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By B. Osko. Shaw University.

Used appropriately 5 mg proscar sale prostate 4k test, they can help not only to carried out at the molecular and disease mechanism establish the curative value of a new medicine but level buy 5 mg proscar with mastercard prostate cancer zinc supplementation. As such, we now have many models to also to ensure that the therapy gets delivered opti- evaluate and have probably reversed the develop- mally. This should not tions a product to deliver the best benefit for all cause us to take our eye off the needs of today and patients, convinces all those delivering the care to the ability of today’s medicines to be used most use the product, and sees a consequent real effectively. The value of a new therapeutic agent is improvement in society’s level of healthcare. Much the past, many good therapeutic agents have not can be done after market approval to ensure that a been used as or when they should have been. This new drug’s utility is both fully understood and was not because patients in trials have not been actually realized. The physicians within pharma- benefited, rather because thevalue message had not ceutical medicine need to oversee and lead this been positioned adequately for the care providers process. This requires that they are trained in eco- and/or for those who have to manage the healthcare nomics and business as well as medicine. Even when well devel- some may well go on to specialized courses in oped and appropriately used for their approved those areas leading to diplomas and even university indication, many drugs take on a new lease of life degrees. Con- rhythmic within the new context of cardiac resus- sequently, there is a real and ongoing role for those citation and coronary care units. It is a drugs of today within the medical and healthcare basic axiom of pharmaceutical medicine that no practices of tomorrow. This is analogous to physicians in their practice learning is true no matter how much human-use data is about a therapy and, as they come to know more available. For example, PhisoHex (hexachloro- about the use of the treatment and their practice phene) gained broad usage as a skin wash and dynamics change, modifying the use of that ther- scrub to combat the spread of infection. The overall process Notwithstanding all this, it became a safety and skill is an important part of the training within issue. This advanced, more and more premature babies were effort may include the issues of quality-of-life able to survive. There was therefore a new poten- industry for pioneering work on subjects as diverse tially ‘at-risk’ group. Hexachlorophene toxicity in as prostaglandins, anti-infectives, and pharmaco- humans was considered to have resulted, and this logical receptors such as the histamine and the led to the product being modified or removed in b-adrenergic receptor. In a relatively recent history the opportunity to carry out seminal work with of healthcare, there have been several such issues, entirely unique concepts, even if many of them for example Zomax, Oraflex, Tylenol tampering, do not become therapies for humans. Human is toxic shock syndrome, Reye’s syndrome, the a unique animal which can, and does, exhibit Dalcon shield, contaminated blood supply, silicon unique responses to a new chemical entity. No implants and the so-called ‘generic drug scandal’, pre-clinical work can be entirely predictive of a to mention but a few. Some is part of the role of a pharmaceutical physician products fail because of safety problems specific to recognize new opportunities and to be alert for to humans, and some because the early promise of any emerging evidence of potential added benefits efficacy in model systems is not realized in and/or new safety issues, as products and those of humans. They lap perhaps seemed to be with clinical pharmacol- are responsible for the products of the pharmaceu- ogy. Indeed, clinical pharmacologists have a real tical industry that are in use today. As such, they are interest in the R&D of the pharmaceutical industry influencing the health of far more people globally and their training is good for entry into the industry. Indeed, Any discussion of the discipline of pharmaceu- some pharmaceutical physicians will work in even tical medicine today would be incomplete without more basic and theoretical science settings, whilst a comment on the impact of biotechnology and the others will work in more commercial settings. This is a course, many within the speciality can and do focus revolution that is driven in a very different way on the development of disease models and the than that in which the pharmaceutical industry has evaluation of new chemical entities in these dis- classically been run. The most modern methods in such areas are tude of small venture capital companies which are vital to the successful development of new drugs, espousing the very cutting edges of research in and the continued and continuous interaction biologics, genetics and technology. They are lar- between the industry and academia is absolutely gely managed by a combination of bioscientists necessary. In this context, the role of pharma- Indeed, the distinction between academia and ceutical medicine takes on its most extreme var- pharmaceutical medicine is becoming blurred. At one end are physician/scientists, who are pharmaceutical industry R&D effort is now lead- the research brain of the venture, and at the other 2. In either of more, there is a growing understanding within these settings, pharmaceutical medicine is needed academia that in the past someone else was capi- and the specialist will apply all of the training talizing on their intellectual endeavours, so we are components that, as already indicated, compose seeing more medical and bioscience academics this new discipline. The biotechnology industry is carrying forward As this progress continues, the two disciplines of some of the best and brightest projects of the research and business are coming to realize that world’s leading academic institutions. Pharmaceutical pure research concepts through applied research medicine is the natural common pathway and the into development and finally to the production of integrating speciality which will fill this need and remarkable new therapeutic products. If try has already created two or three new companies this is so, then pharmaceutical medicine will of substance, with sales of over $1 billion per year become a leadership medical function in the and a capitalization measured in billions. The speciality lies at the con- than these obvious and huge successes, the industry junction of changing societal needs for healthcare, has spawned literally thousands of venture capital the burgeoning biosciences and the understandings efforts and new companies developing drugs, of how to provide improved quality of life and devices, diagnostics and all manner of medical cost–utility for patients today. Amazingly, this is an industry contains and provides includes basic sciences, which has come into being in the last decade or such as chemistry and mathematics, applied two. Already, companies are finding paediatrics to geriatrics and from family medicine that the major transition points in the therapeutic to the individual subspecialities. As such, pharma- product development process, from molecular to ceutical medicine is one of the most challenging, biochemical system, to cellular system, to organ exciting and rewarding areas of medicine.

Superficial sensation was completely absent below the margin of the left buttock and the left groin buy cheap proscar 5 mg mens health 60 years old, with a clear transition to normal above this circumference at the top of the left leg 5mg proscar otc androgen hormonal acne. There was normal withdrawal of the leg to nociceptive stimuli such as firm stroking of the sole and increasing compression of Achilles’ tendon. The superficial reflexes and tendon reflexes were normal and the plantar response was flexor. The clues to this are the cluster of: • the bizarre complex of neurological symptoms and signs which do not fit neuroanatom- ical principles, e. None of these on its own is specific for the diagnosis but put together they are typical. In any case of dissociative disorder the diagnosis is one of exclusion; in this case the neuro- logical examination excludes organic lesions. It is important to realize that this disorder is distinct from malingering and factitious disease. The condition is real to patients and they must not be told that they are faking illness or wasting the time of staff. The management is to explain the dissociation – in this case it is between her will to move her leg and its failure to respond – as being due to stress, and that there is no underlying serious disease such as multiple sclerosis. A very positive attitude that she will recover is essential, and it is important to reinforce this with appropriate physical treatment, in this case physiotherapy. The prognosis in cases of recent onset is good, and this patient made a complete recovery in 8 days. Dissociative disorder frequently presents with neurological symptoms, and the commonest of these are convulsions, blindness, pain and amnesia. Clearly some of these will require full neurological investigation to exclude organic disease. She lives alone but one of her daughters, a retired nurse, moves in to look after her. The patient has a long history of rheumatoid arthritis which is still active and for which she has taken 7 mg of prednisolone daily for 9 years. For 5 days since 2 days before starting the antibiotics she has been feverish, anorexic and confined to bed. On the fifth day she became drowsy and her daughter had increasing difficulty in rousing her, so she called an ambulance to take her to the emergency department. Examination She is small (assessed as 50 kg) but there is no evidence of recent weight loss. Her pulse is 118/min, blood pressure 104/68 mmHg and the jugular venous pressure is not raised. Her joints show slight active inflammation and deformity, in keeping with the history of rheumatoid arthritis. This is a common problem in patients on long-term steroids and arises when there is a need for increased glucocorticoid output, most frequently seen in infections or trauma, including surgery, or when the patient has prolonged vomiting and therefore cannot take the oral steroid effect- ively. It is probably due to a combination of reduced intake of sodium owing to the anorexia, and dilution of plasma by the fluid intake. In secondary hypoaldosteronism the renin–angiotensin–aldosterone system is intact and should operate to retain sodium. This is in contrast to acute primary hypoaldosternism (Addisonian crisis) when the mineralocorticoid secretion fails as well as the glucocorticoid secretion, causing hyponatraemia and hyperkalaemia. Acute secondary hypoaldosteronism is often but erroneously called an Addisonian crisis. Spread of the infection should also be considered, the prime sites being to the brain, with either meningitis or cerebral abscess, or locally to cause a pulmonary abscess or empyema. The patient has a degree of immunosuppression due to her age and the long-term steroid. The dose of steroid is higher than may appear at first sight as the patient is only 50 kg; drug doses are usually quoted for a 70 kg male, which in this case would equate to 10 mg of prednisolone, i. The treatment is immediate empirical intravenous infusion of hydrocortisone and saline. The patient responded and in 5 h her consciousness level was normal and her blood pres- sure had risen to 136/78 mmHg. Chest X-ray showed bilateral shadowing consistent with pneumonia, but no other abnormality. The pain is in the right loin and radiates to the right flank and groin and the right side of the vulva. Since the age of 18 years she has had recurrent urinary tract infections, mainly with dysuria and fre- quency, but she has had at least four episodes of acute pyelonephritis affecting right and left kidneys separately and together. Her mother had frequent urinary tract infections and died at the age of 61 of a stroke. Over the years the patient has taken irregular intermittent prophylactic antibiotics, but for only approximately a total of 20 per cent of the time. Access to any previ- ous medical records is not possible as she cannot remember the details of where she was seen or treated. She has had some imaging of the urinary tract but is unsure of the details of the investigations and their results. Renal stones can cause infection, or chronic infection can cause scarring which provides a nidus for stone formation. The high fever and leucocytosis indicate that she has another episode of acute pyelonephritis.

While discussing a case presentation with a medical student discount proscar 5mg on line prostate cancer untreated, a nearby patient who just returned from getting an ankle radiograph done yells out in pain purchase 5mg proscar with amex prostate cancer vs prostatitis. Physical examination reveals crackles mid- way up both lung fields and a new holosystolic murmur that is loudest at the apex and radiates to the left axilla. The patient does not have hypertension or diabetes mellitus and takes no prescription medications. A friend states that the patient just dropped to the ground shortly after scoring a basket on a fast-break. On examination, you note a prominent systolic ejection murmur along the left sternal border and at the apex. You suspect the diagnosis and ask the patient to perform the Valsalva maneuver while you auscultate his heart. Which of the following is most likely to occur to the intensity of the murmur with this maneuver? The patient complains of acute onset right-sided chest pain that is sharp in character and worse with inspiration. A 57-year-old man complains of chest palpitations and lightheaded- ness for the past hour. Five years ago he underwent a cardiac catheterization with coronary artery stent placement. Which of the following is the most appropriate medication to treat this dysrhythmia? In the past, he experienced chest discomfort after walking 20 minutes that resolved with rest. The episodes of chest pain this morning occurred while he was reading the newspaper. His wife states that he was well until she found him suddenly slump- ing in the chair and losing consciousness for a minute. The patient recalls having some chest discomfort and shortness of breath prior to the episode. As you are examining the patient described in the previous question, he starts to complain of chest discomfort and shortness of breath and has another syncopal episode. The most appropriate initial management includes placing the patient on a cardiac monitor to detect dysrhythmias, establish intravenous access, provide supplemental oxygen, and administer aspirin. This chaotic activity can lead to reduced cardiac output from a loss of coordinated atrial contractions and a rapid ventricular rate, both of which may limit diastolic filling and stroke volume of the ventricles. In general, a patient with stable atrial fibrillation under- goes an echocardiogram to evaluate for thrombus. If no clot is seen on echocardiogram, then heparin is administered and cardioversion can take place immediately. As potassium levels rise, peaked T waves are the first characteristic manifestation. Eventually the tracing assumes a sine- wave pattern, followed by ventricular fibrillation or asystole. The intrinsic reabsorption rate is approximately 1% to 2% a day, and accelerated with the administration of 100% oxygen. Many physicians observe these patients for 6 hours and then repeat the chest x-ray. The most common cause of esophageal perforation is from iatrogenic causes, such as a complication from upper endoscopy. This is noted by feeling air under the skin on palpa- tion of the chest wall or by a crunching sound heard on auscultation, also known as Hamman sign. Lateral displacement of the mediastinal pleura by mediastinal air cre- ates a linear density paralleling the mediastinal contour. On the lateral pro- jection, mediastinal air can be seen in the retrocardiac space. Chest Pain and Cardiac Dysrhythmias Answers 27 (a) Aspiration pneumonia is an inflammation of lung parenchyma pre- cipitated by foreign material entering the tracheobronchial tree. Alcoholics are prone to aspiration pneumonia because of ethanol’s sedating effect. Chest radi- ograph findings are often delayed with atelectasis typically being the first finding. The rub may be caused by friction between inflamed or scarred visceral and parietal pericardium or may result from friction between the parietal pericardium and adjacent pleura. Aortic dis- section (e) usually occurs in patients with chronic hypertension or con- nective tissue disorders. It can be quickly per- formed at the bedside and does not require radiation or contrast. If β-adrenergic receptors are antagonized, α-adrenergic receptors are left unopposed and available 28 Emergency Medicine for increased stimulation by cocaine. This may worsen into coronary and periph- eral vasoconstriction, hypertension, and possibly ischemia. Therefore, benzodi- azepines, which decrease central sympathetic outflow, are the cornerstone in treatment to relieve cocaine-related chest pain. Patients may present with fever, cardiac murmur, cough, pleuritic chest pain, and hemoptysis. Right-sided murmurs, which vary with respiration, are typically pathologic and more specific for the diagnosis. In patients with right-sided endocarditis and septic pulmonary emboli, pul- monary complaints, infiltrates on chest radiographs, and moderate hypoxia have been described in greater than 33% of patients; these symptoms and signs may mislead the physician to identify the lung as the primary source of infection.

The Chief Medical Officer for Scotland has predicted that by 2020 healthcare will run out of antibiotics (cited by Amyes & Thomson 1995) purchase 5 mg proscar otc androgen hormone joint. Such statements may appear sensationalist purchase proscar 5mg online androgen hormone neurotransmitter, but they emphasise the need to reorientate from relying on drugs to preventing and controlling infection. Antibiotics remain useful adjuncts to treatment, but will probably become progressively less effective. The inappropriate use of antibiotics has created more pathogenic, resistant organisms (Parke & Burden 1998), and so unnecessary use is actively discouraged (House of Lords Select Committee on Science and Technology 1998). Early onset pneumonia (from aspiration during trauma) is usually antibiotic- sensitive, but late onset pneumonia (ventilator-associated pneumonia) is usually resistant (Rello et al. Monoclonal antibodies are cloned and genetically engineered human Blymphocytes (Eburn 1993). Heat Moisture Exchangers) should be changed according to manufacturers’ instructions (normally daily); catheter mounts should be changed at the same time as humidifiers Infection control 135 ■ invasive techniques and disconnection of intravenous lines should, when possible, avoid times of dust disturbance (e. Antibiotics and other medical treatments can reduce morbidity and mortality, but preventing infection is humanly (and usually financially) preferable. Hygiene is helped by adequate and appropriate facilities, including sufficient washbasins, aprons and unit guidelines and protocols. All multidisciplinary team members should be actively involved in making decisions, but nurses have an especially valuable role in coordinating and controlling each patient’s environment. Problems from infection are likely to escalate; continuing vigilance and care can minimise infection risks and the spread of microorganisms. Further reading Articles on infection control frequently appear in specialist and general journals. Taylor’s (1978) classic article on handwashing is recommended; issues for nursing practice regularly appear in many general nursing journals. She was transferred from elderly care facilities with rapidly deteriorating respiratory function, copious mucopurulent sputum and atelectasis. Catherine’s previous respiratory tract infections had been treated with oral Amoxycillin (beta lactam class of antibiotics). Issues related to infection control are included in end-of-chapter scenarios in chapters 39 and 40. Chapter 16 Ethics Introduction The value of ethics for healthcare has been increasingly recognised: critical care often adds greater focus and poignancy to ethical dilemmas. Ethics raises questions rather than provides answers; dilemmas have more than one solution. Each person has values; some are formed or shared with peer groups, others are individual. Different values may cause conflict (for example, the care versus cure debate of Chapter 1). Active questioning enables evaluation of beliefs underpinning practice, helping nurses to understand others’ perspectives, but solutions necessarily remain individual. Increasing public expectations (and litigation) of healthcare, and changes within nursing (increased autonomy, responsibility and accountability) are reflected by greater emphasis on ethics in nursing education. A high public and media profile makes intensive care nursing a much-scrutinized area. This chapter provides a basis both for practice and for the remainder of this book; professional development can usefully be extended through discussion with colleagues and further study. This chapter describes the four main ethical principles identified by Beauchamp and Childress (1994): ■ autonomy ■ non-maleficence ■ beneficence ■ justice and the three main ethical theories identified by Rumbold (1993): ■ duty-based ■ goal-based ■ rights-based Other authors may give different arrangements, wording or additional theories and principles. Ethical principles provide a framework with which to work through dilemmas, identifying what is harmful, what is good and what is just. Decisions may differ between individuals because individual morals (values and beliefs) influence decision-making Intensive care nursing 138 processes. Ethical theories identify different sets of beliefs; understanding our own and others’ sets of beliefs (values) helps towards the understanding of differences. Some examples presented in this chapter include legal and professional perspectives; unlike ethics, these expectations can be enforced, and so nurses should consider their individual professional (and legal) accountability. Ethics are guides to decision-making, and decisions are influenced by sources such as ■ religion ■ law ■ society (and social values) ■ peers ■ individual values If growth from novice to expert entails moving from following rules to initiation (Benner 1984), understanding sources of ‘intuitive’ decisions can substantiate accountable evidence-based practice. The literal translation of both is ‘norm’ (Greek ethos, Latin mores), but they have different connotations. Many staff are uncomfortable with applying economics to healthcare, but while decisions should never be made solely on economic grounds, finance cannot be ignored where resources remain finite. Intensive care nursing relies on technology to support and monitor physiological function. Breathing and heartbeat can be replaced by technology (causing redefinition of death as absence of brainstem function), but intervention may prolong dying rather than prolong life: Rachels (1986) draws a distinction between living and the physical process of being alive. Technology may be used inappropriately; no treatment, intervention or observation should become ‘routine’. This much-used term is value-laden: what one person considers acceptable quality, another may not (e. Values vary between the extremes of preserving life at all costs, and always letting ‘nature’ take its course. Ethical principles Autonomy Beauchamp and Childress (1994) suggest that each ethical principle is part of a continuum. Autonomy, the first principle, is usually interpreted as ‘self-rule’—that is, making an informed free choice.

Critically ill patients have low antioxidant levels (especially vitamins C and E) (Davidson & Boom 1995) generic proscar 5 mg on line prostate cancer wikipedia. Giving vitamin E generic proscar 5mg free shipping androgen-independent hormone-refractory metastatic prostate cancer, the most important intracellular chain-breaking antioxidant (Davidson & Boom 1995), appears particularly beneficial. Other antioxidants that may Multiorgan dysfunction syndrome 265 prove useful include intracellular glutathione (Davidson & Boom 1995) and enzymes such as cytosolic superoxide dismutase (which includes zinc, long used for skin healing). Reperfusion of ischaemic tissues which have survived through anaerobic metabolism flushes toxic oxygen metabolites and radicals into the cardiovascular system. These can trigger a further cascade of vasoactive and other endogenous chemicals (see Chapter 23). Apparent recovery can therefore be reversed with one or more vital organs failing for a second time. High incidence and paucity of curative (rather than supportive) treatments has encouraged a search for novel solutions. Such is the need that possible solutions are sometimes pursued with little (or even adverse) benefit. This chapter illustrates how progression from single to multiorgan failure remains the greatest challenge facing intensive care. Clinical scenario Brian Geller, a 62-year-old gentleman, was originally admitted to hospital with severe abdominal pain from ruptured gastric and duodenal ulcers. He is intubated, has a urinary catheter in situ, and an abdominal wound with one drain. This chapter concentrates on pathophysiology and medical interventions and treatments. As much nursing time is devoted to assisting doctors (monitoring, giving prescribed treatments), nurses need to understand pathology and treatments. A 1992 consensus conference modified terminology to Acute Respiratory Distress Syndrome (Bernard et al. Alveoli being inherently unstable and prone to atelectasis, surfactant lack causes high intra-alveolar pressures and barotrauma, accelerating alveolar collapse and pulmonary oedema formation. Terminology again varies, and in practice these two stages are part of a continuum rather than distinct entities; but descriptions are clinically useful to understand disease progression. The early or exudative stage, which begins as endothelial injury causes progressive pulmonary capillary permeability, results in ■ interstitial and alveolar oedema (DiRusso et al. Proliferative/fibrotic stages Early insults to lung tissue cause progression to diffuse problems. Treatment Preventing further ventilator-induced injury and system support are the main-stays of treatment. Conventionally, treatment aimed to normalise blood gases, but the excessive peak airway pressures needed to achieve this accelerate alveolar damage (barotrauma, volotrauma). Current treatment has moved from short-term aims of normalising blood gases to longer-term aims of limiting damage and recruiting alveoli (Artigas et al. Fluid management necessitates balancing adequate perfusion without aggravating pulmonary oedema. Prolonged stays can enable close rapport between families and staff, but can become stressful for everyone; both bedside nurses and nurse managers need to recognise incipient distress. Families may seek hope where little exists, placing excessive trust/reliance/expectations on individual members of staff; as well as being a symptom of denial, this can be particularly stressful for staff. Ventilation Achieving ‘normal’ blood gases with reduced functional alveolar space necessitates forcing larger volumes of gas and/or higher concentrations of oxygen into remaining alveoli. Increased intra-alveolar pressures cause shearing damage (Volotrauma’), while higher concentrations of oxygen may become toxic. Hence, the focus has shifted from normalising blood gases to recruiting alveoli, using smaller tidal volumes and accepting abnormally high arterial carbon dioxide tensions (permissive hypercapnia): Thomsen et al. Permissive hypercapnia should therefore be used cautiously or avoided with: ■ raised intracranial pressure ■ anoxic brain injury (e. Intensive care nursing 270 Pressure limited/controlled ventilation limits peak inflation pressure, and so also limits further volotrauma (Hudson 1995). While preventing or limiting further damage remains the main priority, gas exchange can be optimised by manipulating other aspects of ventilation. Nurses detecting increases in pulmonary pressures (indicative of pulmonary oedema) should alert medical staff. Inverse ratio ventilation increases mean (but not peak) airway pressure (Mulnier & Evans 1995), and prolonged inspiratory phases promote alveolar recruitment, while shorter expiratory phases prevent alveolar collapse. Perfluorocarbon associated gas exchange (liquid ventilation, see Chapter 29) appears to have potential, and is likely to be evaluated rigorously in the near future. However, Lewis and Veldhuizen (1996), while acknowledging that specific dose and intervals remain unknown and the prediction of which patients will benefit remains impossible, argue that exogenous surfactant has proved ineffective because it is given too late. Lung damage occurs in dependent areas, so nursing patients prone for 4 to 8 hours (Brett & Evans 1997) may increase functional residual capacity, improve diaphragmatic motion and help removal of secretions (Mulnier & Evans 1995). Lateral positioning, potentially easier to achieve, also benefits gas exchange (Hinds & Watson 1996). Acute respiratory distress syndrome 271 However, use of the prone position remains controversial (Thomas 1997). Studies consistently show improvements in oxygenation, reduction of shunting, reduced oxygen requirements and reduced mortality (Wong 1998), although available literature may be biased by reluctance to report unsuccessful cases (Ryan & Pelosi 1996). Nursing prone may more usefully prevent potential problems rather than resolve existing ones, and so should be instigated early; too often, like other promising approaches, nursing prone is used once other approaches have failed (Gosheron et al. Recommended duration of prone positioning varies from 30 minutes to 12 hours; Vollman’s (1997) 4–6 hours (drawn from literature review and substantial practice) is recommended until systematic evaluation provides more concrete guidelines.

This and other aspects of drug design and discovery require input from specialists in other fields buy proscar 5 mg fast delivery man health month, such as biology proven proscar 5mg prostate cancer 12 tumors, biochemistry, pharmacology, mathematics, computing and medicine amongst others, and the medicinal chemist to have an outline knowledge of these fields. It attempts to provide a framework for the topics discussed in greater depth in the succeeding chapters. Drugs are strictly defined as chemical substances that are used to prevent or cure diseases in humans, animals and plants. The activity of a drug is its pharmaco- logical effect on the subject, for example, its analgesic or b-blocker action. Furthermore, in addition to their beneficial effects, most drugs have non-beneficial biological effects. Aspirin, which is commonly used to alleviate headaches, may also cause gastric irritation and bleeding. The non-beneficial effects of some drugs, such as cocaine and heroin, are so undesirable that the use of these drugs has to be strictly controlled by legislation. Resistance occurs when a drug is no longer effective in controlling a medical condition. Drug resistance or tolerance, often referred to as tachyphylaxis, arises in people for a variety of reasons. For example, the effectiveness of barbiturates often decreases with repeated use because repeated dosing causes the body to increase its production in the liver of mixed function oxidases that metabolize the drug, thereby reducing the drug’s effectiveness. An increase in the rate of production of an enzyme that metabolizes the drug is a relatively common reason for drug resistance. An- other general reason for drug resistance is the down-regulation of receptors (Appendix 5). Down-regulation occurs when repeated stimulation of a receptor results in the receptor being broken down. This results in the drug being less effective because there are fewer receptors available for it to act on. Drug resistance may also be due to the appearance of a significantly high proportion of drug resistant strains of microorganisms. These strains arise naturally and can rapidly multiply and become the currently predominant strain of that microorganism. For example, antimalarial drugs are proving less effective because of an increase in the proportion of drug resistant strains of the malaria parasite. New drugs are constantly required to combat drug resistance, even though it can be minimized by the correct use of medicines by patients. These products, obtained from animal, vege- table and mineral sources, were sometimes very effective. Information about these ancient remedies was not readily available to users until the invention of the printing press in the 15th century. This invention led to the widespread publication and circulation of herbals and pharmacopoeias. This resulted in a rapid increase in the use, and misuse, of herbal and other remedies. However, improved communications between practitioners in the 18th and 19th centuries resulted in the progressive removal of preparations that were either ineffective or too toxic from herbals and pharmacopoeias. Initially this development was centred around the natural products isolated from plant and animal material, but as knowledge increased a wider range of pharmaceutically active compounds were used as the starting point for the development of drugs. The compounds on which a development is based are now known as lead compounds, while the synthetic compounds developed from a lead are referred to as its analogues. The work of the medicinal chemist is centred around the discovery of new lead compounds with specific medical properties. It includes the devel- opment of more effective and safer analogues from both these new and existing lead compounds. This usually involves synthesizing and testing many hundreds of compounds before a suitable compound is produced. It is currently estimated that for every 10 000 compounds synthesized one is suitable for medical use. The first rational development of synthetic drugs was carried out by Paul Ehrlich and Sacachiro Hata, who produced the antiprotozoal arsphemamine in 1910 by combining synthesis with reliable biological screening and evaluation procedures. Ehrlich, at the begining of the 20th century, had recognized that both the beneficial and toxic properties of a drug were important to its evaluation. He realized that the more effective drugs showed a greater selectiv- ity for the target microorganism than its host. However, in practice index values can only be used as a limited guide to the relative usefulness of different compounds. One of its most successful uses has been in the development in the 1970s of the antiulcer agents cimetidine and ranitidine. In 1905 he proposed that so called receptive substances in the body could accept either a stimulating compound, which would cause a biological response, or a non-stimulating compound, which would prevent a bio- logical response. It is now universally accepted that the binding of a chemical agent, referred to as a ligand (see also section 7. Furthermore, a drug is most effective when its structure or a significant part of its structure, both as regards molecular shape and electron distribution (stereo- electronic structure), is complementary with the stereoelectronic structure of the receptor responsible for the desired biological action. The section of the structure of a ligand that binds to a receptor is known as its pharmacophore.

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