The introduction of a new group may result in an increased rate of metabol- ism cheap singulair 5 mg online asthma treatment vaccine, a reduction in the rate of metabolism or an alternative route for metabolism (see Chapter 9) buy singulair amex asthma symptoms tracker. These changes could also change the duration of action and the nature of any side effects. Fluorine and Increased Decreased water Used to improve ease of chlorine lipophilic solubility. Hydroxy Decreased Increased water Provides a new centre for lipophilic solubility. The presence of the hydroxy group could result in an increase in the rate of elimination of the drug by a new metabolic pathway and/or excretion. Amino groups Decreased Increased water Provides a new centre for lipophilic solubility due to hydrogen bonding, which could character salt formation. Carboxylic and Decreased Increased water Water solubility may be enhanced sulphonic groups lipophilic solubility due to by in vivo salt formation. Carboxylic solubility acid group introduction into small lead molecules may change the type of activity of the analogue whilst sulphonic acid group incorporation does not normally change the type of activity. It is believed that this prevents the molecule from adopting the conformation necessary for antihistamine activity reduced hepatotoxicity. It is believed that this reduction is due to the methyl groups preventing metabolic hydroxylation of these ortho positions. In one position the new group will lead to an enhancement of activity, while in another position it will result in a reduction of activity. For example, the antihypertensive clonidine with its o,o’-dichloro substitution is more potent than its m,p-dichloro analogue (Figure 4. Classical isosteres were originally defined by Erlenmeyer as atoms, ions and molecules with identical shells of electrons. As a result, they may exhibit similar pharmacokinetic and pharmacodynamic properties. In other words, the replacement of a substituent by its isostere is more likely to result in the formation of an analogue with the same type of activity as the lead than the totally random selection of an alternative substituent. However, luck still plays a part, and an isosteric analogue may have a totally different type of activity from its lead (see section 2. These param- eters are used to represent properties such as lipophilicity, shape and electron distribution, which are believed to have a major influence on the drug’s activity. They are normally defined so that they are in the form of numbers, which are derived from practical data that is thought to be related to the property the parameter represents. This makes it possible to either to measure or to calculate these parameters for a group of compounds and relate their values to the biological activity of these compounds by means of mathematical equations using statistical methods such as regression analysis (see Appendix 6). These equations may be used by the medicinal chemist to make a more informed choice as to which analogues to prepare. For example, it is often possible to use statistical data from other compounds to calculate the theoretical value of a specific parameter for an as yet unsynthesized compound. Substituting this value in the appropriate equation relating activity to that parameter, it is possible to calculate the theoretical activity of this unknown compound. Alter- natively, the equation could be used to determine the value ‘x’ of the parameter ‘y’ that would give optimum activity. As a result, only analogues that have values of y in the region of x need be synthesized. The main properties of a drug that appear to influence its activity are its, lipophilicity, the electronic effects within the molecule and the size and shape of the molecule (steric effects). This is usually an important factor in determining how easily a drug passes through lipid membranes (see Appendix 5). The electronic effects of the groups within the molecule will affect its electron distribution, which in turn has a direct bearing on how easily and permanently the molecule binds to its target molecule (see Chapter 7). Drug size and shape will determine whether the drug molecule is able to get close enought to its target site in order to bind to that site. The parameters commonly used to represent these properties are partition coeffi- cients for lipohilicity (see section 4. Consequently, this text will be largely restricted to a discussion of the use of these constants. However, the other parameters mentioned in this and other texts are normally used in a similar fashion. In both instances it is important to consider as wide a range of parameters as possible. The former parameter refers to the whole molecule whilst the latter is related to substituent groups. Partition coefficients (P) A drug has to pass through a number of biological membranes in order to reach its site of action. Consequently, organic medium/aqueous system partition coeffi- cients were the obvious parameters to use as a measure of the ease of movement of the drug through these membranes. The accuracy of the correlation of drug activity with partition coefficients will depend on the solvent system used as a model for the membrane. A variety of organic solvents, such as n-octanol, chloroform and olive oil, are used to represent the membrane (organic medium), whilst both pure water and buffered solutions are used for the aqueous medium. The n-octanol–water system is frequently chosen because it appears to be a good mimic of lipid polarity and has an extensive database. However, more accurate results may be obtained if the organic phase is matched to the area of biological activity being studied. More polar solvents such as chloroform give more consistent values for buccal absorption (soft tissues in the mouth). If this range is small the results may be expressed as a straight line equation having the general form: log (1=C ) ¼ k1 log P þ k2 (4:2) where k1 and k2 are constants. This equation indicates a linear relationship between the activity of the drug and its partition coefficient. Over larger ranges of P values the graph of log 1/C against log P often has a parabolic form 0 (Figure 4. The existence of this maximum value implies that there is an optimum balance between aqueous and lipid 0 solubility for maximum biological activity. Below P the drug will be reluctant 0 to enter the membrane whilst above P the drug will be reluctant to leave the 0 membrane. This means that analogues with partition coefficients near this optimum value are likely to be the most active and worth further investigation. However, when several substituents are present, the value of p for the compound is the sum of the p values of each of the separate substituents. The value of p for a specific substituent will vary with the structural environ- ment of the substituent (Table 4. Consequently, average values or the values relevant to the type of structure being investigated may be used in determining activity relationships. It also depends on the solvent system used to determine the partition coefficients.
But in some cases consciousness may become aversive order genuine singulair on line asthma x ray signs, for instance when we become aware that we are not living up to our own goals or expectations 4 mg singulair amex asthma treatment guidelines 2013, or when we believe that other people perceive us negatively. In these cases we may engage in behaviors that help us escape from consciousness, for example through the use of alcohol or other psychoactive drugs (Baumeister,  1998). Because the brain varies in its current level and type of activity, consciousness is transitory. If we drink too much coffee or beer, the caffeine or alcohol influences the activity in our brain, and our consciousness may change. When we are anesthetized before an operation or experience a concussion after a knock on the head, we may lose consciousness entirely as a result of changes in brain activity. We also lose consciousness when we sleep, and it is with this altered state of consciousness that we begin our chapter. Draw a graphic showing the usual phases of sleep during a normal night and notate the characteristics of each phase. Outline and explain the similarities and differences among the different theories of dreaming. The lives of all organisms, including humans, are influenced by regularly occurring cycles of behaviors known as biological rhythms. One important biological rhythm is the annual cycle that guides the migration of birds and the hibernation of bears. Women also experience a 28-day cycle that guides their fertility and menstruation. But perhaps the strongest and most important biorhythm is the daily circadian rhythm (from the Latin circa, meaning “about‖ or “approximately,‖ and dian, meaning “daily‖) that guides the daily waking and sleeping cycle in many animals. Many biological rhythms are coordinated by changes in the level and duration of ambient light, for instance, as winter turns into summer and as night turns into day. In some animals, such as birds, the pineal gland in the brain is directly sensitive to light and its activation influences behavior, such as mating and annual migrations. The ganglion cells in the retina send signals to a brain area above the thalamus called the suprachiasmatic nucleus, which is the body’s primary circadian “pacemaker. In response, the pineal gland secretes melatonin, a powerful hormone that facilitates the onset of sleep. Research Focus: Circadian Rhythms Influence the Use of Stereotypes in Social Judgments The circadian rhythm influences our energy levels such that we have more energy at some times of day than others. To test this hypothesis, he asked 189 research participants to consider cases of alleged misbehavior by other college students and to judge the probability of the accused students‘ guilt. The accused students were identified as members of particular social groups, and they were accused of committing offenses that were consistent with stereotypes of these groups. One case involved a student athlete accused of cheating on an exam, one case involved a Hispanic student who allegedly physically attacked his roommate, and a third case involved an African American student who had been accused of selling illegal drugs. Each of these offenses had been judged via pretesting in the same student population to be stereotypically (although, of course, unfairly) associated with each social group. The research participants were also provided with some specific evidence about the case that made it ambiguous whether the person had actually committed the crime, and then asked to indicate the likelihood of the student‘s guilt on an 11-point scale (0 = extremely unlikely to 10 = extremely likely). Participants also completed a measure designed to assess their circadian rhythms—whether they were more active and alert in the morning (Morning types) or in the evening (Evening types). The participants were then tested at experimental sessions held either in the morning (9 a. Morning people used their stereotypes more when they were tested in the evening, and evening people used their stereotypes more when they were tested in the morning. Sleep researchers have found that sleeping people undergo a fairly consistent pattern of sleep stages, each lasting about 90 minutes. During this sleep stage our muscles shut down, and this is probably a good thing as it protects us from hurting ourselves or trying to act out the scenes that are playing in our dreams. Each of the sleep stages has its own distinct pattern of brain  activity (Dement & Kleitman, 1957). When we are awake, our brain activity is characterized by the presence of very fast beta waves. When we first begin to fall asleep, the waves get longer (alpha waves), and as we move into stage N1 sleep, which is characterized by the experience of drowsiness, the brain begins to produce even slower theta waves. During stage N1 sleep, some muscle tone is lost, as well as most awareness of the environment. Some people may experience sudden jerks or twitches and even vivid hallucinations during this initial stage of sleep. Normally, if we are allowed to keep sleeping, we will move from stage N1 to stage N2 sleep. During stage N2, muscular activity is further decreased and conscious awareness of the environment is lost. This stage typically represents about half of the total sleep time in normal adults. Stage N2 sleep is characterized by theta waves interspersed with bursts of rapid brain activity known as sleep spindles. Stage N3, also known as slow wave sleep, is the deepest level of sleep, characterized by an increased proportion of very slow delta waves. This is the stage in which most sleep abnormalities, such as sleepwalking, sleeptalking, nightmares, and bed-wetting occur. Some skeletal muscle tone remains, making it possible for affected individuals to rise from their beds and engage in sometimes very complex behaviors, but consciousness is distant. If smoke enters the room or if we hear the cry of a baby we are likely to react, even though we are sound asleep. These occurrences again demonstrate the extent to which we process information outside consciousness. Eventually, as the sleep cycle finishes, the brain resumes its faster alpha and beta waves and we awake, normally refreshed. Sleep Disorders: Problems in Sleeping  According to a recent poll (National Sleep Foundation, 2009), about one-fourth of American adults say they get a good night‘s sleep only a few nights a month or less. These people are suffering from a sleep disorder known asinsomnia, defined as persistent difficulty falling or staying asleep. Most cases of insomnia are temporary, lasting from a few days to several weeks, but in some cases insomnia can last for years. Insomnia can result from physical disorders such as pain due to injury or illness, or from psychological problems such as stress, financial worries, or relationship difficulties. Changes in sleep patterns, such as jet lag, changes in work shift, or even the movement to or from daylight savings time can produce insomnia. Sometimes the sleep that the insomniac does get is disturbed and nonrestorative, and the lack of quality sleep produces impairment of functioning during the day. Ironically, the problem may be compounded by people’s anxiety over insomnia itself: Their fear of being unable to sleep may wind up keeping them awake. Barbiturates, benzodiazepines, and other sedatives are frequently marketed and prescribed as sleep aids, but they may interrupt the natural stages of the sleep cycle, and in the end are likely to do more harm than good.
Another funded research project in clini- to promote adaptation and how they relate to the cal progress focuses on nurse coaching for symptom adaptive modes discount singulair 4 mg with mastercard asthma treatment scale. The second major research effort 4 mg singulair with mastercard pod asthma, to conduct a review and synthesis of research, based again within the basic science of nursing, used a sys- on the Roy Adaptation Model, to identify and lo- tematic controlled comparison of survey data col- cate the literature from a 25-year period, to conduct lected in six hospitals across the United States. One the critical analysis, and to present the ﬁndings in a purpose within the larger study aims was to exam- research monograph (Roy et al. From 1970 ine levels of wellness in relation to levels of adapta- through 1994, a total of 163 studies met the inclu- tion. Only English-language publications measures of physiologic adaptation were related to were included. The sample included 94 articles in levels of wellness, but no evidence was found of a 44 different research and specialty journals from relationship between psychosocial adaptation and ﬁve continents. There was, however, tions and theses from a total of 35 universities and such a relationship in the least acute care setting colleges in the United States and Canada that were and for patients with longer hospital stays. The was suggested that adaptation is a process that takes major concepts of the model were used to organize place over time. Further, Roy (1977) noted that the the presentation of the review of this extensive use measures of levels of wellness were limited and not of the Roy Adaptation Model in nursing research. A model of cognitive information modes and processes; physiologic, self-concept, role processing was developed (Roy, 1988b, 2001), and a function, and interdependence modes; stimuli; and program of research was initiated to contribute to intervention. The Roy quality of the research and for the linkages of the re- Adaptation Model focuses on enhancing the basic search to the model. The studies that met the estab- lished criteria for adequacy of the quality of the The Roy Adaptation Model focuses on research and links to the model were used to test enhancing the basic life processes of the propositions derived from the model. As the studies were analyzed, the ﬁnd- ings were used to state ancillary and practice life processes of the individual and group. This process is demon- A major concentration of nursing activity is to as- strated in the exemplar study reported here. Given the priority of this notion, Roy fo- three categories to assess the potential of research cused efforts on further conceptual and empirical ﬁndings for use in practice: Category 1—high po- work to understand this human ability and nursing tential for implementation based on positive ﬁnd- practice based on that understanding. This review Drawing from knowledge in the neurosciences, her showed the breadth and depth of the Roy model’s early theory development and research on the use in nursing research in qualitative and quantita- model, and her observations in neuroscience nurs- tive research and in instrument development stud- ing practice, Roy proposed a nursing model for ies, using populations of individuals and groups (of cognitive processing (Roy, 1988b, 2001). Cognitive all ages, both in health and in illness, and in all areas processes in human adaptation are described as fol- of nursing practice). A review of the next ﬁve years lows: input processes (arousal and attention, sensa- of research, including 57 identiﬁed studies, is un- tion and perception), central processes (coding, derway, along with a critique, examples, and rec- concept formation, memory, language), output ommendations for the use of instruments to processes (planning and motor responses), and measure concepts of the Roy Adaptation Model emotion. Through these cognitive processes, adap- (visit the Roy Adaptation Association Web site at: tive responses occur. Taylor (1983), in a study of cancer patients, pro- posed a related theory of cognitive adaptation. Finally, Factor 5, knowing and relat- adaptation, in which individuals make cognitive ing, had eight items whose loadings ranged from. This version of In developing a new instrument, Roy sought to the scale was used in the research exemplar de- address issues in the measurement of coping as scribed in this chapter. The items retained were in- identiﬁed by Aldwin (1994) and Schwarzer & clusive of the inferred coping strategies, and the Schwarzer (1996). Further, it was important to have categories were derived from the nursing model for a tool that is useful for nursing assessment and in- cognitive processing. Based on the cognator subsystem of the was based on both the strong theoretical-empirical grand theory, Roy developed a middle-range theory basis for its development and the review by content of Coping and Adaptation Processing (Roy & experts. At that time, Roy gies within these categories were generated by pa- termed these ﬁve factors (1) cognitive processing of tient interviews and nursing care plans based on the self-perception, (2) clear focus and method, (3) Roy model, as well as by deductively derived cate- knowing awareness, (4) sensory regulation, and (5) gories of information processing, with related pa- selective focus. The scores on this version of the tient observations to identify related strategies. It serves to sig- The psychometric properties were established nal needs for cognitive efforts, to help the person to with a data set that included 349 subjects from non- attend, and to interfere with cognition. Examples of probability purposive samples from national mail- items were “keep in touch with emotions,” “put ing lists of patient support groups for persons with things into perspective,” “rechannel feelings,” and long-term neurologic deﬁcits. It involves Thai patients with acute illnesses from three hospi- systematic thinking. Factor 1, resourceful and be viewed in part as a process in which people clas- focused, contained 10 items with factor loadings sify the problem, organize information to accom- ranging from. Factor 2, physical and ﬁxed, had 14 risks of their efforts to their self-structure (Das, items with factor loadings from. Factor 3, alert process requires knowledge of the adaptation en- processing, had nine items with loadings from. Lecky (1961) proposed the Theory ing awareness involves retrieving information from of Self-consistency to conceptualize a person as a one’s mind and recognizing what has worked for holistic and consistent structure. It can be viewed as a self- Self-consistency Theory is that people are moti- regulating process (Carver & Scheier, 1991). The vated to act in a way that is congruent with their overall function of such cognitive processing is to sense of self and thereby maintain intactness when minimize discrepancies between a desirable sense facing potentially challenging situations. It includes tain self-consistency in the transaction between the cognitive input processing of receiving, analyzing, person and the environment (Elliot, 1986, 1988; storing, memory, successive processing, and Lecky, 1961; Rogers, 1961; Roy & Roberts, 1981), arousal-attention (Roy, 1988b, 2001). Example one initiates cognitive and emotional responses items were “gather information,”“recall past strate- (Roy & Andrews, 1991). Examples of items in- clude “try to maintain balance,” “change physical activity,” “picture actions,” and “share concerns to maintain health. Klarkowska, 1987; Ahan and Zhan, 1994) report Some examples of items were “useful to focus,” that older persons with greater self-consistency had “tend not to blame self,”“get away by self,” and “put more positive levels of well-being. Internal con- changes in aging than did those who had less con- sistency reliability of these ﬁve subscales ranged sistency of self-perceptions. Their ﬁnd- individual has two subareas: the physical self and ings suggested that the older people who had a the personal self. The physical self includes two stability of self-concept coped well in stressful en- components: body sensation and body image; and counters. Therefore, the critical task for older the personal self has three components: selfconsis- tency, self-ideal, and moral-ethical-spiritual self. The critical task for older people is to Conceptual Development maintain self-consistency by transcending internal and external losses in the aging Self-consistency was introduced during the devel- process. These authors noted that people strive to maintain a consistent people is to maintain self-consistency by transcend- self-organization and thus avoid disequilibrium ing internal and external losses in the aging process. An example of a reverse-scored item Roy & Andrews, 1991; Wylie, 1989), Zhan devel- was: “I feel mixed up about what I am really like. Therefore, self-perception and self- a score range from 51 to 104, a mean total score of evaluation are consciously available and can be 85. High social within human development are the physical anxiety leads to less self-consistency (Elliot, 1986). Roy’s basic theoretical premises are that individuals are rarely passive in the face of Problem and Signiﬁcance what happens to them.
The degree of drug activity is directly related to the concentration of the drug in the aqueous medium in contact with the substrate molecules 4mg singulair mastercard asthma symptoms hoarse voice. The factors affecting this concentration in a biological system can be classified into the phar- macokinetic phase and the pharmacodynamic phase of drug action purchase 5 mg singulair with amex asthma definition x-ray. The pharma- cokinetic phase concerns the study of the parameters that control the journey of the drug from its point of administration to its point of action. The pharmaco- dynamic phase concerns the chemical nature of the relationship between the drug and its target: in other words, the effect of the drug on the body. Many of the factors that influence drug action apply to all aspects of the pharmacokinetic phase. Furthermore, the rate of drug dissolution, that is, the rate at which a solid drug dissolves in the aqueous medium, controls its activity when a solid drug is administered by enteral routes (see Section 2. Drugs that are too polar will tend to remain in the bloodstream, whilst those that are too nonpolar will tend to be absorbed into and remain within the lipid interior of the membranes (see Appendix 3). The degree of absorption can be related to such parameters as partition coefficient, solubility, pKa, excipients and particle size. For example, the ioniza- tion of the analgesic aspirin is suppressed in the stomach by the acids produced from the parietal cells in the stomach lining. As a result, it is absorbed into the bloodstream in significant quantities in its unionized and hence uncharged form through the stomach membrane. The main route is the circulatory system; however, some distribution does occur via the lymphatic system. In the former case, once the drug is absorbed, it is rapidly distributed throughout all the areas of the body reached by the blood. Drugs are transported dissolved in the aqueous medium of the blood either in a ‘free form’ or reversibly bound to the plasma proteins. Drug Ð Drug À Protein complex Drug molecules bound to plasma proteins have no pharmacological effect until they are released from those proteins. However, it is possible for one drug to displace another from a protein if it forms a more stable complex with that protein. This may result in unwanted side effects, which could cause compli- cations when designing drug regimens involving more than one drug. Moreover, low plasma protein concentrations can affect the distribution of a drug in some diseases, such as rheumatoid arthritis. Sparingly water soluble compounds may be deposited in the blood vessels, leading to restriction in blood flow. Decompositions such as these can result in a higher dose of the drug being needed in order to achieve the desired pharmacological effect, which increases the risk oftoxic side effects in the patient. However, the active form of some drugs is produced by the decom- position of the administered drug. For example, the bacteriacide prontosil, discovered in 1935, is not active but is metabolized in situ to the antibacterial sulphanilamide. These biotransformations occur mainly in the liver but they can also occur in blood and other organs such as the brain, lungs and kidneys (see Section 9. Metabolism of a drug usually reduces the concen- tration of that drug in the systemic circulation, which normally leads to either a lowering or a complete suppression of the pharmacological action and toxic effects of that drug. Metabolism usually involves more than one route and results in the forma- tion of a sucession of metabolites (Figure 2. Each of these metabolites may have a different or similar activity to the parent drug (see Section 9. Consequently, the activities of all the metabolities of a drug must be considered in the development of a potential drug. Metabolities are frequently more water soluble than their parent drug and because of this are usually excreted in the urine. A slow elimination process can result in a build-up of the drug concentration in the body. This may benefit the patient in that the dose required to maintain the therapeutic effect can be reduced, which in turn reduces the chances of unwanted side effects. Conversely, the rapid elimination of a drug means that the patient has to receive either increased doses, with a greater risk of toxic side effects, or more frequent doses, which carries more risk of under- or over-dosing. The main excretion route for drugs and their metabolites is through the kidney in solution in the urine. However, a significant number of drugs and their metabolic products are also excreted via the bowel in the faeces. However, some of the species lost by these processes are reabsorbed by a recycling process known as tubular reabsorption. Tubular reabsorption is a process normally employed in returning compounds such as water, amino acids, salts and glucose that are important to the well-being of the body from the urine to the circulatory system, but it will also return drug molecules. The reabsorp- tion of acidic and basic drugs is reduced if the pH favours salt formation as charged molecules are not readily transported across membranes (see Appendi- ces 3 and 5). Elimination occurs in the liver by biliary clearance, very large molecules being metabolized to smaller compounds before being excreted. However, a fraction of some of the excreted drugs is reabsorbed through the enterohepatic cycle. This reabsorption can be reduced by the use of suitable substances in the dosage form, for example, the ion exchange resin cholestyramine is used to reduce cholesterol levels by preventing its reabsorption. Bioavailability is not constant but varies with the body’s physio- logical condition. It is now known that a drug is most effective when its shape and electron distribution, that is, its stereoelectronic structure, is complementary to the steroelectronic structure of the active site or receptor. The role of the medicinal chemist is to design and synthesize a drug structure that has the maximum beneficial effects with a minimum of toxic side effects. The stereo- chemistry of the drug is particularly important, as stereoisomers often have different biological effects, which range from inactive to highly toxic (see Table 2. At the begining of the 19th century it was largely carried out by individuals but it now requires teamwork, the members of the team being specialists in various fields, such as medicine, biochemistry, chemistry, computerized molecular modelling, pharma- ceutics, pharmacology, microbiology, toxicology, physiology and pathology. It also introduces the stereochemical and water solubility factors that should be taken into account when selecting a structure for a lead compound. These objectives will normally require a detailed assessment of the pathology of the disease and in some cases basic biochemical research will be necessary before initiating a drug design investigation (Figure 3. The information obtained is used by the team to decide what intervention would be most likely to bring about the desired result. Once the point of intervention has been selected, the team has to propose a structure for a lead compound that could possibly bring about the required change. This frequently requires an extensive literature and database search to identify compounds found in the organism (endogenous compounds) and compounds that are not found in the organism (exogenous compounds) that have some biological effect at the intervention site. Molecular modelling techniques (see Chapter 5) are sometimes used to help the team reach a decision. In many cases, a number of structures are found to be suitable, but the expense of producing drugs dictates that the team has to choose only one or two of these compounds to either act as the lead or to be the inspiration for the lead compound.