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Pharmacology_Katzung. Example: HMG-coenzyme A (CoA) reductase inhibitors (statins) are highly effective medications that are widely prescribed to reduce serum lipids for the prevention of cardiovascular events (Chapter 35). Seven statins in use currently are generally safe and well-tolerated, but skeletal muscle toxicity can limit their use. Known risk factors include high statin dose, interacting medications, advanced age, and metabolic comorbidities. Furthermore, the common variant, rs4149056 in SLCO1B1, increases systemic exposure of simvastatin (221% increase in plasma area under the curve for patients homozygous for the rs4149056 variant, eg, SLCO1B1*5/*5; *5/[*15 or *17]; or [*15 or *17]/[*15 or *17]) and was identified to have the single strongest association with simvastatin-induced myopathy in a GWA analysis. For individuals receiving simvastatin with reduced OATP1B1 function (at least one nonfunctional allele), CPIC recommends a lower simvastatin dose or an alternative statin (Table 5–2).


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Pharmacology_Katzung. BREAST CANCER RESISTANCE PROTEIN (BCRP, ABCG2)


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Pharmacology_Katzung. BCRP (encoded by the ABCG2 gene), an efflux transporter in the ATP binding cassette (ABC) superfamily, is located on epithelial cells of the kidney, liver, and intestine as well as on the endothelial cells of the blood-brain barrier. Recent studies have implicated a reduced function variant in ABCG2, which encodes an amino acid change from glutamine to lysine at position 141 of the protein (rs2231142), as a determinant of the pharmacokinetics, response, and toxicity of several drugs. The variant has a low frequency in individuals of African ancestry but is found at an allele frequency of about 30% in East Asians including Chinese and Japanese. Notably, the variant has been associated with changes in response to the xanthine oxidase inhibitor, allopurinol, and the statin rosuvastatin. In addition, the variant has been associated with toxicity to various anticancer drugs. Because of its high allele frequency, particularly in Asian populations, and the fact that the transporter is a


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Pharmacology_Katzung. In addition, the variant has been associated with toxicity to various anticancer drugs. Because of its high allele frequency, particularly in Asian populations, and the fact that the transporter is a determinant of the pharmacokinetics of many drugs, it is likely that this variant will become increasingly important in precision medicine.


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Pharmacology_Katzung. Genetic predispositions to drug response and toxicities are not limited to genes related to pharmacokinetic processes, eg, drug-metabolizing enzymes and drug transporters. Additional genetic sources of variation may include genes involved in pharmacodynamic processes such as drug receptors and drug targets. For example, a polymorphism in HLA loci is associated with a predisposition to drug toxicity. Hypersensitivity reactions to various drugs can range from mild rashes to severe skin toxicities. The most severe hypersensitivity reactions are liver injury, toxic epidermal necrosis (TEN), and Stevens-Johnson syndrome (SJS), in which drugs or their metabolites form antigens. Drug classes associated with hypersensitivity reactions include sulfonamides, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, steroids, anti-epileptic agents, and methotrexate.


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Pharmacology_Katzung. Hypersensitivity reactions have varying prevalence rates in different racial and ethnic populations. For example, carbamazepineinduced skin toxicities have an increased prevalence in East Asian populations. Population-based hypersensitivity reactions have been attributed to genetic polymorphisms in the HLA system, which are part of the major histocompatibility complex (MHC) gene family (see also Chapter 55). Of the several HLA forms, HLA-B, HLA-DQ, and HLA-DR polymorphisms have been associated with many drug-induced hypersensitivity reactions, including reactions to allopurinol, carbamazepine, abacavir, and flucloxacillin (Table 5–4).


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Pharmacology_Katzung. Many HLA-B polymorphisms have been characterized and have varying allele frequencies depending on the racial and ethnic population. A polymorphism in HLA-B may result in altered antigen-binding sites in the HLA molecule, which in turn may recognize different peptides. The selective recognition of particular drug-bound peptides by some HLA-B polymorphism products results in population-selective drug hypersensitivity reactions. Example 1: Abacavir, a nucleoside reverse transcriptase inhibitor used in the treatment of HIV, is associated with hypersensitivity reactions in the skin, particularly SJS, which for with Stevens-Johnson syndrome, toxic epidermal necrosis, or drug-induced liver injury. ALT, alanine transaminase. many years appeared to be idiosyncratic, ie, of unknown mecha-


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Pharmacology_Katzung. ALT, alanine transaminase. many years appeared to be idiosyncratic, ie, of unknown mecha- Stable ordering of tests nism. Although the drug-bound peptide involved in abacavir hypersensitivity has not been isolated or identified, it appears to interact somewhat specifically with the product of HLA-B*57:01, an HLA-B polymorphism found more commonly in European populations (Table 5–1). Other HLA-B polymorphisms are not associated with abacavir-induced hypersensitivity reactions. However, it is noteworthy that HLA-B*57:01, though necessary for SJS or TEN associated with abacavir, is not sufficient. That is, many individuals with the polymorphism do not get the hypersensitivity reaction. This lack of specificity is not understood and clearly warrants further study.


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Pharmacology_Katzung. Abacavir hypersensitivity reactions are known to vary in frequency among ethnic groups, consistent with the population frequencies of the HLA-B*57:01 allele. As a prodrug, abacavir is activated to carbovir triphosphate, a reactive molecule that may be involved in the immunogenicity of abacavir. Abacavir-induced hypersensitivity reactions are probably mediated by the activation of cytotoxic CD8 T cells. In fact, there is an increased abundance of CD8 T cells in the skin of patients with abacavir hypersensitivity reactions. Experiments demonstrating that CD8-positive T cells can be stimulated by lymphoblastoid cell lines expressing HLAB*57:01, but not HLA-B*57:02 or HLA-B*58:01, suggest that the HLA-B*57:01 protein may recognize and bind an abacavir-associated peptide, which is not recognized by the other polymorphisms. Alternatively, the HLA-B*57:01 gene product complex may present the ligand-bound peptide on the cell surface in a structurally different configuration, which is


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Pharmacology_Katzung. recognized by the other polymorphisms. Alternatively, the HLA-B*57:01 gene product complex may present the ligand-bound peptide on the cell surface in a structurally different configuration, which is recognized by cytotoxic T cells.


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Pharmacology_Katzung. Because of the importance of abacavir in therapeutics, genetic testing of the HLA-B*57:01 biomarker associated with abacavir hypersensitivity has been rapidly incorporated into clinical practice, much faster than typical genetic tests (Figure 5–1). CPIC FIGURE 5–1 Increasing use of testing for genetic variants of drug metabolism over time. Adoption of testing in clinical medicine typically undergoes three phases. Testing for HLA-B*5701 was rapidly adopted. (Adapted, with permission, from Lai-Goldman M, Faruki H: Abacavir hypersensitivity: A model system for pharmacogenetic test adoption. Genet Med 2008;10:874. Copyright 2008 Macmillan Publishers Ltd.) recommendations based on genotyping results are shown in Table 5–2.


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Pharmacology_Katzung. Example 2: Flucloxacillin hypersensitivity reactions may lead to drug-induced liver toxicity. In particular, in 51 cases of flucloxacillin hepatotoxicity, a highly significant association was identified with a polymorphism linked to HLA-B*57:01 (Figure 5–2). HLA polymorphisms also contribute to liver injury from other drugs (Table 5–4). For example, reaction to the anticoagulant


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Pharmacology_Katzung. FIGURE 5–2 Results from a flucloxacillin drug-induced liver injury study. Each dot represents an SNP in a genome-wide assay. The x axis represents the position of the SNP on chromosomes. The y axis represents the magnitude of the association of each SNP with liver damage (Cochran-Armitage trend P value) in a case-control study that included 51 liver injury cases and 282 population controls. The high signal peak in chromosome 6 lies in the MHC region and indicates very strong association of injury with that SNP. The horizontal dashed line represents the commonly accepted minimum level for significance in this type of study. (Reproduced, with permission, from Daly AK et al: HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41:816. Copyright 2009 Macmillan Publishers Ltd.) ximelagatran is associated with a HLA-DRB1*07:01 allele. Several drugs used in the treatment of tuberculosis, including isoniazid, rifampin, and ethambutol,


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Pharmacology_Katzung. Copyright 2009 Macmillan Publishers Ltd.) ximelagatran is associated with a HLA-DRB1*07:01 allele. Several drugs used in the treatment of tuberculosis, including isoniazid, rifampin, and ethambutol, also cause liver injury, which appears to be related to HLA polymorphisms.


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Pharmacology_Katzung. Interferon lambda-3 (IFN-λ3; also known as interleukin-28B), encoded by the IFNL3 (or IL28B) gene, belongs to the family of type III IFN-λ cytokines. Type III IFNs share many therapeutic effects with type I IFNs, eg, IFN-a (Chapter 55), such as being directly induced by viruses and acting through JAK-STAT signal transduction pathways (via distinct heterodimeric receptor signaling complexes) to produce antiviral activity in cells. Type III IFNs play a role in hepatitis C virus (HCV) infection. Genetic variants near the IFNL3 gene were found to be most significantly associated with HCV treatment response to pegylated-IFN-a (PEG-IFN-a), in combination with ribavirin (RBV). Approximately twofold greater cure rates were observed in patients with a favorable genotype. While the mechanism underlying this association has yet to be fully elucidated, the rs12979860 variant near IFNL3 is considered the strongest baseline predictor of a cure for patients with HCV-1 receiving PEG-IFN-a/RBV. The


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Pharmacology_Katzung. this association has yet to be fully elucidated, the rs12979860 variant near IFNL3 is considered the strongest baseline predictor of a cure for patients with HCV-1 receiving PEG-IFN-a/RBV. The favorable allele, the rs12979860 variant, is inherited most frequently in Asians (∼90%), and least frequently in Africans (Table 5–1). This frequency distribution is remarkably similar to rates of response to HCV PEG-IFN-a/RBV treatment among the three ethnic groups.


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Pharmacology_Katzung. Pegylated interferon with ribavirin: Chronic HCV affects 160 million people worldwide and is a leading cause of cirrhosis of the liver and liver cancer. The goal for HCV antiviral therapy is to resolve the infection, defined clinically as achievement of sustained virologic response (SVR), ie, undetectable HCV RNA measured 6 months after finishing treatment. For patients receiving PEG-IFN-a/RBV regimens, which are associated with many side effects and poor response, clinical decisions of whether to initiate therapy are largely based on likelihood of SVR. Predictors of SVR include viral factors, as well as patient factors. In addition, Europeans homozygous for the favorable genotype (IFNL3 rs12979860/rs12979860; SVR: 69%) are more likely to achieve SVR compared with the unfavorable genotype (IFNL3 reference/reference or reference/rs12979860; SVR: 33% and 27%, respectively), and similar rates are observed in African patients. Guidelines according to CPIC are shown in Table 5–2.


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Pharmacology_Katzung. In the above examples, variations within single gene loci are described that are significantly associated with altered drug response or toxicity. However, it is expected that polygenic influences, ie, the combinatorial effect of multiple genes on drug response, may more accurately describe individual differences with respect to clinical outcomes. As evidence grows linking newly discovered pharmacogenetic biomarkers with therapeutic response or adverse outcomes, adequately powered clinical studies that consider the impact of newly discovered genes in the context of previously established genetic biomarkers are essential for making strong clinical recommendations. This is best exemplified by warfarin, where the effects of two genes, CYP2C9 and VKORC1, on dose requirement have been clearly defined.


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Pharmacology_Katzung. CYP2C9 is a phase I drug-metabolizing enzyme that acts primarily on acidic drugs including S-warfarin, phenytoin, and NSAIDs (Chapter 4). The gene that encodes CYP2C9 is highly polymorphic, with over 50 alleles defined (www.cypalleles.ki.se/cyp2c9. htm). However, much of the variability in metabolic clearance of CYP2C9 substrates may be accounted for with just two well-studied alleles, CYP2C9*2 and *3. Allele CYP2C9*2 encodes an amino acid change (Arg144Cys) located on the outer surface of the CYP2C9 enzyme, which impairs interaction with the microsomal P450 oxidoreductase and leads to reduced metabolism of CYP2C9 substrates, including a 30–40% reduction in S-warfarin metabolism. Allele CYP2C9*3 encodes an amino acid change (Ile359Leu) on the interior of the enzyme, which results in lowered affinity for many CYP2C9 substrates and a more marked (80– 90%) reduction in S-warfarin metabolism. Both alleles *2 and *3 are more common in European populations compared with African and Asian


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Pharmacology_Katzung. affinity for many CYP2C9 substrates and a more marked (80– 90%) reduction in S-warfarin metabolism. Both alleles *2 and *3 are more common in European populations compared with African and Asian populations (7–13% vs < 5%, respectively) and are therefore most useful to explain CYP2C9 variability in Europeans (Table 5–1). Additional reduced function alleles, eg, CYP2C9*5, *6, *8, and *11, occur more frequently in African populations, and as evidence accumulates, their inclusion in genetic tests may improve our ability to explain warfarin variability in Africans.


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Pharmacology_Katzung. Vitamin K epoxide reductase complex subunit 1 (VKORC1), encoded by the VKORC1 gene, is the target of anticoagulant warfarin and a key enzyme in the vitamin K recycling process (Chapter 34, Figure 34–6). Activated vitamin K is an essential cofactor for activation of blood clotting factors II, VII, IX, and X, as well as endogenous anticoagulant proteins C and S. Rare genetic variants in the coding region of VKORC1 may lead to bleeding disorders, eg, multiple coagulation factor deficiency type 2A, or warfarin resistance. A polymorphism common across all major ethnicities is located in a transcription factor-binding site, VKORC1-1639G>A, which results in reduced expression of VKORC1 in the liver. The most important consequences of the VKORC1 polymorphism are increased sensitivity to warfarin (discussed below). The VKORC1-1639G>A polymorphism occurs most frequently in Asian populations (∼90%) and least often in Africans (∼10%), which explains, in part, the difference in dosing requirements


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Pharmacology_Katzung. below). The VKORC1-1639G>A polymorphism occurs most frequently in Asian populations (∼90%) and least often in Africans (∼10%), which explains, in part, the difference in dosing requirements among major ethnic groups (Table 5–1).


Pharmacology_Katzung

Pharmacology_Katzung. Example: Warfarin, a vitamin K antagonist, is the oldest and most widely prescribed oral anticoagulant worldwide. Within a narrow therapeutic range, warfarin is highly effective for the prevention and treatment of thromboembolic disorders (Chapter 34). Nevertheless, interpatient differences in dosing requirements (up to 20-fold) often lead to complications from subtherapeutic anticoagulation and clotting or supratherapeutic anticoagulation and bleeding, which are among the most common causes for emergency room visits in the United States. Understanding the factors that contribute to variability in individual warfarin maintenance doses may improve therapeutic outcomes.


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Pharmacology_Katzung. Warfarin dosing algorithms that include clinical and known genetic influences on warfarin dose, ie, polymorphisms in CYP2C9 and VKORC1, clearly outperform empiric-dosing approaches based on population averages, as well as dosing based on clinical factors alone (Table 5–2). The pharmacologic action of warfarin is mediated through inactivation of VKORC1, and since the discovery of the VKORC1 gene in 2004, numerous studies have indicated that individuals with decreased VKORC1 expression, eg, carriers of the -1639G>A polymorphism, are at increased risk for excessive anticoagulation following standard warfarin dosages. Furthermore, warfarin is administered as a racemic mixture of Rand S-warfarin, and patients with reduced-function CYP2C9 genotypes are at increased risk for bleeding due to decreased metabolic clearance of the more potent S-warfarin enantiomer. It is predicted that gene-based dosing may help optimize warfarin therapy management and minimize risks for adverse drug reactions.


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Pharmacology_Katzung. Recently, epigenomics, which is the heritable patterns of gene expression not attributable to changes in the primary DNA sequence, has become an active area of research that may provide additional insights into the causes of variability in drug response. Epigenomic mechanisms that can regulate genes involved in pharmacokinetics or drug targets include DNA methylation and his-tone modifications. Although there is still much to be understood, epigenomics may contribute to our knowledge of diseases as well as our understanding of individual phenotypes such as acquired drug resistance.


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Pharmacology_Katzung. Discoveries in pharmacogenomics are increasing as new technologies for genotyping are being developed and as access to patient DNA samples along with drug response information has accelerated. Increasingly, pharmacogenomics discoveries will move beyond single SNPs to multiple SNPs that inform both adverse and therapeutic responses. It is hoped that prescriber-friendly predictive models incorporating SNPs and other biomarkers as well as information on demographics, comorbidities, epigenetic signatures, and concomitant medications will be developed to aid in drug and dose selection. CPIC guidelines and Food and Drug Administration-stimulated product label changes will contribute to the accelerated translation of discoveries to clinical practice. Altman RB, Whirl-Carrillo M, Klein TE: Challenges in the pharmacogenomic annotation of whole genomes. Clin Pharmacol Ther 2013;94:211. Bertilsson DL: Geographical/interracial differences in polymorphic drug oxidation.


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Pharmacology_Katzung. Clin Pharmacokinet 1995;29:192. Browning LA, Kruse JA: Hemolysis and methemoglobinemia secondary to rasburicase administration. Ann Pharmacother 2005;39:1932. Camptosar [irinotecan product label]. New York, NY: Pfizer Inc.; 2012. Cappellini MD, Fiorelli G: Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008;371:64. Caudle KE et al: Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther 2013;94:640. Chasman DI et al: Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Circ Cardiovasc Genet 2012;5:257. Crews KR et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2009;91:321.


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Pharmacology_Katzung. Crews KR et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2009;91:321. Daly AK et al: HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41:816. Elitek [rasburicase product label]. Bridgewater, NJ: Sanofi U.S. Inc.; 2009. Gammal RS et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for UGT1A1 and atazanavir prescribing. Clin Pharmacol Ther 2016;99:363. Giacomini KM et al: International Transporter Consortium commentary on clinically important transporter polymorphisms. Clin Pharmacol Ther 2013;94:23. Howes RE et al: G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: A geostatistical model-based map. PLoS Med 2012;9:e1001339.


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Pharmacology_Katzung. Howes RE et al: G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: A geostatistical model-based map. PLoS Med 2012;9:e1001339. Howes RE et al: Spatial distribution of G6PD deficiency variants across malaria-endemic regions. Malaria J 2013;12:418. Johnson JA et al: Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2009;90:625. Johnson JA, Klein TE, Relling MV: Clinical implementation of pharmacogenetics: More than one gene at a time. Clin Pharmacol Ther 2013;93:384. Kim IS et al: ABCG2 Q141K polymorphism is associated with chemotherapy-induced diarrhea in patients with diffuse large B-cell lymphoma who received frontline rituximab plus cyclophosphamide/doxorubicin/vincristine/ prednisone chemotherapy. Cancer Sci 2008;99:2496. Lai-Goldman M, Faruki H: Abacavir hypersensitivity: A model system for pharmacogenetic test adoption. Genet Med 2008;10:874.


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Pharmacology_Katzung. Lai-Goldman M, Faruki H: Abacavir hypersensitivity: A model system for pharmacogenetic test adoption. Genet Med 2008;10:874. Lavanchy D: Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011;17:107. Matsuura K, Watanabe T, Tanaka Y: Role of IL28B for chronic hepatitis C treatment toward personalized medicine. J Gastroenterol Hepatol 2014;29:241. McDonagh EM et al: PharmGKB summary: Very important pharmacogene information for G6PD. Pharmacogenet Genomics 2012;22:219. Minucci A et al: Glucose-6-phosphate dehydrogenase (G6PD) mutations database: Review of the “old” and update of the new mutations. Blood Cell Mol Dis 2012;48:154. Moriyama T et al: NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 2016;48:367. Muir AJ et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and peginterferon alpha based regimens. Clin Pharmacol Ther 2014;95:141.


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Pharmacology_Katzung. Muir AJ et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and peginterferon alpha based regimens. Clin Pharmacol Ther 2014;95:141. Relling MV et al: Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2009;89:387. Russmann S, Jetter A, Kullak-Ublick GA: Pharmacogenetics of drug-induced liver injury. Hepatology 2010;52:748. Scott SA et al: Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 2013;94:317. Shin J: Clinical pharmacogenomics of warfarin and clopidogrel. J Pharmacy Pract 2012;25:428. Swen JJ et al: Pharmacogenetics: From bench to byte—An update of guidelines. Clin Pharmacol Ther 2009;89:662. Tukey RH, Strassburg CP: Human UDP-glucuronosyltransferases: Metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 2000;40:581.


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Pharmacology_Katzung. Tukey RH, Strassburg CP: Human UDP-glucuronosyltransferases: Metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 2000;40:581. Tukey RH, Strassburg CP, Mackenzie PI: Pharmacogenomics of human UDPglucuronosyltransferases and irinotecan toxicity. Mol Pharmacol 2002;62:446. Wen CC et al: Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin Pharmacol Ther 2015;97:518. WHO Working Group: Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Org 1989;67:601. Wilke RA et al: The Clinical Pharmacogenomics Implementation Consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther 2009;92:112. Xu J-M: Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms. World J Gastroenterol 2013;19:3899.


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Pharmacology_Katzung. Xu J-M: Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms. World J Gastroenterol 2013;19:3899. Yang J et al: Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol 2013;168:4234. Campbell JM et al: Irinotecan-induced toxicity pharmacogenetics: An umbrella review of systematic reviews and meta-analyses. Pharmacogenomics J 2017;17:21. Flockhart DA, Huang SM: Clinical pharmacogenetics. In: Atkinson AJ et al (editors): Principles of Clinical Pharmacology, 3rd ed. Elsevier, 2012. Huang SM, Chen L, Giacomini KM: Pharmacogenomic mechanisms of drug toxicity. In: Atkinson AJ et al (editors): Principles of Clinical Pharmacology, 3rd ed. Elsevier, 2012.


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Pharmacology_Katzung. Huang SM, Chen L, Giacomini KM: Pharmacogenomic mechanisms of drug toxicity. In: Atkinson AJ et al (editors): Principles of Clinical Pharmacology, 3rd ed. Elsevier, 2012. Meulendijks D et al: Improving safety of fluoropyrimidine chemotherapy by individualizing treatment based on dihydropyrimidine dehydrogenase activity: Ready for clinical practice? Cancer Treat Rev 2016;50:23. Relling MV, Giacomini KM: Pharmacogenetics. In: Brunton LL, Chabner BA, Knollmann BC (editors): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th ed. McGraw-Hill, 2011. Relling MV et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype. Clin Pharmacol Ther 2014;96:169. Zanger UM, Schwab M: Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138:103.


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Pharmacology_Katzung. Atazanavir inhibits the polymorphic UGT1A1 enzyme, which mediates the conjugation of glucuronic acid with bilirubin. Decreased UGT1A1 activity results in the accu-mulation of unconjugated (indirect) bilirubin in blood and tissues. When levels are high enough, yellow discoloration of the eyes and skin, ie, jaundice, is the result. The plasma levels of indirect bilirubin concentrations are expected to increase to greater than 2.5 times the upper limit of nor-mal (grade 3 or higher elevations) in approximately 40% of patients taking once-daily atazanavir boosted with ritonavir and at least 5 times the upper limit of normal (grade 4 eleva-tion) in approximately 4.8% of patients. Carriers of the UGT1A1 decreased function alleles (*28/*28 or *28/*37) have reduced enzyme activity and have an increased risk of atazanavir discontinuation. Genotyping showed that the patient was homozygous for the UGT1A1*28 allele polymor-phism. This probably led to the high levels of bilirubin and the


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Pharmacology_Katzung. an increased risk of atazanavir discontinuation. Genotyping showed that the patient was homozygous for the UGT1A1*28 allele polymor-phism. This probably led to the high levels of bilirubin and the subsequent discontinuation of atazanavir secondary to the adverse drug reaction of jaundice.


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Pharmacology_Katzung. Introduction to Autonomic Pharmacology Bertram G. Katzung, MD, PhD A 56-year-old woman is brought to the university eye center with a complaint of “loss of vision.” Because of visual impair-ment, she has lost her driver’s license and has fallen several times in her home. Examination reveals that her eyelids close involuntarily with a frequency and duration sufficient to pre-vent her from seeing her surroundings for more than brief moments at a time. When she holds her eyelids open with her fingers, she can see normally. She has no other muscle dysfunction. A diagnosis of blepharospasm is made. Using a fine needle, several injections of botulinum toxin type A are made in the orbicularis oculi muscle of each eyelid. After observation in the waiting area, she is sent home. Two days later, she reports by telephone that her vision has improved dramatically. How did botulinum toxin improve her vision? How long can her vision be expected to remain normal after this single treatment?


Pharmacology_Katzung

Pharmacology_Katzung. The nervous system is anatomically divided into the central nervous system (CNS; the brain and spinal cord) and the peripheral nervous system (PNS; neuronal tissues outside the CNS). Functionally, the nervous system can be divided into two major subdivisions: autonomic and somatic. The autonomic nervous system (ANS) is largely independent (autonomous) in that its activities are not under direct conscious control. It is concerned primarily with control and integration of visceral functions necessary for life such as cardiac output, blood flow distribution, and digestion. Evidence is accumulating that the ANS, especially the vagus nerve, also influences immune function and some CNS functions such as seizure discharge. Remarkably, some evidence indicates that autonomic nerves can also influence cancer development and progression. The motor portion of the somatic subdivision is largely concerned with consciously controlled functions such as movement, respiration, and posture. Both the


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Pharmacology_Katzung. cancer development and progression. The motor portion of the somatic subdivision is largely concerned with consciously controlled functions such as movement, respiration, and posture. Both the autonomic and the somatic systems have important afferent (sensory) inputs that provide information regarding the internal and external environments and modify motor output through reflex arcs of varying complexity.


Pharmacology_Katzung

Pharmacology_Katzung. The nervous system has several properties in common with the endocrine system. These include high-level integration in the brain, the ability to influence processes in distant regions of the body, and extensive use of negative feedback. Both systems use chemicals for the transmission of information. In the nervous system, chemical transmission occurs between nerve cells and between nerve cells and their effector cells. Chemical transmission takes place through the release of small amounts of transmitter substances from the nerve terminals into the synaptic cleft. The transmitter crosses the cleft by diffusion and activates or inhibits the postsynaptic cell by binding to a specialized receptor molecule. In a few cases, retrograde transmission may occur from the postsynaptic cell to the presynaptic neuron terminal and modify its subsequent activity.


Pharmacology_Katzung

Pharmacology_Katzung. By using drugs that mimic or block the actions of chemical transmitters, we can selectively modify many autonomic functions. These functions involve a variety of effector tissues, including cardiac muscle, smooth muscle, vascular endothelium, exocrine glands, and presynaptic nerve terminals. Autonomic drugs are useful in many clinical conditions. Unfortunately, a very large number of drugs used for other purposes (eg, allergies, mental illness) have unwanted effects on autonomic function. Medulla NE, D ˜, D1 Spinal cord ACh ACh ACh ACh ACh ACh ACh ACh N N N N N N M M NE Adrenal medulla Epi, NE Voluntary motor nerve ˜, °


Pharmacology_Katzung

Pharmacology_Katzung. Medulla NE, D ˜, D1 Spinal cord ACh ACh ACh ACh ACh ACh ACh ACh N N N N N N M M NE Adrenal medulla Epi, NE Voluntary motor nerve ˜, ° The ANS lends itself to division on anatomic grounds into two major portions: the sympathetic (thoracolumbar) division and the parasympathetic (traditionally “craniosacral,” but see Box: Sympathetic Sacral Outflow) division (Figure 6–1). Motor neurons in both divisions originate in nuclei within the CNS and give rise to preganglionic efferent fibers that exit from the brain stem or spinal cord and terminate in motor ganglia. The sympathetic preganglionic fibers leave the CNS through Cardiac and smooth muscle, gland cells, nerve terminals Cardiac and smooth muscle, gland cells, nerve terminals


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Pharmacology_Katzung. FIGURE 6–1 Schematic diagram comparing some anatomic and neurotransmitter features of autonomic and somatic motor nerves. Only the primary transmitter substances are shown. Parasympathetic ganglia are not shown because most are in or near the wall of the organ innervated. Cholinergic nerves are shown in blue, noradrenergic in red. Note that some sympathetic postganglionic fibers release acetylcholine rather than norepinephrine. Sympathetic nerves to the renal vasculature and kidney may release dopamine as well as norepinephrine during stress. The adrenal medulla, a modified sympathetic ganglion, receives sympathetic preganglionic fibers and releases epinephrine and nor-epinephrine into the blood. Not shown are the sacral preganglionic fibers that innervate the rectum, bladder, and genitalia. These fibers are probably sympathetic preganglionic nerves with cholinergic postganglionic fibers (see Box: Sympathetic Sacral Outflow). ACh, acetylcholine; D, dopamine; Epi, epinephrine; M,


Pharmacology_Katzung

Pharmacology_Katzung. These fibers are probably sympathetic preganglionic nerves with cholinergic postganglionic fibers (see Box: Sympathetic Sacral Outflow). ACh, acetylcholine; D, dopamine; Epi, epinephrine; M, muscarinic receptors; N, nicotinic receptors; NE, norepinephrine.


Pharmacology_Katzung

Pharmacology_Katzung. CHAPTER 6 Introduction to Autonomic Pharmacology the thoracic, lumbar, and (according to new information) sacral spinal nerves. The parasympathetic preganglionic fibers leave the CNS through the cranial nerves (especially the third, seventh, ninth, and tenth).


Pharmacology_Katzung

Pharmacology_Katzung. Most thoracic and lumbar sympathetic preganglionic fibers are short and terminate in ganglia located in the paravertebral chains that lie on either side of the spinal column. Most of the remaining sympathetic preganglionic fibers are somewhat longer and terminate in prevertebral ganglia, which lie in front of the vertebrae, usually on the ventral surface of the aorta. From the ganglia, post-ganglionic sympathetic fibers run to the tissues innervated. Some preganglionic parasympathetic fibers terminate in parasympathetic ganglia located outside the organs innervated: the ciliary, pterygopalatine, submandibular, and otic ganglia. However, the majority of parasympathetic preganglionic fibers terminate on ganglion cells distributed diffusely or in networks in the walls of the innervated organs. Several pelvic ganglia are innervated by sacral preganglionic nerves that are ontogenetically similar to sympathetic preganglionic fibers (see Box: Sympathetic Sacral Outflow). Note that the terms


Pharmacology_Katzung

Pharmacology_Katzung. Several pelvic ganglia are innervated by sacral preganglionic nerves that are ontogenetically similar to sympathetic preganglionic fibers (see Box: Sympathetic Sacral Outflow). Note that the terms “sympathetic” and “parasympathetic” are anatomic designations and do not depend on the type of transmitter chemical released from the nerve endings nor on the kind of effect—excitatory or inhibitory—evoked by nerve activity.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to these clearly defined peripheral motor portions of the ANS, large numbers of afferent fibers run from the periphery to integrating centers, including the enteric plexuses in the gut, the autonomic ganglia, and the CNS. Many of the sensory pathways that end in the CNS terminate in the hypothalamus and medulla and evoke reflex motor activity that is carried to the effector cells by the efferent fibers described previously. There is increasing evidence that some of these sensory fibers also have peripheral motor functions. The enteric nervous system (ENS) is a large and highly organized collection of neurons located in the walls of the gastrointestinal (GI) system (Figure 6–2). With over 150 million neurons, it EC EC EC EC EC EPAN IPAN IN ACh, CGRP EN NP 5HT NP postganglionic fibers preganglionic fibers ACh INEN IPAN ACh, CGRP ACh NE ACh NPNP NE ACh EN IN IPAN 5HT 5HT 5HT5HT ACh SCAC ACSC SC


Pharmacology_Katzung

Pharmacology_Katzung. EC EC EC EC EC EPAN IPAN IN ACh, CGRP EN NP 5HT NP postganglionic fibers preganglionic fibers ACh INEN IPAN ACh, CGRP ACh NE ACh NPNP NE ACh EN IN IPAN 5HT 5HT 5HT5HT ACh SCAC ACSC SC FIGURE 6–2 A highly simplified diagram of the intestinal wall and some of the circuitry of the enteric nervous system (ENS). The ENS receives input from both the sympathetic and the parasympathetic systems and sends afferent impulses to sympathetic ganglia and to the central nervous system. Many transmitter or neuromodulator substances have been identified in the ENS; see Table 6–1. ACh, acetylcholine; AC, absorptive cell; CGRP, calcitonin gene-related peptide; CM, circular muscle layer; EC, enterochromaffin cell; EN, excitatory neuron; EPAN, extrinsic primary afferent neuron; 5HT, serotonin; IN, inhibitory neuron; IPAN, intrinsic primary afferent neuron; LM, longitudinal muscle layer; MP, myenteric plexus; NE, norepinephrine; NP, neuropeptides; SC, secretory cell; SMP, submucosal plexus.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 6–1 Some of the transmitter substances found in autonomic nervous system, enteric nervous system, and nonadrenergic, noncholinergic neurons.1 1See Chapter 21 for transmitters found in the central nervous system.


Pharmacology_Katzung

Pharmacology_Katzung. is sometimes considered a third division of the ANS. It is found in the wall of the GI tract from the esophagus to the distal colon and is involved in both motor and secretory activities of the gut. It is particularly important in the control of motor activity of the colon. The ENS includes the myenteric plexus (the plexus of Auerbach) and the submucous plexus (the plexus of Meissner). These neuronal networks receive preganglionic fibers from the parasympathetic system and postganglionic sympathetic axons. They also receive sensory input from within the wall of the gut. Fibers from the neuronal cell bodies in these plexuses travel forward, backward, and in a circular direction to the smooth muscle of the gut to control motility and to secretory cells in the mucosa. Sensory fibers transmit chemical and mechanical information from the mucosa and from stretch receptors to motor neurons in the plexuses and to postganglionic neurons in the sympathetic ganglia. The parasympathetic and


Pharmacology_Katzung

Pharmacology_Katzung. chemical and mechanical information from the mucosa and from stretch receptors to motor neurons in the plexuses and to postganglionic neurons in the sympathetic ganglia. The parasympathetic and sympathetic fibers that synapse on enteric plexus neurons appear to play a modulatory role, as indicated by the observation that deprivation of input from both ANS divisions does not abolish GI activity. In fact, selective denervation may result in greatly enhanced motor activity.


Pharmacology_Katzung

Pharmacology_Katzung. The ENS functions in a semiautonomous manner, using input from the motor outflow of the ANS for modulation of GI activity and sending sensory information back to the autonomic centers in the CNS. The ENS also provides the necessary synchronization of impulses that, for example, ensures forward, not backward, propulsion of gut contents and relaxation of sphincters when the gut wall contracts.


Pharmacology_Katzung

Pharmacology_Katzung. The anatomy of autonomic synapses and junctions determines the localization of transmitter effects around nerve endings. Classic synapses such as the mammalian neuromuscular junction and most neuron-neuron synapses are relatively “tight” in that the nerve terminates in small boutons very close to the tissue innervated, so that the diffusion path from nerve terminal to postsynaptic receptors is very short. The effects are thus relatively rapid and localized. In contrast, junctions between autonomic neuron terminals and effector cells (smooth muscle, cardiac muscle, glands) differ from classic synapses in that transmitter is often released from a chain of varicosities in the postganglionic nerve fiber in the region of the smooth muscle cells rather than from boutons, and autonomic junctional clefts are wider than somatic synaptic clefts. CHAPTER 6 Introduction to Autonomic Pharmacology


Pharmacology_Katzung

Pharmacology_Katzung. As noted in the previous editions of this book and other stan-dard texts, it has long been believed that, like the cranial nerve cholinergic system described earlier, the cholinergic nerves that innervate the pelvic organs (rectum, bladder, and reproduc-tive organs) are part of the parasympathetic nervous system. However, a recent study (see Espinoza-Medina reference at the end of this chapter) suggests that the preganglionic sacral fibers are actually derived from embryonic sympathetic precur-sor cells and that the postganglionic fibers innervated by them are therefore members of the sympathetic cholinergic class. This claim is based on several lines of evidence, as follows: (1) Cranial parasympathetic preganglionic neurons express the homeo-gene Phox2b and the transcription factors Tbx20, Tbx2, and Tbx3; thoracic sympathetic and sacral preganglionic neurons do not. Sacral preganglionic neurons do express transcription fac-tor Foxp1, which is not expressed by cranial neurons. (2)


Pharmacology_Katzung

Pharmacology_Katzung. Tbx2, and Tbx3; thoracic sympathetic and sacral preganglionic neurons do not. Sacral preganglionic neurons do express transcription fac-tor Foxp1, which is not expressed by cranial neurons. (2) Cranial parasympathetic preganglionic fibers exit the CNS via dorsolat-eral exit points; the sympathetic and sacral preganglionic nerves exit the spinal cord via ventral root exits. (3) At an early stage of development, cranial preganglionic neurons express the vesicu-lar acetylcholine transporter (VAChT; VAT in Figure 6–3) but not nitric oxide synthase (NOS); sympathetic and sacral nerves at the same stage express NOS but not VAChT (even though they do express VAChT later in their development). These observa-tions require independent confirmation but constitute strong evidence in favor of changing the traditional “craniosacral” synonym for the parasympathetic nervous system to “cranial autonomic” nervous system.


Pharmacology_Katzung

Pharmacology_Katzung. Effects are thus slower in onset, and discharge of a single motor fiber often activates or inhibits many effector cells. An important traditional classification of autonomic nerves is based on the primary transmitter molecules—acetylcholine or norepinephrine—released from their terminals and varicosities. A large number of peripheral ANS fibers synthesize and release acetylcholine; they are cholinergic fibers; that is, they work by releasing acetylcholine. As shown in Figure 6–1, these include all preganglionic efferent autonomic fibers and the somatic (nonautonomic) motor fibers to skeletal muscle as well. Thus, almost all efferent fibers leaving the CNS are cholinergic. In addition, most parasympathetic postganglionic and some sympathetic postganglionic fibers are cholinergic. A significant number of parasympathetic postganglionic neurons use nitric oxide or peptides as the primary transmitter or as cotransmitters.


Pharmacology_Katzung

Pharmacology_Katzung. Most postganglionic sympathetic fibers (Figure 6–1) release norepinephrine (also known as noradrenaline); they are noradrenergic (often called simply “adrenergic”) fibers; that is, they work by releasing norepinephrine (noradrenaline). As noted, some sympathetic fibers release acetylcholine. Dopamine is a very important transmitter in the CNS, and it may be released by some peripheral sympathetic fibers under certain circumstances. Adrenal medullary cells, which are embryologically analogous to post-ganglionic sympathetic neurons, release a mixture of epinephrine and norepinephrine. Finally, most autonomic nerves also release several cotransmitter substances (described in the following text), in addition to the primary transmitters just described. Five key features of neurotransmitter function provide potential targets for pharmacologic therapy: synthesis, storage, release, termination of action of the transmitter, and receptor effects. These processes are discussed next.


Pharmacology_Katzung

Pharmacology_Katzung. The terminals and varicosities of cholinergic neurons contain large numbers of small membrane-bound vesicles concentrated near the portion of the cell membrane facing the synapse (Figure 6–3) as well as a smaller number of large dense-cored vesicles located farther from the synaptic membrane. The large vesicles contain a high concentration of peptide cotransmitters (Table 6–1), whereas the smaller clear vesicles contain most of the acetylcholine. Vesicles may be synthesized in the neuron cell body and carried to the terminal by axonal transport. They may also be recycled several times within the terminal after each exocytotic release of transmitter. Ultra-fast neuronal firing appears to be supported by rapid recycling of clathrin-coated vesicles from endosomes in the nerve terminal. Vesicles are provided with vesicle-associated membrane proteins (VAMPs), which serve to align them with release sites on the inner neuronal cell membrane and participate in triggering the release of


Pharmacology_Katzung

Pharmacology_Katzung. Vesicles are provided with vesicle-associated membrane proteins (VAMPs), which serve to align them with release sites on the inner neuronal cell membrane and participate in triggering the release of transmitter. The release site on the inner surface of the nerve terminal membrane contains synaptosomal nerve-associated proteins (SNAPs), which interact with VAMPs. VAMPs and SNAPs are collectively called fusion proteins.


Pharmacology_Katzung

Pharmacology_Katzung. Acetylcholine (ACh) is synthesized in the cytoplasm from acetyl-CoA and choline through the catalytic action of the enzyme choline acetyltransferase (ChAT). Acetyl-CoA is synthesized in mitochondria, which are present in large numbers in the nerve ending. Choline is transported from the extracellular fluid into the neuron terminal by a sodium-dependent membrane choline transporter (CHT; Figure 6–3). This symporter can be blocked by a group of research drugs called hemicholiniums. Once synthesized, acetylcholine is transported from the cytoplasm into the vesicles by a vesicle-associated transporter (VAT) that is driven by proton efflux (Figure 6–3). This antiporter can be blocked by the research drug vesamicol. Acetylcholine synthesis is a rapid process capable of supporting a very high rate of transmitter release. Storage of acetylcholine is accomplished by the packaging


Pharmacology_Katzung

Pharmacology_Katzung. Na+ Ca2+ Calcium channel Choline Axon Nerve terminal ACh ATP, P VAMPs SNAPs Presynaptic receptors Hemicholiniums Hetero-receptor Vesamicol Acetylcholine autoreceptor Botulinum toxin ACh CHT H+ ACh ATP, P ACh AcCoA + Choline ChATVAT


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 6–3 Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl-CoA (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine (ACh) is then transported into the storage vesicle by a vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Release of transmitters occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft (see text). This step can be blocked by botulinum


Pharmacology_Katzung

Pharmacology_Katzung. calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft (see text). This step can be blocked by botulinum toxin. Acetylcholine’s action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosomal nerve-associated proteins; VAMPs, vesicle-associated membrane proteins.


Pharmacology_Katzung

Pharmacology_Katzung. of “quanta” of acetylcholine molecules (usually 1000–50,000 Vesicles are concentrated on the inner surface of the nerve termimolecules in each vesicle). Most of the vesicular acetylcholine nal facing the synapse through the interaction of so-called SNARE (a positively charged quaternary amine) is bound to negatively proteins on the vesicle (a subgroup of VAMPs called v-SNAREs, charged vesicular proteoglycan (VPG). especially synaptobrevin) and on the inside of the terminal


Pharmacology_Katzung

Pharmacology_Katzung. CHAPTER 6 Introduction to Autonomic Pharmacology cell membrane (SNAPs called t-SNAREs, especially syntaxin and SNAP-25). Physiologic release of transmitter from the vesicles is dependent on extracellular calcium and occurs when an action potential reaches the terminal and triggers sufficient influx of calcium ions via N-type calcium channels. Calcium interacts with the VAMP synaptotagmin on the vesicle membrane and triggers fusion of the vesicle membrane with the terminal membrane and opening of a pore into the synapse. The opening of the pore and inrush of cations results in release of the acetylcholine from the proteoglycan and exocytotic expulsion into the synaptic cleft. One depolarization of a somatic motor nerve may release several hundred quanta into the synaptic cleft. One depolarization of an autonomic postganglionic nerve varicosity or terminal probably releases less and releases it over a larger area. In addition to acetylcholine, several cotransmitters are released at the


Pharmacology_Katzung

Pharmacology_Katzung. of an autonomic postganglionic nerve varicosity or terminal probably releases less and releases it over a larger area. In addition to acetylcholine, several cotransmitters are released at the same time (Table 6–1). The acetylcholine vesicle release process is blocked by botulinum toxin through the enzymatic cleavage of two amino acids from one or more of the fusion proteins.


Pharmacology_Katzung

Pharmacology_Katzung. After release from the presynaptic terminal, acetylcholine molecules may bind to and activate an acetylcholine receptor (cholinoceptor). Eventually (and usually very rapidly), all of the acetylcholine released diffuses within range of an acetylcholinesterase (AChE) molecule. AChE very efficiently splits acetylcholine into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter (Figure 6–3). Most cholinergic synapses are richly supplied with acetylcholinesterase; the half-life of acetylcholine molecules in the synapse is therefore very short (a fraction of a second). Acetylcholinesterase is also found in other tissues, eg, red blood cells. (Other cholinesterases with a lower specificity for acetylcholine, including butyrylcholinesterase [pseudocholinesterase], are found in blood plasma, liver, glia, and many other tissues.)


Pharmacology_Katzung

Pharmacology_Katzung. Adrenergic neurons (Figure 6–4) transport the precursor amino acid tyrosine into the nerve ending, convert it to dopa, and then synthesize a catecholamine transmitter (dopamine, norepinephrine, or epinephrine; Figure 6–5), and store it in membrane-bound vesicles. In most sympathetic postganglionic neurons, norepinephrine is the final product. In the adrenal medulla and certain areas of the brain, some norepinephrine is further converted to epinephrine. In dopaminergic neurons, synthesis terminates with dopamine. Several processes in these nerve terminals are potential sites of drug action. One of these, the conversion of tyrosine to dopa by tyrosine hydroxylase, is the rate-limiting step in catecholamine transmitter synthesis. It can be inhibited by the tyrosine analog metyrosine. A high-affinity antiporter for catecholamines located in the wall of the storage vesicle (vesicular monoamine transporter, VMAT) can be inhibited by the reserpine alkaloids. Reserpine and related drugs


Pharmacology_Katzung

Pharmacology_Katzung. high-affinity antiporter for catecholamines located in the wall of the storage vesicle (vesicular monoamine transporter, VMAT) can be inhibited by the reserpine alkaloids. Reserpine and related drugs (tetrabenazine, deutetrabenazine) cause depletion of transmitter stores. Another transporter (norepinephrine transporter, NET) carries norepinephrine and similar molecules back into the cell cytoplasm from the synaptic cleft (Figure 6–4; NET). NET is also commonly called uptake 1 or reuptake 1 and is partially responsible for the termination of synaptic activity. NET can be inhibited by cocaine and certain antidepressant drugs, resulting in an increase of transmitter activity in the synaptic cleft (see Box: Neurotransmitter Uptake Carriers).


Pharmacology_Katzung

Pharmacology_Katzung. Release of the vesicular transmitter store from noradrenergic nerve endings is similar to the calcium-dependent process previously described for cholinergic terminals. In addition to the primary transmitter (norepinephrine), adenosine triphosphate (ATP), dopamine-β-hydroxylase, and peptide cotransmitters are simultaneously released from the same vesicles. Indirectly acting and mixed-action sympathomimetics, eg, tyramine, amphetamines, and ephedrine, are capable of releasing stored transmitter from noradrenergic nerve endings by a calcium-independent process. These drugs are poor agonists (some are inactive) at adrenoceptors, but they are excellent substrates for monoamine transporters. As a result, they are avidly taken up into noradrenergic nerve endings by NET. In the nerve ending, they are then transported by VMAT into the vesicles, displacing norepinephrine, which is subsequently expelled into the synaptic space by reverse transport via NET. Amphetamines also inhibit monoamine


Pharmacology_Katzung

Pharmacology_Katzung. are then transported by VMAT into the vesicles, displacing norepinephrine, which is subsequently expelled into the synaptic space by reverse transport via NET. Amphetamines also inhibit monoamine oxidase and have other effects that result in increased norepinephrine activity in the synapse. Their action does not require vesicle exocytosis.


Pharmacology_Katzung

Pharmacology_Katzung. As noted in Chapters 1, 4, and 5, several large families of trans-port proteins have been identified. The most important of these are the ABC (ATP-binding cassette) and SLC (solute carrier) trans-porter families. As indicated by the name, the ABC carriers use ATP for transport. The SLC proteins are cotransporters and, in most cases, use the movement of sodium down its concentration gradient as the energy source. Under some circumstances, they also transport transmitters in the reverse direction in a sodium-independent fashion. NET, SLC6A2, the norepinephrine transporter, is a member of the SLC family, as are similar transporters responsible for the reuptake of dopamine (DAT, SLC6A3) and 5-HT (serotonin, SERT, SLC6A4) into the neurons that release these transmit-ters. These transport proteins are found in peripheral tissues and in the CNS wherever neurons using these transmitters are located. NET is important in the peripheral actions of cocaine and the amphetamines. In the CNS, NET


Pharmacology_Katzung

Pharmacology_Katzung. are found in peripheral tissues and in the CNS wherever neurons using these transmitters are located. NET is important in the peripheral actions of cocaine and the amphetamines. In the CNS, NET and SERT are important targets of several antidepressant drug classes (see Chapter 30). The most important inhibitory transmitter in the CNS, γ-aminobutyric acid (GABA), is the substrate for at least three SLC transporters: GAT1, GAT2, and GAT3. GAT1 is the target of an antiseizure medication (see Chapter 24). Other SLC proteins transport glutamate, the major excitatory CNS transmitter.


Pharmacology_Katzung

Pharmacology_Katzung. +VMAT+TyrosineAxon AMPsHetero-receptorHNE ATP, P TyrA DopamineDopaMetyrosineNorepinephrineautoreceptorTyrosinehydroxylaseNE, ATP, P NETNaV


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 6–4 Schematic diagram of a generalized noradrenergic junction (not to scale). Tyrosine is transported into the noradrenergic nerve ending or varicosity by a sodium-dependent carrier (A). Tyrosine is converted to dopamine (see Figure 6–5 for details), and transported into the vesicle by the vesicular monoamine transporter (VMAT), which can be blocked by reserpine and tetrabenazine. The same carrier transports norepinephrine (NE) and several related amines into these vesicles. Dopamine is converted to NE in the vesicle by dopamine-β-hydroxylase. Physiologic release of transmitter occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of norepinephrine, cotransmitters, and dopamine-β-hydroxylase. Release can be blocked by drugs such as guanethidine and bretylium. After release, norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the


Pharmacology_Katzung

Pharmacology_Katzung. and dopamine-β-hydroxylase. Release can be blocked by drugs such as guanethidine and bretylium. After release, norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter (NET), which can be blocked by cocaine and certain antidepressants, or into postjunctional or perijunctional cells. Regulatory receptors are present on the presynaptic terminal. SNAPs, synaptosome-associated proteins; VAMPs, vesicle-associated membrane proteins.


Pharmacology_Katzung

Pharmacology_Katzung. Bretylium, guanethidine Cocaine, tricyclic antidepressants Norepinephrine and epinephrine can be metabolized by several an estimate of catecholamine turnover can be obtained from meaenzymes, as shown in Figure 6–6. Because of the high activity of surement of total metabolites (sometimes referred to as “VMA and monoamine oxidase in the mitochondria of the nerve terminal, metanephrines”) in a 24-hour urine sample. However, metabolism there is significant turnover of norepinephrine even in the resting is not the primary mechanism for termination of action of nor-terminal. Since the metabolic products are excreted in the urine, epinephrine physiologically released from noradrenergic nerves. CHAPTER 6 Introduction to Autonomic Pharmacology


Pharmacology_Katzung

Pharmacology_Katzung. CHAPTER 6 Introduction to Autonomic Pharmacology FIGURE 6–5 Biosynthesis of catecholamines. The rate-limiting step, conversion of tyrosine to dopa, can be inhibited by metyrosine (α-methyltyrosine). The alternative pathway shown by the dashed arrows has not been found to be of physiologic significance in humans. However, tyramine and octopamine may accumulate in patients treated with monoamine oxidase inhibitors. (Reproduced, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011. Copyright © The McGraw-Hill Companies, Inc.) Termination of noradrenergic transmission results from two processes: simple diffusion away from the receptor site (with eventual metabolism in the plasma or liver) and reuptake into the nerve terminal by NET (Figure 6–4) or into perisynaptic glia or other cells.


Pharmacology_Katzung

Pharmacology_Katzung. As previously noted, the vesicles of both cholinergic and adrenergic nerves contain other substances in addition to the primary transmitter, sometimes in the same vesicles and sometimes in a separate vesicle population. Some of the substances identified to date are listed in Table 6–1. Many of these substances are also primary transmitters in the nonadrenergic, noncholinergic nerves described in the text that follows. They appear to play several roles in the function of nerves that release acetylcholine or nor-epinephrine. In some cases, they provide a faster or slower action to supplement or modulate the effects of the primary transmitter. They also participate in feedback inhibition of the same and nearby nerve terminals. Growth of neurons and transmitter expression in specific neurons is a dynamic process. For example, neurotrophic factors released from target tissues influence growth and synapse formation by neurons. In addition, the transmitters released from a


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 6–6 Metabolism of catecholamines by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). (Reproduced, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011. Copyright © The McGraw-Hill Companies, Inc.) specific population of neurons can change in response to environmental factors such as the light-dark cycle. Historically, structure-activity analyses, with careful comparisons of the potency of series of autonomic agonist and antagonist analogs, led to the definition of different autonomic receptor subtypes, including muscarinic and nicotinic cholinoceptors, and α, β, and dopamine adrenoceptors (Table 6–2). Subsequently, binding of isotope-labeled ligands permitted the purification and characterization of several of the receptor molecules. Molecular biology now provides techniques for the discovery and expression of genes that code for related receptors within these groups (see Chapter 2).


Pharmacology_Katzung

Pharmacology_Katzung. The primary acetylcholine receptor subtypes were named after the alkaloids originally used in their identification: muscarine and nicotine, thus muscarinic and nicotinic receptors. In the case of receptors associated with noradrenergic nerves, the use of the names of the agonists (noradrenaline, phenylephrine, isoproterenol, and others) was not practicable. Therefore, the term adrenoceptor is widely used to describe receptors that respond to catecholamines such as norepinephrine. By analogy, the term cholinoceptor denotes receptors (both muscarinic and nicotinic) that respond to acetylcholine. In North America, receptors were colloquially named after the nerves that usually innervate them; thus, CHAPTER 6 Introduction to Autonomic Pharmacology TABLE 6–2 Major autonomic receptor types. 1Cardiac β3-receptor function is poorly understood, but activation does not appear to result in stimulation of rate or force.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 6–2 Major autonomic receptor types. 1Cardiac β3-receptor function is poorly understood, but activation does not appear to result in stimulation of rate or force. adrenergic (or noradrenergic) receptors and cholinergic receptors. The general class of adrenoceptors can be further subdivided into α-adrenoceptor, β-adrenoceptor, and dopamine-receptor types on the basis of both agonist and antagonist selectivity and on genomic grounds. Development of more selective blocking drugs has led to the naming of subclasses within these major types; for example, within the α-adrenoceptor class, α1 and α2 receptors differ in both agonist and antagonist selectivity. Examples of such selective drugs are given in the chapters that follow. NONADRENERGIC, NONCHOLINERGIC (NANC) NEURONS


Pharmacology_Katzung

Pharmacology_Katzung. NONADRENERGIC, NONCHOLINERGIC (NANC) NEURONS It has been known for many years that autonomic effector tissues (eg, gut, airways, bladder) contain nerve fibers that do not show the histochemical characteristics of either cholinergic or adrenergic fibers. Both motor and sensory NANC fibers are present. Although peptides are the most common transmitter substances found in these nerve endings, other substances, eg, nitric oxide synthase and purines, are also present in many nerve terminals (Table 6–1). Capsaicin, a neurotoxin derived from chili peppers, can cause the release of transmitter (especially substance P) from such neurons and, if given in high doses, destruction of the neuron.


Pharmacology_Katzung

Pharmacology_Katzung. The enteric system in the gut wall (Figure 6–2) is the most extensively studied system containing NANC neurons in addition to cholinergic and adrenergic fibers. In the small intestine, for example, these neurons contain one or more of the following: nitric oxide synthase (which produces nitric oxide, NO), calcitonin gene-related peptide, cholecystokinin, dynorphin, enkephalins, gastrin-releasing peptide, 5-hydroxytryptamine (5-HT, serotonin), neuropeptide Y, somatostatin, substance P, and vasoactive intestinal peptide (VIP). Some neurons contain as many as five different transmitters.


Pharmacology_Katzung

Pharmacology_Katzung. The sensory fibers in the nonadrenergic, noncholinergic systems are probably better termed “sensory-efferent” or “sensorylocal effector” fibers because, when activated by a sensory input, they are capable of releasing transmitter peptides from the sensory ending itself, from local axon branches, and from collaterals that terminate in the autonomic ganglia. These peptides are potent agonists in many autonomic effector tissues. Autonomic function is integrated and regulated at many levels, from the CNS to the effector cells. Most regulation uses negative feedback, but several other mechanisms have been identified. Negative feedback is particularly important in the responses of the ANS to the administration of autonomic drugs.


Pharmacology_Katzung

Pharmacology_Katzung. At the highest level—midbrain and medulla—the two divisions of the ANS and the endocrine system are integrated with each other, with sensory input, and with information from higher CNS centers, including the cerebral cortex. These interactions are such that early investigators called the parasympathetic system a trophotropic one (ie, leading to growth) used to “rest and digest” and the sympathetic system an ergotropic one (ie, leading to energy expenditure), which is activated for “fight or flight.” Although such terms offer little insight into the mechanisms involved, they do provide simple descriptions applicable to many of the actions of the systems (Table 6–3). For example, slowing of the heart and stimulation of digestive activity are typical energy-conserving and energy-storing actions of the parasympathetic system. In contrast, cardiac stimulation, increased blood sugar, and cutaneous vasoconstriction are responses produced by sympathetic discharge that are suited to fighting


Pharmacology_Katzung

Pharmacology_Katzung. of the parasympathetic system. In contrast, cardiac stimulation, increased blood sugar, and cutaneous vasoconstriction are responses produced by sympathetic discharge that are suited to fighting or surviving attack.


Pharmacology_Katzung

Pharmacology_Katzung. At a more subtle level of interactions in the brain stem, medulla, and spinal cord, there are important cooperative interactions between the parasympathetic and sympathetic systems. For some organs, sensory fibers associated with the parasympathetic system exert reflex control over motor outflow in the sympathetic system. Thus, the sensory carotid sinus baroreceptor fibers in the glossopharyngeal nerve have a major influence on sympathetic outflow from the vasomotor center. This example is described in greater detail in the following text. Similarly, parasympathetic sensory fibers in the wall of the urinary bladder significantly influence sympathetic inhibitory outflow to that organ. Within the ENS, sensory fibers from the wall of the gut synapse on both preganglionic and postganglionic motor neurons that control intestinal smooth muscle and secretory cells (Figure 6–2). A. Integration of Cardiovascular Function


Pharmacology_Katzung

Pharmacology_Katzung. Autonomic reflexes are particularly important in understanding cardiovascular responses to autonomic drugs. As indicated in Figure 6–7, the primary controlled variable in cardiovascular function is mean arterial pressure. Changes in any variable contributing to mean arterial pressure (eg, a drug-induced increase in peripheral vascular resistance) evoke powerful homeostatic secondary responses that tend to compensate for the directly evoked change. The homeostatic response may be sufficient to reduce the change in mean arterial pressure and to reverse the drug’s effects on heart rate. A slow infusion of norepinephrine provides a useful example. This agent produces direct effects on both vascular and cardiac muscle. It is a powerful vasoconstrictor and, by increasing peripheral vascular resistance, increases mean arterial pressure. In the absence of reflex control—in a patient who has had a heart transplant, for example—the drug’s effect on the heart is also stimulatory; that is, it


Pharmacology_Katzung

Pharmacology_Katzung. resistance, increases mean arterial pressure. In the absence of reflex control—in a patient who has had a heart transplant, for example—the drug’s effect on the heart is also stimulatory; that is, it increases heart rate and contractile force. However, in a subject with intact reflexes, the negative feedback response to increased mean arterial pressure causes decreased sympathetic outflow to the heart and a powerful increase in parasympathetic (vagus nerve) discharge at the cardiac pacemaker. This response is mediated by increased firing by the baroreceptor nerves of the carotid sinus and the aortic arch. Increased baroreceptor activity causes the decreased central sympathetic outflow and increased vagal outflow. As a result, the net effect of ordinary pressor doses of norepinephrine in a normal subject is to produce a marked increase in peripheral vascular resistance, an increase in mean arterial pressure, and often, a slowing of heart rate. Bradycardia, the reflex compensatory


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Pharmacology_Katzung. in a normal subject is to produce a marked increase in peripheral vascular resistance, an increase in mean arterial pressure, and often, a slowing of heart rate. Bradycardia, the reflex compensatory response elicited by this agent, is the exact opposite of the drug’s direct action; yet it is completely predictable if the integration of cardiovascular function by the ANS is understood.


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B. Presynaptic Regulation

Pharmacology_Katzung. B. Presynaptic Regulation


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Pharmacology_Katzung. The principle of negative feedback control is also found at the presynaptic level of autonomic function. Important presynaptic feedback inhibitory control mechanisms have been shown to exist at most nerve endings. A well-documented mechanism involves the α2 receptor located on noradrenergic nerve terminals. This receptor is activated by norepinephrine and similar molecules; activation diminishes further release of norepinephrine from these nerve endings (Table 6–4). The mechanism of this G protein– mediated effect involves inhibition of the inward calcium current that causes vesicular fusion and transmitter release. Conversely, a presynaptic β receptor appears to facilitate the release of norepinephrine from some adrenergic neurons. Presynaptic receptors that respond to the primary transmitter substance released by the nerve ending are called autoreceptors. Autoreceptors are usually inhibitory, but in addition to the excitatory β receptors on noradrenergic fibers, many cholinergic


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Pharmacology_Katzung. substance released by the nerve ending are called autoreceptors. Autoreceptors are usually inhibitory, but in addition to the excitatory β receptors on noradrenergic fibers, many cholinergic fibers, especially somatic motor fibers, have excitatory nicotinic autoreceptors.


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Pharmacology_Katzung. Control of transmitter release is not limited to modulation by the transmitter itself. Nerve terminals also carry regulatory receptors that respond to many other substances. Such heteroreceptors may be activated by substances released from other nerve terminals that synapse with the nerve ending. For example, some vagal fibers in the myocardium synapse on sympathetic noradrenergic nerve terminals and inhibit norepinephrine release. Alternatively, the ligands for these receptors may diffuse to the receptors from the blood or from nearby tissues. Some of the transmitters and receptors identified to date are listed in Table 6–4. Presynaptic TABLE 6–3 Direct effects of autonomic nerve activity on some organ systems. Autonomic drug effects are similar but not identical (see text).


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Pharmacology_Katzung. 1Less important actions are shown in brackets. 2Specific receptor type: α, alpha; β, beta; M, muscarinic. 3Vascular smooth muscle in skeletal muscle has sympathetic cholinergic dilator fibers. 4The endothelium of most blood vessels releases EDRF (endothelium-derived relaxing factor), which causes marked vasodilation, in response to muscarinic stimuli. Parasympa thetic fibers innervate muscarinic receptors in vessels in the viscera and brain, and sympathetic cholinergic fibers innervate skeletal muscle blood vessels. The muscarinic receptors in the other vessels of the peripheral circulation are not innervated and respond only to circulating muscarinic agonists. 5Cerebral blood vessels dilate in response to M5 receptor activation. 6Probably through presynaptic inhibition of parasympathetic activity. 7The cholinergic innervation of the rectum and the genitourinary organs may be anatomically sympathetic; see Box: Sympathetic Sacral Outflow.


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Pharmacology_Katzung. FIGURE 6–7 Autonomic and hormonal control of cardiovascular function. Note that two feedback loops are present: the autonomic nervous system loop and the hormonal loop. The sympathetic nervous system directly influences four major variables: peripheral vascular resistance, heart rate, force, and venous tone. It also directly modulates renin production (not shown). The parasympathetic nervous system directly influences heart rate. In addition to its role in stimulating aldosterone secretion, angiotensin II directly increases peripheral vascular resistance and facilitates sympathetic effects (not shown). The net feedback effect of each loop is to compensate for changes in arterial blood pressure. Thus, decreased blood pressure due to blood loss would evoke increased sympathetic outflow and renin release. Conversely, elevated pressure due to the administration of a vasoconstrictor drug would cause reduced sympathetic outflow, reduced renin release, and increased parasympathetic (vagal)


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Pharmacology_Katzung. renin release. Conversely, elevated pressure due to the administration of a vasoconstrictor drug would cause reduced sympathetic outflow, reduced renin release, and increased parasympathetic (vagal) outflow.


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Pharmacology_Katzung. TABLE 6–4 Autoreceptor, heteroreceptor, and modulatory effects on nerve terminals in peripheral synapses.1 1A provisional list. The number of transmitters and locations will undoubtedly increase with additional research. Late, slow EPSP FIGURE 6–8 Excitatory and inhibitory postsynaptic potentials (EPSP and IPSP) in an autonomic ganglion cell. The postganglionic neuron shown at the left with a recording electrode might undergo the membrane potential changes shown schematically in the recording. The response begins with two EPSP responses to nicotinic (N) receptor activation, the first not reaching threshold. The second, suprathreshold, EPSP evokes an action potential, which is followed by an IPSP, probably evoked by M2 receptor activation (with possible participation from dopamine receptor activation). The IPSP is, in turn, followed by a slower, M1-dependent EPSP, and this is sometimes followed by a still slower peptide-induced excitatory postsynaptic potential.


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Pharmacology_Katzung. regulation by a variety of endogenous chemicals probably occurs at all synapses. C. Postsynaptic Regulation Postsynaptic regulation can be considered from two perspectives: modulation by previous activity at the primary receptor (which may upor down-regulate receptor number or desensitize receptors; see Chapter 2), and modulation by other simultaneous events.


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Pharmacology_Katzung. The first mechanism has been well documented in several receptor-effector systems. Up-regulation and down-regulation are known to occur in response to decreased or increased activation, respectively, of the receptors. An extreme form of up-regulation occurs after denervation of some tissues, resulting in denervation supersensitivity of the tissue to activators of that receptor type. In skeletal muscle, for example, nicotinic receptors are normally restricted to the end plate regions underlying somatic motor nerve terminals. Surgical or traumatic denervation results in marked proliferation of nicotinic cholinoceptors over all parts of the fiber, including areas not previously associated with any motor nerve junctions. A pharmacologic supersensitivity related to denervation supersensitivity occurs in autonomic effector tissues after administration of drugs that deplete transmitter stores and prevent activation of the postsynaptic receptors for a sufficient period of time. For example,


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Pharmacology_Katzung. occurs in autonomic effector tissues after administration of drugs that deplete transmitter stores and prevent activation of the postsynaptic receptors for a sufficient period of time. For example, prolonged administration of large doses of reserpine, a norepinephrine depleter, can cause increased sensitivity of the smooth muscle and cardiac muscle effector cells served by the depleted sympathetic fibers.


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Pharmacology_Katzung. The second mechanism involves modulation of the primary transmitter-receptor event by events evoked by the same or other transmitters acting on different postsynaptic receptors. Ganglionic transmission is a good example of this phenomenon (Figure 6–8). The postganglionic cells are activated (depolarized) as a result of binding of an appropriate ligand to a neuronal nicotinic (NN) acetylcholine receptor. The resulting fast excitatory postsynaptic potential (EPSP) evokes a propagated action potential if threshold is reached. This event is often followed by a small and slowly developing but longer-lasting hyperpolarizing afterpotential—a slow inhibitory postsynaptic potential (IPSP). This hyperpolarization involves opening of potassium channels by M2 cholinoceptors. The IPSP is followed by a small, slow excitatory postsynaptic potential caused by closure of potassium channels linked to M1 cholinoceptors. Finally, a late, very slow EPSP may be evoked by peptides released from other


Pharmacology_Katzung

Pharmacology_Katzung. by a small, slow excitatory postsynaptic potential caused by closure of potassium channels linked to M1 cholinoceptors. Finally, a late, very slow EPSP may be evoked by peptides released from other fibers. These slow potentials serve to modulate the responsiveness of the postsynaptic cell to subsequent primary excitatory presynaptic nerve activity. (See Chapter 21 for additional examples.)


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Pharmacology_Katzung. Because transmission involves both common (eg, ganglionic) and different (eg, effector cell receptor) mechanisms in different segments of the ANS, some drugs produce less selective effects, whereas others are highly specific in their actions. A summary of the steps in transmission of impulses, from the CNS to the autonomic effector cells, is presented in Table 6–5. Drugs that block action potential propagation (local anesthetics and some natural toxins) are very nonselective in their action, since they act on a process that is common to all neurons. On the other hand, drugs that act on the biochemical processes involved in transmitter synthesis and storage are more selective, since the biochemistry of each transmitter differs, eg, norepinephrine synthesis is very different from acetylcholine synthesis. Activation or blockade of effector cell receptors offers maximum flexibility and selectivity of effect attainable with


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Pharmacology_Katzung. TABLE 6–5 Steps in autonomic transmission: Effects of some drugs. 1Toxin of puffer fish, California newt. 2Toxin of Gonyaulax (red tide organism). 3Norepinephrine, dopamine, acetylcholine, angiotensin II, various prostaglandins, etc. 4Toxin of marine snails of the genus Conus. 5Black widow spider venom. 6Serotonin, norepinephrine reuptake inhibitors. NET, norepinephrine transporter; SNRI, serotonin-norepinephrine reuptake inhibitors; VAT, vesicle-associated transporter; VMAT, vesicular monoamine transporter.


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Pharmacology_Katzung. The eye is a good example of an organ with multiple auto-nomic functions, controlled by several autonomic receptors. As shown in Figure 6–9, the anterior chamber is the site of several autonomic effector tissues. These tissues include three muscles (pupillary dilator and constrictor muscles in the iris and the ciliary muscle) and the secretory epithelium of the ciliary body. Parasympathetic nerve activity and muscarinic cholinomi-metics mediate contraction of the circular pupillary constrictor muscle and of the ciliary muscle. Contraction of the pupillary constrictor muscle causes miosis, a reduction in pupil size. Miosis is usually present in patients exposed to large systemic or small topical doses of cholinomimetics, especially organophosphate cholinesterase inhibitors. Ciliary muscle contraction causes accom-modation of focus for near vision. Marked contraction of the ciliary muscle, which often occurs with cholinesterase inhibitor intoxication, is called cyclospasm. Ciliary


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Pharmacology_Katzung. contraction causes accom-modation of focus for near vision. Marked contraction of the ciliary muscle, which often occurs with cholinesterase inhibitor intoxication, is called cyclospasm. Ciliary muscle contraction also puts tension on the trabecular meshwork, opening its pores and facilitating outflow of the aqueous humor into the canal of Schlemm. Increased outflow reduces intraocular pressure, a very useful result in patients with glaucoma. All of these effects are pre-vented or reversed by muscarinic blocking drugs such as atropine. Alpha adrenoceptors mediate contraction of the radially oriented pupillary dilator muscle fibers in the iris and result in mydriasis. This occurs during sympathetic discharge and when α-agonist drugs such as phenylephrine are placed in the conjunctival sac. Beta adrenoceptors on the ciliary epithelium facilitate the secretion of aqueous humor. Blocking these recep-tors (with β-blocking drugs) reduces the secretory activity and reduces intraocular


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Pharmacology_Katzung. sac. Beta adrenoceptors on the ciliary epithelium facilitate the secretion of aqueous humor. Blocking these recep-tors (with β-blocking drugs) reduces the secretory activity and reduces intraocular pressure, providing another therapy for glaucoma.


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Pharmacology_Katzung. currently available drugs: adrenoceptors are easily distinguished from cholinoceptors. Furthermore, individual receptor subgroups can often be selectively activated or blocked within each major type. Some examples are given in the Box: Pharmacology of the Eye. Even greater selectivity may be attainable in the future using drugs that target post-receptor processes, eg, receptors for second messengers. The next four chapters provide many more examples of this useful diversity of autonomic control processes.


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Pharmacology_Katzung. FIGURE 6–9 Structures of the anterior chamber of the eye. Tissues with significant autonomic functions and the associated ANS receptors (α, β, M) are shown in this schematic diagram. Aqueous humor is secreted by the epithelium of the ciliary body, flows into the space in front of the iris, flows through the trabecular meshwork, and exits via the canal of Schlemm (arrow). Blockade of the β adrenoceptors associated with the ciliary epithelium causes decreased secretion of aqueous. Blood vessels (not shown) in the sclera are also under autonomic control and influence aqueous drainage. Andersson K-E: Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev 2011;63:811. Barrenschee M et al: SNAP-25 is abundantly expressed in enteric neuronal networks and upregulated by the neurotrophic factor GDNF. Histochem Cell Biol 2015;143:611.


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Pharmacology_Katzung. Barrenschee M et al: SNAP-25 is abundantly expressed in enteric neuronal networks and upregulated by the neurotrophic factor GDNF. Histochem Cell Biol 2015;143:611. Birdsall NJM: Class A GPCR heterodimers: Evidence from binding studies. Trends Pharmacol Sci 2010;31:499. Broten TP et al: Role of endothelium-derived relaxing factor in parasympathetic coronary vasodilation. Am J Physiol 1992;262:H1579. Burnstock G: Non-synaptic transmission at autonomic neuroeffector junctions. Neurochem Int 2008;52:14. Burnstock G: Purinergic signalling in the gut. Adv Exp Med Biol 2016;891:91. Centers for Disease Control and Prevention: Paralytic shellfish poisoning— Southeast Alaska, May-June 2011. MMWR Morb Mortal Wkly Rep 2011;60:1554. Dulcis D et al: Neurotransmitter switching in the adult brain regulates behaviour. Science 2013;340:449. Espinoza-Medina I et al: The sacral autonomic outflow is sympathetic. Science 2016;354:893.


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Pharmacology_Katzung. Dulcis D et al: Neurotransmitter switching in the adult brain regulates behaviour. Science 2013;340:449. Espinoza-Medina I et al: The sacral autonomic outflow is sympathetic. Science 2016;354:893. Fagerlund MJ, Eriksson LI: Current concepts in neuromuscular transmission. Br J Anaesthesia 2009;103:108. Fisher J: The neurotoxin domoate causes long-lasting inhibition of the kainate receptor GluK5 subunit. Neuropharmacology 2014;85:9. Furchgott RF: Role of endothelium in responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol 1984;24:175. Galligan JJ: Ligand-gated ion channels in the enteric nervous system. Neurogastroenterol Motil 2002;14:611. Goldstein DS et al: Dysautonomias: Clinical disorders of the autonomic nervous system. Ann Intern Med 2002;137:753. Hills JM, Jessen KR: Transmission: γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and dopamine. In: Burnstock G, Hoyle CHV (editors): Autonomic Neuroeffector Mechanisms. Harwood Academic, 1992.


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Pharmacology_Katzung. Holzer P, Reichmann F, Farzi A: Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 2012;46:261. Johnston GR, Webster NR: Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesthesiol 2009;102:453. Langer SZ: Presynaptic receptors regulating transmitter release. Neurochem Int 2008;52:26. Luther JA, Birren SJ: Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties. Auton Neurosci 2009;151:46. Magnon C: Autonomic nerve development contributes to prostate cancer progression. Science 2013;341:1236361. Mikoshiba K: IP3 receptor/Ca2+ channel: From discovery to new signaling concepts. J Neurochem 2007;102:1426. Raj SR, Coffin ST: Medical therapy and physical maneuvers in the treatment of the vasovagal syncope and orthostatic hypotension. Prog Cardiovasc Dis 2013;55:425. Rizo J: Staging membrane fusion. Science 2012;337:1300.


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Pharmacology_Katzung. Rizo J: Staging membrane fusion. Science 2012;337:1300. Shibasaki M, Crandall CG: Mechanisms and controllers of eccrine sweating in humans. Front Biosci (Schol Ed) 2011;2:685. Symposium: Gastrointestinal reviews. Curr Opin Pharmacol 2007;7:555. Tobin G, Giglio D, Lundgren O: Muscarinic receptor subtypes in the alimentary tract. J Physiol Pharmacol 2009;60:3. Vanderlaan RD et al: Enhanced exercise performance and survival associated with evidence of autonomic reinnervation in pediatric heart transplant recipients. Am J Transplant 2012;12:2157. Vernino S, Hopkins S, Wang Z: Autonomic ganglia, acetylcholine antibodies, and autoimmune gangliopathy. Auton Neurosci 2009;146:3. Verrier RL, Tan A: Heart rate, autonomic markers, and cardiac mortality. Heart Rhythm 2009;6(Suppl 11):S68. Watanabe S et al: Clathrin regenerates synaptic vesicles from endosomes. Nature 2014;515:228.


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Pharmacology_Katzung. Watanabe S et al: Clathrin regenerates synaptic vesicles from endosomes. Nature 2014;515:228. Westfall DP, Todorov LD, Mihaylova-Todorova ST: ATP as a cotransmitter in sympathetic nerves and its inactivation by releasable enzymes. J Pharmacol Exp Ther 2002;303:439. Whittaker VP: Some currently neglected aspects of cholinergic function. J Mol Neurosci 2010;40:7. Blepharospasm and other manifestations of involuntary muscle spasm can be disabling and, in the case of large muscles, painful. Contraction of skeletal muscle is triggered by exocytotic release of acetylcholine (ACh) from motor nerves in response to calcium influx at the nerve ending. Release of ACh can be reduced or blocked by botulinum toxin, which interferes with the fusion of nerve ending ACh vesicles with the nerve ending membrane (see text). Depend-ing on dosage, botulinum blockade has an average duration of 1 to 3 months. Achilles J. Pappano, PhD


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Pharmacology_Katzung. Achilles J. Pappano, PhD In late morning, a coworker brings 43-year-old JM to the emergency department because he is agitated and unable to continue picking vegetables. His gait is unsteady, and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented. How would you proceed to evaluate and treat JM? What should be done for his coworker?


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Pharmacology_Katzung. Acetylcholine-receptor stimulants and cholinesterase inhibitors make up a large group of drugs that mimic acetylcholine (cholinomimetics) (Figure 7–1). Cholinoceptor stimulants are classified pharmacologically by their spectrum of action, depending on the type of receptor—muscarinic or nicotinic—that is activated. Cholinomimetics are also classified by their mechanism of action because some bind directly to (and activate) cholinoceptors whereas others act indirectly by inhibiting the hydrolysis of endogenous acetylcholine.


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Pharmacology_Katzung. Early studies of the parasympathetic nervous system showed that the alkaloid muscarine mimicked the effects of parasympathetic nerve discharge; that is, the effects were parasympathomimetic. Application of muscarine to ganglia and to autonomic effector tissues (smooth muscle, heart, exocrine glands) showed that the parasympathomimetic action of the alkaloid occurred through an action on receptors at effector cells (smooth muscle, glands), not those in ganglia. The effects of acetylcholine itself and of other cholinomimetic drugs at autonomic neuroeffector junctions are called parasympathomimetic effects and are mediated by muscarinic receptors. In contrast, low concentrations of the alkaloid nicotine stimulated autonomic ganglia and skeletal muscle neuromuscular junctions but not autonomic effector cells. The ganglion and skeletal muscle receptors were therefore labeled nicotinic. When acetylcholine was later identified as the physiologic transmitter at both muscarinic and nicotinic


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Pharmacology_Katzung. effector cells. The ganglion and skeletal muscle receptors were therefore labeled nicotinic. When acetylcholine was later identified as the physiologic transmitter at both muscarinic and nicotinic receptors, both receptors were recognized as cholinoceptor subtypes.


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Pharmacology_Katzung. Cholinoceptors are members of either G protein-linked (muscarinic) or ion channel (nicotinic) families on the basis of their structure and transmembrane signaling mechanisms. Muscarinic receptors contain seven transmembrane domains whose third cytoplasmic loop is coupled to G proteins that function as transducers (see Figure 2–11). These receptors regulate the production of intracellular second messengers and modulate certain ion channels via their G proteins. Agonist selectivity is determined by the subtypes of muscarinic receptors and G proteins that are present in a given cell (Table 7–1). In native cells and in cell expression systems, muscarinic receptors form dimers or oligomers that are thought to function in receptor movement between the endoplasmic reticulum and plasma membrane and in signaling. FIGURE 7–1 The major groups of cholinoceptor-activating drugs, receptors, and target tissues. ACh, acetylcholine.


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Pharmacology_Katzung. FIGURE 7–1 The major groups of cholinoceptor-activating drugs, receptors, and target tissues. ACh, acetylcholine. Conceivably, agonist or antagonist ligands could signal by changing the quaternary structure of the receptor, that is, the ratio of monomeric to oligomeric receptors. Muscarinic receptors are located on plasma membranes of cells in the central nervous system and in autonomic ganglia (see Figure 6–8), in organs innervated by parasympathetic nerves as well as on some tissues that are not innervated by these nerves, eg, endothelial cells (Table 7–1), and on those tissues innervated by postganglionic sympathetic cholinergic nerves. Nicotinic receptors are part of a transmembrane polypeptide whose subunits form cation-selective ion channels (see Figure 2–9). These receptors are located on plasma membranes of postganglionic cells in all autonomic ganglia, of muscles innervated by somatic motor fibers, and of some central nervous system neurons (see Figure 6–1).


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Pharmacology_Katzung. Nonselective cholinoceptor stimulants in sufficient dosage can produce very diffuse and marked alterations in organ system function because acetylcholine has multiple sites of action where it initiates both excitatory and inhibitory effects. Fortunately, drugs are available that have a degree of selectivity, so that desired effects can often be achieved while avoiding or minimizing adverse effects. Selectivity of action is based on several factors. Some drugs stimulate either muscarinic receptors or nicotinic receptors selectively. Some agents stimulate nicotinic receptors at neuromuscular junctions preferentially and have less effect on nicotinic receptors in ganglia. Organ selectivity can also be achieved by using appropriate routes of administration (“pharmacokinetic selectivity”). For example, muscarinic stimulants can be administered topically to the surface of the eye to modify ocular function while minimizing systemic effects.


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Pharmacology_Katzung. TABLE 7–1 Subtypes and characteristics of cholinoceptors. 1Pentameric structure in Torpedo electric organ and fetal mammalian muscle has two α1 subunits and one each of β1, δ, and γ subunits. The stoichiometry is indicated by subscripts, eg, [(α1)2 β1 δ γ]. In adult muscle, the γ subunit is replaced by an ε subunit. There are 12 neuronal nicotinic receptors with nine α (α2-α10) subunits and three (β2-β4) subunits. The subunit composition varies among different mammalian tissues. DAG, diacylglycerol; IP3, inositol trisphosphate. Data from Millar NS, Gotti C: Diversity of vertebrate nicotinic receptors. Neuropharmacology 2009;56:237.


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Pharmacology_Katzung. DAG, diacylglycerol; IP3, inositol trisphosphate. Data from Millar NS, Gotti C: Diversity of vertebrate nicotinic receptors. Neuropharmacology 2009;56:237. Direct-acting cholinomimetic agents bind to and activate muscarinic or nicotinic receptors (Figure 7–1). Indirect-acting agents produce their primary effects by inhibiting acetylcholinesterase, which hydrolyzes acetylcholine to choline and acetic acid (see Figure 6–3). By inhibiting acetylcholinesterase, the indirect-acting drugs increase the endogenous acetylcholine concentration in synaptic clefts and neuroeffector junctions. The excess acetylcholine, in turn, stimulates cholinoceptors to evoke increased responses. These drugs act primarily where acetylcholine is physiologically released and are thus amplifiers of endogenous acetylcholine.


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Pharmacology_Katzung. Some cholinesterase inhibitors also inhibit butyrylcholinesterase (pseudocholinesterase). However, inhibition of butyrylcholinesterase plays little role in the action of indirect-acting cholinomimetic drugs because this enzyme is not important in the physiologic termination of synaptic acetylcholine action. However, butyrylcholinesterase serves as a biological scavenger to prevent or reduce the extent of cholinesterase inhibition by organophosphate agents (see Chapter 8). Some quaternary cholinesterase inhibitors have a modest direct action as well, eg, neostigmine, which activates neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase.