Pharmacology_Katzung

Pharmacology_Katzung. Bronchodilators, such as inhaled albuterol, are rapidly effective, safe, and inexpensive. Patients with only occasional symptoms of asthma require no more than an inhaled bronchodilator taken on an as-needed basis. If symptoms require this “rescue” therapy more than twice a week, if nocturnal symptoms occur more than twice a month, or if the FEV1 is less than 80% of predicted, additional treatment is needed. The treatment first recommended is a low dose of an ICS, although a leukotriene receptor antagonist may be used as an alternative.


Pharmacology_Katzung

Pharmacology_Katzung. An important caveat for patients with mild asthma is that although the risk of a severe, life-threatening attack is low, it is not zero. All patients with asthma should be instructed in a simple action plan for severe, frightening attacks: to take up to four puffs of albuterol every 20 minutes over 1 hour. If no improvement is noted after the first four puffs, additional treatments should be taken while on the way to an emergency department or other higher level of care.


Pharmacology_Katzung

Pharmacology_Katzung. Inhaled muscarinic antagonists have so far earned a limited place in the treatment of asthma. The effects of short-acting agents (eg, ipratropium bromide) on baseline airway resistance are nearly as great as, but no greater than, those of the sympathomimetic drugs, so they are used largely as alternative therapies for patients intolerant of β-adrenoceptor agonists. The airway effects of antimuscarinic and sympathomimetic drugs given in full doses have been shown to be additive only in reducing hospitalization rates in patients with severe airflow obstruction who present for emergency care.


Pharmacology_Katzung

Pharmacology_Katzung. The long-acting antimuscarinic agents tiotropium and aclidinium have not yet earned a place in the treatment for asthma, although the addition of tiotropium to an ICS has been shown to be as effective as the addition of an LABA. As a treatment for COPD, these agents improve functional capacity, presumably through their action as bronchodilators, and reduce the frequency of exacerbations through currently unknown mechanisms. If asthmatic symptoms occur frequently, or if significant airflow obstruction persists despite bronchodilator therapy, inhaled corticosteroids should be started. For patients with severe symptoms or severe airflow obstruction (eg, FEV1 < 50% of predicted), initial treatment with a high dose of an ICS in combination with an LABA is appropriate. Once clinical improvement is noted, usually after 4–6 weeks, the dose of treatment should be stepped down to no more than is necessary to control symptoms and maintain pulmonary function.


Pharmacology_Katzung

Pharmacology_Katzung. An issue for ICS treatment is patient adherence. Analysis of prescription renewals shows that only a minority of patients take corticosteroids regularly. This may be a function of a general “steroid phobia” fostered by emphasis in the lay press on the hazards of long-term oral corticosteroid therapy and by ignorance of the difference between glucocorticoids and anabolic steroids, taken to enhance muscle strength by now-infamous athletes. This fear of corticosteroid toxicity makes it hard to persuade patients whose symptoms have improved after starting treatment that they should continue it for protection against attacks. This context accounts for the interest in reports that instructing patients with mild but persistent asthma to take ICS therapy only when their symptoms worsen is nearly as effective in maintaining pulmonary function and preventing attacks as is taking the ICS twice each day.


Pharmacology_Katzung

Pharmacology_Katzung. Two options for asthma inadequately controlled by a standard dose of an ICS are to (1) double the dose of ICS or (2) combine it with another drug. The addition of theophylline or a leukotriene receptor antagonist modestly increases asthma control, but the most impressive benefits are afforded by addition of a long-acting inhaled β2-receptor agonist (LABA, eg, salmeterol or formoterol). Many studies have shown this combination to be more effective than doubling the dose of the ICS. Combinations of an ICS and an LABA in a single inhaler are now available in fixed-dose preparations (eg, fluticasone and salmeterol [Advair]; budesonide and formoterol [Symbicort]; mometasone and formoterol [Dulera]; fluticasone and vilanterol [Breo]). The rapid onset of action of formoterol enables novel use of its combination with a low dose of budesonide. The combination of 80 mcg of budesonide plus 12.5 mcg of formoterol taken twice daily and additionally for relief of symptoms (ie, taken as both a


Pharmacology_Katzung

Pharmacology_Katzung. of its combination with a low dose of budesonide. The combination of 80 mcg of budesonide plus 12.5 mcg of formoterol taken twice daily and additionally for relief of symptoms (ie, taken as both a “controller” and a “reliever”) is as effective an inhalation of a four-times-higher dose of budesonide with albuterol alone taken for relief of symptoms. Use of this flexible dosing strategy is widespread in Europe but is not approved in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Until recently, a shadow hung over the use of combination ICS-LABA therapy for moderate and severe asthma, generated by evidence of a statistically significant increase in the very low risk of fatal or near-fatal asthma attacks from use of an LABA even when taken in combination with an ICS. This evidence prompted the FDA to require the addition of a “black box” warning to the package insert issued with each ICS-LABA inhaler. The major message of the warning is that a possible increase in risk of a severe rare event, including asthma fatality, from the use of an LABA should be discussed with the patient in presenting options for treatment.


Pharmacology_Katzung

Pharmacology_Katzung. The concerns underlying the “black box” warning have been assuaged by two large, placebo-controlled, double-blind FDA-mandated trials showing no significant increase in severe asthma exacerbations or asthma fatalities from the addition of an LABA to ICS treatment in patients with moderate to severe asthma. Despite these reassuring findings, patients prescribed combination treatment should also be provided with explicit instructions to continue use of a rapid-acting inhaled β agonist, such as albuterol, for relief of acute symptoms and, as for all patients with asthma, to follow an explicit action plan for severe attacks.


Pharmacology_Katzung

Pharmacology_Katzung. A leukotriene pathway antagonist taken as an oral tablet is an alternative to ICS treatment in patients with symptoms occurring more than twice a week or those who are awakened from sleep by asthma more than twice a month. This place in asthma therapy was once held by cromolyn and nedocromil, but neither is now available for asthma in the USA. Although these treatments are not as effective as a low dose of an ICS, both avoid the issue of “steroid phobia” described above and are commonly used in the treatment of children. The leukotriene receptor antagonist montelukast is the most widely prescribed of these treatments, especially by primary care providers. This drug, taken orally, is easy to administer and is rarely associated with troublesome adverse effects. This maintenance therapy is widely used for treating children in the USA, particularly those who have concurrent symptomatic allergic rhinitis, which is also effectively treated by montelukast.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment with omalizumab, the monoclonal humanized anti-IgE antibody, and with any of the monoclonal anti-IL-5 antibodies is reserved for patients with chronic severe asthma inadequately controlled by ICS/LABA treatment. Omalizumab reduces lymphocytic, eosinophilic bronchial inflammation, oral and inhaled corticosteroid dose requirements, and the frequency and severity of exacerbations. It is reserved for patients with demonstrated IgEmediated sensitivity (by positive skin test or radioallergosorbent test [RAST] to common allergens) and an IgE level within a range that can be reduced sufficiently by twice-weekly subcutaneous injection. Other options for treatment of severe asthma uncontrolled by ICS/ LABA therapy, especially if associated with peripheral eosinophilia, are the monoclonal antibodies reviewed earlier—mepolizumab, reslizumab, and benralizumab.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to their high cost, several factors have limited the use of targeted therapies. First, they must be given parenterally at 2to 4-week intervals. Second, some can cause anaphylactic reactions or other hypersensitivity reactions, albeit in a small percentage (<0.5%) of patients, so they cannot be self-administered but must be monitored for a period of time after the injection in a setting equipped to manage anaphylaxis. In addition, a small number of patients receiving mepolizumab developed herpes zoster infection, and administration of the varicella-zoster vaccine to adults age 50 or older 4 weeks prior to initiation with mepolizumab is recommended.


Pharmacology_Katzung

Pharmacology_Katzung. For the 5–10% of the asthmatic population with severe asthma inadequately controlled by standard therapies, the development of an alternative treatment is an important unmet medical need. This is particularly important for patients with “T2-low” asthma, who are less likely to respond to corticosteroids and for whom targeted therapies against IgE or IL-5 are unlikely to be of benefit. The initial promise of oral methotrexate or gold salt injections has not been fulfilled. While the benefit from treatment with cyclosporine seems real, this drug’s toxicity makes this finding only a source of hope that other immunomodulatory therapies will ultimately emerge. Advances in understanding the immunopathogenesis of asthma may permit the identification of specific phenotypes of asthma and identification of biomarkers of their importance in particular patients. In this respect, asthma may benefit from the rapid advances in treatments developed for other chronic inflammatory conditions such as


Pharmacology_Katzung

Pharmacology_Katzung. of biomarkers of their importance in particular patients. In this respect, asthma may benefit from the rapid advances in treatments developed for other chronic inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease.


Pharmacology_Katzung

Pharmacology_Katzung. The treatment of acute attacks of asthma in patients reporting to the hospital requires close, continuous clinical assessment and repeated objective measurement of lung function. For patients with mild attacks, inhalation of a β-receptor agonist is as effective as subcutaneous injection of epinephrine. Severe attacks require treatment with oxygen, frequent or continuous administration of aerosolized albuterol, and systemic treatment with prednisone or methylprednisolone (0.5 mg/kg every 6–12 hours). Even this aggressive treatment is not invariably effective, and patients must be watched closely for signs of deterioration. General anesthesia, intubation, and mechanical ventilation of asthmatic patients cannot be undertaken lightly but may be lifesaving if respiratory failure supervenes.


Pharmacology_Katzung

Pharmacology_Katzung. The high prevalence of asthma in the developed world and its rapid increases in the developing world call for a strategy for primary prevention. Strict antigen avoidance during infancy, once thought to be sensible, has now been shown to be ineffective. In fact, growing up from birth on a farm with domestic animals or in a household where cats or dogs are kept as pets appears to protect against developing asthma. The best hope seems to lie in understanding the mechanisms by which microbial exposures during infancy foster development of a balanced immune response and then mimicking the effects of natural environmental exposures through administration of harmless microbial commensals (probiotics) or of nutrients that foster their growth (prebiotics) in the intestinal tract during the critical period of immune development in early infancy. Identifying the particular microbes whose growth should be fostered, or the microbial products responsible for inducing appropriate maturation of


Pharmacology_Katzung

Pharmacology_Katzung. period of immune development in early infancy. Identifying the particular microbes whose growth should be fostered, or the microbial products responsible for inducing appropriate maturation of immune function, has become an active focus of epidemiologic, basic, and translational research.


Pharmacology_Katzung

Pharmacology_Katzung. COPD is now the third most common cause of death in the United States and accounts for more than $40 billion per year in direct and indirect health care costs. COPD resembles asthma in that it is also characterized by airflow limitation, although the obstruction of COPD is not fully reversible with treatment. The airflow limitation of COPD, believed to reflect an abnormal inflammatory response of the lung to noxious particles or gases, especially to cigarette smoke, absolutely progresses if the exposure continues and appears to progress, albeit more slowly, even if the exposure ceases. The belief that COPD develops in only 15–30% of habitual smokers is now challenged by radiographic demonstration of important, progressive changes in bronchial wall thickness and loss of lung tissue even in smokers with measures of pulmonary function in the normal range. Although COPD differs from asthma, many of the same drugs are used in its treatment. This section discusses the drugs that are useful


Pharmacology_Katzung

Pharmacology_Katzung. smokers with measures of pulmonary function in the normal range. Although COPD differs from asthma, many of the same drugs are used in its treatment. This section discusses the drugs that are useful in both conditions; a more comprehensive guide to their use is available in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for classification and treatment of COPD (http://goldcopd.org).


Pharmacology_Katzung

Pharmacology_Katzung. Although asthma and COPD are both characterized by airway inflammation, reduction in maximum expiratory flow, and episodic exacerbations of airflow obstruction, most often triggered by viral respiratory infection, they differ in many important respects. Compared to asthma, COPD occurs in older patients, is associated with neutrophilic rather than eosinophilic inflammation, is poorly responsive even to high-dose ICS therapy, and is associated with progressive, inexorable loss of pulmonary function over time, especially with continued cigarette smoking.


Pharmacology_Katzung

Pharmacology_Katzung. Despite these differences, the approaches to treatment are similar, although the benefits expected (and achieved) are less for COPD than for asthma. For relief of acute symptoms, inhalation of a short-acting β agonist (eg, albuterol), of an anticholinergic drug (eg, ipratropium bromide), or of the two in combination is usually effective. For patients with persistent symptoms of exertional dyspnea and limitation of activities, regular use of a long-acting bronchodilator, whether an LABA or a long-acting anticholinergic, or the two together, is indicated. Theophylline may have a particular place in the treatment of COPD, as it may improve contractile function of the diaphragm, thus improving ventilatory capacity. The nonmethylxanthine, roflumilast, a selective phosphodiesterase inhibitor that improves pulmonary function and reduces exacerbation frequency, is now approved as a treatment for COPD.


Pharmacology_Katzung

Pharmacology_Katzung. The place of ICS therapy is less central to treatment of COPD than of asthma, in part because of its lower efficacy for this condition and in part because of reports of its use being associated with heightened risk of bacterial pneumonia. Its use is thus recommended only for patients with severe airflow obstruction or with a history of prior exacerbations. Acute exacerbations of COPD are a major driver of the morbidity, mortality, and health care costs of COPD. Because of the greater age of the patients affected and the prevalence of comorbidities, especially cardiovascular disease, the mortality of acute exacerbations is greater than that of exacerbation of asthma, but management does not differ greatly except in the routine use of antibiotics, which are given because exacerbations of COPD frequently involve bacterial infection of the lower airways.


Pharmacology_Katzung

Pharmacology_Katzung. Because of their importance in driving the morbidity and mortality of COPD, much attention has been paid to approaches to prevention of COPD exacerbations. For patients with a history of two or more exacerbations, daily treatment with an ICS is appropriate, and a recent large study showed significant reduction in exacerbation frequency from daily treatment with azithromycin. An innovative, although initially counterintuitive, hypothesis is now also under examination: that treatment with the selective β1-receptor antagonist, metoprolol succinate, will reduce exacerbations in patients with moderate to severe COPD. The hypothesis is counterintuitive because nonselective β-blocker therapy so predictably worsens airflow obstruction in asthmatic patients that it has long been considered contraindicated for patients with COPD. Several developments and observations have changed this view. These include the development of selective β1-receptor antagonists and the recognition that the use of


Pharmacology_Katzung

Pharmacology_Katzung. for patients with COPD. Several developments and observations have changed this view. These include the development of selective β1-receptor antagonists and the recognition that the use of β-blocking agents—once also considered contraindicated for acute myocardial infarction and congestive heart failure—reduces mortality from these conditions. Epidemiologic surveys show significant reductions in overall mortality and exacerbations in COPD patients taking a β-receptor antagonist. Whether these effects reflect the therapeutic effect of β-blockers on mortality from coincident cardiovascular disease or reflect some direct effect on airway function is unknown, but the hypothesis is currently under study in a large, prospective, placebo-controlled study of metoprolol treatment of COPD patients at risk for exacerbations (https://clinicaltrials.gov/ct2/ show/NCT02587351).


Pharmacology_Katzung

Pharmacology_Katzung. • Albuterol Prompt, efficacious bronchodilation Selective β2 agonist • Salmeterol Slow onset, primarily preventive action; potentiates corticosteroid effects Selective β2 agonist Metaproterenol, terbutaline: Similar to albuterol; terbutaline available as an oral drug Formoterol, vilanterol: Similar to salmeterol Asthma, chronic obstructive pulmonary disease (COPD) • drug of choice in acute Bronchodilation, prevention of asthma exacerbations Aerosol inhalation • duration several hours • also available for nebulizer and parenteral use • Toxicity: Tremor, tachycardia • Overdose: arrhythmias • Toxicity: Tremor, tachycardia • Overdose:


Pharmacology_Katzung

Pharmacology_Katzung. Aerosol inhalation • duration several hours • also available for nebulizer and parenteral use • Toxicity: Tremor, tachycardia • Overdose: arrhythmias • Toxicity: Tremor, tachycardia • Overdose: CORTICOSTEROIDS, INHALED •FluticasoneAlters gene expression Reduces mediators of inflammation •powerfulprophylaxisofexacerbations Asthma•adjunctinCOPD•hayfever(nasal)Aerosol•durationhours•Toxicity: Limitedbyaerosolapplication•candidalinfection, vocal cord changes •Beclomethasone, budesonide, flunisolide, others: Similar to fluticasone •TheophyllineUncertain: •phosphodiesteraseinhibition •adenosinereceptor antagonist Bronchodilation, cardiac stimulation, increased skeletal muscle strength (diaphragm) Asthma, COPD Oral•duration8–12hbutextended-releasepreparationsoftenused•Toxicity: Multiple (see text) •Roflumilast: Similar to theophylline, but with better therapeutic ratio


Pharmacology_Katzung

Pharmacology_Katzung. Subclass, Drug Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities •MepolizumabHumanized anti-IL-5 antibody; reduces circulating and tissue eosinophils Reduces frequency of asthma exacerbations Severe asthma inadequately controlled by above agents, with associated eosinophilia Parenteral•duration2–4wk•Toxicity: Injection site reactions (anaphylaxis extremely rare) •DupilumabHumanized antibody against IL-4α receptor for IL-4 and IL-13 Reduces frequency of asthma exacerbations; improves pulmonary function Severe asthma inadequately controlled by ICS/LABA therapy Parenteral injection every 2–4 wk Reslizumab and benralizumab: Similar to mepolizumab Albuterol Generic, Proventil, ProAir, Ventolin Epinephrine Generic, Adrenaline Metaproterenol Generic, Alupent Terbutaline Breathaire, Brethine SHORT-ACTING ANTIMUSCARINIC BRONCHODILATOR Ipratropium Generic, Atrovent Budesonide Pulmicort Flunisolide AeroBid, Aerospan


Pharmacology_Katzung

Pharmacology_Katzung. Metaproterenol Generic, Alupent Terbutaline Breathaire, Brethine SHORT-ACTING ANTIMUSCARINIC BRONCHODILATOR Ipratropium Generic, Atrovent Budesonide Pulmicort Flunisolide AeroBid, Aerospan Vilanterol/fluticasone Breo Vilanterol/umeclidinium Anoro LEUKOTRIENE INHIBITORS Montelukast Generic, Singulair Beclomethasone QVAR, Beclovent, Vanceril PHOSPHODIESTERASE INHIBITORS, METHYLXANTHINES Dyphylline Dilor, Dylix, Lufyllin Theophylline Generic, Elixophyllin, Slo-Phyllin, Uniphyl, Theo-Dur, Theo-24 Pathophysiology of Airway Disease Fahy JV: Type 2 inflammation in asthma: Present in most, absent in many. Nat Rev Immunol 2015;15:57. Kim HY, DeKruyff RH, Umetsu DT: The many paths to asthma: Phenotype shaped by innate and adaptive immunity. Nat Immunol 2010;7:577. Locksley RM: Asthma and allergic inflammation. Cell 2010;140:777. Lotvall J et al: Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011;127:355.


Pharmacology_Katzung

Pharmacology_Katzung. Lotvall J et al: Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011;127:355. Martinez FD, Vercelli D: Asthma. Lancet 2013;382:1360. Bateman ED et al: Overall asthma control: The relationship between current control and future risk. J Allergy Clin Immunol 2010;125:600. Bel EH: Mild asthma. N Engl J Med 2013;369:2362. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program: Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute; Revised August 2007. NIH publication no. 07-4051. https://www.nhlbi.nih.gov/ health-pro/guidelines/current/asthma-guidelines. Ducharme FM et al: Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev 2010;4:CD005533.


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Pharmacology_Katzung. Papi A et al: Beclomethasone-formoterol as maintenance and reliever treatment in patients with asthma: A double-blind, randomised controlled trial. Lancet Respir Med 2013;1:23. Stempel DA et al: Serious asthma events with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med 2016;374:1822. Stempel DA et al: Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med 2016;375:840. Barnes PJ: Theophylline. Am J Respir Crit Care Med 2013;188:901. Rabe KF: Roflumilast for the treatment of chronic obstructive pulmonary disease. Expert Rev Respir Med 2010;4:543. Guevara J et al: Inhaled corticosteroids versus sodium cromoglycate in children and adults with asthma. Cochrane Database Syst Rev 2006; 2:CD003558. Barnes P: How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 2006;148:245.


Pharmacology_Katzung

Pharmacology_Katzung. Barnes P: How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 2006;148:245. Beasley R et al: Combination corticosteroid/beta-agonist inhaler as reliever therapy: A solution for intermittent and mild asthma? J Allergy Clin Immunol 2014;133:39. Boushey HA et al: Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519. Suissa S et al: Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000;343:332. D’Amato M et al: Anticholinergic drugs in asthma therapy. Curr Opin Pulm Med 2016;22:527. Lee AM, Jacoby DB, Fryer AD: Selective muscarinic receptor antagonists for airway diseases. Curr Opin Pharmacol 2001;1:223. Peters SP et al: Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363:1715. Calhoun WJ: Anti-leukotrienes for asthma. Curr Opin Pharmacol 2001;1:230.


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Pharmacology_Katzung. Peters SP et al: Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363:1715. Calhoun WJ: Anti-leukotrienes for asthma. Curr Opin Pharmacol 2001;1:230. Laidlaw TM et al: Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes. Blood 2012;119:3790. Wang L et al: Cost-effectiveness analysis of fluticasone versus montelukast in children with mild-to-moderate persistent asthma in the Pediatric Asthma Controller Trial. J Allergy Clin Immunol 2011;127:161. Busse WW et al: Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med 2011;364:1005. Walker S et al: Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev 2006;2:CD003559. Fainardi V, Pisi G, Chetta A: Mepolizumab in the treatment of severe eosinophilic asthma. Immunotherapy 2016;8:27.


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Pharmacology_Katzung. Fainardi V, Pisi G, Chetta A: Mepolizumab in the treatment of severe eosinophilic asthma. Immunotherapy 2016;8:27. Walsh GM: Biologics targeting IL-5, IL-4 or IL-13 for the treatment of asthma: an update. Expert Rev Clin Immunol 2017;13(2):143. Wenzel S et al: Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: A randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388:31. Future Directions of Asthma Therapy Chang TS et al: Childhood asthma clusters and response to therapy in clinical trials. J Allergy Clin Immunol 2014;133:363. Haldar P et al: Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178:218. Lotvall J et al: Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011; 127:355.


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Pharmacology_Katzung. Lotvall J et al: Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011; 127:355. Moore WC et al: Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181:315. Woodruff PG et al: T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009;180:388. Management of Acute Asthma Lazarus SC: Clinical practice. Emergency treatment of asthma. N Engl J Med 2010;363:755. Klauth M, Heine H: Allergy protection by cowshed bacteria: Recent findings and future prospects. Pediatr Allergy Immunol 2016;27:340. Lynch SV et al: Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. J Allergy Clin Immunol 2014; 134:593. Martinez FD: New insights into the natural history of asthma: Primary prevention on the horizon. J Allergy Clin Immunol 2011;128:939.


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Pharmacology_Katzung. Martinez FD: New insights into the natural history of asthma: Primary prevention on the horizon. J Allergy Clin Immunol 2011;128:939. Stein MM et al: Innate immunity and asthma risk in Amish and Hutterite farm children. N Engl J Med 2016;375:411. Treatment of COPD Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for Diagnosis, Management, and Prevention of COPD. http://www .goldcopd.org. Huisman EL et al: Comparative efficacy of combination bronchodilator therapies in COPD: A network meta-analysis. Int J Chron Obstruct Pulmon Dis 2015;10:1863. Kew KM, Dias S, Cates CJ: Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: A network meta-analysis. Cochrane Database Syst Rev 2014;1:CD010844. Niewoehner DE: Clinical practice. Outpatient management of severe COPD. N Engl J Med 2010;362:1407. Vogelmeier C et al: Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093.


Pharmacology_Katzung

Pharmacology_Katzung. This patient demonstrates the destabilizing effects of a respiratory infection on asthma, and her mother’s comments demonstrate the common (and dangerous) phobia about “overuse” of bronchodilator or steroid inhalers. The patient has signs of imminent respiratory failure, including her refusal to lie down, her fear, and her tachycardia, which can-not be attributed to her minimal treatment with albuterol. Critically important immediate steps are to administer high-flow oxygen and to start albuterol by nebulization. Adding ipratropium (Atrovent) to the nebulized solution is recom-mended. A corticosteroid (0.5–1.0 mg/kg of methylpred-nisolone) should be administered intravenously. It is also advisable to alert the intensive care unit, because a patient with severe bronchospasm who tires can slip into respiratory failure quickly, and intubation can be difficult. Fortunately, most patients treated in hospital emergency departments do well. Asthma mortality is rare (fewer than 4000 deaths


Pharmacology_Katzung

Pharmacology_Katzung. slip into respiratory failure quickly, and intubation can be difficult. Fortunately, most patients treated in hospital emergency departments do well. Asthma mortality is rare (fewer than 4000 deaths per year among a population of more than 20 million asthmatics in the USA), and when it occurs, it is often out of hospital. Presuming this patient recovers, she needs adjustments to her therapy before discharge. The strongest predictor of severe attacks of asthma is their occur-rence in the past. Thus, this patient’s therapy needs to be stepped up to a higher level, like a high-dose inhaled cortico-steroid in combination with a long-acting βagonist. Both the patient and her parents need instruction on the importance of regular adherence to therapy, with reassurance that it can be “stepped down” to a lower dose of inhaled corticosteroid (although still in combination with a long-acting β agonist) once her condition stabilizes. They also need instruction on an action plan for managing


Pharmacology_Katzung

Pharmacology_Katzung. down” to a lower dose of inhaled corticosteroid (although still in combination with a long-acting β agonist) once her condition stabilizes. They also need instruction on an action plan for managing severe symptoms. This can be as simple as advising that if the patient has a severe, frightening attack, she can take up to four puffs of albuterol every 15 minutes, but if the first treatment does not bring significant relief, she should take the next four puffs while on her way to an emergency department or urgent care clinic. She should also be given a prescription for prednisone, with instructions to take 40–60 mg orally for severe attacks, but not to wait for it to take effect if she remains severely short of breath even after albuterol inhalations. Asthma is a chronic disease, and good care requires close follow-up and creation of a provider-patient partnership for optimal management. If she has had several previous exacerbations, she should be considered a candidate for monoclonal


Pharmacology_Katzung

Pharmacology_Katzung. care requires close follow-up and creation of a provider-patient partnership for optimal management. If she has had several previous exacerbations, she should be considered a candidate for monoclonal anti-IgE antibody therapy with omalizumab, which effectively reduces the rate of asthma exacerbations—even those associated with viral respiratory infection—in patients with allergic asthma. Alternatively, if the patient is found to have blood eosino-philia, treatment with an anti-IL-5 monoclonal antibody (eg, mepolizumab) should be considered as well.


Pharmacology_Katzung

Pharmacology_Katzung. Introduction to the Pharmacology of CNS Drugs John A. Gray, MD, PhD* Drugs acting in the central nervous system (CNS) were among the first to be discovered by primitive humans and are still the most widely used group of pharmacologic agents. These include medications used to treat a wide range of neurologic and psychiatric conditions as well as drugs that relieve pain, suppress nausea, and reduce fever, among other symptoms. In addition, many CNS-acting drugs are used without prescription to increase the sense of well-being.


Pharmacology_Katzung

Pharmacology_Katzung. Due to their complexity, the mechanisms by which various drugs act in the CNS have not always been clearly understood. In recent decades, however, dramatic advances have been made in the methodology of CNS pharmacology. It is now possible to study the action of a drug on individual neurons and even single receptors within synapses. The information obtained from such studies is the basis for several major developments in studies of the CNS. First, it is clear that nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission. While a few agents such as general anesthetics and alcohol may have nonspecific actions on membranes (although these exceptions are not * The author thanks Dr. Roger A. Nicoll for his contributions to previouseditions. fully accepted), even these non–receptor-mediated actions result in demonstrable alterations in synaptic transmission.


Pharmacology_Katzung

Pharmacology_Katzung. Second, drugs are among the most valuable tools for studying CNS function, from understanding the mechanism of convulsions to the laying down of long-term memory. Both agonists that mimic natural transmitters (and in many cases are more selective than the endogenous substances) and antagonists are extremely useful in such studies. Third, unraveling the actions of drugs with known clinical efficacy has led to some of the most fruitful hypotheses regarding the mechanisms of disease. For example, information about the action of antipsychotic drugs on dopamine receptors has provided the basis for important hypotheses regarding the pathophysiology of schizophrenia. Studies of the effects of a variety of agonists and antagonists on γ-aminobutyric acid (GABA) receptors have resulted in new concepts pertaining to the pathophysiology of several diseases, including anxiety and epilepsy.


Pharmacology_Katzung

Pharmacology_Katzung. A full appreciation of the effects of a drug on the CNS requires an understanding of the multiple levels of brain organization, from genes to circuits to behavior. This chapter provides an introduction to the functional organization of the CNS and its synaptic transmitters as a basis for understanding the actions of the drugs described in the following chapters. The CNS is composed of the brain and spinal cord and is responsible for integrating sensory information and generating motor output and other behaviors needed to successfully interact with the environment and enhance species survival. The human brain contains about 100 billion interconnected neurons surrounded by various supporting glial cells. Throughout the CNS, neurons are either clustered into groups called nuclei or are present in layered structures such as the cerebellum or hippocampus. Connections among neurons both within and between these clusters form the circuitry that regulates information flow through the CNS.


Pharmacology_Katzung

Pharmacology_Katzung. Neurons are electrically excitable cells that process and transmit information via an electrochemical process. There are many types of neurons in the CNS, and they are classified in multiple ways: by function, by location, and by the neurotransmitter they release. The typical neuron, however, possesses a cell body (or soma) and specialized processes called dendrites and axons (Figure 21–1). Dendrites, which form highly branched complex dendritic “trees,” receive and integrate the input from other neurons and conduct this information to the cell body. The axon carries the output signal of a neuron from the cell body, sometimes over long distances. Neurons may have hundreds of dendrites but generally have only one axon, although axons may branch distally to contact multiple targets. The axon terminal makes contact with other neurons at specialized junctions called synapses where neurotransmitter chemicals are released that interact with receptors on other neurons.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to neurons, there are a large number of nonneuronal support cells, called glia, that perform a variety of essential functions in the CNS. Astrocytes are the most abundant cell in the brain and play homeostatic support roles, including providing metabolic nutrients to neurons and maintaining extracellular ion concentrations. In addition, astrocyte processes are closely associated with neuronal synapses where they are involved in the removal and recycling of neurotransmitters after release and play increasingly appreciated roles in regulating neurotransmission (see below).


Pharmacology_Katzung

Pharmacology_Katzung. Oligodendrocytes are cells that wrap around the axons of projection neurons in the CNS forming the myelin sheath (Figure 21–1). Similar to the Schwann cells in peripheral neurons, the myelin sheath created by the oligodendrocytes insulates the axons and increases the speed of signal propagation. Damage to oligodendrocytes occurs in multiple sclerosis, and thus, they are a target of drug discovery efforts. Microglia are specialized macrophages derived from the bone marrow that settle in the CNS and are the major immune defense system in the brain. The cells are actively involved in neuroinflammatory processes in many pathological states including neurodegenerative diseases.


Pharmacology_Katzung

Pharmacology_Katzung. The blood-brain barrier (BBB) is a protective functional separation of the circulating blood from the extracellular fluid of the CNS that limits the penetration of substances, including drugs. This separation is accomplished by the presence of tight junctions between the capillary endothelial cells as well as a surrounding layer of astrocyte end-feet. As such, to enter the CNS, drugs must either be highly hydrophobic or engage specific transport mechanisms. For example, the second-generation antihistamines cause less drowsiness because they were developed to be significantly more polar than older antihistamines, limiting their crossing of the BBB (see Chapter 16). Many nutrients, such as glucose and the essential amino acids, have specific transporters that allow them to cross the BBB. l-DOPA, a precursor of the neurotransmitter dopamine, can enter the brain using an amino acid transporter, whereas dopamine cannot cross the BBB. Thus, the orally administered drug l-DOPA, but not


Pharmacology_Katzung

Pharmacology_Katzung. l-DOPA, a precursor of the neurotransmitter dopamine, can enter the brain using an amino acid transporter, whereas dopamine cannot cross the BBB. Thus, the orally administered drug l-DOPA, but not dopamine, can be used to boost CNS dopamine levels in the treatment of Parkinson’s disease. Some parts of the brain, the so-called circumventricular organs, lack a normal BBB. These include regions that sample the blood, such as the area postrema vomiting center, and regions that secrete neurohormones into the circulation.


Pharmacology_Katzung

Pharmacology_Katzung. Dendrites NeuronAstrocyteOligodendrocyteSynapses Axon initial segment Axon Myelin sheath FIGURE 21–1 Neurons and glia in the CNS. A typical neuron has a cell body (or soma) that receives the synaptic responses from the dendritic tree. These synaptic responses are integrated at the axon initial segment, which has a high concentration of voltage-gated sodium channels. If an action potential is initiated, it propagates down the axon to the synaptic terminals, which contact other neurons. The axon of long-range projection neurons are insulated by a myelin sheath derived from specialized membrane processes of oligodendrocytes, analogous to the Schwann cells in the peripheral nervous system. Astrocytes perform supportive roles in the CNS, and their processes are closely associated with neuronal synapses.


Pharmacology_Katzung

Pharmacology_Katzung. The membranes of neurons contain two types of channels defined on the basis of the mechanisms controlling their gating (opening and closing): voltage-gated and ligand-gated channels (Figure 21–2A and B). Voltage-gated channels respond to changes in the membrane potential of the cell. The voltage-gated sodium channel described in Chapter 14 for the heart is an example of this type of channel. In nerve cells, these channels are highly concentrated on the initial segment of the axon (Figure 21–1), which initiates the all-or-nothing fast action potential, and along the length of the axon where they propagate the action potential to the nerve terminal. There are also many types of voltage-sensitive calcium and potassium channels on the cell body, dendrites, and initial segment, which act on a much slower time scale and modulate the rate at which the neuron discharges. For example, some types of potassium channels opened by depolarization of the cell result in slowing of further


Pharmacology_Katzung

Pharmacology_Katzung. act on a much slower time scale and modulate the rate at which the neuron discharges. For example, some types of potassium channels opened by depolarization of the cell result in slowing of further depolarization and act as a brake to limit further action potential discharge. Plant and animal toxins that target various voltage-gated ion channels have been invaluable for studying the functions of these channels (see Box: Natural Toxins: Tools for Characterizing Ion Channels; Table 21–1).


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 21–2 Types of ion channels and neurotransmitter receptors in the CNS. A shows a voltage-gated channel in which a voltage sensor component of the protein controls the gating (broken arrow) of the channel. B shows a ligand-gated channel in which the binding of the neurotransmitter to the ionotropic channel receptor controls the gating (broken arrow) of the channel. C shows a G protein-coupled (metabotropic) receptor, which, when bound, activates a heterotrimeric G protein. D and E show two ways metabotropic receptors can regulate ion channels. The activated G protein can interact directly to modulate an ion channel (D) or the G protein can activate an enzyme that generates a diffusible second messenger (E), eg, cAMP, which can interact with the ion channel or can activate a kinase that phosphorylates and modulates a channel.


Pharmacology_Katzung

Pharmacology_Katzung. Evolution is tireless in the development of natural toxins. A vast number of variations are possible with even a small number of amino acids in peptides, and peptides make up only one of a broad array of toxic compounds. For example, the predatory marine snail genus Conus includes over 3000 different species. Each species kills or paralyzes its prey with a venom that contains 50–200 different peptides or proteins. Furthermore, there is little duplication of peptides among Conus species. Other animals with useful toxins include snakes, frogs, spiders, bees, wasps, and scorpions. Plant spe-cies with toxic (or therapeutic) substances are referred to in several other chapters of this book. Since many toxins act on ion channels, they provide a wealth of chemical tools for studying the function of these channels. In fact, much of our current understanding of the properties of ion channels comes from studies utilizing only a small percentage of the highly potent and selective toxins that are


Pharmacology_Katzung

Pharmacology_Katzung. of these channels. In fact, much of our current understanding of the properties of ion channels comes from studies utilizing only a small percentage of the highly potent and selective toxins that are now available. The toxins typically target voltage-sensitive ion channels, but a number of very useful toxins block ligand-gated ion channels receptors. Table 21–1 lists some of the toxins most commonly used in research, their mode of action, and their source.


Pharmacology_Katzung

Pharmacology_Katzung. Neurotransmitters exert their effects on neurons by binding to two distinct classes of receptor. The first class is referred to as ligand-gated channels, or ionotropic receptors. These receptors consist of multiple subunits, and binding of the neurotransmitter ligand directly opens the channel, which is an integral part of the receptor complex (see Figure 22–6). These channels are insensitive or only weakly sensitive to membrane potential. Activation of these channels typically results in a brief (a few milliseconds to tens of milliseconds) opening of the channel. Ligand-gated channels are responsible for fast synaptic transmission typical of hierarchical pathways in the CNS (see following text).


Pharmacology_Katzung

Pharmacology_Katzung. The second class of neurotransmitter receptor is referred to as metabotropic receptors (Figure 21–2C). These are seventransmembrane G protein-coupled receptors of the type described in Chapter 2. The binding of neurotransmitter to this type of receptor does not result in the direct gating of a channel. Rather, binding to the receptor engages a G protein, which results in the production of second messengers that mediate intracellular signaling cascades such as those described in Chapter 2.


Pharmacology_Katzung

Pharmacology_Katzung. In neurons, activation of metabotropic neurotransmitter receptors often leads to the modulation of voltage-gated channels. These interactions can occur entirely within the plane of the membrane and are referred to as membrane-delimited pathways (Figure 21–2D). In this case, the G protein (often the βγ subunit) interacts directly with a voltage-gated ion channel. In general, two types of voltage-gated ion channels are the targets of this type of signaling: calcium channels and potassium channels. When G proteins interact with calcium channels, they inhibit channel TABLE 21–1 Some toxins used to characterize ion channels.


Pharmacology_Katzung

Pharmacology_Katzung. function. This mechanism accounts for the inhibition of neurotransmitter release that occurs when presynaptic metabotropic receptors are activated. In contrast, when these receptors are post-synaptic, they activate (cause the opening of) potassium channels, resulting in a slow postsynaptic inhibition. Metabotropic receptors can also modulate voltage-gated channels less directly by the generation of diffusible second messengers (Figure 21–2E). A classic example of this type of action is provided by the β adrenoceptor, which generates cAMP via the activation of adenylyl cyclase (see Chapter 2). Whereas membrane-delimited actions occur within microdomains in the membrane, second messenger-mediated effects can occur over considerable distances. Finally, an important consequence of the involvement of G proteins in receptor signaling is that, in contrast to the brief effect of ionotropic receptors, the effects of metabotropic receptor activation can last tens of seconds to minutes.


Pharmacology_Katzung

Pharmacology_Katzung. involvement of G proteins in receptor signaling is that, in contrast to the brief effect of ionotropic receptors, the effects of metabotropic receptor activation can last tens of seconds to minutes. Metabotropic receptors predominate in the diffuse neuronal systems in the CNS (see below).


Pharmacology_Katzung

Pharmacology_Katzung. The communication between neurons in the CNS occurs through chemical synapses in the majority of cases. (A few instances of electrical coupling between neurons have been documented, and such coupling may play a role in synchronizing neuronal discharge. However, it is unlikely that these electrical synapses are an important site of drug action.) The events involved in synaptic transmission can be summarized as follows.


Pharmacology_Katzung

Pharmacology_Katzung. An action potential propagating down the axon of the presynaptic neuron enters the synaptic terminal and activates voltage-sensitive calcium channels in the membrane of the terminal (see Figure 6–3). The calcium channels responsible for the release of neurotransmitter are generally resistant to the calcium channel-blocking agents discussed in Chapter 12 (eg, verapamil) but are sensitive to blockade by certain marine toxins and metal ions (see Tables 21–1 and 12–4). As calcium flows into the terminal, the increase in intraterminal calcium concentration promotes the fusion of synaptic vesicles with the presynaptic membrane. The neurotransmitter contained in the vesicles is released into the synaptic cleft and diffuses to the receptors on the postsynaptic membrane. The neurotransmitter binds to its receptor and opens channels (either directly or indirectly as described above) causing a brief change in membrane conductance (permeability to ions) of the postsynaptic cell. The time delay


Pharmacology_Katzung

Pharmacology_Katzung. to its receptor and opens channels (either directly or indirectly as described above) causing a brief change in membrane conductance (permeability to ions) of the postsynaptic cell. The time delay from the arrival of the presynaptic action potential to the onset of the postsynaptic response is approximately 0.5 ms. Most of this delay is consumed by the release process, particularly the time required for calcium channels to open.


Pharmacology_Katzung

Pharmacology_Katzung. The first systematic analysis of synaptic potentials in the CNS was in the early 1950s by Eccles and associates, who recorded intracellularly from spinal motor neurons. When a microelectrode enters a cell, there is a sudden change in the potential recorded by the electrode, which is typically about −60 mV (Figure 21–3A). This is the resting membrane potential of the neuron. Two types of pathways—excitatory and inhibitory—impinge on the motor neuron.


Pharmacology_Katzung

Pharmacology_Katzung. When an excitatory pathway is stimulated, a small depolarization or excitatory postsynaptic potential (EPSP) is recorded. This potential is due to the excitatory transmitter acting on an ionotropic receptor, causing an increase in cation permeability. As additional excitatory synapses are activated, there is a graded summation of the EPSPs to increase the size of the depolarization (Figure 21–3A, spatial summation, middle). When a sufficient number of excitatory synapses are activated, the excitatory post-synaptic potential depolarizes the postsynaptic cell to threshold, and an all-or-none action potential is generated. Alternatively, if there is a repetitive firing of an excitatory input, the temporal summation of the EPSPs may also reach the action potential threshold (Figure 21–3A, right).


Pharmacology_Katzung

Pharmacology_Katzung. When an inhibitory pathway is stimulated, the postsynaptic membrane is hyperpolarized owing to the selective opening of chloride channels, producing an inhibitory postsynaptic potential (IPSP) (Figure 21–3B, middle). However, because the equilibrium potential for chloride (see Chapter 14) is only slightly more negative than the resting potential (~ −65 mV), the hyperpolarization is small and contributes only modestly to the inhibitory action. The opening of the chloride channel during the inhibitory postsynaptic potential makes the neuron “leaky” so that changes in membrane potential are more difficult to achieve. This shunting effect decreases the change in membrane potential during the excitatory postsynaptic potential. As a result, an EPSP


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 21–3 Postsynaptic potentials and action potential generation. A shows the voltage recorded upon entry of a micro-electrode into a postsynaptic cell and subsequent recording of a resting membrane potential of −60 mV. Stimulation of an excitatory pathway (E1, left) generates transient depolarization called an excitatory postsynaptic potential (EPSP). Simultaneous activation of multiple excitatory synapses (E1 + E2, middle) increases the size of the depolarization, so that the threshold for action potential generation is reached. Alternatively, a train of stimuli from a single input can temporally summate to reach the threshold (E1 + E2, right). B demonstrates the interaction of excitatory and inhibitory synapses. On the left, a suprathreshold excitatory stimulus (E3) evokes an action potential. In the center, an inhibitory pathway (I) generates a small hyperpolarizing current called an inhibitory postsynaptic potential (IPSP). On the right, if the previously suprathreshold


Pharmacology_Katzung

Pharmacology_Katzung. action potential. In the center, an inhibitory pathway (I) generates a small hyperpolarizing current called an inhibitory postsynaptic potential (IPSP). On the right, if the previously suprathreshold excitatory input (E3) is given shortly after the inhibitory input (I), the IPSP prevents the excitatory potential from reaching threshold.


Pharmacology_Katzung

Pharmacology_Katzung. that evoked an action potential under resting conditions fails to evoke an action potential during the IPSP (Figure 21–3B, right). A second type of inhibition is presynaptic inhibition. It was first described for sensory fibers entering the spinal cord, where excitatory synaptic terminals receive synapses called axoaxonic synapses (described later). When activated, axoaxonic synapses reduce the amount of transmitter released from the terminals of sensory fibers. It is interesting that presynaptic inhibitory receptors are present on almost all presynaptic terminals in the brain even though axoaxonic synapses appear to be restricted to the spinal cord. In the brain, transmitter can spill out of the synapse and activate presynaptic receptors, either on the same synapse (autoreceptors) or on neighboring synapses.


Pharmacology_Katzung

Pharmacology_Katzung. Virtually all the drugs that act in the CNS produce their effects by modifying some step in chemical synaptic transmission. Figure 21–4 illustrates some of the steps that can be altered. These transmitter-dependent actions can be divided into presynaptic and postsynaptic categories. MetabolismSynthesis Storage Release Ionic conductance Receptor Degradation Uptake 3 10 7 8 9 4 1 2 6 65 Presynaptic neuron Action potential propagation Retrograde signaling Postsynaptic neuron Glia FIGURE 21–4 Sites of drug action. Schematic drawing of steps at which drugs can alter synaptic transmission. (1) Action potential in pre-synaptic fiber; (2) synthesis of transmitter; (3) storage; (4) metabolism; (5) release; (6) reuptake into the nerve ending or uptake into a glial cell; (7) degradation; (8) receptor for the transmitter; (9) receptor-induced increase or decrease in ionic conductance; (10) retrograde signaling.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs acting on the synthesis, storage, metabolism, and release of neurotransmitters fall into the presynaptic category. Synaptic transmission can be depressed by blockade of transmitter synthesis or storage. For example, reserpine depletes monoamine synapses of transmitters by interfering with intracellular storage. Blockade of transmitter catabolism inside the nerve terminal can increase transmitter concentrations and has been reported to increase the amount of transmitter released per impulse. Drugs can also alter the release of transmitters. The stimulant amphetamine induces the release of catecholamines from adrenergic synapses (see Chapters 6, 9, and 32). Capsaicin causes the release of the peptide substance P from sensory neurons, and tetanus toxin blocks the release of transmitters. After a CNS transmitter has been released into the synaptic cleft, its action is terminated either by uptake or by degradation. For most neurotransmitters, there are uptake mechanisms into the


Pharmacology_Katzung

Pharmacology_Katzung. After a CNS transmitter has been released into the synaptic cleft, its action is terminated either by uptake or by degradation. For most neurotransmitters, there are uptake mechanisms into the synaptic terminal and also into surrounding neuroglia. Cocaine, for example, blocks the uptake of catecholamines at adrenergic synapses and thus potentiates the action of these amines. Acetylcholine, however, is inactivated by enzymatic degradation, not reuptake. Anticholinesterases block the degradation of acetylcholine and thereby prolong its action (see Chapter 7). No uptake mechanism has been found for any of the numerous CNS peptides, and it has yet to be demonstrated whether specific enzymatic degradation terminates the action of peptide transmitters.


Pharmacology_Katzung

Pharmacology_Katzung. In the postsynaptic region, the transmitter receptor provides the primary site of drug action. Drugs can act either as neurotransmitter agonists, such as the opioids, which mimic the action of enkephalin, or they can block receptor function. Receptor antagonism is a common mechanism of action for CNS drugs. An example is strychnine’s blockade of the receptor for the inhibitory transmitter glycine. This block, which underlies strychnine’s convulsant action, illustrates how the blockade of inhibitory processes results in excitation. Drugs can also act directly on the ion channel of ionotropic receptors. For example, the anesthetic ketamine blocks the NMDA subtype of glutamate ionotropic receptors by binding in the ion channel pore. In the case of metabotropic receptors, drugs can act at any of the steps downstream of the receptor. Perhaps the best example is provided by the methylxanthines, which can modify neurotransmitter responses mediated through the second-messenger cAMP. At high


Pharmacology_Katzung

Pharmacology_Katzung. of the steps downstream of the receptor. Perhaps the best example is provided by the methylxanthines, which can modify neurotransmitter responses mediated through the second-messenger cAMP. At high concentrations, the methylxanthines elevate the level of cAMP by blocking its metabolism and thereby prolong its action.


Pharmacology_Katzung

Pharmacology_Katzung. The traditional view of the synapse is that it functions like a valve, transmitting information in one direction. However, it is now clear that the synapse can generate signals that feed back onto the presynaptic terminal to modify transmitter release. Endocannabinoids are the best documented example of such retrograde signaling (see below). Postsynaptic activity leads to the synthesis and release of endocannabinoids, which then bind to receptors on the presynaptic terminal. Although the gas nitric oxide (NO) has long been proposed as a retrograde messenger, its physiologic role in the CNS is still not well understood.


Pharmacology_Katzung

Pharmacology_Katzung. The selectivity of CNS drug action is based on two primary factors. First, with a few exceptions, different neurotransmitters are released by different groups of neurons. These transmitters are often segregated into neuronal systems that subserve broadly different CNS functions. That this segregation occurs has provided neuroscientists with a powerful pharmacologic approach for analyzing CNS function and treating pathologic conditions. Second, there is a multiplicity of receptors for each neurotransmitter. For example, there are at least 14 different serotonin receptors encoded by different genes. These receptors often have differential cellular distributions throughout the CNS, allowing for the development of drugs that selectively target particular receptors and CNS functions. Most of the neuronal systems in the CNS can be divided into two broad categories: hierarchical systems and nonspecific or diffuse neuronal systems.


Pharmacology_Katzung

Pharmacology_Katzung. Most of the neuronal systems in the CNS can be divided into two broad categories: hierarchical systems and nonspecific or diffuse neuronal systems. Hierarchical systems include all the pathways directly involved in sensory perception and motor control. These pathways are generally clearly delineated, being composed of large myelinated fibers that can often conduct action potentials at a rate of more than 50 m/s. The information is typically phasic and occurs in bursts of action potentials. In sensory systems, the information is processed sequentially by successive integrations at each relay nucleus on its way to the cortex. A lesion at any link incapacitates the system.


Pharmacology_Katzung

Pharmacology_Katzung. Within each nucleus and in the cortex, there are two types of cells: relay or projection neurons and local circuit neurons (Figure 21–5A). The projection neurons form the interconnecting pathways that transmit signals over long distances. Their cell bodies are relatively large, and their axons can project long distances but also emit small collaterals that synapse onto local interneurons. These neurons are excitatory, and their synaptic influences, which involve ionotropic receptors, are very short-lived. The excitatory transmitter released from these cells is, in most instances, glutamate.


Pharmacology_Katzung

Pharmacology_Katzung. Local circuit neurons are typically smaller than projection neurons, and their axons arborize in the immediate vicinity of the cell body. Most of these neurons are inhibitory, and they release either GABA or glycine. They synapse primarily on the cell body of the projection neurons but can also synapse on the dendrites of projection neurons as well as with each other. Two common types of pathways for these neurons (Figure 21–5A) include recurrent feedback pathways and feed-forward pathways. A special class of local circuit neurons in the spinal cord forms axoaxonic synapses


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 21–5 Hierarchical pathways in the CNS. A shows parts of three excitatory relay neurons (blue) and two types of local inhibitory interneuron pathways, recurrent and feed-forward. The inhibitory neurons are shown in gray. B shows the pathway responsible for axoaxonic presynaptic inhibition in which the axon of an inhibitory neuron (gray) synapses onto the presynaptic axon terminal of an excitatory fiber (blue) to inhibit its neurotransmitter release.


Pharmacology_Katzung

Pharmacology_Katzung. on the terminals of sensory axons (Figure 21–5B). Although there are a great variety of synaptic connections in these hierarchical systems, the fact that a limited number of transmitters are used by these neurons indicates that any major pharmacologic manipulation of this system will have a profound effect on the overall excitability of the CNS. For instance, selectively blocking GABAA receptors with a drug such as picrotoxin results in generalized convulsions. Thus, although the mechanism of action of picrotoxin is specific in blocking the effects of GABA, the overall functional effect appears to be quite nonspecific, because GABA-mediated synaptic inhibition is so widely utilized in the brain.


Pharmacology_Katzung

Pharmacology_Katzung. Neuronal systems containing many of the other neurotransmitters, including the monoamines and acetylcholine, differ in fundamental ways from the hierarchical systems. These neurotransmitters are produced by only a limited number of neurons whose cell bodies are located in small discrete nuclei, often in the brain stem. For example, noradrenergic cell bodies are found primarily in a compact cell group called the locus coeruleus located in the caudal pontine central gray matter and number only approximately 12,000 neurons on each side of the human brain. However, from these limited nuclei, these neurons project widely and diffusely throughout the brain and spinal cord (Figure 21–6). Because the axons from these diffusely projecting neurons are fine and unmyelinated, they conduct very slowly, at about 0.5 m/s. The axons branch repeatedly and are extraordinarily divergent. Branches from the same neuron can innervate several functionally different parts of the CNS, synapsing onto and


Pharmacology_Katzung

Pharmacology_Katzung. at about 0.5 m/s. The axons branch repeatedly and are extraordinarily divergent. Branches from the same neuron can innervate several functionally different parts of the CNS, synapsing onto and modulating neurons within the hierarchical systems. In the neocortex, these fibers have a tangential organization and therefore can influence large areas of cortex. In addition, most neurotransmitters utilized by diffuse neuronal systems, including norepinephrine, act predominantly on metabotropic receptors and therefore initiate long-lasting synaptic effects. Based on these observations, it is clear that the monoamine systems cannot be conveying topographically specific types of information; rather, vast areas of the CNS must be affected simultaneously and in a rather uniform way. It is not surprising, then, that these systems have been implicated in such global functions as sleeping and waking, attention, appetite, and emotional states.


Pharmacology_Katzung

Pharmacology_Katzung. VTA Locus coeruleus A1, A2, A5, A7 SN FIGURE 21–6 Diffuse neurotransmitter pathways in the CNS. For each of the neurotransmitter pathways shown, the cell bodies are located in discrete brain stem or basal forebrain nuclei and project widely throughout the CNS. These diffuse systems largely modulate the function of the hierarchical pathways. Serotonin neurons, for example, are found in the midline raphe nuclei in the forebrain and send extraordinarily divergent projections to nearly all regions of the CNS. Other diffusely projecting neurotransmitter pathways include the histamine and orexin systems (not shown). A1–A7, adrenergic brain stem nuclei; Ch5-Ch8, cholinergic brain stem nuclei; DB, diagonal band of Broca; MSN, medial septal nucleus; SN, substantia nigra; VTA, ventral tegmental area.


Pharmacology_Katzung

Pharmacology_Katzung. Because drug selectivity is based on the fact that different pathways use different transmitters, a primary goal of neuroscience has been to identify the neurotransmitters in CNS pathways. Establishing that a chemical substance is a transmitter has been far more difficult for central synapses than for peripheral synapses. The following criteria were established for transmitter identification. 1. Localization: A suspected transmitter must reside in the presynaptic terminal of the pathway of interest. 2. Release: A suspected transmitter must be released from a neuron in response to neuronal activity and in a calcium-dependent manner. 3. Synaptic Mimicry: Application of the candidate substance should produce a response that mimics the action of the transmitter released by nerve stimulation, and application of a selective antagonist should block the response.


Pharmacology_Katzung

Pharmacology_Katzung. Using the criteria above, a vast number of small molecules have been isolated from the brain, and studies using a variety of approaches suggest that the agents listed in Table 21–2 are neurotransmitters. A brief summary of some of these compounds follows. The amino acids of primary interest to the pharmacologist fall into two categories: the acidic amino acid glutamate and the neutral amino acids glycine and GABA. These compounds are present in high concentrations in the CNS and are extremely potent modifiers of neuronal excitability. A. Glutamate


Pharmacology_Katzung

Pharmacology_Katzung. A. Glutamate Excitatory synaptic transmission is mediated by glutamate, which is present in very high concentrations in excitatory synaptic vesicles (~100 mM). Glutamate is released into the synaptic cleft by Ca2+-dependent exocytosis. The released glutamate acts on postsynaptic glutamate receptors and is cleared by glutamate transporters present on surrounding glia (Figure 21–7). In glia, glutamate is converted to glutamine by glutamine synthetase, released from the glia, taken up by the nerve terminal, and converted back to glutamate by the enzyme glutaminase. The high concentration of glutamate in synaptic vesicles is achieved by the vesicular glutamate transporter (VGLUT).


Pharmacology_Katzung

Pharmacology_Katzung. Almost all neurons that have been tested are strongly excited by glutamate. This excitation is caused by the activation of both ionotropic and metabotropic receptors, which have been extensively characterized by molecular cloning. The ionotropic receptors are divided into three subtypes based on the action of selective agonists: α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainic acid (KA), and N-methyl-d-aspartate (NMDA). All the ionotropic receptors are composed of four subunits. AMPA receptors, which are present on all neurons, are heterotetramers assembled from four subunits (GluA1–GluA4). The majority of AMPA receptors contain the GluA2 subunit and are permeable to Na+ and K+, but not to Ca2+. Some AMPA receptors, typically present on inhibitory interneurons, lack the GluA2 subunit and are also permeable to Ca2+.


Pharmacology_Katzung

Pharmacology_Katzung. Kainate receptors are not as uniformly distributed as AMPA receptors, being expressed at high levels in the hippocampus, cerebellum, and spinal cord. They are formed from a number of subunit combinations (GluK1–GluK5). Although GluK4 and GluK5 are unable to form channels on their own, their presence in the receptor changes the receptor’s affinity and kinetics. Similar to AMPA receptors, kainate receptors are permeable to Na+ and K+ and in some subunit combinations can also be permeable to Ca2+. Domoic acid, a toxin produced by algae and concentrated in shellfish, is a potent agonist at kainate and AMPA receptors. Consumption of contaminated shellfish has been implicated in illness in animals and humans.


Pharmacology_Katzung

Pharmacology_Katzung. NMDA receptors are as ubiquitous as AMPA receptors, being present on essentially all neurons in the CNS. All NMDA receptors require the presence of the subunit GluN1. The channel also contains one or two GluN2 subunits (GluN2A–GluN2D). Unlike AMPA and kainate receptors, all NMDA receptors are highly permeable to Ca2+ as well as to Na+ and K+. NMDA receptor function is controlled in a number of intriguing ways. In addition to glutamate binding, the channel also requires the binding of glycine to a separate site in order for the channel to open. However, the regulation and physiologic role of glycine binding remain unclear. Another important feature is that while AMPA and kainate receptor activation results in channel opening at resting membrane potential, NMDA receptor activation does not. This is because, at resting membrane potential, the NMDA receptor pore is blocked by extracellular Mg2+. Only when the neuron is strongly depolarized, as occurs with intense activation of the synapse


Pharmacology_Katzung

Pharmacology_Katzung. This is because, at resting membrane potential, the NMDA receptor pore is blocked by extracellular Mg2+. Only when the neuron is strongly depolarized, as occurs with intense activation of the synapse or by activation of neighboring synapses, is the Mg2+ expelled, allowing the channel to open. Thus, there are three requirements for NMDA receptor channel opening: Glutamate and glycine must bind the receptor, and the membrane must be depolarized. The rise in intracellular Ca2+ that accompanies NMDA receptor channel opening results in a long-lasting enhancement in synaptic strength that is referred to as long-term potentiation (LTP). This enhancement of synaptic strength, which is one major type of synaptic plasticity, can last for many hours or even days and is generally accepted as an important cellular mechanism underlying learning and memory.


Pharmacology_Katzung

Pharmacology_Katzung. The metabotropic glutamate receptors are G protein-coupled receptors that act indirectly on ion channels via G proteins. Metabotropic receptors (mGluR1–mGluR8) have been divided into three groups (I, II, and III). A variety of agonists and antagonists have been developed that interact selectively with the different groups. Group I receptors are typically located postsynaptically and activate phospholipase C, leading to inositol trisphosphate-mediated intracellular Ca2+ release. In contrast, group II and group III receptors are typically located on presynaptic nerve terminals and act as inhibitory autoreceptors. Activation of these receptors causes the inhibition of Ca2+ channels, resulting in inhibition of transmitter release. These receptors are activated only when the concentration of glutamate rises to high levels during repetitive stimulation of the synapse. Activation of these receptors also causes the inhibition of adenylyl cyclase and decreases cAMP generation.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 21–2 Summary of neurotransmitter pharmacology in the central nervous system. TABLE 21–2 Summary of neurotransmitter pharmacology in the central nervous system. (Continued) Note: Many other central transmitters have been identified (see text). ACET, (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione; ACPD, trans-1-amino-cyclopentyl-1,3-dicarboxylate; AMPA, DL-α-amino-3-hydroxy-5-methylisoxazole-4-propionate; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol trisphosphate; LSD, lysergic acid diethylamide; MCPG, α-methyl-4-carboxyphenylglycine; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline.


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Pharmacology_Katzung. FIGURE 21–7 Schematic diagram of a glutamate synapse. Glutamine is imported into the glutamatergic neuron (A) and converted into glutamate by glutaminase. The glutamate is then concentrated in vesicles by the vesicular glutamate transporter (VGLUT). Upon release into the synapse, glutamate can interact with AMPA and NMDA ionotropic receptor channels (AMPAR, NMDAR) and with metabotropic receptors (mGluR) on the postsynaptic cell (B). Synaptic transmission is terminated by active transport of the glutamate into a neighboring glial cell (C) by a glutamate transporter. It is converted into glutamine by glutamine synthetase and transported back into the glutamatergic axon terminal. B. GABA and Glycine


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Pharmacology_Katzung. B. GABA and Glycine Both GABA and glycine are inhibitory neurotransmitters, which are typically released from local interneurons. Interneurons that release glycine are restricted to the spinal cord and brain stem, whereas interneurons releasing GABA are present throughout the CNS, including the spinal cord. It is interesting that some interneurons in the spinal cord can release both GABA and glycine. Glycine receptors are pentameric structures that are selectively permeable to Cl –. Strychnine, which is a potent spinal cord convulsant and has been used in some rat poisons, selectively blocks glycine receptors.


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Pharmacology_Katzung. GABA receptors are divided into two main types: GABAA and GABAB. Inhibitory postsynaptic potentials in many areas of the brain have a fast and slow component. The fast component is mediated by GABAA receptors and the slow component by GABAB receptors. The difference in kinetics stems from the differences in coupling of the receptors to ion channels. GABAA receptors are ionotropic receptors and, like glycine receptors, are pentameric structures that are selectively permeable to Cl –. These receptors are selectively inhibited by picrotoxin and bicuculline, both of which cause generalized convulsions. A great many subunits for GABAA receptors have been cloned; this accounts for the large diversity in the pharmacology of GABAA receptors, making them key targets for clinically useful agents (see Chapter 22). GABAB receptors are metabotropic receptors that are selectively activated by the anti-spastic drug baclofen. These receptors are coupled to G proteins that, depending on their cellular


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Pharmacology_Katzung. Chapter 22). GABAB receptors are metabotropic receptors that are selectively activated by the anti-spastic drug baclofen. These receptors are coupled to G proteins that, depending on their cellular location, either inhibit Ca2+ channels or activate K+ channels. The GABAB component of the inhibitory postsynaptic potential is due to a selective increase in K+ conductance. This inhibitory postsynaptic potential is long-lasting and slow because the coupling of receptor activation to K+ channel opening is indirect and delayed. GABAB receptors are localized to the perisynaptic region and thus require the spillover of GABA from the synaptic cleft. GABAB receptors are also present on the axon terminals of many excitatory and inhibitory synapses. In this case, GABA spills over onto these presynaptic GABAB receptors, inhibiting transmitter release by inhibiting Ca2+ channels. In addition to their coupling to ion channels, GABAB receptors also inhibit adenylyl cyclase and decrease cAMP


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Pharmacology_Katzung. presynaptic GABAB receptors, inhibiting transmitter release by inhibiting Ca2+ channels. In addition to their coupling to ion channels, GABAB receptors also inhibit adenylyl cyclase and decrease cAMP generation.


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Pharmacology_Katzung. Acetylcholine was the first compound to be identified pharmacologically as a transmitter in the CNS. Eccles showed in the early 1950s that excitation of spinal cord Renshaw cells by recurrent axon collaterals from spinal motor neurons was blocked by nicotinic antagonists. Furthermore, Renshaw cells were extremely sensitive to nicotinic agonists. This early success at identifying a transmitter for a central synapse was followed by disappointment because it remained the sole central synapse for which the transmitter was known until the late 1960s, when comparable data became available for GABA and glycine. Second, the motor axon collateral synapse remains one of the best-documented examples of a cholinergic nicotinic synapse in the mammalian CNS, despite the rather widespread distribution of nicotinic receptors as defined by in situ hybridization studies.


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Pharmacology_Katzung. Most CNS responses to acetylcholine are mediated by a large family of G protein-coupled muscarinic receptors. At a few sites, acetylcholine causes slow inhibition of the neuron by activating the M2 subtype of receptor, which opens potassium channels. A far more widespread muscarinic action in response to acetylcholine is a slow excitation that in some cases is mediated by M1 receptors. These muscarinic effects are much slower than either nicotinic effects on Renshaw cells or the effect of amino acids. Furthermore, this M1 muscarinic excitation is unusual in that acetylcholine produces it by decreasing the membrane permeability to potassium, ie, the opposite of conventional transmitter action.


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Pharmacology_Katzung. Eight major CNS nuclei of acetylcholine neurons have been characterized with diffuse projections. These include neurons in the neostriatum, the medial septal nucleus, and the reticular formation that appear to play an important role in cognitive functions, especially memory. Presenile dementia of the Alzheimer type is reportedly associated with a profound loss of cholinergic neurons. However, the specificity of this loss has been questioned because the levels of other putative transmitters, eg, somatostatin, are also decreased.


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Pharmacology_Katzung. Monoamines include the catecholamines (dopamine and norepinephrine) and 5-hydroxytryptamine. The diamine neurotransmitter, histamine, has several similarities to these monoamines. Although these compounds are present in very small amounts in the CNS, they can be localized using extremely sensitive histochemical methods. These pathways are the site of action of many drugs; for example, the CNS stimulants cocaine and amphetamine appear to act primarily at catecholamine synapses. Cocaine blocks the reuptake of dopamine and norepinephrine, whereas amphetamines cause presynaptic terminals to release these transmitters. A. Dopamine


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Pharmacology_Katzung. A. Dopamine The major pathways containing dopamine are the projection linking the substantia nigra to the neostriatum and the projection linking the ventral tegmental region to limbic structures, particularly the limbic cortex. The therapeutic action of the antiparkinsonism drug levodopa is associated with the former area (see Chapter 28), whereas the therapeutic action of the antipsychotic drugs is thought to be associated with the latter (see Chapter 29). In addition, dopamine-containing neurons in the ventral hypothalamus play an important role in regulating pituitary function. Five dopamine receptors have been identified, and they fall into two categories: D1-like (D1 and D5) and D2-like (D2, D3, D4). All dopamine receptors are metabotropic. Dopamine generally exerts a slow inhibitory action on CNS neurons. This action has been best characterized on dopamine-containing substantia nigra neurons, where D2-receptor activation opens potassium channels via the Gi coupling protein.


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B. Norepinephrine

Pharmacology_Katzung. B. Norepinephrine


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Pharmacology_Katzung. Most noradrenergic neurons are located in the locus coeruleus or the lateral tegmental area of the reticular formation. Although the density of fibers innervating various sites differs considerably, most regions of the CNS receive diffuse noradrenergic input. All noradrenergic receptor subtypes are metabotropic. When applied to neurons, norepinephrine can hyperpolarize them by increasing potassium conductance. This effect is mediated by α2 receptors and has been characterized most thoroughly on locus coeruleus neurons. In many regions of the CNS, norepinephrine actually enhances excitatory inputs by both indirect and direct mechanisms. The indirect mechanism involves disinhibition; that is, inhibitory local circuit neurons are inhibited. The direct mechanism involves blockade of potassium conductances that slow neuronal discharge. Depending on the type of neuron, this effect is mediated by either α1 or β receptors. Facilitation of excitatory synaptic transmission is in accordance with


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Pharmacology_Katzung. conductances that slow neuronal discharge. Depending on the type of neuron, this effect is mediated by either α1 or β receptors. Facilitation of excitatory synaptic transmission is in accordance with many of the behavioral processes thought to involve noradrenergic pathways, eg, attention and arousal.


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C. 5-Hydroxytryptamine

Pharmacology_Katzung. C. 5-Hydroxytryptamine


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Pharmacology_Katzung. Most 5-hydroxytryptamine (5-HT, serotonin) pathways originate from neurons in the midline raphe nuclei of the pons and upper brain stem. 5-HT is contained in unmyelinated fibers that diffusely innervate most regions of the CNS, but the density of the innervation varies. 5-HT acts on more than a dozen receptor subtypes. Except for the 5-HT3 receptor, all of these receptors are metabotropic. The ionotropic 5-HT3 receptor exerts a rapid excitatory action at a very limited number of sites in the CNS. In most areas of the CNS, 5-HT has a strong inhibitory action. This action is mediated by 5-HT1A receptors and is associated with membrane hyperpolarization caused by an increase in potassium conductance. It has been found that 5-HT1A receptors and GABAB receptors activate the same population of potassium channels. Some cell types are slowly excited by 5-HT owing to its blockade of potassium channels via 5-HT2 or 5-HT4 receptors. Both excitatory and inhibitory actions can occur on the same


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Pharmacology_Katzung. potassium channels. Some cell types are slowly excited by 5-HT owing to its blockade of potassium channels via 5-HT2 or 5-HT4 receptors. Both excitatory and inhibitory actions can occur on the same neuron. 5-HT has been implicated in the regulation of virtually all brain functions, including perception, mood, anxiety, pain, sleep, appetite, temperature, neuroendocrine control, and aggression. Given the broad roles of 5-HT in CNS function and the rich molecular diversity of 5-HT receptors, it is not surprising that many therapeutic agents target the 5-HT system (see Chapters 16, 29, 30, and 32).


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Pharmacology_Katzung. D. Histamine In the CNS, histamine is exclusively made by neurons in the tuberomammillary nucleus (TMN) in the posterior hypothalamus. These neurons project widely throughout the brain and spinal cord where they modulate arousal, attention, feeding behavior, and memory (see Chapter 16). There are four histamine receptors (H1 to H4), all of which are metabotropic. Centrally acting antihistamines are generally used for their sedative properties, and antagonism of H1 receptors is a common side effect of many drugs including some tricyclic antidepressants and antipsychotics.


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Pharmacology_Katzung. A great many CNS peptides have been discovered that produce dramatic effects both on animal behavior and on the activity of individual neurons. In many cases, peptide hormones discovered in the periphery (see Chapter 17) also act as neurotransmitters in the CNS. As most of these peptides were initially named based on their peripheral functions, the names are often unrelated to their CNS function. The pathways for many of the peptides have been mapped with immunohistochemical techniques and include opioid peptides (eg, enkephalins, endorphins), neurotensin, substance P, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropin-releasing hormone.


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Pharmacology_Katzung. Unlike the classical neurotransmitters above, which are packaged in small synaptic vesicles, neuropeptides are generally packaged in large, dense core vesicles. As in the peripheral autonomic nervous system, peptides often coexist with a conventional non-peptide transmitter in the same neuron, but the release of the neuropeptides and the small-molecule neurotransmitters can be independently regulated. Released neuropeptides may act locally or may diffuse long distances and bind to distant receptors. Most neuropeptide receptors are metabotropic and, like monoamines, primarily serve modulatory roles in the nervous system. Neuropeptides have been implicated in a wide range of CNS functions including reproduction, social behaviors, appetite, arousal, pain, reward, and learning and memory. Thus, neuropeptides and their receptors are active targets of drug discovery efforts.


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Pharmacology_Katzung. A good example of the approaches used to define the role of these peptides in the CNS comes from studies on substance P and its association with sensory fibers. Substance P is contained in and released from small unmyelinated primary sensory neurons in the spinal cord and brain stem and causes a slow excitatory postsynaptic potential in target neurons. These sensory fibers are known to transmit noxious stimuli, and it is therefore surprising that— although substance P receptor antagonists can modify responses to certain types of pain—they do not block the response. Glutamate, which is released with substance P from these synapses, presumably plays an important role in transmitting pain stimuli. Substance P is certainly involved in many other functions because it is found in many areas of the CNS that are unrelated to pain pathways.


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Pharmacology_Katzung. Orexins are peptide neurotransmitters produced in neurons in the lateral and posterior hypothalamus that, like the monoamine systems, project widely throughout the CNS. Orexins are also called hypocretins due to the near simultaneous discovery by two independent laboratories. Like most neuropeptides, orexin is released from large, dense core vesicles and bind to two G protein-coupled receptors. Orexin neurons also release glutamate and are thus excitatory. The orexin system, like the monoamine systems, projects widely throughout the CNS to influence physiology and behavior. In particular, orexin neurons exhibit firing patterns associated with wakefulness and project to and activate monoamine and acetylcholine neurons involved in sleep-wake cycles (see also Chapter 22). Animals lacking orexin or its receptors have narcolepsy and disrupted sleep-wake patterns. In addition to promoting wakefulness, the orexin system is involved in energy homeostasis, feeding behaviors, autonomic


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Pharmacology_Katzung. orexin or its receptors have narcolepsy and disrupted sleep-wake patterns. In addition to promoting wakefulness, the orexin system is involved in energy homeostasis, feeding behaviors, autonomic function, and reward.


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Pharmacology_Katzung. A. Endocannabinoids The primary psychoactive ingredient in cannabis, Δ9tetrahydrocannabinol (Δ9-THC), affects the brain mainly by CB1 Presynaptic neuron Postsynaptic neuron mGluR1/5 PLC DAG 2-AG 2-AG Exogenous cannabinoids (e.g. THC) DAG lipase ˜°˛


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Pharmacology_Katzung. CB1 Presynaptic neuron Postsynaptic neuron mGluR1/5 PLC DAG 2-AG 2-AG Exogenous cannabinoids (e.g. THC) DAG lipase ˜°˛ FIGURE 21–8 Endogenous cannabinoid system. Activation of postsynaptic group I metabotropic glutamate receptors (mGluR1/5) leads to the G protein-mediated membrane-delimited activation of phospholipase C (PLC) that produces the second messengers inositol trisphosphate (IP3, not shown) and diacylglycerol (DAG). DAG can then be converted to the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) by DAG lipase. 2-AG is then released by unknown mechanisms to diffuse across the synaptic cleft where it acts as a full agonist at CB1 cannabinoid receptors on the presynaptic terminals. Activation of CB1 receptors by either endocannabinoids or exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC) results in the inhibition of presynaptic neurotransmitter release.


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Pharmacology_Katzung. activating a specific cannabinoid receptor, CB1. CB1 receptors are expressed at high levels in many brain regions, and they are primarily located on presynaptic terminals (Figure 21–8). Several endogenous brain lipids, including anandamide and 2-arachidonylglycerol (2-AG), have been identified as CB1 ligands. These ligands are not stored, as are classic neurotransmitters, but instead are rapidly synthesized by neurons in response to calcium influx or activation of metabotropic receptors (eg, by acetylcholine and glutamate). In further contradistinction to classic neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: they are released from postsynaptic neurons and travel backward across synapses, activating CB1 receptors on presynaptic neurons and suppressing transmitter release. This suppression can be transient or long lasting, depending on the pattern of activity. Cannabinoids may affect memory, cognition, and pain perception by this mechanism.


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Pharmacology_Katzung. B. Nitric Oxide The CNS contains a substantial amount of nitric oxide synthase (NOS) within certain classes of neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMDA receptors, which increases intracellular calcium, results in the generation of nitric oxide. Although a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial. Nitric oxide diffuses freely across membranes and thus has been hypothesized to be a retrograde messenger, although this has not been demonstrated conclusively. Perhaps the strongest case for a role of nitric oxide in neuronal signaling in the CNS is for long-term depression of synaptic transmission in the cerebellum. C. Purines


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Pharmacology_Katzung. C. Purines Receptors for purines, particularly adenosine, ATP, UTP, and UDP, are found throughout the body, including the CNS. High concentrations of ATP are found in and released from catecholaminergic synaptic vesicles, and ATP may get converted to adenosine extracellularly by nucleotidases. Adenosine in the CNS acts on metabotropic A1 receptors. Presynaptic A1 receptors inhibit calcium channels and inhibit release of both amino acid and monoamine transmitters. ATP co-released with other neurotransmitters can bind to two classes of receptors. The P2X family of ATP receptors includes nonselective ligand-gated cation channels, whereas the P2Y family is metabotropic. The physiological roles for ATP co-release remain elusive, but pharmacological studies suggest these receptors are involved in memory, wakefulness, and appetite and may play roles in multiple neuropsychiatric disorders.


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Pharmacology_Katzung. Berger M, Gray JA, Roth BL: The expanded biology of serotonin. Annu Rev Med 2009;60:355. Castillo PE et al: Endocannabinoid signaling and synaptic function. Neuron 2012;76:70. Catterall WA: Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 2011;3:a003947. Catterall WA: Voltage-gated sodium channels at 60: Structure, function and pathophysiology. J Physiol 2012;590:2577. Daneman R: The blood-brain barrier in health and disease. Ann Neurol 2012;72:648. Dingledine R et al: The glutamate receptor ion channels. Pharmacol Rev 1999;51:7. Gotter AL et al: International Union of Basic and Clinical Pharmacology.


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Pharmacology_Katzung. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacol Rev 2012;64:389. Jan LY, Jan YN: Voltage-gated potassium channels and the diversity of electrical signalling. J Physiol 2012;590:2591. Khakh BS, North RA: Neuromodulation by extracellular ATP and P2X receptors in the CNS. Neuron 2012;76:51. Lewis RJ et al: Conus venom peptide pharmacology. Pharmacol Rev 2012;64:259. Mody I, Pearce RA: Diversity of inhibitory neurotransmission through GABA(A) receptors. Trends Neurosci 2004;27:569. Südhof TC, Rizo J: Synaptic vesicle exocytosis. Cold Spring Harb Perspect Biol 2011;3:a005637. Traynelis SF et al: Glutamate receptor ion channels: Structure, regulation, and function. Pharmacol Rev 2010;62:405.


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Pharmacology_Katzung. Anthony J. Trevor, PhD not overweight, and she takes no prescription drugs. She drinks decaffeinated coffee but only one cup in the morning; however, she drinks as many as six cans per day of diet cola. She drinks a glass of wine with her evening meal but does not like stronger spirits. What other aspects of this patient’s history would you like to know? What therapeutic measures are appropriate for this patient? What drug, or drugs, (if any) would you prescribe? At her annual physical examination, a 53-year-old middle school teacher complains that she has been having difficulty falling asleep, and after falling asleep, she awakens several times during the night. These episodes now occur almost nightly and are interfering with her ability to teach. She has tried various over-the-counter sleep remedies, but they were of little help and she experienced “hangover” effects on the day following their use. Her general health is good, she is


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Pharmacology_Katzung. Assignment of a drug to the sedative-hypnotic class indicates that it is able to cause sedation (with concomitant relief of anxiety) or to encourage sleep (hypnosis). Because there is considerable chemical variation within the group, this drug classification is based on clinical uses rather than on similarities in chemical structure. Anxiety states and sleep disorders are common problems, and sedative-hypnotics are widely prescribed drugs worldwide.


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Pharmacology_Katzung. An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect. The degree of central nervous system (CNS) depression caused by a sedative should be the minimum consistent with therapeutic efficacy. A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep. Hypnotic effects involve more pronounced depression of the CNS than sedation, and this can be achieved with many drugs in this class simply by increasing the dose. Graded dose-dependent depression of CNS function is a characteristic of most sedative-hypnotics. However, individual drugs differ in the relationship between the dose and the degree of CNS depression. Two examples of such dose-response relationships are shown in Figure 22–1. The linear slope for drug A is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. With such drugs, an increase in dose higher than that needed for hypnosis may lead to a state of general


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Pharmacology_Katzung. A is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. With such drugs, an increase in dose higher than that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, these sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death. Deviations from a linear dose-response relationship, as shown for drug B, require proportionately greater dosage increments to achieve CNS depression more profound than hypnosis. This appears to be the case for benzodiazepines and for certain newer hypnotics that have a similar mechanism of action.


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Pharmacology_Katzung. The benzodiazepines are widely used sedative-hypnotics. All of the structures shown in Figure 22–2 are 1,4-benzodiazepines, and most contain a carboxamide group in the seven-membered heterocyclic ring structure. A substituent in the 7 position, such as a halogen or a nitro group, is required for sedative-hypnotic activity. The structures of triazolam and alprazolam include the addition of a triazole ring at the 1,2-position. FIGURE 22–1 Dose-response curves for two hypothetical sedative-hypnotics. The chemical structures of some older and less commonly used sedative-hypnotics, including several barbiturates, are shown in Figure 22–3. Glutethimide and meprobamate are of distinctive chemical structure but are practically equivalent to barbiturates in their pharmacologic effects. They are rarely used. The sedative-hypnotic class also includes compounds of simpler chemical structure, including ethanol (see Chapter 23) and chloral hydrate.