Richard J. Gray, MD, FACS

• Associate Professor of Surgery
• Department of Surgery
• Consultant, Section of Surgical Oncology
• Mayo Clinic
• Phoenix, Arizona

Compare the pupillary level on the affected side with the unaffected side medications ibs safe rulide 150 mg, since it may be lower from prolapse of the orbital contents into the maxillary sinus medications kidney damage buy rulide with a visa. Subtle abnormalities may be appreciated as an asymmetric corneal light reflex (Hirschberg reflex) symptoms nausea dizziness order rulide line. Subcutaneous emphysema symptoms for diabetes purchase rulide 150mg with visa, a soft-tissue teardrop along the roof of the maxillary sinus on plain film treatment 2 lung cancer order rulide online from canada, or an airfluid level in the maxillary sinus on plain film should also be interpreted as evidence of an orbital floor fracture symptoms iron deficiency buy rulide 150 mg lowest price. Patients with orbital wall fracture may present with subcutaneous emphysema after blowing their nose or air bubbles emanating from the tear duct. Carefully examine the eye for visual acuity, hyphema, or retinal detachment, and nose for septal hematoma. Treat patients without eye injury or entrapment conservatively with ice and analgesics, and refer for follow-up in 2 to 3 days. Strongly consider an ophthalmology consultation in patients with a true blowout fracture, as 30% of these patients sustain a significant globe injury. Immediately refer patients with entrapment, as muscle necrosis may occur if muscle blood supply is compromised by the entrapment. Enophthalmos, limited upward gaze, diplopia with upward gaze, or infraorbital anesthesia from entrapment or injury to the infraorbital nerve should heighten suspicion of an orbital floor fracture. Sustained from blunt trauma to infraorbital rim causing buckling of the orbital floor. Infraorbital hypesthesias and lack of entrapment suggest the buckling mechanism of injury. The right inferior rectus muscle is entrapped within this orbital floor fracture limiting upward gaze. Periorbital ecchymosis and swelling is seen in this patient with a medial wall orbital fracture. The patient blew her nose after the injury and the swelling became more prominent. A step-off in the dental line or ecchymosis or hematoma to the floor of the mouth is often present. Mandibular fractures may be open to the oral cavity, as manifested by gum lacerations. Other clinical features include inferior alveolar or mental nerve paresthesia, loose or missing teeth, dysphagia, trismus, or ecchymosis of the floor of the mouth (considered pathognomonic). Multiple mandibular fractures are present in more than 50% of cases because of the ringlike structure of the mandible. Injuries creating unstable mandibular fractures may create airway obstruction because the support for the tongue is lost. Mandibular fractures are also classified based on the anatomic location of the fracture. Dislocation of the mandibular condyles may also result from blunt trauma and will always have associated malocclusion, typified by an inability to close the mouth. Treat nondisplaced fractures with analgesics, soft diet, and referral to oral surgery in 1 to 2 days. Displaced fractures, open fractures, and fractures with associated dental trauma need more urgent referral. Treat all mandibular fractures with antibiotics effective against anaerobic oral flora (clindamycin, amoxicillin/clavulanate) and give tetanus prophylaxis if needed. The jaw will deviate toward the side of a unilateral condylar fracture on maximal opening of the mouth. A nonfractured mandible should be able to hold a tongue blade between the molars tightly enough to break it off. There should be no pain in attempting to rotate the tongue blade between the molars. Bilateral parasymphyseal fractures may cause acute airway obstruction in the supine patient. This is relieved by pulling the subluxed mandible and soft tissue forward and, in patients in whom the cervical spine has been cleared, by elevating the patient to a sitting position. Management and Disposition A dental panoramic film is the best diagnostic image for evaluating mandibular trauma. Hemorrhage or ecchymosis in the sublingual area is pathognomonic for mandibular fracture. Dental panoramic view showing two nondisplaced mandibular fractures that are amenable to conservative therapy. Dental panoramic view demonstrating a mandibular fracture with obvious misalignment due to the distracting forces of the masseter muscle. Blunt external ear trauma may cause a hematoma (otohematoma) of the pinna, which, if untreated, may result in cartilage necrosis and chronic scarring or further cartilage formation and permanent deformity ("cauliflower ear"). Open injuries include lacerations (with and without cartilage exposure) and avulsions. Management and Disposition Pinna hematomas must undergo incision and drainage or large needle aspiration using sterile technique, followed by a pressure dressing to prevent reaccumulation of the hematoma. A hematoma has developed, characterized by swelling, discoloration, ecchymosis, and flocculence. Immediate incision and drainage or aspiration is indicated, followed by an ear compression dressing. Reevaluation in 24 hours is recommended to ensure a drainable hematoma has not formed. Repeated trauma to the pinna or undrained hematomas can result in cartilage necrosis and subsequent deforming scar formation. The avulsed part was wrapped in sterile gauze soaked with saline and placed in a sterile container on ice. Direct closure of the cartilage is rarely necessary and is indicated only for proper alignment, which helps lessen later distortion. Lacerations to the lateral aspect of the pinna should be minimally debrided because of the lack of tissue at this site to cover the exposed cartilage. Pinna hematomas may take hours to develop, so give patients with blunt ear trauma careful discharge instructions, with a follow-up in 12 to 24 hours to check for hematoma development. Failure to adequately drain a hematoma, reaccumulation of the hematoma owing to a faulty pressure dressing, or inadequate follow-up increases the risk of infection of the pinna (perichondritis) or of a disfiguring cauliflower ear. Copiously irrigate injuries with lacerated cartilage, which can usually be managed by primary closure of the overlying skin. Posterior table involvement can lead to mucopyocele or epidural empyema as late sequelae. Involvement of the posterior wall of the frontal sinus may occur and result in cranial injury or dural tear. Frontal fractures may be part of a complex of facial fractures, as seen in frontonasoethmoid fractures, but generally more extensive facial trauma is required. Digital palpation is sensitive for identifying frontal fractures, although false positives from lacerations extending through the periosteum can occur. Communication of irrigating solutions with the nose or mouth indicates a breach in the frontal sinus. Fractures involving the posterior table require urgent neurosurgical consultation. Treat frontal sinus fractures with broad-spectrum antibiotics against both skin and sinus flora. Any laceration over the frontal sinuses should be explored to rule out a fracture. Fracture of the outer table of the frontal sinus is seen under this forehead laceration. Patients present with periorbital edema, ecchymosis, a marked decrease in visual acuity, and an afferent pupillary defect in the involved eye. The exophthalmos, which may be obscured by periorbital edema, can be better appreciated from a superior view. Visual acuity may be affected by the direct trauma to the eye (retinal detachment, hyphema, globe rupture), compression of the retinal artery, or, more rarely, neuropraxia of the optic nerve. Emergent lateral canthotomy and cantholysis to decompress the orbit can be sight-saving. The retrobulbar hematoma and exophthalmos may not develop for hours after the injury. A subtle exophthalmos may be detected by looking down over the head of the patient and viewing the eye from the coronal plane. Elevated intraocular pressure, relative afferent pupillary defect, and diminished visual acuity in patients with traumatic exophthalmos should strongly be considered for emergent lateral canthotomy and cantholysis. Proptosis, hyphema, periorbital ecchymosis, and marked swelling in the patient with a retrobulbar hematoma from severe head and face trauma. Complete enucleation of the right eye after a mechanical fall and hitting their face on the corner of a table. Midface injuries extend from the supraorbital rim superiorly to the oral commissure inferiorly and to the external auditory meatus posteriorly. Mandibular injuries extend from the oral commissure superiorly and to the lower border of the mandible inferiorly. Shotgun wounds typically involve both facial zones and will involve one or both eyes in 50% of patients. Due to the likelihood of multisystem injury (vascular, ocular, cranial, face) penetrating facial trauma, the patient should be transferred to a facility with comprehensive subspecialty trauma care. Management and Disposition After the primary survey, strongly consider intubation in patients with any gunshot injury to the mandible, blood or swelling in the oropharynx, or any close range (<7 m) shotgun injury. Removal of any projectile should only be performed after significant structure injury has been excluded and preparation for the consequences of removal is complete. Uncal herniation occurs when the uncus of the temporal lobe is displaced inferiorly through the medial edge of the tentorium. A contusion to the eye may also result in a dilated, nonresponsive pupil and arouse suspicion for severe head injury and uncal herniation but typically these patients will be alert. These conditions often cause midline shift of cerebral structures and compression of the quadrigeminal cistern. Initial management focuses on maintaining cerebral perfusion pressure and normal tissue oxygenation as hypotension and hypoxia significantly contribute to secondary brain injury. If a patient has a unilateral dilated pupil after head and face trauma but is awake and talking, be suspicious for isolated traumatic anisocoria. A temporal lobe contusion in an initially neurologically intact patient may continue to expand and cause uncal herniation. The quadrigeminal cistern should be seen on this slice and is completely effaced, suggesting herniation. Presenting symptoms for Neisseria gonorrhoeae infection include a hyperacute bilateral conjunctivitis with copious purulent discharge, lid swelling, chemosis, and preauricular adenopathy. More common etiologies include Chlamydia trachomatis, viruses (herpes simplex), and bacteria (Staphylococcus aureus, Streptococcal pneumoniae, Haemophilus species). For chlamydial conjunctivitis, the clinical features range from mild swelling with a watery discharge to marked lid swelling with a red and thickened conjunctiva with a blood-stained discharge. Fluorescein staining of herpes simplex conjunctivitis demonstrates epithelial dendrites. Bacterial neonatal conjunctivitis that is neither gonococcal nor chlamydial may be treated with erythromycin antibiotic ointment and should be reevaluated in 24 hours. Management and Disposition With any form of neonatal conjunctivitis, Gram stain and culture are indicated. Thick purulent drainage in a newborn diagnosed with neonatal gonococcal conjunctivitis. A scant crusty discharge is seen in this newborn who was diagnosed in follow-up with nasolacrimal duct obstruction. Blindness can result from gonococcal eye infection in the neonate because the organism can invade the cornea. Nasolacrimal duct obstruction is common (up to 20%) in newborns and may present with findings suggestive of conjunctivitis. Advise parents that infants treated with macrolides are at risk for developing hypertrophic pyloric stenosis. Streptococcus pneumoniae and Haemophilus influenzae occur more frequently in children. Hyperacute bacterial conjunctivitis, the most severe form of acute purulent conjunctivitis, is associated with N gonorrhoeae. Symptoms are hyperacute in onset, and findings include a purulent, thick, copious discharge, eyelid swelling and tenderness, marked conjunctival hyperemia, chemosis, and preauricular adenopathy. The condition is serious and threatens sight because Neisseria species are capable of invading an intact corneal epithelium. Corneal findings include epithelial defects, marginal infiltrates, and an ulcerative keratitis that can progress to perforation. Mucopurulent discharge and conjunctival injection in an adult with conjunctivitis. Red flags include a significantly decreased visual acuity, ciliary flush, and corneal opacity. Worsening symptoms during topical treatment with Neosporin or a sulfonamide suggest a contact allergic reaction. N gonorrhoeae conjunctivitis must be considered in the sexually active adult with a prominent, thick, copious discharge. Fluoroquinolones should be prescribed for contact lens wearers because of concern for Pseudomonas infection in these patients. Management and Disposition Encourage frequent hand washing and warm moist compresses.

A national communitybased programme to improve the nutrition of children in India was established in the 1980s symptoms uti in women order generic rulide canada. Because the programme had to be implemented in a phased approach treatment trends purchase rulide 150mg mastercard, the National Institute of Nutrition in Hyderabad under took a stepped wedge design where 29 villages were selected and 15 were chosen as the intervention and 14 were control villages who all received the intervention after a delay of three years treatment nerve damage trusted 150 mg rulide. A follow-up study symptoms 9 dpo buy cheap rulide 150mg on-line, conducted when the children were around 16 years of age symptoms in early pregnancy cheap rulide 150mg fast delivery, showed that children born in the intervention villages were taller medications you should not take before surgery order 150mg rulide, had better measures of insulin metabolism and less stiff arteries though measures of obesity were similar (Kinra et al. Despite adjusting for other variables, it is still possible that confounding by other factors remains so that areas that spend more money on mental health services are also areas with better social networks or family support (for which there is probably no routine data) and in fact it is the latter factors rather than the expenditure that is the protective factor. This enabled a comparison both within Scotland, before and after the ban, as well as comparing this with any changes in England. Example: Legislation on pesticide sales and suicide mortality It is quite common to plot longer term time trends or do time series analyses with the timing of any major change highlighted. As noted in Chapter 11 qualitative research methods can be used to observe and inform aspects of randomised trials. Qualitative methods are particularly useful when a complex public health intervention is being developed as they can be used to find out whether the intervention is acceptable both to those for whom the intervention is being provided and to those responsible for delivering it and to answer questions about whether or not it is feasible to deliver the intervention. Black N (1996) Why we need observational studies to evaluate the effectiveness of health care. Public health policy and target setting the way in which societies respond to population health problems is generally by agreeing what needs to be done to tackle serious concerns and improve the health of the public. As the policies adopted, particularly at a national level, have grown both in their span and implications it has been found necessary to back them up with the practical strategies need to support their implementation and, hopefully, success. In the last ten years, they have been increasingly used as a tool in performance management, not just in health but across the entire public sector. However, setting targets is a complex, imperfect process and there is no inevitably that their use will lead to improvements in outcomes or performance. Setting targets also provides one approach to the assessment of progress in relation to a defined health policy or programme by defining a benchmark against which progress can be measured. In the health sector high-level targets are considered by many as necessary in order to achieve the goals and objectives set out in health policies and are primarily set for either one or both of the following reasons: (1) to ensure that activity is directed towards the achievement of health outcomes; and/or (2) to facilitate the monitoring of progress in order to ensure that health policy goals and objectives are being met. At a global level, important examples are the Millennium Development Goals (see Chapter 22). At their best they are used to: (1) ensuring consistency in the care or service provided; and (2) challenging the individual, organisation or system to do better. They can relate to inputs, demand, activity, infrastructure, outcomes, outputs and processes. Indicators are developed to measure movement towards, or away from, a pre-defined target and are a mechanism for keeping track of progress towards an overall goal. The under-five mortality rate is also used as an indicator to monitor progress towards this overall target. The targets set were often phrased in terms of hospital beds or health professionals per head of population, their geographical spread and the number of individuals who did or did not have access to health services. In the late 1970s, the focus of health policies shifted from service expansion to reducing health care expenditure through improving the efficiency of health services delivery. Both of these could link policy action to the potential health benefits for the population. Both national and supranational policies started to translate policy priorities into health targets. The targets quantitatively indicated what level of health in the populations should be attained and by when. They included infant mortality rates, prevalence of hypertension, deaths due to motor-vehicle accidents, and mortality rates due to coronary heart disease or lung cancer. Health targets were widely supported at this time as a helpful way of prioritising actions and focusing efforts, however, they were criticised for following a mainly disease based model. The new health policy had two key aims; to improve life expectancy and to narrow the gap in health between the worst off and best off in society. Targets were also now increasingly used as a management tool integral to the governance of health services both to monitor progress in improving health and to manage the performance of services. However, there was widespread concern about the large number of indicators and the top down bias and centrally driven nature of these targets. There were numerous examples of organisations and services that engaged in undesirable practices in order to achieve their targets and opponents of this system strongly criticise targets for creating poor quality services (Fulop, 2000; Seddon, 2008). The value of targets Targets help drive improvement in a number of ways: r Identify priorities and help define an agreed direction: targets indicate which areas are high Health care targets 187 priorities for action and can be used to focus attention, efforts and resources on achieving the desired health outcome. Targets can provide individuals with a clear understanding of why some things need to happen and their role in making them happen. Targets can motivate staff if they are challenging but realistic and there is a sense of ownership. In this way targets that are not met can still lead to improvements and so should not be seen as a sign of failure. Problems with targets Target setting is an imperfect process, many targets are not set well and do not result in improvement. An understanding of the deficiencies and failures of targets can be highly instructive and aid the process of improvement. Common problems identified with setting targets include: r Perverse incentives: A perverse incentive is an incentive that has an unintended and undesirable effect, which is against the interest of the policy makers. Indicators should be reviewed to make them more reflective of the intended health outcome; this can be achieved with the use of a balanced suite of indicators and focusing on outcomes as far as possible. Acute trusts were penalised financially for not achieving this target and, in some instances, resorted to drafting extra staff into accident and emergency departments, operations being cancelled, and patients having to wait in ambulances until staff were confident of meeting the target (Bevan, 2006). The introduction of uncertainty in the way that performance is assessed, for example varying the targets from time to time, can reduce the potential for gaming. For example, it could be argued that it is contradictory to set local targets to reduce alcohol related harm whilst promoting other national policies that oppose changes in alcohol pricing and encourage alcohol consumption (Hadfield, 2009). This may occur because the performance indicators do not accurately reflect the whole picture and may require indicators that are more representative or the use of multiple indicators. For example the installation of brighter street lights to reduce crime may conflict with the goal of reducing use of energy or promoting dark skies. Wrong type of indicators: the indicators do not provide an appropriate assessment of the outcome for which they have been set. For example four week quit rates for smoking cessation are used as an indicator of success; however, this is based on self reports and is not a reliable indicator of successful long term quitting (Ash, 2009). Targets should only be set if there is a robust mechanism for monitoring progress and indicators should be reviewed to ensure that they are consistent with what they are asked define. For example the 2008 Health Survey for England used two new methods to measure physical activity; all participants were questioned about their activity as done in previous years and a sub sample was also asked to wear pedometers for a week. The survey results highlighted enormous discrepancies between the two methods, emphasising the importance of using reliable methods to track trends over time (Cavill et al. Lack of ownership of targets: Targets that are not agreed by partners risk a lack of ownership and are unlikely to attract sufficient support to achieve the intended improvements. Those responsible for the target need to be clearly identified and made aware of how they will be held accountable for the target. For example the percentage of individuals that eat healthily is ambiguous, instead the percentage of adults (18 or older) that eat five or more portions of fruit and vegetables in a day is operationally precise and less open to interpretation. More complicated diseases that are more difficult to measure and not amenable to targets, such as many psychiatric conditions, are frequently ignored. It is clearly desirable that targets should measure aspects of public health and service delivery that are truly important rather than those that are easily measured. The target should be clear, unambiguous and easy to understand by those who are required to use them. Open ended targets should be avoided as they do not encourage focussed efforts on improving performance. A criticism of target setting is that national policies are often not consistent or openly conflict with local strategies making it difficult to maintain momentum and enthusiasm for strategies at a local level Consultation with key individuals and organisations: the knowledge and experience of people responsible for the delivery of the target should be used to inform the targets to ensure that targets are appropriate, achievable and realistic and to encourage ownership of the target. It is inappropriate to set targets for an activity that cannot be directly influenced or controlled. Evidence based: the development of realistic targets requires an understanding of the epidemiology of disease and the estimated health benefits that would be achievable with the current interventions. Indicators/measures: indicators are used as proxy measures and so need to be a plausible measure of the outcome of interest. Indicators are used to measure progress and therefore need to sensitive and responsive to changes in the outcome. The data should be of good quality (complete, accurate and timely) and be comparable across individuals, organisations and services. However, targets are just one method for improving outcomes and may not always be suitable. Therefore before setting a target it is important to first consider if a target is 190 Health care targets necessary and appropriate; if a target is needed then it is essential that it is properly constructed and will result in genuine improvements in outcomes. Seddon J (2008) Systems Thinking in the Public Sector: the Failure of a Reform Regime and a Manifesto for a Better Way. Heymann and Shah Ebrahim London School of Hygiene and Tropical Medicine Learning objectives In this chapter you will learn: What are the global burdens of disease and how they differ between low-middle income and high income countries What are the wider determinants of health and the potential impact of demographic changes, migration and globalisation What is the role for global initiatives to address these problems and What are the possible solutions to improve global health Global health can be defined as health problems, issues and concerns that transcend national boundaries, may be influenced by circumstances or experiences in other countries, and are best addressed by cooperative actions and solutions. However, data collection is often limited in many developing countries; medically certified information is available for less than a third of deaths worldwide. Global health relies on people from a range of different disciplines, often outside of conventional health sciences, working together. Global health Epidemiology, Evidence-based Medicine and Public Health Lecture Notes, Sixth Edition. These communicable diseases pose a great challenge because (a) lack of effective vaccines (except for measles), (b) those at risk or already infected are unable to access medicines and other goods such as bed-nets and condoms. However, governments of many low income countries must also become more engaged in ensuring the systems that will deliver these goods to health facilities. Most maternal deaths happen around the time of delivery, most commonly due to haemorrhage. Surprisingly, a large proportion of maternal death takes place in hospitals; these include women who come to the hospital in a moribund state too late to benefit from care, but also those who arrive with treatable complications but do not receive timely and effective interventions and those admitted for normal delivery that subsequently develop complications. The majority of these deaths occur in the neonatal period, during which time preterm birth complications and birth asphyxia are particularly important. Interventions directed towards health education of families and communities to promote adoption of evidence-based home-care practices and improved care seeking, could avert majority of neonatal deaths in low income settings, but the coverage of these interventions remains poor. Most deaths from hunger do not occur in high profile emergencies but in unnoticed circumstances. Suboptimal breast feeding, especially nonexclusive breast feeding in the first six months of life, is an important cause of child mortality, while maternal short stature and iron deficiency anaemia increase the risk of death of the mother at delivery. The transition is happening at a much faster pace, and before the disappearance of the diseases of the old world. The speed of the transition is driven by: (a) (b) (c) (d) ageing population, greater urbanisation, migration and increasingly globalisation. As a result of these forces, ischaemic heart disease and cerebrovascular disease are now the commonest causes of death in low- and high-income countries. Their risk factors Global health 195 (obesity, higher consumption of calorie and fat rich diets, salt intake, physical inactivity and tobacco use) are well established. Most noncommunicable diseases require longterm treatment, and often expensive, treatments which people from low- and middle-income countries are least able to afford to pay, particularly as these countries usually lack free health care or health insurance coverage and health costs are borne by out-of-pocket expenses. The cost of treating chronic diseases and their risk factors is sizeable, ranging from 0. In many western countries, the rates of cardiovascular disease have fallen dramatically and are probably explained by reductions in tobacco use, less saturated fat intake, and lower salt. The north Karelia project in Finland, launched in 1972, used a multi-component approach (media activities, participation of health care and other workers and community organisations, environmental changes through collaborations with industry etc. More promising was a population intervention on the island of Mauritius, when the Government banned the import of palm oil (a saturated oil), substituting this with Soya bean oil (a polyunsaturated oil). Injuries Often injuries are overlooked in global health but are a major cause of avoidable death and disability. Exceptions are falls with are less common in developing countries, reflecting the younger age distribution and injuries due to wars which are about 300 times as common. Prevention is based on the conventional epidemiological understanding of host, vector and environment. Trends are not encouraging: car ownership is rising globally but injury rates are not falling. In developing countries with adequate data increases in death rates from road injuries have increased by 40 to 200% between 1975 and 1998. Whereas in developed countries dramatic falls have occurred, reflecting the increased emphasis on road safety and implementation of effective strategies. The process of migration itself, apart from stress and physical danger, also facilitates the transfer of the infectious agents that cause emerging and re-emerging infectious diseases. Infections can today spread around the globe and emerge in new geographic areas with amazing ease and speed. The effect of greenhouse gases is to trap more heat in the lower atmosphere leading to global warming. Spikes of high temperatures also cause heat stroke and directly cause many deaths in rural areas of south Asia where there is no protection from high temperatures.

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Disulfiram should not be administered until the patient has abstained from alcohol for at least 12 h aquapel glass treatment order rulide 150mg free shipping. Disulfiram or its metabolites can inhibit many enzymes with sulfhydryl groups symptoms bone cancer generic rulide 150mg fast delivery, producing a wide spectrum of biological effects medicine and manicures order rulide 150mg on-line. Benzodiazepines are the treatment of choice for management of acute alcohol withdrawal and to prevent the progression from minor withdrawal symptoms to major ones symptoms hypothyroidism cheap rulide, such as seizures and delirium tremens (see Chapter 24) medications j tube rulide 150mg line. It is also approved for treatment of opioid overdose and dependence (see Chapters 18 and 24) treatment 20 nail dystrophy effective 150 mg rulide. There is evidence that naltrexone blocks activation of brain receptors by opioid peptides that are thought to be critical for the rewarding effects of drugs of abuse. It is typically administered after detoxification at a dose of 50 mg/d for several months. The most common side effect of naltrexone is nausea, which subsides if the patient abstains from alcohol. There is some evidence of dysphoria associated with administration of naltrexone, and it is contraindicated in patients with depressive disorders. Doses of naltrexone exceeding 300 mg can cause liver damage; the drug is contraindicated in patients with liver failure or acute hepatitis and should be used only after careful consideration in patients with active liver disease. Nalmefene, an opioid receptor antagonist structurally similar to naltrexone, is used to treat opioid overdose and may also be used to manage addictive behaviors. Gabapentin, which interacts with the 2 subunit of neuronal voltagegated Ca2+ channels, is primarily used to treat epileptic seizures and neuropathic pain. Varenicline, which is approved for smoking cessation, also reduces alcohol consumption in preclinical and clinical models (Rahman et al. Vital Signs: Binge Drinking Prevalence, Frequency, and Intensity Among Adults-United States, 2010. Reward craving and withdrawal relief craving: assessment of different motivational pathways to alcohol intake. Heterogeneity of alcohol use disorder: understanding mechanisms to advance personalized treatment. A review of the interactions between alcohol and the endocannabinoid system: implications for alcohol dependence and future directions for research. Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. The first state is dependence, or "physical" dependence, produced when there is progressive pharmacological adaptation to the drug resulting in tolerance. For some (16% of those who try cocaine), the experience produces strong conditioned associations to environmental cues that signal the availability of the drug or the behavior. The individual becomes drawn into compulsive repetition of the experience, focusing on the immediate pleasure despite negative long-term consequences and neglect of important social responsibilities. The distinction between dependence and addiction is important because patients with pain sometimes are deprived of adequate opioid medication by their physician simply because they have shown evidence of tolerance or they exhibit withdrawal symptoms if the analgesic medication is stopped or reduced abruptly. The most recent revision of the classification system (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; see American Psychiatric Association, 2013) makes a clear distinction between normal tolerance and a drug use disorder involving compulsive drug seeking. Many variables operate simultaneously to influence the likelihood that a beginning drug user will lose control and develop an addiction. Agent (Drug) Variables Reinforcement refers to the capacity of drugs to produce effects that make the user wish to take them again. The more strongly reinforcing a drug is, the greater is the likelihood that the drug will be abused. When coca leaves are chewed, cocaine is absorbed slowly; this produces low cocaine levels in the blood and few, if any, behavioral problems. This does not imply that the pharmacological addiction liability of nicotine is twice that of cocaine. The risk of addiction is specific to the drug indicated and refers to the percentage who met criteria for addiction among those who reported having used the agent at least once. The National Institute on Drug Abuse conducted a related study in 2014: available at. Polymorphism of genes that encode enzymes involved in absorption, metabolism, and excretion of a drug and its receptor-mediated responses may contribute to the effects of the drug across the addiction cycle. While innate tolerance increases vulnerability to alcoholism, impaired metabolism may protect against it (see Chapter 23). People with anxiety, depression, insomnia, or even shyness may find that certain drugs give them relief. However, the apparent beneficial effects are transient, and repeated use of the drug may lead to tolerance and eventually compulsive, uncontrolled drug use. With repeated use of the drug, however, the curve shifts to the right (tolerance). We can define multiple aspects of tolerance and give examples of some general mechanisms and dosing schedules that contribute: Innate tolerance refers to genetically determined lack of sensitivity to a drug the first time that it is experienced. Pharmacodynamic tolerance refers to adaptive changes that have taken place within systems affected by the drug so that response to a given concentration of the drug is altered (usually reduced). Learned tolerance refers to a reduction in the effects of a drug due to compensatory mechanisms that are acquired by past experiences. A common example is learning to walk a straight line despite the motor impairment produced by alcohol intoxication. When a drug affects homeostatic balance by producing sedation and changes in blood pressure, pulse rate, gut activity, and so on, there is usually a reflexive counteraction or adaptation in the direction of maintaining the status quo. This mechanism follows classical (Pavlovian) principles of learning and results in drug tolerance under circumstances where the drug is "expected. Sensitization, in contrast to acute tolerance during a binge, requires a longer interval between doses, usually about 1 day. Cross-tolerance occurs when repeated use of a drug in a given category confers tolerance not only to that drug but also to other drugs in the same pharmacological category. Detoxification is a form of treatment of drug dependence that involves giving gradually decreasing doses of the drug to prevent withdrawal symptoms, thereby weaning the patient from the drug of dependence. The typical addicted user is craving the "high" and seems willing to risk overdose by going beyond the safe level. A person in this adapted or physically dependent state requires continued administration of the drug to maintain normal function. If administration of the drug is stopped abruptly, there is another imbalance, and the affected systems must readjust to a new equilibrium without the drug. The appearance of a withdrawal syndrome when administration of the drug is terminated is the only actual evidence of physical dependence. Pharmacokinetic variables are of considerable importance in the amplitude and duration of the withdrawal syndrome. Patients who take medicine for appropriate medical indications and in correct dosages still may show tolerance, physical dependence, and withdrawal symptoms if the drug is stopped abruptly rather than gradually. A physician prescribing a medication that normally produces tolerance must understand the difference between dependence and addiction and be mindful of withdrawal symptoms if the dose is reduced. Alcohol is so widely available that it is combined with practically all other categories of drugs. When confronted with a patient exhibiting signs of overdose or withdrawal, the physician must be aware of these possible combinations because each drug may require a different and specific treatment. Ethanol More than 90% of American adults report experience with ethanol (commonly called "alcohol"). In the setting of such complications, the syndrome of delirium tremens becomes likely. Alcohol addiction produces cross-tolerance to other sedatives, such as benzodiazepines. This tolerance is operative in abstinent alcoholics, but while the alcoholic is drinking, the sedating effects of alcohol add to those of other sedatives. This is particularly true for benzodiazepines, which are relatively safe in overdose when given alone but potentially are lethal in combination with alcohol. The chronic use of alcohol and other sedatives is associated with the development of depression and the risk of suicide. More severe recent memory impairment is associated with specific brain damage caused by nutritional deficiencies common in alcoholics. As the blood level increases, the sedating effects increase, with eventual coma and death occurring at high blood alcohol levels. The innate tolerance to alcohol varies greatly among individuals and is related to family history of alcoholism (Wilhelmsen et al. The alcohol withdrawal syndrome generally depends on the size of the average daily dose and usually is "treated" by resumption of alcohol ingestion. Although most mild cases of alcohol withdrawal never come to medical attention, severe cases require general evaluation; attention to hydration and electrolytes; vitamins, especially high-dose thiamine; and a sedating medication that has cross-tolerance with alcohol. Anticonvulsants such as carbamazepine have been shown to be effective in alcohol withdrawal, but not as well as benzodiazepines. The effect varied from strong to weak, but overall, reduction in heavy drinking was a consistent finding (Pettinati et al. Naltrexone works best in combination with behavioral treatment programs that encourage adherence to medication and abstinence from alcohol. A depot preparation with a duration of 30 days is now available; it greatly improves medication adherence. Depot naltrexone can also be used in the prevention of relapse in opioid addiction (Lee et al. Benzodiazepines Benzodiazepines are used mainly for the treatment of anxiety disorders and insomnia (see Chapters 15 and 17). These agents are widely used, and abuse of prescription benzodiazepines is not uncommon. Insomnia often is a symptom of an underlying chronic problem, such as depression or respiratory dysfunction. Whether from prescribed hypnotic or self-administered alcohol, medication-induced rebound insomnia requires detoxification by gradual dose reduction. Physicians should not recommend a bedtime drink of alcohol to relieve insomnia; the result is usually disordered sleep. Because nicotine provides the reinforcement for cigarette smoking, the most common cause of preventable death and disease in the U. Although more than 80% of smokers express a desire to quit, only 35% try to stop each year, and fewer than 5% are successful in unaided attempts to quit. Nicotine itself produces reinforcement; users compare nicotine to stimulants such as cocaine or amphetamine, although its effects are of lower magnitude. With 10 puffs per cigarette, the 1-pack-per-day smoker reinforces the habit 200 times daily. Depressed mood (dysthymic disorder, affective disorder) is associated with nicotine dependence, but it is not known whether depression can predispose one to begin smoking or whether depression develops secondarily during the course of nicotine dependence. The nicotine withdrawal syndrome can be alleviated by nicotine replacement therapy. A sustained-release preparation of the antidepressant bupropion (see Chapter 15) improves abstinence rates among smokers and remains a useful option. It has high receptor affinity, thus blocking access to nicotine, so if the treated smoker relapses, there is little reward, and abstinence is more likely to be maintained. Moreover, some patients continue to take the medication for years in appropriate doses according to medical directions and are able to function effectively as long as they take the medication. Withdrawal symptoms may occur during this outpatient detoxification, but in most cases the symptoms are mild. Some authorities recommend transferring the patient to a benzodiazepine with a long t1/2 during detoxification; others recommend the anticonvulsants carbamazepine and phenobarbital. Abusers of high doses of benzodiazepines usually require inpatient detoxification. Frequently, benzodiazepine abuse is part of a combined dependence involving alcohol, opioids, and cocaine. Detoxification can be a complex clinical pharmacological challenge requiring knowledge of the pharmacokinetics of each drug. No specific medications have been found to be useful in the rehabilitation of sedative abusers, but specific psychiatric disorders such as depression or schizophrenia, if present, require appropriate medications. Pharmacological Interventions Barbiturates Abuse problems with barbiturates resemble those seen with benzodiazepines in many ways, and treatment of abuse and addiction to barbiturates should be handled similarly to interventions for the abuse of alcohol and benzodiazepines. These idealized curves are based on the findings of experiments by Benowitz et al. Injection of a heroin solution produces a variety of sensations, described as warmth, taste, or high and intense pleasure ("rush") often compared with sexual orgasm. There are some differences among the opioids in their acute effects; for instance, morphine produces a prominent histamine-releasing effect (causing itching), and meperidine is notable for producing excitation or confusion. Even experienced opioid addicts, however, cannot distinguish between heroin and the common opioid hydromorphone, often used for pain in hospitalized patients.

This chapter concentrates on pharmacotherapy for angina pectoris and myocardial ischemia symptoms synonym cheap 150mg rulide visa. Pathophysiology of Angina Pectoris Angina pectoris symptoms checker order rulide 150mg with amex, the primary symptom of ischemic heart disease treatment trends order on line rulide, is caused by transient episodes of myocardial ischemia that are due to an imbalance in the myocardial oxygen supply-demand relationship medicine research cheap rulide 150 mg fast delivery. Regardless of the precipitating factors symptoms 10 dpo purchase rulide 150 mg without a prescription, the sensation of angina is similar in most patients treatment hyperthyroidism buy on line rulide. Typical angina is experienced as a heavy, pressing substernal discomfort (rarely described as a "pain"), often radiating to the left shoulder, flexor aspect of the left arm, jaw, or epigastrium. However, a significant minority of patients note discomfort in a different location or of a different character. In typical stable angina, the pathological substrate is usually fixed atherosclerotic narrowing of an epicardial coronary artery, on which exertion or emotional stress superimposes an increase in myocardial O2 demand. Atherosclerotic plaques with thinner fibrous caps appear to be more "vulnerable" to rupture. While some patients have only silent ischemia, most patients who have silent ischemia have symptomatic episodes as well. In most trials, the agents that are efficacious in typical angina also are efficacious in reducing silent ischemia. Therapy directed at abolishing all silent ischemia has not been shown to be of additional benefit over conventional therapy. Increased O2 supply by dilating the coronary vasculature may play an additional role and is the major effect of nitrovasodilators and Ca2+ channel blockers in variant angina. Antianginal agents may provide prophylactic or symptomatic treatment, but blockers also reduce mortality, apparently by decreasing the incidence of sudden cardiac death associated with myocardial ischemia and infarction. This figure shows the primary hemodynamic sites of action of pharmacological agents that can reduce O2 demand (left side) or enhance O2 supply (right side). Stents, angioplasty, and coronary bypass surgery are mechanical interventions that increase O2 supply. In patients with stable cardiovascular disease, clopidogrel conferred no benefit over aspirin and was associated with signs of harm in patients with multiple risk factors (Bhatt et al. In some subsets of patients, percutaneous or surgical revascularization may have a survival advantage over medical treatment alone (Kappetein et al. Subsequently, William Murrell surmised that the action of nitroglycerin mimicked that of amyl nitrite and established the use of sublingual nitroglycerin for relief of the acute anginal attack and as a prophylactic agent to be taken prior to exertion. The empirical observation that organic nitrates could dramatically and safely alleviate the symptoms of angina pectoris led to their widespread acceptance by the medical profession. Indeed, Alfred Nobel himself was prescribed nitroglycerin by his physicians when he developed angina in 1890. Amyl nitrite is a highly volatile liquid that must be administered by inhalation and is of limited therapeutic utility. Reduced phosphorylation of myosin light chain is the result of decreased myosin light-chain kinase activity and increased myosin light-chain phosphatase activity and promotes vasorelaxation and smooth muscle relaxation in many tissues. In addition, sublingual nitroglycerin administration may produce bradycardia and hypotension, probably owing to activation of the Bezold-Jarisch reflex. In patients with autonomic dysfunction and an inability to increase sympathetic outflow (multiple-system atrophy and pure autonomic failure are the most common forms, much less commonly seen in the autonomic dysfunction associated with diabetes), the fall in blood pressure consequent to the venodilation produced by nitrates cannot be compensated. At low-to-medium doses, preferential venodilation decreases venous return, leading to a fall in left and right ventricular chamber size and end-diastolic pressures, reduced wall stress, and thereby reduced cardiac O2 demand (see discussion that follows). Systemic vascular resistance and arterial pressure are not or only mildly decreased, leaving coronary perfusion pressure unaffected. Mechanisms of Antianginal Efficacy of Organic Nitrates Effects on Myocardial O2 Requirements. Increasing venous capacitance with nitrates decreases venous return to the heart, decreases ventricular end-diastolic volume, and thereby decreases O2 consumption. An additional benefit of reducing preload is that it increases the pressure gradient for perfusion across the ventricular wall, which favors subendocardial perfusion. Nitrovasodilators preferentially decrease preload by dilating venous capacitance vessels. In addition, an improvement in the lusitropic state of the heart may be seen with more rapid early diastolic filling. This may be secondary to the relief of ischemia rather than primary, or it may be due to a reflex increase in sympathetic activity. While this may contribute to their antianginal efficacy, the effect appears to be modest and in some settings may be confounded by the potential of nitrates to alter the pharmacokinetics of heparin, reducing its antithrombotic effect. When considering the effect of vasodilators in the ischemic heart, it is important to realize that myocardial ischemia itself is a powerful stimulus to coronary vasodilation and part of an autoregulatory mechanism. In the presence of atherosclerotic coronary artery narrowing, ischemia distal to the lesion stimulates vasodilation of downstream resistance arterioles and thereby helps maintain adequate perfusion of the ischemic area under rest. If the stenosis is severe, much of the capacity to dilate is used to maintain resting blood flow. Accordingly, dipyridamole is not used therapeutically but can be used as a stress test to provoke angina pectoris (Bodi et al. Nitrovasodilators, in contrast, do not have a major effect on the smaller resistance arteries (and therefore do not cause steal phenomena) but can dilate the large, epicardial sections of the coronary arteries upstream of a stenosis and also in a stenosis (concept of the "dynamic stenosis"; Brown et al. Indeed, many incidences of atypical chest pain and "angina" are due to biliary or esophageal spasm, and these also can be relieved by nitrates. Tolerance Frequently repeated or continuous exposure to high doses of nitrovasodilators lead to tolerance, that is, marked attenuation in the magnitude of most of their pharmacological effects. Multiple mechanisms have been proposed to account for nitrate tolerance, including volume expansion, neurohumoral activation, cellular depletion of sulfhydryl groups, and the generation of free radicals (Parker and Parker, 1998). If protection is inadequate, workers may experience severe headaches, dizziness, and postural weakness during the first several days of employment ("Monday disease"). Patients whose anginal pattern suggests its precipitation by increased left ventricular filling pressures. A recent study failed to demonstrate beneficial effects of molsidomine on endothelial dysfunction (Barbato et al. Headache is common and can be severe, usually decreasing over a few days if treatment is continued and often controlled by decreasing the dose. It also may be seen with very low doses of nitrates in patients with autonomic dysfunction. In the event that patients develop significant hypotension following combined administration of sildenafil and a nitrate, fluids and adrenergic receptor agonists, if needed, may be used for support. Conditions such as hypertension, anemia, thyrotoxicosis, obesity, heart failure, cardiac arrhythmias, and acute emotional stress can precipitate anginal symptoms in many patients. Patients should be counseled to stop smoking, lose weight, and maintain a low-fat, high-fiber diet; hypertension and hyperlipidemia should be corrected; and daily aspirin (or clopidogrel if aspirin is not tolerated) and statins (see Chapter 33) should be prescribed. The use of drugs that modify the perception of pain is a poor approach to the treatment of angina because the underlying myocardial ischemia is not relieved. Anginal pain may be prevented when the drugs are used prophylactically immediately prior to exercise or stress. In 1967, Fleckenstein suggested that the negative inotropic effect resulted from inhibition of excitation-contraction coupling and that the mechanism involved reduced movement of Ca2+ into cardiac myocytes. Verapamil was the first clinically available Ca2+ channel blocker; it is a congener of papaverine. However, in variant angina, coronary constriction results in reduced blood flow and ischemic pain. Whereas long-acting nitrates alone are occasionally efficacious in abolishing episodes of variant angina, additional therapy with Ca2+ channel blockers usually is required. The utility of nitrovasodilators to relieve pulmonary congestion and to increase cardiac output in congestive heart failure is addressed in Chapter 28. In both smooth muscle and cardiac myocytes, Ca2+ is a trigger for contraction, albeit by different mechanisms. Although these drugs are commonly grouped together as "calcium channel blockers," there are fundamental differences among verapamil, diltiazem, and the dihydropyridines with respect to pharmacodynamics, drug interactions, and toxicities. In cardiac myocytes, the entry of extracellular Ca2+ causes a larger Ca2+ release from intracellular stores (Ca2+-induced Ca2+ release) and thereby initiates the contraction twitch. Many hormones and autocoids increase Ca2+ influx through so-called receptor-operated channels, whereas increases in external concentrations of K+ and depolarizing electrical stimuli increase Ca2+ influx through voltage-gated, or "potential operated," channels. Voltage-gated channels contain domains of homologous sequence that are arranged in tandem within a single large subunit. All approved Ca2+ channel blockers bind to the 1 subunit of the L-type Ca2+ channel, which is the main pore-forming unit of the channel. This approximately 250,000-Da subunit is associated with a disulfide-linked 2 subunit of about 140,000 Da and a smaller intracellular subunit. The incidence o primary craniosynostosis is approximately 1 per 2,000 births (Kliegman et al. The cause o craniosynostosis is unknown, but genetic actors appear to be important. The prevailing hypothesis is that abnormal development o the cranial base creates exaggerated orces on the dura mater (outer covering membrane o the brain) that disrupt normal cranial sutural development. These malormations are more common in males than in emales and are oten associated with other skeletal anomalies. Premature closure o the sagittal suture, in which the anterior ontanelle is small or absent, results in a long, narrow, wedge-shaped cranium, a condition called scaphocephaly. When premature closure o the coronal or the lambdoid suture occurs on one side only, the cranium is twisted and asymmetrical, a condition known as plagiocephaly. Premature closure o the coronal suture results in a high, tower-like cranium, called oxycephaly or turricephaly. Obliteration o sutures usually begins at the bregma and continues sequentially in the sagittal, coronal, and lambdoid sutures. In these individuals, the bone marrow has lost its blood cells and at, giving it a gelatinous appearance. The basic unctional components include the neurocranium, the container o the brain and internal ears, and viscerocranium, providing paired orbits, nasal cavities, and teeth-bearing plates (alveolar processes) o the oral cavity. Although some mobility between cranial bones is advantageous during birth, they become fxed together by essentially immovable joints (sutures), allowing independent movement o only the mandible. Abundant fssures and oramina acilitate communication and passage o neurovascular structures between unctional components. Relatively thin (but mostly curved) at bones provide the necessary strength to maintain cavities and protect contents. However, the bones and processes o the neurocranium also provide proximal attachment or the strong muscles o mastication (chewing) that attach distally to the mandible. The high traction orces generated across the nasal cavity and orbits, sandwiched between the muscle attachments, are resisted by thickened portions o the bones orming stronger pillars or buttresses. The mostly superfcial surace o the cranium provides both visible and palpable landmarks. Internal eatures o the cranial base reect the major ormations o the brain that rest on it. Bony ridges radiating rom the centrally located sella turcica divide it into three cranial ossae. The hindbrain, consisting o the pons, cerebellum, and medulla, occupies the posterior cranial ossa, with the medulla continuing through the oramen magnum where it is continuous with the spinal cord. Thus, birth deects, scarring, or other alterations resulting rom pathology or trauma have marked consequences beyond their physical eects. The individuality o the ace results primarily rom anatomical variations in the shape and relative prominence o the eatures o the underlying cranium; in the deposition o atty tissue; in the color and eects o aging on the overlying skin; and in the abundance, nature, and placement o hair on the ace and scalp. The relatively large size o the buccal atpads in inants prevents collapse o the cheeks during sucking and produces their chubby-cheeked appearance. The ethmoid bone, orbital cavities, and superior parts o the nasal cavities have nearly completed their growth by the 7th year. Expansion o the orbits and growth o the nasal septum carry the maxillae inero-anteriorly. Considerable acial growth occurs during childhood as the paranasal sinuses develop and permanent teeth erupt. Our interactions with others take place largely via the ace (including the ears) and thus the term interace or a site o interactions. Whereas the shape and eatures o the ace provide our identity, much o our eect on others and their perceptions about us result rom the way we use acial muscles to make the slight alterations in the eatures that constitute acial expression. Scalp the scalp consists o skin (normally hair bearing) and subcutaneous tissue that cover the neurocranium rom the superior nuchal lines on the occipital bone to the supra-orbital margins o the rontal bone. The scalp is composed o ve layers, the rst three o which are connected intimately and move as a unit. Skin: thin, except in the occipital region, contains many sweat and sebaceous glands and hair ollicles.