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The enlarged vesicular pool will increase exocytotic release of transmitter cheap 160 mg super p-force with amex, while an increase in cytoplasmic monoamines will both reduce carrier-mediated removal of transmitter from the synapse (because the favourable concentration gradient is reduced) and could even lead to net export of transmitter by the membrane transporter generic super p-force 160 mg with visa. Like amphetamine, tyramine reduces the pH gradient across the vesicle membrane which, in turn, causes the vesicular transporter to fail. As a result, transmitter accumulates in the cytoplasm and is exported into the synapse via the membrane-bound transporter. The ensuing (impulse- independent) sympathetic arousal can be disastrous, culminating in a hypertensive crisis and stroke. These isoenzymes are the products of different genes on the X-chromosome and share about 70% sequence homology. The prototype, imipramine, turned out to be ineffective in treating the positive symptoms experienced by schizophrenics but it did relieve their depression (negative symptoms). In fact, imipramine is still the standard agent against which novel antidepressants are compared in clinical trials. Set against this background is the finding that the inhibition of [3H]noradrenaline uptake by the neuroleptic, chlorpromazine, is even greater than that of imipramine and yet chlorpromazine has no apparent antidepressant effects. These are explained by their high affinity for histamine H1-anda1-adrenoceptors and all five of the muscarinic (M-) receptor subtypes. They consequently induce sedation (possibly through H1-receptor antagonism), anticholinergic effects, such as dry mouth and blurred vision (M-receptor antagonism), orthostatic hypotension and dizziness (a1- adrenoceptor antagonism). Other side-effects include loss of libido and stimulation of appetite which leads to weight gain. Little is known about the physiological bases of these actions which, although not life- threatening, are important because they undermine patient compliance. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. However, it is now known to act as an a2-adrenoceptor antagonist, an action that will increase the release of noradrenaline through blockade of autoreceptors on the cell bodies and terminals of noradrenergic neurons (see Chapter 8). Of course, it is likely that this drug will also blockpostsynaptic a2-adrenoceptors, unless it specifically targets a different subtype of this receptor family, but this evidently does not prevent its therapeutic effects. However, this action of mianserin might well limit or reduce any co-existing anxiety and insomnia. Although it has little antimuscarinic activity, its antidepressant activity is compromised because it is highly sedative, probably because of its appreciable H1-receptor antagonism, and it is also an a1-adrenoceptor antagonist. The first selective serotonin reuptake inhibitor, zimelidine, was tested in the clinic in 1971 but, although it proved to be an effective antidepressant, it was subsequently withdrawn because it could apparently induce the serious neurological disorder, Guillain-Barre syndrome. However, its active metabolite, norfluoxetine, is an even more effective inhibitor of noradrenaline uptake (Ki: 0. After chronic administration, the concentration of fluoxetine in the plasma of patients is between 0. Thus, even accounting for pharmacokinetic factors, such as protein binding, the brain concentrations of fluoxetine and norfluoxetine could well be high enough to inhibit noradrenaline reuptake. The extent to which any of these receptor interactions affects the efficacy of these compounds is not known. It is hoped that this approach might increase the response rate of patients who are resistant to more selective drug treatments and even reduce the therapeutic lag that dogs their predecessors. As yet, there is not enough information on these compounds to know whether or not this has turned out to be the case. These are triazolopyridine derivatives and include trazodone and the more recent addition, nefazodone. A related compound that has recently been introduced into the clinic is nefazodone. It has a lower affinity for the receptors that are responsible for the unwanted side-effects of trazodone, in particular a1-adrenoceptors and muscarinic receptors. Ultimately, agonist drugs that directly activate monoamine receptors would appear to be a logical development in this field. Unfortunately, the peripheral side-effects of such compounds could well limit their acceptability even if we were to discover what subset of receptors to target. Yet an outstanding problem in treating depression is that the therapeutic response is both slow and progressive: a significant improvement usually takes at least 2±3 weeks and sometimes much longer. Obviously, if we are to explain the therapeutic effects of antidepressants, we must search for long-term neurochemical changes that occur after their prolonged administration. They found that repeated, but not a single, administration to rats of any of the antidepressants which were available at that time (i. Shortly afterwards, it was found that this desensitisation was usually paralleled by downregulation of b1-(butnotb2-) adrenoceptors. This action is even shared by repeated electroconvulsive shock(Stanford and Nutt 1982) but not by drugs that are ineffective in relieving depression (e. A logical conclusion from this workwas that depression is caused by hyperresponsive b-adrenoceptors. However, proliferation of receptors is the normal response to a deficit in transmitter release and so the opposite change, downregulation of b-adrenoceptors by antidepressants, would follow an increase in the concentration of synaptic noradrenaline. This would be consistent with both their proposed mechanism of action and the monoamine theory for depression. Nonetheless, there are many reasons to be confident that b-adrenoceptor desensitisa- tion does not explain the therapeutic effects of antidepressants. First, with the development of more selective ligands for use in radioligand binding studies, it became evident that b-adrenoceptor downregulation can occur after only 2±3 days of drug treatment (Heal et al. Evidently, we must lookelsewhere to find an explanation for the neurobiology of depression and its treatment. Indeed, apart from developing compounds that help patients who currently do not respond to any existing treatment, the most pressing problem in this field is to reduce the delay in treatment response. Yet, despite the numerous investigations of the effects of antidepressants on a wide range of transmitter receptors, few consistent findings have emerged. Results tend to vary not only from laboratory to laboratory and between different brain regions but they also vary with the species and compound tested. So far, the neurochemical changes induced by long-term drug treatment have not been tested in combination with procedures such as learned helplessness, but it cannot be assumed that they will be the same as those in normal (non-depressed) subjects. Some studies find reduction in locus coeruleus, only b-adrenoceptor binding (cortex) 1-adrenoceptors, only. This suggests that depression is associated with a defect in the regulation of glucocorticoid secretion and the locus of this disorder could be glucocorticoid receptors in the hippocampus. Since this happens even in cultured fibroblasts it is thought to involve an action at the level of the genome. However, different antidepressants seem to achieve this through different mechanisms. Yet, all this effort has so far failed to identify disruption of any single transmitter or hormone system as the sole culprit. This points to disruption of the interactions between these different systems as the cause of the problem. Also, a2-adrenoceptors, which normally limit release of noradrenaline, are desensitised after chronic exposure to excess cortisol. From this perspective, any single neurochemical factor could have far-reaching effects on all these (and other) neurohumoral systems and could lead to the mood and behavioural changes that culminate in depression. In other words, whereas the expression of an abnormal neuro- chemical response would be linked with one transmitter system, the problem could lie in another. If this is so, the prospects for finding either a marker for, or a definitive cause of, depression are gloomy, if not misguided. However, experience proves that depression can be reversed by drugs that augment serotonergic and noradrenergic transmission (and reinstated by a deficit in the synthesis of these monoamines). This would explain why, despite numerous neurochemical options for the causes of depression, all antidepressants developed so far (and even those discovered by chance) target these neuronal systems. Whatever the cause of depression, therefore, its relief seems to rest on appropriate secretion of these monoamines. What remains to be seen is whether it will be possible to accelerate the neuro- chemical readjustments triggered by antidepressant drugs that target these systems, so as to reduce the latency in their therapeutic effects. Is this because existing antidepressants simply fail to initiate the appropriate combination of changes in monoaminergic transmission in these patients or do they have a disorder that affects neuronal systems that function in parallel with (or override) the monoamines?

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The other part of the calculation involves determination of the Velocity Time Integral using the apical five chamber view purchase super p-force 160mg amex. In the fourth row of images buy super p-force 160mg fast delivery, an apical five chamber view is Congestive Heart Failure – Andrew Patterson, M. The apical five chamber view can be used to calculate the Velocity Time Integral using pulse doppler imaging. On the left, the pulse doppler beam is directed in the line of the left ventricular outflow tract. On the right, a pulse doppler measurement is taken just proximal to the aortic valve and the Velocity Time Integral is calculated by determining the area under the curve. The left ventricle stroke volume can be calculated by multiplying the Cross Sectional Area of the left ventricle outflow tract and the Velocity Time Integral. The details of the measurements described in this figure legend are beyond the scope of this course. However, the idea that left ventricle preload and stroke volume/cardiac output can be easily determined using echocardiography should be appreciated (i. Increasing “preload” (1) will improve ventricular output in normal, hyperdynamic, and failing hearts within certain limits. Venodilators (4) and diuretics (5) can decrease ventricular volume by causing “pooling” of blood outside the central venous system and by reducing intravascular volume, respectively. Clinically, it is useful to plot “preload” versus ventricular output (the Starling relationship). By doing so, one can easily identify normal, hypodynamic, and hyperdynamic ventricular function. The inotropic state of the cardiac muscle as well as the “afterload” determines the Starling Curve on which the heart “moves. Thompson) presents to your clinic with shortness of breath that has become progressively more severe during the past month. Thompson reports that during the past month she developed an intolerance to lying flat and now requires four pillows to prop her head up when sleeping. She also describes fatigue that has worsened over the course of the past six weeks. She had been breastfeeding, but her fatigue and shortness of breath have forced her to transition the baby to formula feeds. Auscultation of the chest reveals bilateral crackles, a third heart sound, and a pansystolic murmur best heart at the apex consistent with mitral regurgitation. If you were to repeat the transthoracic echocardiogram, would you expect to see a difference in the wall motion or dimensions of the left ventricle compared to the prior examination? You decide to begin an infusion of dobutamine (an inotropic and afterload reducing agent). If you were to repeat the transthoracic echocardiogram once again, would you expect the wall motion of the left ventricle to change after institution of the dobutamine infusion? The pressure volume-loop (see Figure 8) diagrams the relationship between intraventricular pressure and volume throughout the cardiac cycle. The point of maximum volume and minimal pressure is located at the bottom right part of the loop (B). During the first part of the loop, pressure rises but volume remains constant (isovolumic contraction). When left ventricle pressure exceeds aortic root pressure, the aortic valve opens. At this point (C), ejection of blood from the ventricle begins and volume within the ventricle diminishes. When the ventricle reaches its maximum activated state (D), the aortic valve closes and isovolumic relaxation begins. Pressure-volume loops can be used to describe “preload,” compliance, “afterload,” and contractility (see Figure 9). Pressure-volume loops can be used to accurately depict clinically relevant information, such as stroke volume, “preload”, compliance, contractility, and “afterload. Changes in the pressure-volume loop that one might expect for a “volume-overloaded” heart failure patient are depicted. Jones) is going to be admitted to the Intensive Care Unit post-operatively after undergoing revision of a left total hip replacement. He has a history of coronary artery disease and is status post two myocardial infarctions during the past five years. His intraoperative course has been complicated by an acute 1500 mL blood loss and an episode of hypotension (80/40 mm Hg). The Anesthesiologist immediately administered two units of packed red blood cells, one unit of fresh frozen plasma, and 1. However, before these fluids could be administered the patient’s pulmonary artery pressures increased from 20/12 to 47/30 mm Hg. As the fluid was administered, the patient’s blood pressure initially increased to 120/70, and the ischemic changes resolved. Unfortunately, with the administration of two additional units of packed red blood cells and one unit of fresh frozen plasma, his blood pressure decreased again to 100/50. His central venous pressure rose to 25 mm Hg, and his cardiac output dropped to 3. If you had performed a transesophageal echocardiogram at the beginning of the surgery, would you have expected to observe wall motion abnormalities in the areas affected by his previous myocardial infarctions? How do you think the position on the Starling Curve changed at the time of the acute blood loss episode? What might you expect to see by transesophageal echocardiography in terms of ventricular wall motion during cardiac ischemia? During the episode of cardiac ischemia, what information might an echocardiogram provide that a pulmonary artery catheter could not? Jones’ hematocrit increased, his oxygen carrying capacity improved, and the cardiac ischemia resolved. Why did the additional packed red blood cells and fresh frozen plasma cause him to deteriorate again? Where did his heart lie on the Starling Curve after this additional fluid administration? You are debating whether to start a nitroglycerin infusion (venodilator and coronary artery dilator) versus an inotropic agent to improve his ventricular output after the second episode of hypotension. Would you expect them to keep his heart on the same Starling Curve but change it’s position on that curve? After the administration of a venodilator like nitroglycerin, what might you observe by transesophageal echocardiography in terms of intra-ventricular chamber volume? Acute Heart Failure versus Chronic Heart Failure versus Acute Decompensation of Chronic Heart Failure B. It has been shown to decrease total hospital stay by 3 days, to decrease the cost of treatment, and to decrease time to initiation of definitive therapy in the emergency room by 30 minutes. Higher levels have been correlated with worse left ventricular systolic function, a poorer prognosis, and a higher likelihood of functional deterioration and mortality. Age dependent cut offs are used to rule in congestive heart failure (>450 pg/mL for patients less than 50 years old; >900 pg/mL for patients 50 to 75 years old; >1800 pg/mL for patients older than 75 years). No identified structural or functional abnormalities of the pericardium, myocardium, or cardiac valves. Intracardiac Obstruction (Valvular Disease Stenosis, Hypertrophic Cardiomyopathy with Aortic Outflow Obstruction, Tumor) 2. Intracardiac (Valvular Insufficiency and Regurgitation, Left to Right Shunt… Atrial Septal Defect or Ventricular Septal Defect) 2. Extracardiac (Anatomic Shunts… Patent Ductus Arteriosis, metabolic derangement… Beriberi, Thyrotoxicosis) D. In both instances, the endpoint is deterioration of cardiac output and hypoperfusion of vital organs 1. Elevated filling pressures may be brought about by enhanced re-absorption of water in the kidney. If intra-ventricular volume increases too much, elevated filling pressures can compromise subendocardial blood flow, causing or worsening cardiac ischemia.

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Specialists in addic- tion psychology/psychiatry should be involved in the treatment plan early super p-force 160mg with amex. We reported that in patient substance abuse treatment during pregnancy was associ- ated with increased birth weight and head circumference super p-force 160mg without prescription, and fewer perinatal complica- tions compared to untreated matched substance-abusing pregnant controls (Little et al. Obstetrical goals of substance abuse treatment Minimization of maternal and fetal/infant morbidity and mortality is the obstetrical goal of substance abuse treatment during pregnancy. In one study, prenatal care was the main determinant of pregnancy outcome among substance abusers, not attaining abstinence (MacGregor et al. Regardless of continued substance use, regular prenatal care was associated with better pregnancy outcomes than those who did not have prenatal care. This observation is important to obstetrical goals in the treatment of the gravid substance user (risks to both the mother and the fetus) because it implies that the single most important intervention in the pregnancy of a substance abuser is to provide prena- tal care early and regularly. When considering treatment for the pregnant substance abuser, the risks from contin- ued substance use (for example, maintenance) versus risk of withdrawal, and the benefits Alternatives to traditional treatment for substance dependence during pregnancy 303 of withdrawal, i. However, recent clinical experience does not support these increased risks with withdrawal (Luty et al. Currently, with- drawal of the gravid patient from substances of abuse is generally advocated, although no generally accepted regimen is recommended for use during pregnancy. As with nonpreg- nant adults, a benzodiazepine and antidepressant or a benzodiazepine and a low-dose alpha-blocker (e. The primary danger of the alpha-blockers is maternal hypotension, which may impede placental perfusion. In France, buprenorphine has been used, and the inci- dence of adverse pregnancy outcomes was no different from controls (Auriacombe et al. Blood pressure and fetal heart rate should be monitored closely with this regimen. Doppler flow studies may prove useful for monitoring umbilical blood flow in these patients. Naltrexone has been used to treat several substance dependencies during pregnancy without apparent untoward effects, but no long-term follow-up studies have been pub- lished (Hulse et al. An alternative therapy with little or no potential for abuse is buprenorphine/naloxone (Suboxone), but there are no studies of its use during pregnancy. Disulfiram (Anabuse), a deterrent for alcohol abuse, should not be used at any time dur- ing pregnancy because of its strong copper-chelating properties. Copper is essential to normal fetal neuronal formation and migration, and any impediment in these processes may result in fetal brain malformations. New approaches for detoxification have included drug combinations, such as clonidine and naltrexone, and other drug regimens (Hulse et al. A combined regimen of these two drugs has been successfully employed for rapid opioid withdrawal for outpatient treatment. The combination of naloxone with midazolam or methohexitone can be used for inpatient settings. Investigators also found that this treatment can be used by using the partial opioid- receptor agonist buprenorphine for either heroin or methadone addiction. Limited expe- rience with clonidine transdermal patches has shown that these can be successfully applied in suppressing symptoms of withdrawal (MacGregor et al. Importantly, the use of low-dose clonidine does not seem to be associated with adverse effects on the course of pregnancy (Boutroy, 1989). Moreover, limited experience with this regimen seems to indicate that it is effec- tive and does not pose serious risks to advanced pregnancies (beyond 32 weeks). However, these results come from uncontrolled, anecdotal studies and the ability to extrapolate is very limited. This drug has a slower onset and a longer half-life than methadone, and because it is a prodrug, its onset is slower when administered intravenously than when given orally. Risks of withdrawal Data from the 1970s suggested an increased frequency of fetal deaths and maternal mor- bidity associated with opiate withdrawal, especially later in pregnancy (Finnegan et al. Pregnancies reported in these case reports and series were complicated by several other factors in addition to heroin addiction (i. Risks of maintenance The most common maintenance protocol for heroin-addicted gravidas involves the use of methadone. The efficacy of this regimen in such pregnancies is somewhat controver- sial (Edelin et al. Babies born to mothers on methadone, as with heroin, may experience withdrawal symptoms. Furthermore, withdrawal symptoms of methadone-exposed infants are more severe than those of heroin-exposed infants, with more seizures and a greater number of days of displaying withdrawal symptoms in the maintained group (Blinick et al. In addition, it was found that fetal growth retar- dation is more severe among methadone-exposed infants than among heroin-exposed infants (Blinick, 1973), a finding that was not supported by other studies (Lifschitz et al. Methadone withdrawal using dose tapering employing adjuvants such as numbutal were not associated with adverse pregnancy outcomes in a more recent study in a large public hospital where a number of studies of substance abuse were undertaken (Dashe et al. The available information is often confounded by many factors, including poor maternal health, lack of prenatal care, malnutrition, presence of infectious diseases, and the use of a myriad of substances. The sections that follow are a summary of the known maternal-fetal effects of the 16 social and illicit substances most commonly used during pregnancy. This chapter concludes with a section that sum- marizes the complex issues that attend polydrug use during pregnancy. Each substance is described, highlights of human embryo-fetal risks are reviewed, and perinatal effects are defined. Specific social and illicit substances used during pregnancy 305 Alcohol use during pregnancy and maternal alcoholism Alcohol is a central nervous system depressant and its abuse during pregnancy has adverse effects on both the mother and the fetus. We found that the prevalence of drinking four or more drinks [2 ounces (59 ml) of absolute alcohol] per day was 1. The prevalence of fetal alcohol syndrome varies widely among countries and is estimated at one per 100 live births in northern France (Daehaene et al. It is estimated that as many as 5 percent of congenital anomalies may be due to maternal alcohol intake during pregnancy (Sokol, 1981), although precise estimates of alcohol-induced birth defects are difficult to ascertain. Alcohol abuse during pregnancy appears to be the most frequent known teratogenic cause of mental retardation (Abel and Sokol, 1987; Clarren and Smith, 1978). Maternal effects Alcohol abuse during pregnancy generally affects the course of pregnancy negatively and reported adverse pregnancy outcomes related to alcohol consumption include stillbirths, premature deliveries, decreased placental weight, and spontaneous abortion (Parazzini et al. Such outcomes may occur even at low levels of alcohol consumption – less than four drinks per day (Little, 1977; Plant, 1984; Sokol et al. Some studies on the effects of alcohol use of various durations during pregnancy has shown that occasional binge drinking by moderate drinkers did not negatively affect birth outcome (Autti-Ramo et al. Continuous drinking throughout pregnancy appears to cause fetal damage in a dose-dependent manner (Halmesmaki, 1988). In 306 Substance abuse during pregnancy addition, the frequency of sexually transmitted diseases and other infections is higher among women who abuse alcohol during pregnancy. These anomalies repeatedly occurred among infants born to women who were chronic alcoholics, drinking eight or more such beverages every day (Clarren and Smith, 1978; Larroque, 1992; Sokol et al. The investigators found that at 5 years of age the children whose mothers had continued drinking during pregnancy showed more alcohol-related deficits than non-alcohol- exposed children or children whose mothers stopped drinking in the second trimester of pregnancy. Transient withdrawal symptoms, including tremors, hypertonia, and irri- tability, were reported among infants born to women who chronically drank alcohol late in pregnancy (Coles et al. In addition, there is genetic polymorphism for alcohol dehydrogenase, implying a pharma- cogenetic etiologic role in the severity of effects. Importantly, medical and psychological support for cessation of drinking should be offered. Since many of these women may also abuse other sub- stances, they should also be advised to stop using these agents. Alcohol summary Fetal alcohol syndrome is one of the three leading causes of mental retardation. In addition, this syndrome is a leading cause of poor pregnancy outcome and childhood morbidity (congenital anom- alies, including mental retardation). Approximately 6 percent of pregnant women tested positive for methamphetamines at delivery in one study (Little et al.

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Another new feature of this edition is designed to enhance the book’s appeal to all readers: the multiple sections on the “Clinical–Molecular Interface discount super p-force 160 mg without prescription. Many co-workers order super p-force 160mg overnight delivery, colleagues and reviewers have given their time, expertise and insights to aid the development of this third edition. Chris Barden (Department of Chemistry, Dalhousie University) provided detailed remarks on the entire book. Joshua Tracey checked molecular structures for accuracy, providing extensive assistance with molecular formulae; Vanessa Stephenson checked references and the suggested reading citations; and Dawnelda Wight provided clerical assistance with tables. Cheryl Weaver, Felix Meier, Vanessa Stephenson, Valerie Compagna-Slater, Michael Carter, Buhendwa Musole, Kathryn Tiedje, and Colin Weaver provided additional assistance with figures and diagrams. Purdy, Head, Division of Clinical Neurology, Dalhousie University, for his generous “protection of time” to provide the many hours necessary for the revision of this book. We also thank the editorial staff of Oxford University Press, Jeffrey House in particular, and Edith Barry, for working on the second and third edition, and for their never-ending patience. As with previous editions, we look forward to a continuing dialogue with our readers so that future editions can be further improved. How does a researcher sit down, paper in hand (or, better yet, a blank computer screen), and start the process of creating a molecule as a potential drug with which to treat human disease? When a researcher does design a molecule, how does she or he know if it has what it takes to be a drug? The previous century ended with an explosion of activity in gene-related studies and stem cell research; the new one is emerging as the “Century of Biomedical Research. Concerns about the capacity of “Mad Cow” disease to infect humans have focused attention on the safety of our food supply. Long-recognized diseases, such as stroke and Alzheimer’s dementia, are becoming more common as a greater proportion of the human population reaches old age. Not surprisingly, the need for drug discovery to address these important diseases is increasingly being recognized as a societal priority. Not only is drug discovery important to the medical health of humankind, it is also an important component of our economic health. As the world’s population increases and health problems expand accordingly, the need to dis- cover new therapeutics will become even more pressing. In this effect, the design of drug molecules arguably offers some of the greatest hopes for success. Medicinal chemistry is a science unto itself, a central science positioned to provide a molecular bridge between the basic science of biology and the clinical science of medicine (analogous to chemistry being the central science between the traditional disciplines of biology and physics). Basic concepts about drugs, receptors, and drug–receptor interactions (chapters 1–3). Basic concepts about drug–receptor interactions applied to human disease (chapters 4–9). The first phase comprises the essential building blocks of drug design and may be divided into three logical steps: 1. Knowledge of these three steps provides the necessary background required for a researcher to sit down, paper in hand, and start the process of creating a molecule as a potential drug for treating human disease. Drug molecules are “small” organic molecules (molecular weight usually below 800 g/mol, often below 500). When designing a molecule to be a drug-like molecule and, hopefully, a drug, the designer must have the ability to use diverse design tools. Some of these parts enable the drug to interact with its receptor, while other parts permit the body to absorb, distribute, metabolize, and excrete the drug molecule. Once a drug-like molecule successfully becomes a candidate for the treatment of a disease, it has graduated to the status of drug molecule. All receptors may be macromolecules, but all macromolecules are certainly not receptors. Certain properties must be present if a macromolecule is going to have what it takes to be a druggable target. The receptor macromolecule must be intimately connected with the disease in question, but not integral to the normal biochemistry of a wide range of processes. Step 3 involves designing a specific drug-like molecule to fit into a particular drug- gable target. During this task many molecules will be considered, but only one (or two) will emerge as promising starting points around which to further elaborate the design process. Synthetic organic chem- istry is a crucial component of this step in drug development. The process of drug design must be validated by actually making and testing the drug molecule. An ideal synthesis should be simple, be efficient, and produce the drug in high yield and high purity. Once the basics of drug design are in place, the drug designer next focuses upon the task of connecting a drug–receptor interaction to a human disease—this is the goal of the second phase. For example, how does one design a drug for the treatment of cancer or Alzheimer’s disease? This phase of drug design requires an understanding of bio- chemistry and of the molecular pathology of the disease being treated. The human body normally moves through time with its various molecular processes functioning in a balanced, harmonious state, called homeostasis. For a drug molecule, the goal is to rectify this perturbation (via the action of molecular therapeutics) and to return the body to a state of healthy homeostasis. First, one may ask what are the body’s normal inner (endogenous) control systems for maintaining homeostasis through day-to-day or minute-to-minute adjustments? These control systems (for example, neurotransmitters, hormones, immunomodulators) are the first line of defense against perturbations of homeostasis. Is it possible for the drug designer to exploit these existing control systems to deal with some pathological process? If there are no endogenous control systems, how about identifying other targets on endogenous cellular structures or macromolecules that will permit control where endogenous control has not previously existed? Alternatively, instead of pursuing these endogenous approaches, it is sometimes easier simply to attack the cause of the pathology. If there is a harmful microorganism or toxin in the environment (exogenous), then it may be possible to directly attack this exogenous threat to health and inactivate it. Accordingly, this phase of drug development, which connects the drug–receptor interaction to human disease, may be divided into three logical approaches: 1. A full understanding of the three steps of phase 1 and the three approaches of phase 2 will enable the researcher to design drugs. A Drug as a Composite of Molecular Fragments For the practical implementation of this idealistic strategy, drug molecules are concep- tualized as being assembled from biologically active building blocks (biophores) that are covalently “snapped together” to form an overall molecule. Thus, a drug molecule is a multiphore, composed of a fragment that enables it to bind to a receptor (phar- macophore), a fragment that influences its metabolism in the body (metabophore), and one or more fragments that may contribute to toxicity (toxicophores). The drug designer should have the ability to optimize the pharmacophore while minimizing the number of toxicophores. To achieve this design strategy, these fragments or building blocks may be replaced or interchanged to modify the drug structure. Certain building blocks (called bioisosteres), which are biologically equivalent but not necessarily chemically equivalent, may be used to promote the optimization of the drug’s biological properties. Surgical procedures are labour intensive and time demanding; they help a limited number of individuals, one at a time, mostly in rich or developed nations. Medical therapy, on the other hand, is based on drug molecules and thus has the capacity to positively influence the lives of more people, often over a shorter time frame. Medical therapeutics offer hope in both developed and developing parts of the world—hopefully to rich and poor alike. Penicillin has saved countless lives through the effective treatment of devastat- ing infectious diseases. Before penicillin, a diagnosis of meningococcal meningitis was invariably a death sentence. Similarly, drugs for the treatment of high blood pressure have substantially reduced the impact of this “silent killer” that leads to myocardial infarction (heart attack) or cerebral infarction (stroke).