out

Clonidine• Mechanism: neural pre-synaptic α2 agonist (?) • Uses: mild hypertension

Zhou et al. (1999). British Journal of Pharmacology, 126, 1522-1530.

129SV mouse

Wild-type α2A Knock-Out

Clonidine• Mechanism: neural pre-synaptic α2 agonist• Uses: mild hypertension, ADHD• Side-Effects: dry mouth & sedation (↓), sexual

β Adrenergic AgonistsDrug Mechanism Use(s) Adverse Effects

Isoproterenol1 β1β2 agonist bradycardia (emergency )

palpitations, headaches, tachycardia, flushing

Dobutamine β1 agonistα1 agonist/α1 antagonist

congestive heart failure (short-term)

↑ size of myocardial infarct↑ risk of arrhythmia

Albuterol β2 agonist bronchospasm(short-term)

anxiety, headache, dry-mouth

Salmeterol β2 agonist bronchospasm(long-term)

upper respiratory tract inflammation

Formoterol β2 agonist bronchospasm nasopharyngitis, headache

1Pronunciation: http://dictionary.reference.com/browse/Isoproterenol?s=ts

References: G & G; Lippincott’s; pdr.net

Comparison of β Agonists for Asthma

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 = 2.0

Salpeter et al. (2006). Annals of Internal Medicine, 144, 904-912.

->

Long Acting B Agonists FDA Warning

http://www.pdr.net/drugpages/concisemonograph.aspx?concise=1691

Neuroanatomy of Food Intake

Meyer & Quezner (2005). Psychopharmacology. p. 135.

Hypothalamus1) Lateral: hunger center “gas”2) Ventro-medial: satiety center “brakes”

1 2

Norepinephrine & Food Intake

Meyer & Quezner (2005). Psychopharmacology. p. 135.

α1 & β12 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.

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-out

Boozer 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 demand

Starts 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 Transporter

PD = 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 : <15,000Income 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 childrenIn home

2.7 (0.3) 1.3 (0.3)**

Piper et al. (2011). Pharmacol Biochem Behav, 98, 432-439.

p < *.05, **.01, or ***.005

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.

*** 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.

Common Sympathomimetic Drugs

Drug Schedule FDA ApprovedFor

AcuteMechanisms

High-Dose

methamphetamine(Desoxyn)

II ADHDobesity

Per: αβ agonistCen: DA, NE, 5-HT

↓DAT↓ SERT

amphetamine(Adderall)

II ADHDnarcolepsy

Per: αβ agonistCen: DA, NE, 5-HT

↓DAT

Methylphenidate(Ritalin)

II ADHDnarcolepsy

Per: αβ agonistCen: 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 2010

Chai 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?

Meyer & Quenzer (2008). Psychopharmacology. p. 283; Rocha (2003). Eur J Pharmacol, 479, 107-115.

C57 mouse

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

implicated in (urban) ER visits• poly-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)

Reserpine

• component of Rauwolfia serpentina (Indian snakeroot)• mechanism: long-term VMAT inhibitor• effects– ↓ blood pressure– depression– sedation

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

Yohimbine

• Content of African tree bark• Pre-synaptic α2 antagonist• Inconsistent bioavailability (5 to 80%)• Purported male aphrodisiac (ED)

Pausinystalia yohimbe

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

Controversy Over Phenylephrine

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

Terminology Refresherpositive ionotropic action (p. 282): increased strength of ventricular contractionpositive chronotropic action (p. 282): increased rate of heart contractionhyperhidrosis (p. 296): excessive sweating

General Refresher 0 to 31:50: http://www.youtube.com/watch?v=bMnz7dgHztg&feature=related