Medical Pharmacology: Autonomic Pharmacology and Asthma

**"Asthma Guidelines 2020"**

Attribution: Bauchner H Cloutier M Lovinsky-Desir S O'Connor G Asthma Guidelines Update 2020 - Diagnosis and Management 12/2020 JAMA Network JAMA Network Youtube Channel: https://www.youtube.com/channel/UC4p6bEngiRCN7TyTxZVJ3OQ

"**Asthma Explained Clearly: Asthma Symptoms and Diagnosis"**

Attribution: Seheult R Asthma Explained Clearly: Asthma Symptoms and Diagnosis MedCram-Medical Lectures Explained CLEARLY 12/2013 https://www.youtube.com/watch?v=6feGnZjxyHo MedCram-Medical Lectures Explained Clearly Youtube Channel: https://www.youtube.com/channel/UCG-iSMVtWbbwDDXgXXypARQ

Between acute exacerbations there may be limited symptoms associated with asthma.

Even pulmonary function tests may be normal.
However, acute exacerbations results in many symptoms including wheezing, cough, and dyspnea.
- In an acute asthma attack, wheezing will probably be most prominent, reflecting turbulent airflow through narrowed airways.
- Although wheezing often becomes more prominent with progressive airway constriction, it is also possible that when obstruction becomes sufficient, wheezing declines as there is insufficient airflow to create sounds.
  - Cough associated with asthma can be nonproductive or associated with significant sputum.
- Even in the absence of infection, sputum may be discolored, yellow, reflecting eosinophilic content and debris.

Obstructive severity, predicts the extent of dyspnea.

With significant airflow obstruction, dyspnea may be very prominent with patients sitting up to ease breathing.
Chest tightness may be associated with asthmatic patients with dyspnea, reflecting symptoms that otherwise would suggest angina.
Severity of expiratory airflow obstruction is reflected in FEV₁ as well as in maximum mid-expiratory flow rate. Spirometric data, as discussed earlier, helps to quantify the extent of pulmonary impairment and provide a baseline against which therapeutic management may be compared.
Compare the two spirograms below:

**Spirometry: Normal [left]; Asthmatic Patient [right]**^60,60a

The figure on the left represents a normal spirographic volume-time relationships a normal spirogram.
The figure on the right represents spirographic volume-time relationships of a patient in bronchospasm.
In the obstructive airway case (right) the FEV₁ is < 80% of the vital capacity.
Peak flow and maximum mid-expiratory flow (FEF_25-75) are also attenuated in the obstructive disease example.^60,60a

In terms of pulmonary function test results for individuals experiencing acute asthma, FEV₁ is often < 35% of normal with a maximum mid-expiratory flow rate of < 20% of normal. Also, flow-volume spirometric loops show what is referred to as an "downward scooping" seen in the expiratory part of the loop.
- Comparative Flow-Volume Loops^60,60a
- Severity of airway obstruction and pulmonary function test parameters⁶⁰
  - Mild (no symptoms): FEV₁ as % of predicted = 65%-80%; FEF_25%-75% as % of predicted = 60%-75%; PaO₂ (estimated, mmHg) = >60; PaCO₂ (estimated, mmHg)= < 40
  - Moderate: FEV₁ as % of predicted = 50%-64%; FEF_25%-75% as % of predicted = 45%-59%; PaO₂ (estimated, mmHg) = >60; PaCO₂ (estimated, mmHg)= < 45
  - Marked: FEV₁ as % of predicted = 35%-49%; FEF_25%-75% as % of predicted = 30%-44%; PaO₂ (estimated, mmHg) = <60; PaCO₂ (estimated, mmHg)= > 50
  - Severe (e.g. status asthmaticus): FEV₁ as % of predicted < 35%; FEF_25%-75% as % of predicted < 30%; PaO₂ (estimated, mmHg) = <60; PaCO₂ (estimated, mmHg)= > 50

Asthma as a group of disorders⁶⁰
1. Allergen-induced
2. Exercise-induced
3. Nocturnal asthma (sleep-induced airway smooth muscle tone changes; reduced circulating catecholamine levels; reduced cough reflex)
4. Aspirin-induced
  - Aspirin along with many nonsteroidal anti-inflammatory drugs can induce bronchospasm in up to 20% of adult asthma patients.
    - Sensitive patients may exhibit airflow obstruction worsening and other symptoms within fifteen minutes to four hours following aspirin doses as little as 10 mg.
    - Aspirin-mediated inhibition of cyclooxygenase-promoted metabolism of arachidonic acid to prostaglandins which has the effect of increasing arachidonic acid conversion to leukotrienes, which are bronchoconstrictive, represents a possible mechanism of aspirin-induced bronchoconstriction.
    - About 5% of asthmatic patients are sensitive to certain food preservatives and antioxidants, some of which are present even in medications used to manage asthma.

Occupational asthma⁶⁰
- Occupational asthma which affects about 5% to 10% of the world population is probably the most common occupational lung disease.
  - About 15% of newly identified asthma cases appear related to occupational exposure (USA).
  - Chlorine and ammonia are probably the most common causes of occupational asthma that do not exhibit significant latency between exposure and effect.
  - By contrast, other occupational agents may be IgE-dependent. Such immune system dependency requires a longer time period before symptoms manifest.
  - In terms of the operating room environment, latex sensitivity may cause an increase in expiratory obstruction in sensitive individuals.
Infectious asthma⁶⁰
- This designation is for asthma (increased airway resistance) caused by acute inflammation due to pathogens, such as viruses, bacteria, or mycoplasma.
  - Bronchoconstriction due to this cause attenuates rapidly as the infection is treated

Pharmacological Interventions⁶⁰
- In recognition of the underlying inflammatory disease which characterizes asthma, administration of inhaled corticosteroids has become an important first-line of therapy in managing inflammatory component.
  - Acute increases in bronchomotor tone are managed often to the use of β₂ adrenergic agonists. Anticholinergic agents, particularly ipratropium are effective in reducing parasympathetic tone which in turn reduces bronchomotor tone.
  - Anti-inflammatory agents (corticosteroids & cromolyn):
    - Corticosteroids which reduce inflammation are used in a prophylactic context in asthma, given that their effects are not immediate. Corticosteroids which appear effective in controlling chronic asthma, reducing the likelihood of an acute attack, is preferably given by inhalation.
      - Oral administration would presumably increased the likelihood of systemic side effects.
        
        The inhaled drug directly promotes an anti-inflammatory effect at the bronchial smooth musclel. Reduction in airway inflammation has the effect of reducing airway hyperreactivity although the period maximum benefit may be obtained only after the treatment has been in place for several months. Agents which are available for administration by inhalation include beclomethasone, triamcinolone, flunisolide, fluticasone, and budesonide
      - Pharmacokinetics: Most of an inhaled corticosteroids dose is swallowed (80%-90%). This drug and will be available systemically eventually passing to the liver. This leaves about 10% to 20% of the drug available for action at the bronchial level. This drug still has access to the systemic circulation, but drug's lipophilic character favors entry into the airway cells, their principal site of action, where the steroids can inhibit gene transcription for cytokines that promote airway inflammation.
      - Side-Effects:
        
        Local and systemic side effects occur following corticosteroids inhalation.
        
        Local effects include: hoarseness (dysphonia), pharyngitis, glossitis, oropharyngeal candidiasis.
        
        Laryngeal muscle myopathy may cause dysphonia, which will be reversed following cessation of treatment.
        
        Infection incidence is not increased by inhaled corticosteroids.
        
        Systemic side effects are determined by the amount of systemic absorption.
        
        Although corticosteroids may suppress the hypothalamic-pituitary- adrenal axis, inhaled corticosteroids amounts used in asthma management are not likely to have significant effect on pituitary-adrenal function. The inhaled corticosteroids do not appear to exert metabolic effects, alter bone metabolism, or interfere with growth.
        
        Furthermore, parturients may be safely administered inhaled corticosteroids.
    - Cromolyn:
      - The classification of cromolyn as an anti-inflammatory agent is based on its apparent ability to inhibit chemical mediator release from mast cells, thus inhibiting inflammation. This agent is inhaled and is effective prophylaxsis, when used, for example, prior to expected exposure to a provocative activity or substance. For example, it should be used prior to exercise in patients known to have exercise-induced bronchospasm.
    - Leukotriene Inhibors: These agents are discussed in another section.
Beta adrenergic agonists⁶⁰
- As discussed earlier these agents bind to β₂ adrenergic receptors and activate them.
  - Activation of the second messenger system results in an increase in cAMP production and ultimately in relaxation of smooth muscle.
    - These agents are helpful in management of acute bronchospasm with albuterol perhaps being the most commonly used agent.
  - Albuterol is administered by metered-dose inhaler, using 2-3 deep inhalations, separated by 1-5 minutes.
    - This dosage may be repeated every 4-6 hours. Side effects are minimized by this route of administration; however, some systemic effects occur and are understood in terms of β adrenergic receptor stimulation. Side effects include cardiac arrhythmias, including tachycardia, as well as potassium intracellular shifting.

Interaction of Sympathomimetic Drugs with Some Agents Used in Anesthesia⁶¹
β- adrenergic agonists used in management of asthma, drugs that include terbutaline, aminophylline, and theophylline. Sympathomimetic agents can interact with volatile anesthetics.⁶¹ A consequence of this interaction may be induction of cardiac arrhythmias. Halothane is one example of a volatile anesthetic that sensitizes the heart to exogenous catecholamines. In this context, sensitization means that a reduced amount of epinephrine (IV) would be required to induce a premature ventricular contraction (PVC) in the presence of halothane compared to that in a normal, unanesthetized individual. If halothane is used, a dosage of 0.15 ml/kg of a 1:100000 epinephrine solution over a 10 minute. (Not to exceed 0.45 ml/kg of a 1:100000) is thought to be safe. Furthermore, lidocaine given in combination with epinephrine provides additional safety margin. Enflurane and isoflurane appear to cause less myocardial sensitization compared to halothane. Halothane is a potent bronchodilator and accordingly may be the best choice for anesthetizing asthmatic patients. However, if the asthmatic patient is already taking exogenous catecholamines or xanthines, halothane might not be most appropriate. The mechanism of action by which xanthines promote bronchodilation appear to include xanthine-mediated endogenous norepinephrine release as well as possible inhibition of phosphodiesterase, which breaks down cAMP. This latter mechanism may be questionable because of the high concentrations required for xanthine-mediated phosphodiesterase inhibition.⁶¹ However perhaps 40% of aminophylline's positive inotropic effect may be due to promotion of endogenous norepinephrine release. Plasma theophylline concentrations of 5 mg/L is required to decrease the high airway resistance; furthermore, if levels exceed 20 mg/L, toxicity may occur.⁶¹ Theophylline is metabolized by the liver, exhibiting a half-life of about four h in adults with a clearance of 1.2 ml/min./kg. [Aminophylline is composed of 85% theophylline and 15% ethylenediamine]. Because of toxicity concerns, factors that reduce clearance become important. Such factors include liver disease or pulmonary edema which can reduce theophylline clearance by 50% (liver) and 33% (pulmonary edema). In the laboratory setting, aminophylline and halothane interaction has been documented. The administration of 1% halothane with high dose, bolus aminophylline resulted in a significant number of ventricular arrhythmias in dogs (12/16) with 8/16 exhibiting ventricular tachycardia fibrillation. Based on this analysis, it would appear reasonable to wait three drug half-lives following the last aminophylline dose prior to administering anesthesia to an asthmatic patient. An alternative to halothane for those patients who require aminophylline or other sympathomimetic agents might be the substitution of halothane by enflurane or isoflurane which either of which is less likely to sensitize myocardium to catecholamines.

Anticholinergic agents⁶⁰

Individuals exhibit varying degrees of parasympathetic bronchiolar tone, which is bronchoconstrictive in effect.

Accordingly, the effects of antimuscarinic agents will be proportional to the degree of underlying parasympathetic tone.

Metered-dose inhalation of ipratropium is effective in reducing parasympathetic-mediated bronchiolar smooth muscle tone.

Ipratropium is effective in management of bronchoconstriction in COPD patients; moreover it is helpful in management of asthma although the magnitude of the effect would be typically less than that observed with beta 2 adrenergic agonists.

Significant bronchodilator effect caused by ipratropium would usually be observed within 15-30 minutes of administration and the effect may persist at some level for 4-6 hours.

Ipratropium possesses a quaternary nitrogen and is therefore permanently positively charged.

This condition of permanent positive charge explains the relatively limited systemic effects as a result of poor adsorption

Ipratropium Bromide (Atrovent)

Management of status asthmaticus⁶⁰
- Definition: Status asthmaticus is a bronchospastic state that does not resolve during the initial, standard treatment, and bronchospasm is sufficiently severe such that a condition could be life-threatening.
- In the emergence setting, effective treatment typically involves administration of β₂receptor agonist by inhaler. For patients under 45 years of age, β₂ agonist dosage may be repeated every 15-20 minutes up to 3-4 repetitions prior to significant systemic effects (hemodynamic). Concurrently, corticosteroids would be administered by IV.
  - Regimens for corticosteroid administration include either:
    - (a) cortisol 2mg/kg IV to be followed by 0.5 mg/kg/hour or
    - (b) methylprednisolone at 60-125 mg IV every 6 hours.
  - Administration of supplemental oxygen may be required to ensure arterial oxygen saturation > 95%.
    - Cortisol (left); Methylprednisolone (Right)

References
Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.199-242 Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p. 260 Carotic Baroreceptors: CRRx: Mediine ReEnvisioned http://www.cvrx.com/patients/index.php?id=41 Westfall, TC and Westfall DP Adrenergic Agonists and Antagonists in Goodman and Gilman's The Pharmacological Basis of Therapeutics, eleventh editions, (Brunton LL, Lazo JS and Parker KL, eds), McGraw-Hill Medical Publishing Division, New York, 237-295, 2006. Catecholamine Biosynthesis: The Interactive Library; Edinformatics.com: http://www.edinformatics.com/interactive_molecules/info/adrenaline.htm . Standaert DG and Young AB Treatment of Central Nervous System Degenerative Disorders In Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp536-537. Adrenergic Neuronal Diagram adapted from http://www.drugabuse.gov/pubs/teaching/Teaching4/Teaching.html Guanetidine (Ismelin™, brand name not available in the U.S.) pharmacology: Clinical Pharmacology, RxList: The Internet Drug Index, http://www.rxlist.com/ismelin-drug.htm . Williams FM and Turner TJ Adrenergic Pharmacology in Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition (Golan DE, Tashijan Jr AH, Armstrong EJ and Armstrong AW, eds) Wolters Kluwer-Lippincott Williams & Wilkins, Philadelphia, 129-144, 2008. Moss J and Glick D Autonomic Function in Anesthetic Pharmacology: Physiological Principles and Clinical Practice: A Companion to Miller's Anesthesia (Evers AS and Maze M, eds) Churchill Livingstone, Philadelphia, Chapter 14, 209-226, 2004. Presynaptic Proteins, Synaptic Vesicle Docking and Membrane Fusion, http://neuromuscular.wustl.edu/pathol/snare.htm#cachan, Neuromuscular Disease Center, Washington University, St. Louis, MO USA (http://neuromuscular.wustl.edu/index.html) Sudhof TC The Synaptic Vesicle Cycle, Annual Review of Neuroscience, July 200, Vol. 27, pp 509-547. Phenochomocytoma picture (http://health-pictures.com/pheochromocytoma.htm); Geneva Foundation of Medical Education and Research, Pheochromocytoma, http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=1&cat2=113&cat3=22&cat4=2&stype=n . Brown H, Goldberg PA, Selter JG, Cabin HS, Marieb NJ, Udelsman R and Setaro JF Hemorrhagic Pheochromocytoma Associated with Systemic Corticosteroid Therapy and Presenting as Myocardial Infarction with Severe Hypertension. Clinical Case Seminar, J Clin Endocrinol Metab 2005 90: 563-569. (http://jcem.endojournals.org/cgi/content/full/90/1/563). "Clevidine (Cleviprex) for IV Treatment of Severe Hypertension", Table 1. Some Parenteral Drugs for Hypertensive Emergencies. The Medical Letter^® on Drugs and Therapeutics, Volume 50 (Issue 1295) September 22, 2008. Katzung, BG Introduction to Autonomic Pharmacology (Section II: Autonomic Drugs) in: Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 75-92, 2007. Sympathetic Nerve Pathway: Neuroeffector Junction ("Simplified diagram of a sympathetic neuroeffector junction displaying genes which may be involved"); PharmGKb modified slightly to highlight uptake1, uptake-2, uptake 1 block, and location of intravesicular norephinephrine synthesis. (Pharmacogenomics Knowledge Base). http://www.pharmgkb.org/search/pathway/neurotransmitter/neuroeffector.jsp . T.E. Klein, J.T. Chang, M.K. Cho, K.L. Easton, R. Fergerson, M. Hewett, Z. Lin, Y. Liu, S. Liu, D.E. Oliver, D.L. Rubin, F. Shafa, J.M. Stuart and R.B. Altman, "Integrating Genotype and Phenotype Information: An Overview of the PharmGKB Project" (220k PDF), The Pharmacogenomics Journal (2001) 1, 167-170. Tellioglu T, Robertson D (November 2001). "Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications". Expert Rev Mol Med 2001: 1–10. Kekuda R, Prasad PD, Wu X, Wang H, Fei YJ, Leibach FH, Ganapathy V (Aug 1998). "Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta". J Biol Chem 273 (26): 15971–9. Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S. (Jun 2006). "Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain.". Neuropharmacology 50 (8): 941–952. Bourne HR and von Zastrow M "Drug Receptors and Pharmacodyamics" Chapter 2 in Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 17-27, 2007. Muller M Lecture Material Online: Lecture 6: "Cellular Communication" http://www.uic.edu/classes/bios/bios100/summer2003/lect06.htm. Bowman T and Jove R STAT Proteins and Cancer: From the Molecular Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida http://www.moffitt.org/moffittapps/ccj/v6n6/dept6h.htm . Tong L, Warren TC, King J, Betageri R, Rose J, Jakes S (March 1996). "Crystal structures of the human p56lck SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 A and 1.8 A resolution". J. Mol. Biol. 256 (3): 601–10. Sadowski I, Stone JC, Pawson T (December 1986). "A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps". Mol. Cell. Biol. 6 (12): 4396–4408. Russell RB, Breed J, Barton GJ (June 1992). "Conservation analysis and structure prediction of the SH2 family of phosphotyrosine binding domains". FEBS Lett. 304 (1): 15–20. von Zastrow M and Bourne HR "Drug Receptors and Pharmacodynamics" Chapter 2 in Basic and Clinical Pharmacology (11th edition), (Katzung BG, Masters, SB and Trevor AJ, eds) McGraw-Hill Medical , New York, on-line version (Access Medicine) 2009. Powledge TM (2004) Nicotine as Therapy. PLoS Biol 2(11): e404. doi:10.1371/journal.pbio.0020404 (http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020404) Green T, Heinemann SF and Gusella JF Molecular Neurobiology and Genetics: Investigation of Neuron Function and Dysfunction (Review) Neuron, Vol. 20, 427-444, March, 1998 (Cell Press (c), 1998). Unwin N Nicotinic acetylcholine receptor at 9 Å resolution. J. Mol. Biol. 229, 1101-1124. Eyford, T Adenylyl cyclase http://proteopedia.org/wiki/index.php/Adenylyl_cyclase . 31 a. Hurley JH. Structure, mechanism, and regulation of mammalian adenylyl cyclase. J Biol Chem. 1999 Mar 19;274(12):7599-602. 31 b, Zhang G, Liu Y, Ruoho AE, Hurley JH. Structure of the adenylyl cyclase catalytic core. Nature. 1997 Mar 20;386(6622):247-53. Goodsell DS illustrator, The Scrips Research Institute, public domain work, http://en.wikipedia.org/wiki/Adenylate_cyclase . Ranganathan R, Ross E (1997). "PDZ domain proteins: scaffolds for signaling complexes.". Curr Biol 7 (12): R770–3 PDZ domain http://en.wikipedia.org/wiki/PDZ_domain Biaggioni I and Robertson D Adrenoceptor Agonists & Sympathomimetic Drugs (Chapter 9) in in Basic and Clinical Pharmacology (11th edition), (Katzung BG, Masters, SB and Trevor AJ, eds) McGraw-Hill Medical , New York, on-line version (Access Medicine) 2009. Korte E "PIP2 cleavage by PLC to release IP3 and DAG", public domain, http://en.wikipedia.org/wiki/File:PIP2_cleavage_to_IP3_and_DAG.jpg . McVary KT A review of combination therapy in patients with benign prostatic hyperplasia, Clinical Therapeutics 2007 29 (3): 387-398. Caine M The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J Urol. 1986; 136: 1-4. Shapiro E Hartanto V and Lepor H. The response to alpha blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle. Prostate. 1992; 21: 297-307. Brittsan AG and Kranias EG Review: Phosphlakmban and Cardiac Contractile Function. J. Mol Cell Cardiol 32. 2131-2139. Lomize A Phospholamban Pentamer, protein image from OPM database, public domain media (http://en.wikipedia.org/wiki/File:1zll_opm.gif) Foex P and Highan H. Myocardial Performance: Physiological Principles and Clinical Practice: A Companion to Miller's Anesthesia (Evers AS and Maze M, eds) Churchill Livingstone, Philadelphia, Chapter 14, 284-2285, 2004. 42(a) Weiss HR Effect of coronary artery occlusion on regional arterial and venous O2 saturation, O2 extraction, blood flow and O2 consumption in the dog heart. Circulation Research 47(3) 400-407, September 1980. Khouri EM Gregg DE and Rayford CR Effect of exercise on cardiac output, left coronary flow and myocardial metabolism in the unanesthetized dog. Circulation Research 17(5) 327-437, November 1965. Epicardial Vessels: Gray's Anatomy, 20th U.S. edition of Gray's Anatomy of the Human Body, originally publishedin 1918, public domain. Beta-2 Adrenergic Receptor, figure public domain (http://en.wikipedia.org/wiki/File:2RH1.png); original crystallographic citations: 45 (a) Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007). "High-resolution crystal structure of an engineered human β₂-adrenergic G protein-coupled receptor". Science 318 (5854): 1258–65. 45 (b) Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007). "GPCR engineering yields high-resolution structural insights into β₂-adrenergic receptor function". Science 318 (5854): 1266–73. Westfall, TC and Westfall DP Neurotransmission: The Autonomic and Somatic Motor Nervous System in Goodman and Gilman's The Pharmacological Basis of Therapeutics, eleventh editions, (Brunton LL, Lazo JS and Parker KL, eds), McGraw-Hill Medical Publishing Division, New York, 137-181, 2006. Emorine LJ Marullo S Briend-Sutren MM Patey G Tate K Delavier-Klutchko C Strosberg AD Molecular characterization of the human β₃-adrenergic receptor. Science, Vol. 245, No. 4922, Sep. 8, 1989, pp. 1118-1121. Walston J Silver K Bogardus C Knowler W Celi FS Austin S Manning B Strosberg AD Stern MP Raben N Sorkin JD Roth J Shuldiner AR Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the β₃-adrenergic receptor gene. New England J. of Medicine, Vol. 333 No. 6, August 10, 1995, pp. 343-347. Hoffman BB Adrenoceptor-Activating & Other Sympathomimetic Drugs in: Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 121-140, 2007. Goodsell, DS, Tyrosine Hydroxylase, The Scripps Research Institute, public domain image, http://en.wikipedia.org/wiki/File:Tyrosine_Hydroxylase.png . Chemical Synapse, http://schools-wikipedia.org/wp/c/Chemical_synapse.htm . Frang H Cockcroft V Karskela T Scheinin M Marjamaki A Phenoxybenzamine binding reveals the helical orientation of the third transmembrane domain of adrenergic receptors JBC, 276, 31279-31284, June 6, 2001. http://www.jbc.org/content/276/33/31279.full Barrett KE Barman SM Boitano S Brooks H "The Adrenal Medulla & Adrenal Cortex" in: Ganong's Review of Medical Physiology, 23e, Chapter 22, on-line version, 2010. Achermann JC and Jameson JL "Disorders of Sex Development" in Harrison's Principles of Internal Medicine (eds, Fauci AS Braunwald E Kasper DL Hauser SL Longo DL Jameson JL Loscalzo J), 17th edition, pp 2345-2346, 2008, McGraw-Hill Medical, New York. Goldenberg M Aranow H Jr Smith AA Faber M Pheochromocytoma and essential hypertensive vascular disease. Arch. Intern. Med. 86: 823-826, 1950. Carrim YO "The Cardiovascular system, heart muscle; The heart as a pump." http://samedical.blogspot.com/2010/08/heart-muscle-heart-as-pump.html . "Madhero88" "A graphical representation of the electrical conduction system of the heart showing the sinoatrial node, atrioventricular none, bundle of His, Purkinje fibers and Bachmann's bundle, http://en.wikipedia.org/wiki/File:ConductionsystemoftheheartwithouttheHeart.png . Ewy GA Cardiopulmonary and Cardiocerebral Resuscitation, Chapter 50, in Hurst's The Heart, 12th edition (eds, Fuster V O'Rourke RA Wash RA Poole-Wilson P; associate eds: King II SB Roberts R Nash IS Prystowsky EN; Editors of the online edition: senior editors: Walsh RA and Simon DI; associate Editors; Hoit BD Fang JC Costa M), 2008, on-line edition. 58a. American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation, 2005; 112 (Suppl IV): IV-1-IV-211. Mohrman DE and Heller LJ "Vascular Control" Chapter 7, in Cardiovascular Physiology, 6th edition, The McGraw-Hill Companies, Inc, 2006, on-line edition. Stoelting, RK and Dierdorf, SF, "Asthma" in Anesthesia and Co-Existing Disease, 4th edition, Chapter 14, pp 194-204, Churchill-Livingstone, Philadelphia, 2002 60a. Kingston, HGG, Hirshman, CA Perioperative management of the patient with asthma. Anesth Analg 1984; 63: 844-55. (second sourced from reference 1) Roisen, MF, "Anesthetic Implications of Concurrent Diseases" in Anesthesia, 5th edition, (Miller, R.D, editor), Chapter 25, pp 996-997, Churchill-Livingstone, Philadephia 2000