Alita Loveless, MD

• Instructor
• Department of Obstetrics and Gynecology
• Texas Tech University Health Sciences Center
• Lubbock, Texas

It has been known for many years that reserpine treatment womens health 8 week challenge purchase fluoxetine master card, which is known to deplete monoamines breast cancer awareness 2014 generic 10mg fluoxetine mastercard, is associated with depression in a subset of patients women's health clinic grand falls windsor order fluoxetine australia. Similarly breast cancer 5 year survival cheap fluoxetine 10mg free shipping, depressed patients who respond to serotonergic antidepressants such as fluoxetine often rapidly suffer relapse when given diets free of tryptophan womens health toning station order generic fluoxetine canada, a precursor of serotonin synthesis women's health center vassar order fluoxetine 10mg mastercard. Patients who respond to noradrenergic antidepressants such as desipramine are less likely to relapse on a tryptophan-free diet. Moreover, depleting catecholamines in depressed patients who have previously responded to noradrenergic agents likewise tends to be associated with relapse. Administration of an inhibitor of norepinephrine synthesis is also associated with a rapid return of depressive symptoms in patients who respond to noradrenergic but not necessarily in patients who had responded to serotonergic antidepressants. Another line of evidence supporting the monoamine hypothesis comes from genetic studies. A functional polymorphism exists for the promoter region of the serotonin transporter gene, which regulates how much of the transporter protein is available. Subjects who are homozygous for the s (short) allele may be more vulnerable to developing major depression and suicidal behavior in response to stress. In addition, homozygotes for the s allele may also be less likely to respond to and tolerate serotonergic antidepressants. Conversely, subjects with the l (long) allele tend to be more resistant to stress and may be more likely to respond to serotonergic antidepressants. Studies of depressed patients have sometimes shown an alteration in monoamine function. A reduction in the primary serotonin metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid is associated with violent and impulsive behavior, including violent suicide attempts. However, this finding is not specific to major depression and is associated more generally with violent and impulsive behavior. Finally, perhaps the most convincing line of evidence supporting the monoamine hypothesis is the fact that (at the time of this writing) all available antidepressants appear to have significant effects on the monoamine system. Attempts to develop antidepressants that work on other neurotransmitter systems have not been effective to date. The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system. In addition to the monoamines, the excitatory neurotransmitter glutamate appears to be important in the pathophysiology of depression. A number of studies of depressed patients have found elevated glutamate content in the cerebrospinal fluid of depressed patients and decreased glutamine/glutamate ratios in their plasma. In addition, postmortem studies have revealed significant increases in the frontal and dorsolateral prefrontal cortex of depressed patients. Likewise, structural neuroimaging studies have consistently found volumetric changes in the brain areas of depressed patients in which glutamate neurons and their connections are most abundant, including the amygdala and hippocampus. Antidepressants are known to impact glutamate neurotransmission in a variety of ways. Depression appears to be associated with changes in serotonin or norepinephrine signaling in the brain (or both) with significant downstream effects. Similarly, the chronic administration of antidepressants significantly reduces depolarization-evoked release of glutamate in animal models. Stress is known to enhance the release of glutamate in rodents, and antidepressants inhibit stress-induced presynaptic release of glutamate in these models. Given the effect of antidepressants on the glutamate system, there has been a growing interest in the development of pharmaceutical agents that might modulate the glutamate system. Multiple studies have suggested that a single dose of intravenous ketamine at subanesthetic doses produces rapid relief of depression, even in treatment-resistant patients, that may persist for 1 week or longer. Unfortunately, ketamine is associated with cognitive, dissociative, and psychotomimetic properties that make it impractical as a long-term treatment for depression. Neuroendocrine Factors in the Pathophysiology of Depression Depression is associated with a number of hormonal abnormalities. These abnormalities include a blunting of response of thyrotropin to thyrotropin-releasing hormone and elevations in circulating thyroxine during depressed states. Clinical hypothyroidism often presents with depressive symptoms, which resolve with thyroid hormone supplementation. Thyroid hormones are also commonly used in conjunction with standard antidepressants to augment therapeutic effects of the latter. Estrogen deficiency states, which occur in the postpartum and postmenopausal periods, are thought to play a role in the etiology of depression in some women. Likewise, severe testosterone deficiency in men is sometimes associated with depressive symptoms. Hormone replacement therapy in hypogonadal men and women may be associated with an improvement in mood and depressive symptoms. One of the weaknesses of the monoamine hypothesis is the fact that amine levels increase immediately with antidepressant use, but maximum beneficial effects of most antidepressants are not seen for many weeks. The time required to synthesize neurotrophic factors has been proposed as an explanation for this delay of antidepressant effects. These differences and the differences in their molecular targets provide the basis for distinguishing several subgroups. Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Integration of Hypotheses Regarding the Pathophysiology of Depression the several pathophysiologic hypotheses just described are not mutually exclusive. It is evident that the monoamine, neuroendocrine, and neurotrophic systems are interrelated in important ways. Venlafaxine was discovered in the process of evaluating chemicals that inhibit binding of imipramine. However, this minor difference results in a substantial change in their pharmacologic profiles. Imipramine is highly anticholinergic and is a relatively strong serotonin as well as norepinephrine reuptake inhibitor. In contrast, desipramine is much less anticholinergic and is a more potent and somewhat more selective norepinephrine reuptake inhibitor than is imipramine. Their loss of popularity stems in large part from relatively poorer tolerability compared with newer agents, difficulty of use, and lethality in overdose. The most common use of trazodone in current practice is as an unlabeled hypnotic, since it is highly sedating and not associated with tolerance or dependence. Vortioxetine has demonstrated efficacy in major depression in a number of controlled clinical studies. Tetracyclic and Unicyclic Antidepressants A number of antidepressants do not fit neatly into the other classes. Its unique structure results in a different side-effect profile than most antidepressants (described below). Mirtazapine was introduced in 1994 and, like bupropion, is one of the few antidepressants not commonly associated with Nefazodone is chemically related to trazodone. Although still available generically, nefazodone is no longer commonly prescribed. The primary indications for both nefazodone and trazodone are major depression, although both have also been used in the treatment of anxiety disorders. It has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds. Amoxapine is the N-demethylated metabolite of loxapine, an older antipsychotic drug. Vilazodone has a multi-ring structure that allows it to bind potently to the serotonin transporter but minimally to the dopamine and norepinephrine transporter. Their primary use now is in the treatment of depression unresponsive to other antidepressants. However, even within classes, the pharmacokinetics of individual antidepressants varies considerably. Fluoxetine is metabolized to an active product, norfluoxetine, which may have plasma concentrations greater than those of fluoxetine. Despite the relatively short half-lives, both drugs are available in formulations that allow once-daily dosing. Unlike most antidepressants, desvenlafaxine is conjugated and does not undergo extensive oxidative metabolism. As a result, most are dosed once daily at night because of their sedating effects. Both drugs are bound to protein and have limited bioavailability because of extensive metabolism. Because of their short half-lives split dosing is generally required when these drugs are used as antidepressants. However, trazodone is often prescribed as a single dose at night as a hypnotic in lower doses than are used in the treatment of depression. It is tightly bound to protein and has linear and dose-proportional pharmacokinetics. Tetracyclic and Unicyclic Agents Bupropion is rapidly absorbed and has a mean protein binding of 85%. It undergoes extensive hepatic metabolism and has a substantial first-pass effect. It has three active metabolites including hydroxybupropion; the latter is being developed as an antidepressant. Bupropion has a biphasic elimination with the first phase lasting about 1 hour and the second phase lasting 14 hours. One of the active metabolites, 7-hydroxyamoxapine, is a potent D2 blocker and is associated with antipsychotic effects. Mirtazapine is demethylated followed by hydroxylation and glucuronide conjugation. Tranylcypromine is ring hydroxylated and N-acetylated, whereas acetylation appears to be a minor pathway for phenelzine. For example, selegiline is available in both transdermal and sublingual forms that bypass both gut and liver. These routes decrease the risk of food interactions and provide substantially increased bioavailability. Ultimately, the increased availability of monoamines for binding in the synaptic cleft results in a cascade of events that enhance the transcription of some proteins and the inhibition of others. When extracellular serotonin binds to receptors on the transporter, conformational changes occur in the transporter and serotonin, Na+, and Cl- are moved into the cell. Binding of intracellular K+ then results in the release of serotonin inside the cell and return of the transporter to its original conformation. Drugs That Block Both Serotonin and Norepinephrine Transporters A large number of antidepressants have mixed inhibitory effects on both serotonin and norepinephrine transporters. Like the serotonin transporter, it is a 12-transmembrane domain complex that allosterically binds norepinephrine. Inhibition of this receptor in both animal and human studies is associated with substantial antianxiety, antipsychotic, and antidepressant effects. Tetracyclic and Unicyclic Antidepressants the actions of bupropion remain poorly understood. Bupropion and its major metabolite hydroxybupropion are modest to moderate inhibitors of norepinephrine and dopamine reuptake in animal studies. However, these effects seem less than are typically associated with antidepressant benefit. In animal studies, bupropion appears to substantially increase the presynaptic availability of norepinephrine, and dopamine to a lesser extent. Most antidepressants are approved for both acute and long-term treatment of major depression. If an inadequate response is obtained, therapy is often switched to another agent or augmented by addition of another drug.

A formaldehyde-glutaraldehyde fixative of high osmolarity for use in electron microscopy women's health clinic grand falls windsor order fluoxetine 10mg without a prescription. Concurrent infection of the urinary tract with Encephalitozoon cuniculi and Enterocytozoon bieneusi in a renal transplant recipient pregnancy exercise videos buy fluoxetine 20mg with amex. The role of electron microscopy in evaluating ciliary dysfunction: report of a workshop breast cancer in situ purchase fluoxetine 10 mg with visa. Femtosecond laser-assisted anterior lamellar keratoplasty in stromal keratitis caused by an endoreticulatus-like microsporidia menstruation through history effective fluoxetine 10 mg. The use of lead citrate at high pH as an electron opaque stain based on metal chelation pregnancy nutrition guide buy genuine fluoxetine line. Cytochemistry and electron microscopy: the preservation of cellular ultrastructure and enzymic activity by aldehyde fixation women's health clinic ut austin cheap fluoxetine 10mg on line. Oolong tea extract as a substitute for uranyl acetate in staining for ultrathin sections. Role of transmission electron microscopy in tissue diagnosis: diseases of the kidney, skeletal muscle and myocardium. Crystalloidal paraprotein deposits in the cornea: an ultrastructural study of two new cases with tubular crystalloids that contain IgG light chains and IgG heavy chains. Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Microsporidia of the genus Trachipleistophora - causative agents of human microsporidiosis - description of Trachipleistophora anthropophthera n. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Examination of electron stains as a substitute for uranyl acetate for the ultrathin sections of bacterial cells. The contemporary use of electron microscopy in the diagnosis of ciliary disorders and sperm centriolar abnormalities. Such slide scanners typically include slide loading mechanisms, a motorized stage, a light path, image capture device and software to create the composite image. Although the data files which represent these images are large, software techniques enable these images to be viewed on screen in a manner analogous to how a slide may be viewed on a physical microscope. Digital representation of slides enables histology images to be distributed, viewed and shared over computer networks rather than relying on physical handling of the glass slide. Benefits of digital images over physical glass slides Digital images have several advantages over glass slides. Unlike a physical object, a digital image file can be moved from one physical location to another almost instantaneously. Indeed, an image file can be viewed at the same time by two, or more pathologists, in different locations and potentially separated by thousands of miles. With appropriate data-security arrangements, digital images should be more durable than glass slides which are physical, fragile and prone to fading. The overhead of sorting, filing, storing and retrieving glass slides is particularly burdensome on larger laboratories and a fully digital workflow has the potential to significantly reduce this. Digital images Images can be represented in numerical form in a variety of manners. The text on this page, for example, is ultimately represented by the printing software, not as letters and words but as collections of lines and curves. The commonest method for representing complex real world scenes, including histology images, is to consider the image as a grid of individual points, each with brightness and, for color images, hue. In all commonly encountered digital image formats pixels are square, although other shapes, in particular hexagons, are in principle possible. This approach represents images Introduction Whole-slide imaging refers to the creation of a digital representation of the image presented by a glass histology slide, at a level of detail comparable to that seen with a light microscope. The perceived quality of a digital image of this type relates to the total number of pixels (resolution) and a parameter called pixel depth. Resolution the size of the smallest resolvable detail in a whole slide image is defined by the original absolute size of the area represented by each pixel. Broadly however, when viewed under appropriate conditions, images in which each pixel represents a square of side 0. Histology as digital images Whole slide images are distinguished by their sheer size. The required file size may be compressed up to 30-fold using compression techniques without impact on diagnostic utility (Krupinski et al. It is worth noting that discernable artifacts may be introduced into the images at lower levels of compression without necessarily impacting on the diagnostic utility of the image (Foran, 1997). Moreover, greater degrees of compression may be possible for non-H&E tinctorial stains than for H&E without undermining the practical utility of the image (Sharma et al. The way in which pathologists interact with images also influences the way image data are stored. Files may include the same image at multiple resolutions to support rapid zooming in and/or out as images are streamed over Pixel depth Image quality is not defined solely by resolution. Most formats for the realistic representation of real life images use 24 bits, 8 to represent the intensity of each of the 3 colors red, green and blue. This enables 256 different intensity levels to be represented for each of these colors, a total of 16,777,216 different tones. As the magnification is increased, the relevant individual tiles from deeper tiers are displayed. Files may also store metadata such as a timestamp, image file type, image size, pixel depth, make and model of the scanner and objective, and resolution data such as microns/pixel. Additional hardware may typically include mechanical apparatus to sequentially load slides, operator controls, a visual display area and computer control hardware. The smallest single slide systems may have a footprint of only 500 x 500 mm, whilst high capacity scanners holding 200-300 slides may be 750 x 1200 mm or more. Prior to image acquisition, the slide scanner may register the sample number by reading a barcode printed on the glass slide. A scanner may also perform a low resolution overview scan to determine where the tissue is on a slide and only scan that area, minimizing overall scan time and therefore file size. Two commonly used methods of image acquisition are line scanning and tile scanning. In line scanning, the slide is moved in a linear fashion so that the camera captures strips of the image. A strobe light source and high frame rate camera are typically employed to reduce movement, the blur artifact. Reconstruction of a tile scanned image is computationally more complex but modern multi-core processors negate the effect this has on overall scan time. The topography of tissue on a glass slide can vary by up to 20% of the tissue thickness over a distance of 1 mm. An image scanned using one focal plane would appear blurry in places, making it diagnostically useless. This requires the generation of a focus map either by the operator or automatically from the overview scan image. The scanner could apply autofocus on a tile-by-tile basis in the case of tile scanning or at several points along a strip of image in line scanning. This near continuous autofocus would result in prohibitively slow image acquisition. Instead, in a trade-off between speed and image fidelity, the scanner generates a representative autofocus map, or focuses on every third or fifth tile of an image. Special cases Large blocks these mega or jumbo blocks can also be scanned, but the scanner needs to be designed to accommodate larger slides. There is an increase in slide acquisition time and file size owing to the larger tissue area which needs to be scanned. Large slides may interrupt the workflow of a digital laboratory as they may require loading in separate batches to the standard size slides. One alternative to scanning 480 22 Digital pathology mega blocks is to create composite blocks of a sample then scan these as standard sized slides. Image stitching software can be used to create a virtual mega block from the composite blocks. Cytology preparations the 3-dimensional nature of a typical cytology slide presents challenges. This problem is addressed by acquiring multiple images of the cytology slide at different focal points which are treated as a stack of 2-dimensional images, a process called z-stacking, where the z refers to the z-axis of a 3-dimensional image (x, y, z). Images must be captured in several planes of focus, with consequent multiplication of the total file size and the time taken to capture the image. When viewing these composite z-stack images on a monitor, additional image processing is required to allow the smooth transition between virtual planes of focus. Some vendors supply the fluorescence modules, or a dedicated scanner may be required. Measures to ensure good quality digital images the quality of the virtual image depends upon the production of a high quality physical slide and quality control processes relating to the scanner itself. When using a conventional light microscope, a pathologist can work around artifacts including tissue folds, wax on the coverslip, air bubbles and tissue not covered by the coverslip. A slide scanner will faithfully reproduce all of these artifacts, potentially diminishing the quality of the scanned slide. Standard laboratory quality control procedures should ensure the production of the highest quality slides and the presence of artifacts need to be audited. Additionally, the scanner operator should re-check and if necessary clean or re-coverslip slides prior to scanning. Attention should also be paid to minimizing vibration during the scanning process. The slide scanner should be regularly serviced and cleaned to ensure consistent lighting and focusing. A daily test slide should be scanned to assess the basic function of the scanner and detect major errors such as poor sample detection and abnormal color profiles. This procedure will also generate diagnostic information such as scanner temperature, time-to-focus and time-to-scan, all of which can create variance in digital image consistency and laboratory throughput. Color calibration of the scanner has been shown to increase diagnostic confidence and produce digital slides which are subjectively similar to slides viewed under a light microscope. The color values of this patch are known and can be compared with the on-board reference of the scanner. Using a glass slide a pathologist may be able to compensate for this by focusing up and down through the depth of the tissue but such compensation is not possible on a digitally acquired image. Accessing and viewing whole slide images Image streaming the sheer size of virtual slide images raises significant technical challenges around distributing image data over networks. When slides are being viewed, software techniques are used so that only the part of the image being viewed at any one time is passed over the network, requiring only a fraction of the data transfer. A pyramidal image format assists with the image streaming process, with deeper subsections of the image transmitted as the pathologist increases magnification. The rapid transmission of image data is achieved by only sending the area of the pyramid which is currently being viewed and potentially the surrounding image tiles. This allows smooth transition between magnifications and when panning without preloading the entire file, which would otherwise require a prohibitively large amount of network bandwidth. A key challenge in developing client software has been to provide zooming and panning in a manner which is intuitive for pathologists accustomed to physical microscopes. The speed at which the image can be refreshed is important, as a noticeable lag between operating the panning controls and the ultimate refreshing of the image will impact on the usability of the system. Many manufacturers have developed interfaces which only require a web browser to view and navigate images, although relatively fast computers with capable graphics cards are required. Arrangements for such access should be established in advance, taking into account institutional network security policies. Tape drives have fallen somewhat out of fashion in recent years, but the current generation of tape storage systems offer high storage capacities at low prices. One strategy for minimizing the costs of a large clinical slide archive whilst maximizing its performance is to specify different tiers of storage. The initial acquisition of a slide image requires the highest drive speeds as the entire image file is captured. Unreported images should be stored on high performance disks with the fastest available data-read times on servers able to deliver images to multiple pathologists at the same time. However, once reported, the images for these cases could be moved to a cheaper, less highly specified medium. If governance or regulatory frameworks mandate longer term archival storage of images, then tape drives may provide the most cost-effective solution. This is analogous to the arrangements for glass slide filing in most laboratories, where the most recent cases are in immediately accessible storage occupying valuable laboratory space, whilst older cases may be stored in cheaper offsite space, trading retrieval times for cost. If it is accepted that a digital image must be held for a period of time for quality assurance purposes, then thought must also be given to how that storage is backed up. Some image navigation controls are visible at the top right and tools for measuring, for example, can be invoked by keyboard shortcuts or mouse controls (Hamamatsu). Hardware installation and image file storage Installation of a digital pathology system may be relatively straightforward for a small standalone scanner for which low slide volumes are anticipated. Even for such a simple arrangement however, adequate space, computer network access, a power supply (ideally dedicated and uninterruptible) and a robust table to accommodate the scanner will be required. The initial image scanning process generates particularly high data transfer requirements, far higher than the subsequent viewing of the images. For this reason, the network connection between the scanner hardware and server hardware should be as fast as possible.

The lipoxygenase pathway of arachidonate metabolism yields leukotrienes menstruation definition 20 mg fluoxetine sale, which have a powerful chemotactic effect on eosinophils questions menstrual cycle order fluoxetine 10 mg line, neutrophils pregnancy fruit comparison generic 10mg fluoxetine free shipping, and macrophages and promote bronchoconstriction and alterations in vascular permeability womens health of mansfield cheap fluoxetine 20 mg with visa. During inflammation menstrual disorder fluoxetine 10 mg line, stimulation of the neutrophil membranes produces oxygen-derived free radicals and other reactive molecules such as hydrogen peroxide and hydroxyl radicals pregnancy cramps purchase 20mg fluoxetine free shipping. The interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus perpetuating the inflammatory process. Most of these drugs are well absorbed, and food does not substantially change their bioavailability. While renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives. These indices often combine joint tenderness and swelling, patient response, and laboratory data. Furthermore, most of the nonopioid analgesics (aspirin, etc) have anti-inflammatory effects, so they are appropriate for the treatment of both acute and chronic inflammatory conditions. The glucocorticoids also have powerful anti-inflammatory effects and when first introduced were considered to be the ultimate answer to the treatment of inflammatory arthritis. However, the glucocorticoids continue to have a significant role in the long-term treatment of arthritis. The risk is higher among users of celecoxib and diclofenac, and lower among users of ibuprofen and naproxen. Several large epidemiologic studies have shown a 50% reduction in relative risk for this neoplasm when the drugs are taken for 5 years or longer. Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates. Clinical Uses: Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting (see Chapter 34). The antiplatelet action of aspirin contraindicates its use by patients with hemophilia. Although previously not recommended during pregnancy, aspirin may be valuable in treating preeclampsia-eclampsia. Nabumetone is a prodrug; the half-life and urinary excretion are for its active metabolite. Central nervous system: Headaches, tinnitus, dizziness, and rarely, aseptic meningitis. Gastrointestinal: Abdominal pain, dyspepsia, nausea, vomiting, and rarely, ulcers or bleeding. These drugs include magnesium choline salicylate, sodium salicylate, and salicyl salicylate. All nonacetylated salicylates are effective anti-inflammatory drugs, and they do not inhibit platelet aggregation. Diclofenac, 150 mg/d, appears to impair renal blood flow and glomerular filtration rate. Diclofenac in rectal suppository form can be considered for preemptive analgesia and postoperative nausea. In Europe, diclofenac is also available as an oral mouthwash and for intramuscular administration. Diflunisal Although diflunisal is derived from salicylic acid, it is not metabolized to salicylic acid or salicylate. It undergoes an enterohepatic cycle with reabsorption of its glucuronide metabolite followed by cleavage of the glucuronide to again release the active moiety. It is not as selective as celecoxib and may be considered "preferentially" selective rather than "highly" selective. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses, its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above). Flurbiprofen is also available in a topical ophthalmic formulation for inhibition of intraoperative miosis. Flurbiprofen intravenously is effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat. A preparation combining diclofenac and misoprostol decreases upper gastrointestinal ulceration but may result in diarrhea. In doses of about 2400 mg daily, ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory effect. A liquid gel preparation of ibuprofen, 400 mg, provides prompt relief and good overall efficacy in postsurgical dental pain. In comparison with indomethacin, ibuprofen decreases urine output less and also causes less fluid retention. The drug is relatively contraindicated in individuals with nasal polyps, angioedema, and bronchospastic reactivity to aspirin. The concomitant administration of ibuprofen and aspirin antagonizes the irreversible platelet inhibition induced by aspirin. Thus, treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. Furthermore, the use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory effect. Common adverse effects are listed on page 645 rare hematologic effects include agranulocytosis and aplastic anemia. Renal impairment results in a doubling of its half-life and a 30% increase in the area under the curve. Naproxen is effective for the usual rheumatologic indications and is available in a slow-release formulation, as an oral suspension, and over the counter. An ophthalmic preparation is efficacious for conjunctival inflammation and to reduce pain after traumatic corneal abrasion. Epidural injections produce a degree of pain relief similar to that achieved with methylprednisolone in postlaminectomy syndrome. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding (relative risk up to 9. Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life. Among the more severe adverse reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome; all have been observed. The effects of disease-modifying therapies may take 2 weeks to 6 months to become clinically evident. The conventional synthetic agents include small molecule drugs such as methotrexate, azathioprine, chloroquine and hydroxychloroquine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, and sulfasalazine. Gold salts, which were once extensively used, are no longer recommended because of their significant toxicities and questionable efficacy. Mechanism of action: Abatacept is a co-stimulation modulator biologic that inhibits the activation of T cells (see also Chapter 55). Abatacept is also available as a subcutaneous formulation and is given as 125 mg subcutaneously once weekly. All patients should be screened for latent tuberculosis and viral hepatitis before starting this medication. Live vaccines should be avoided in patients while taking abatacept and up to 3 months after discontinuation. Infusion-related reactions and hypersensitivity reactions, including anaphylaxis, have been reported but are rare. Antiabatacept antibody formation is infrequent (<5%) and has no effect on clinical outcomes. There is a possible increase in lymphomas but not other malignancies when using abatacept. Azathioprine is also used in scleroderma; however, in one study, it was found to be less effective than cyclophosphamide in controlling the progression of scleroderma lung disease. Thus it is not clear what place, if any, azathioprine has for treating scleroderma. Pharmacokinetics: Antimalarials are rapidly absorbed and 50% protein-bound in the plasma. They are very extensively tissue-bound, particularly in melanin-containing tissues such as the eyes. The drugs are deaminated in the liver and have blood elimination half-lives of up to 45 days. Adverse Effects: Although ocular toxicity (see Chapter 52) may occur at dosages greater than 250 mg/d for chloroquine and greater than 6. Other toxicities include dyspepsia, nausea, vomiting, abdominal pain, rashes, and nightmares. Its metabolism is bimodal in humans, with rapid metabolizers clearing the drug four times faster than slow metabolizers. It is also used for the prevention of kidney transplant rejection in combination with other immune suppressants. Adverse Effects: Leukopenia, thrombocytopenia, and, to a lesser extent, anemia are predictable. High doses can be cardiotoxic and neurotoxic, and sterility may occur after chronic dosing at antirheumatic doses, especially in women. Bladder cancer is very rare but must be looked for, even 5 years after cessation of use. Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%. In one study, combined treatment with methotrexate and leflunomide resulted in a 46. Other adverse effects associated with leflunomide are mild alopecia, weight gain, and increased blood pressure. It is active in this condition at much lower doses than those needed in cancer chemotherapy (see Chapter 54). As a result, the inflammatory functions of neutrophils, macrophages, dendritic cells, and lymphocytes are suppressed. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immuneinflammatory cells. Additionally, it inhibits proinflammatory cytokines linked to rheumatoid synovitis. The drug is approximately 70% absorbed after oral administration (see Chapter 54). Both the parent compound and the metabolite are polyglutamated within cells where they stay for prolonged periods. Hydroxychloroquine can reduce the clearance or increase the tubular reabsorption of methotrexate. Methotrexate is excreted principally in the urine, but up to 30% may be excreted in bile. This metabolite inhibits dihydroorotate dehydrogenase, leading to a decrease in ribonucleotide synthesis and the arrest of stimulated cells in the G1 phase of cell growth. Consequently, leflunomide inhibits T-cell proliferation and reduces production of autoantibodies by B cells. Pharmacokinetics: Leflunomide is completely absorbed from the gut and has a mean plasma half-life of 19 days. Progressive dose-related hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare (<1%).

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Their pharmacology and clinical use are described in greater detail in Chapter 31 women's health questions menopause discount fluoxetine 10mg visa. In addition to their use as part of a balanced anesthesia regimen breast cancer 49ers cheap fluoxetine 10mg on-line, opioids in large doses have been used in combination with large doses of benzodiazepines to achieve a general anesthetic state breast cancer metastasis purchase fluoxetine from india, particularly in patients with limited circulatory reserve who undergo cardiac surgery women's health volunteer opportunities discount fluoxetine uk. When administered in large doses menstruation without ovulation order fluoxetine 10mg overnight delivery, potent opioids such as fentanyl can induce chest wall (and laryngeal) rigidity menstruation heart palpitations order genuine fluoxetine online, thereby acutely impairing mechanical ventilation. Furthermore, large doses of potent opioids may speed up the development of tolerance and complicate postoperative pain management. Hypnosis presumably results from stimulation of 2 receptors in the locus coeruleus, and the analgesic effect originates at the level of the spinal cord. The sedative effect produced by dexmedetomidine has a different quality than that produced by other intravenous anesthetics in that it more completely resembles a physiologic sleep state through activation of endogenous sleep pathways. Cardiovascular Effects Dexmedetomidine infusion results in moderate decreases in heart rate and systemic vascular resistance and, consequently, a decrease in systemic blood pressure. A bolus injection may produce a transient increase in systemic blood pressure and pronounced decrease in heart rate, an effect that is probably mediated through activation of peripheral 2 adrenoceptors. Every case tests the ability of the anesthesiologist to produce the depth of anesthesia required to allow invasive surgery to proceed and to achieve this safely despite frequent major medical problems. Fraga M et al: the effects of isoflurane and desflurane on intracranial pressure, cerebral perfusion and cerebral arteriovenous oxygen content difference in normocapnic patients with supratentorial brain tumors. Balanced anesthesia would begin with intravenous agents that cause minimal changes in blood pressure and heart rate such as a lowered dose of propofol or etomidate, combined with potent analgesics such as fentanyl (see Chapter 31) to block undesirable stimulation of autonomic reflexes. Maintenance of anesthesia could incorporate inhaled anesthetics that ensure unconsciousness and amnesia, additional intravenous agents to provide intraoperative and postoperative analgesia, and, if needed, neuromuscular blocking drugs (see Chapter 27) to induce muscle relaxation. The choice of inhaled agent(s) would be made based on the desire to maintain sufficient myocardial contractility, systemic blood pressure, and cardiac output for adequate perfusion of critical organs throughout the operation. What anesthetics would be most appropriate for providing postoperative analgesia via an indwelling epidural or peripheral nerve catheter What local anesthetic agents would be most appropriate if surgical anesthesia were to be administered using a spinal or an epidural technique, and what potential Simply stated, local anesthesia refers to loss of sensation in a limited region of the body. This is accomplished by disruption of afferent neural traffic via inhibition of impulse generation or propagation. Such blockade may bring with it other physiologic changes such as muscle paralysis and suppression of somatic or visceral reflexes, and these effects might be desirable or undesirable depending on the particular circumstances. Nonetheless, in most cases, it is the loss of sensation, or at least the achievement of localized analgesia, that is the primary goal. Although local anesthetics are often used as analgesics, it is their ability to provide complete loss of all sensory modalities that is their distinguishing characteristic. The contrast with general anesthesia should be obvious, but it is perhaps worthwhile to emphasize that with local anesthesia the drug is delivered directly to the target organ, and the systemic circulation serves only to diminish or terminate its effect. However, in routine clinical practice, it is achieved with a rather narrow spectrum of compounds, and recovery is normally spontaneous, predictable, and without residual effects. The development of these compounds has a rich history (see Box: Historical Development of Local Anesthesia), punctuated by serendipitous observations, delayed starts, and an evolution driven more by concerns for safety than improvements in efficacy. In addition to the general physical properties of the molecules, specific stereochemical configurations are associated with differences in the potency of stereoisomers (eg, levobupivacaine, ropivacaine). Because ester links are more prone to hydrolysis than amide links, esters usually have a shorter duration of action. Local anesthetics are weak bases and are usually made available clinically as salts to increase solubility and stability. In the body, they exist either as the uncharged base or as a cation (see Chapter 1, Ionization of Weak Acids and Weak Bases). As the early investigator Mattison commented, "the risk of untoward results have robbed this peerless drug of much favor in the minds of many surgeons, and so deprived them of a most valued ally. However, benzocaine proved to have limited utility due to its marked hydrophobicity, and was thus relegated to topical anesthesia, a use for which it still finds limited application in current clinical practice. The first useful injectable local anesthetic, procaine, was introduced shortly thereafter by Einhorn, and its structure has served as the template for the development of the most commonly used modern local anesthetics. Unfortunately, tetracaine demonstrated significant toxicity when employed for high-volume peripheral blocks, ultimately reducing its common usage to spinal anesthesia. Both procaine and tetracaine shared another drawback: their ester linkage conferred instability, and particularly in the case of procaine, the free aromatic acid released during ester hydrolysis of the parent compound was believed to be the source of relatively frequent allergic reactions. Lidocaine was the first in a series of amino-amide local anesthetics that would come to dominate the second half of the 20th century. Lidocaine had a more favorable duration of action than procaine, and less systemic toxicity than tetracaine. Nonetheless, some applications required more prolonged block than that afforded by lidocaine, a pharmacologic void that was filled with the introduction of bupivacaine, a more lipophilic and more potent anesthetic. Unfortunately, bupivacaine was found to have greater propensity for significant effects on cardiac conduction and function, which at times proved lethal. Recognition of this potential for cardiac toxicity led to changes in anesthetic practice, and significant toxicity became sufficiently rare for it to remain a widely used anesthetic for nearly every regional technique in modern clinical practice. Nonetheless, this inherent cardiotoxicity would drive developmental work leading to the introduction of two recent additions to the anesthetic armamentarium, levobupivacaine and ropivacaine. Thus, pKa can be seen as an effective way to consider the tendency for compounds to exist in a charged or uncharged form, ie, the lower the pKa, the greater the percentage of uncharged weak bases at a given pH. This issue of ionization is of critical importance because the cationic form is the most active at the receptor site. However, the story is a bit more complex, because the receptor site for local anesthetics is at the inner vestibule of the sodium channel, and the charged form of the anesthetic penetrates biologic membranes poorly. Drug may also reach the receptor laterally through what has been termed the hydrophobic pathway. As a clinical consequence, local anesthetics are less effective when they are injected into infected tissues because the low extracellular pH favors the charged form, with less of the neutral base available for diffusion across the membrane. Conversely, adding bicarbonate to a local anesthetic-a strategy sometimes used in clinical practice-will raise the effective concentration of the nonionized form and thus shorten the onset time of a regional block. Pharmacokinetics When local anesthetics are used for local, peripheral, and central neuraxial anesthesia-their most common clinical applications-systemic absorption, distribution, and elimination serve only to diminish or terminate their effect. Extracellular anesthetic exists in equilibrium between charged and uncharged forms. The charged cation penetrates lipid membranes poorly; intracellular access is thus achieved by passage of the uncharged form. Intracellular re-equilibration results in formation of the more active charged species, which binds to the receptor at the inner vestibule of the sodium channel. Anesthetic may also gain access more directly by diffusing laterally within the membrane (hydrophobic pathway). Absorption Systemic absorption of injected local anesthetic from the site of administration is determined by several factors, including dosage, site of injection, drug-tissue binding, local tissue blood flow, use of a vasoconstrictor (eg, epinephrine), and the physicochemical properties of the drug itself. Anesthetics that are more lipid soluble are generally more potent, have a longer duration of action, and take longer to achieve their clinical effect. Application of a local anesthetic to a highly vascular area such as the tracheal mucosa or the tissue surrounding intercostal nerves results in more rapid absorption and thus higher blood levels than if the local anesthetic is injected into a poorly perfused tissue such as subcutaneous fat. When vasoconstrictors are used with local anesthetics, the resultant reduction in blood flow serves to reduce the rate of systemic absorption and thus diminishes peak serum levels. This effect is generally most evident with the shorter-acting, less potent, and less lipid-soluble anesthetics. Localized-As local anesthetic is usually injected directly at the site of the target organ, distribution within this compartment plays an essential role with respect to achievement of clinical effect. Solutions are termed hyperbaric, isobaric, and hypobaric, and will respectively descend, remain relatively static, or ascend, within the subarachnoid space due to gravity when the patient sits upright. Systemic-The peak blood levels achieved during major conduction anesthesia will be minimally affected by the concentration of anesthetic or the speed of injection. The disposition of these agents can be well approximated by a two-compartment model. The initial alpha phase reflects rapid distribution in blood and highly perfused organs (eg, brain, liver, heart, kidney), characterized by a steep exponential decline in concentration. There is considerable variation in the rate of liver metabolism of individual amide compounds, with prilocaine (fastest) > lidocaine > mepivacaine > ropivacaine bupivacaine and levobupivacaine (slowest). As a result, toxicity from amide-type local anesthetics is more likely to occur in patients with hepatic disease. For example, the average elimination half-life of lidocaine may be increased from 1. Many other drugs used in anesthesia are metabolized by the same P450 isozymes, and concomitant administration of these competing drugs may slow the hepatic metabolism of the local anesthetics. Decreased hepatic elimination of local anesthetics would also be anticipated in patients with reduced hepatic blood flow. For example, the hepatic elimination of lidocaine in patients anesthetized with volatile anesthetics (which reduce liver blood flow) is slower than in patients anesthetized with intravenous anesthetic techniques. Delayed metabolism due to impaired hepatic blood flow may likewise occur in patients with heart failure. During excitation, the sodium channels open, and a fast, inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. These ionic fluxes are similar to , but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues. Sodium channel isoforms-Each sodium channel consists of a single alpha subunit containing a central ion-conducting pore associated with accessory beta subunits. The pore-forming alpha subunit is actually sufficient for functional expression, but the kinetics and voltage dependence of channel gating are modified by the beta subunit. A variety of different sodium channels have been characterized by electrophysiologic recording, and subsequently isolated and cloned, while mutational analysis has allowed for identification of the essential components of the local anesthetic binding site. Nine members of a mammalian family of sodium channels have been so characterized and classified as Nav1. The potential toxicity of the local anesthetics is affected by the protective effect afforded by uptake by the lungs, which serve to attenuate the arterial concentration, though the time course and magnitude of this effect have not been adequately characterized. Metabolism and Excretion the local anesthetics are converted to more water-soluble metabolites in the liver (amide type) or in plasma (ester type), which are excreted in the urine. Since local anesthetics in the uncharged form diffuse readily through lipid membranes, little or no urinary excretion of the neutral form occurs. Acidification of urine promotes ionization of the tertiary amine base to the more watersoluble charged form, leading to more rapid elimination. Estertype local anesthetics are hydrolyzed very rapidly in the blood by circulating butyrylcholinesterase to inactive metabolites. For example, the half-lives of procaine and chloroprocaine in plasma are less than a minute. However, excessive concentrations may accumulate in patients with reduced or absent plasma hydrolysis secondary to atypical plasma cholinesterase. Channel blockade-Biologic toxins such as batrachotoxin, aconitine, veratridine, and some scorpion venoms bind to receptors within the channel and prevent inactivation. This results in prolonged influx of sodium through the channel and depolarization of the resting potential. However, in contrast to the local anesthetics, the toxin binding site is located near the extracellular surface. Such fine-tuned analgesic therapy has the theoretical potential of providing effective analgesia, while limiting the significant adverse effects produced by nonspecific sodium channel blockers. When progressively increasing concentrations of a local anesthetic are applied to a nerve fiber, the threshold for excitation increases, impulse conduction slows, the rate of rise of the action potential declines, action potential amplitude decreases, and, finally, the ability to generate an action potential is completely abolished. These progressive effects result from binding of the local anesthetic to more and more sodium channels. If the sodium current is blocked over a critical length of the nerve, propagation across the blocked area is no longer possible. In myelinated nerves, the critical length appears to be two to three nodes of Ranvier. At the minimum dose required to block propagation, the resting potential is not significantly altered. As a result, the refractory period is lengthened and the nerve conducts fewer action potentials. Elevated extracellular calcium partially antagonizes the action of local anesthetics owing to the calcium-induced increase in the surface potential on the membrane (which favors the low-affinity rested state). Conversely, increases in extracellular potassium depolarize the membrane potential and favor the inactivated state, enhancing the effect of local anesthetics.

Reserpine Reserpine womens health neenah wi purchase fluoxetine 20mg with amex, an alkaloid extracted from the roots of an Indian plant menopause 1 ovary buy discount fluoxetine 20mg on line, Rauwolfia serpentina menopause irritability buy 20mg fluoxetine with visa, was one of the first effective drugs used on a large scale in the treatment of hypertension menstrual joy studies buy generic fluoxetine online. This effect occurs throughout the body menopause patch generic 20 mg fluoxetine, resulting in depletion of norepinephrine breast cancer quotes and poems buy fluoxetine with a mastercard, dopamine, and serotonin in both central and peripheral neurons. Chromaffin granules of the adrenal medulla are also depleted of catecholamines, although to a lesser extent than are the vesicles of neurons. Depletion of peripheral amines probably accounts for much of the beneficial antihypertensive effect of reserpine, but a central component cannot be ruled out. Reserpine readily enters the brain, and depletion of cerebral amine stores causes sedation, mental depression, and parkinsonism symptoms. At lower doses used for treatment of mild hypertension, reserpine lowers blood pressure by a combination of decreased cardiac output and decreased peripheral vascular resistance. Toxicity At the low doses usually administered, reserpine produces little postural hypotension. Most of the unwanted effects of reserpine result from actions on the brain or gastrointestinal tract. High doses of reserpine characteristically produce sedation, lassitude, nightmares, and severe mental depression; occasionally, these occur even in patients receiving low doses (0. Although these central effects are uncommon, it should be stressed that they may occur at any time, even after months of uneventful treatment. Patients with a history of mental depression should not receive reserpine, and the drug should be stopped if depression appears. Reserpine rather often produces mild diarrhea and gastrointestinal cramps and increases gastric acid secretion. Propranolol Propranolol was the first blocker shown to be effective in hypertension and ischemic heart disease. Propranolol has now been largely replaced by cardioselective blockers such as metoprolol and atenolol. All -adrenoceptor-blocking agents are useful for lowering blood pressure in mild to moderate hypertension. In severe hypertension, blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. Beta blockers have been shown to reduce mortality after a myocardial infarction and some also reduce mortality in patients with heart failure; they are particularly advantageous for treating hypertension in patients with these conditions (see Chapter 13). Propranolol decreases blood pressure primarily as a result of a decrease in cardiac output. Other blockers may decrease cardiac output or decrease peripheral vascular resistance to various degrees, depending on cardioselectivity and partial agonist activities. Propranolol inhibits the stimulation of renin production by catecholamines (mediated by 1 receptors). Although most effective in patients with high plasma renin activity, propranolol also reduces blood pressure in hypertensive patients with normal or even low renin activity. Beta blockers might also act on peripheral presynaptic adrenoceptors to reduce sympathetic vasoconstrictor nerve activity. In mild to moderate hypertension, propranolol produces a significant reduction in blood pressure without prominent postural hypotension. Propranolol can be administered twice daily, and slow-release once-daily preparations are available. Toxicity the principal toxicities of propranolol result from blockade of cardiac, vascular, or bronchial receptors and are described in more detail in Chapter 10. When blockers are discontinued after prolonged regular use, some patients experience a withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, and increase of blood pressure. Although the incidence of these complications is probably low, blockers should not be discontinued abruptly. The withdrawal syndrome may involve upregulation or supersensitivity of adrenoceptors. Labetalol, Carvedilol, & Nebivolol these drugs have both -blocking and vasodilating effects. Labetalol is formulated as a racemic mixture of four isomers (it has two centers of asymmetry). Two of these isomers-the (S,S)- and (R,S)-isomers-are relatively inactive, a third (S,R)- is a potent blocker, and the last (R,R)- is a potent blocker. Blood pressure is lowered by reduction of systemic vascular resistance (via blockade) without significant alteration in heart rate or cardiac output. Because of its combined - and -blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies. The S(-) isomer is a nonselective -adrenoceptor blocker, but both S(-) and R(+) isomers have approximately equal -blocking potency. The isomers are stereoselectively metabolized in the liver, which means that their elimination half-lives may differ. Carvedilol reduces mortality in patients with heart failure and is therefore particularly useful in patients with both heart failure and hypertension. Nebivolol is a 1-selective blocker with vasodilating properties that are not mediated by blockade. The vasodilating effect may be due to an increase in endothelial release of nitric oxide via induction of endothelial nitric oxide synthase. The hemodynamic effects of nebivolol therefore differ from those of pure blockers in that peripheral vascular resistance is acutely lowered (by nebivolol) as opposed to increased acutely (by the older agents). Dosing is generally started at 5 mg/d, with dose escalation as high as 40 mg/d, if necessary. The efficacy of nebivolol is similar to that of other antihypertensive agents, but several studies report fewer adverse effects. Metoprolol & Atenolol Metoprolol and atenolol, which are cardioselective, are the most widely used blockers in the treatment of hypertension. Metoprolol is approximately equipotent to propranolol in inhibiting stimulation of 1 adrenoceptors such as those in the heart but 50to 100-fold less potent than propranolol in blocking 2 receptors. Relative cardioselectivity is advantageous in treating hypertensive patients who also suffer from asthma, diabetes, or peripheral vascular disease. Although cardioselectivity is not complete, metoprolol causes less bronchial constriction than propranolol at doses that produce equal inhibition of 1-adrenoceptor responses. Sustained-release metoprolol is effective in reducing mortality from heart failure and is particularly useful in patients with hypertension and heart failure. Atenolol is not extensively metabolized and is excreted primarily in the urine with a half-life of 6 hours; it is usually dosed once daily. Atenolol is reported to be less effective than metoprolol in preventing the complications of hypertension. A possible reason for this difference is that once-daily dosing does not maintain adequate blood levels of atenolol. Nadolol, Carteolol, Betaxolol, & Bisoprolol Nadolol and carteolol, nonselective -receptor antagonists, are not appreciably metabolized and are excreted to a considerable extent in the urine. Betaxolol and bisoprolol are 1-selective blockers that are primarily metabolized in the liver but have long halflives. Because of these relatively long half-lives, these drugs can be administered once daily. Increases in dosage to obtain a satisfactory therapeutic effect should take place no more often than every 4 or 5 days. Patients with reduced renal function should receive correspondingly reduced doses of nadolol and carteolol. Esmolol Esmolol is a 1-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases. Esmolol is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure, in which case a drug with a short duration of action that can be discontinued quickly is advantageous. Pindolol, Acebutolol, & Penbutolol Pindolol, acebutolol, and penbutolol are partial agonists, ie, blockers with some intrinsic sympathomimetic activity. These agents produce less reflex tachycardia when lowering blood pressure than do nonselective antagonists such as phentolamine. Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels. As expected, blood pressure is reduced more in the upright than in the supine position. Retention of salt and water occurs when these drugs are administered without a diuretic. The drugs are more effective when used in combination with other agents, such as a blocker and a diuretic, than when used alone. Owing to their beneficial effects in men with prostatic hyperplasia and bladder obstruction symptoms, these drugs are used primarily in men with concurrent hypertension and benign prostatic hyperplasia. All the vasodilators that are useful in hypertension relax smooth muscle of arterioles, thereby decreasing systemic vascular resistance. Because sympathetic reflexes are intact, vasodilator therapy does not cause orthostatic hypotension or sexual dysfunction. Vasodilators work best in combination with other antihypertensive drugs that oppose the compensatory cardiovascular responses. Terazosin is also extensively metabolized but undergoes very little first-pass metabolism and has a half-life of 12 hours. Doxazosin is usually given once daily starting at 1 mg/d and progressing to 4 mg/d or more as needed. Although long-term treatment with these blockers causes relatively little postural hypotension, a precipitous drop in standing blood pressure develops in some patients shortly after the first dose is absorbed. For this reason, the first dose should be small and should be administered at bedtime. Although the mechanism of this first-dose phenomenon is not clear, it occurs more commonly in patients who are salt- and volume-depleted. Aside from the first-dose phenomenon, the reported toxicities of the 1 blockers are relatively infrequent and mild. Some patients develop a positive test for antinuclear factor in serum while on prazosin therapy, but this has not been associated with rheumatic symptoms. The 1 blockers do not adversely and may even beneficially affect plasma lipid profiles, but this action has not been shown to confer any benefit on clinical outcomes. It has been available for many years, although it was initially thought not to be particularly effective because tachyphylaxis to its antihypertensive effects developed rapidly. The benefits of combination therapy are now recognized, and hydralazine may be used more effectively, particularly in severe hypertension. The combination of hydralazine with nitrates is effective in heart failure and should be considered in patients with both hypertension and heart failure, especially in African-American patients. Pharmacokinetics & Dosage Hydralazine is well absorbed and rapidly metabolized by the liver during the first pass, so that bioavailability is low (averaging 25%) and variable among individuals. As a consequence, rapid acetylators have greater first-pass metabolism, lower blood levels, and less antihypertensive benefit from a given dose than do slow acetylators. Even more than with hydralazine, the use of minoxidil is associated with reflex sympathetic stimulation and sodium and fluid retention. Toxicity Tachycardia, palpitations, angina, and edema are observed when doses of co-administered blockers and diuretics are inadequate. Headache, sweating, and hypertrichosis (the latter particularly bothersome in women) are relatively common. Topical minoxidil (as Rogaine) is used as a stimulant to hair growth for correction of baldness. The higher dosage was selected as the dose at which there is a small possibility of developing the lupus erythematosus-like syndrome described in the next section. However, higher dosages result in greater vasodilation and may be used if necessary. Nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. The action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme. In the absence of heart failure, blood pressure decreases, owing to decreased vascular resistance, whereas cardiac output does not change or decreases slightly. In patients with heart failure and low cardiac output, output often increases owing to afterload reduction. In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias. The syndrome is not associated with renal damage and is reversed by discontinuance of hydralazine. Peripheral neuropathy and drug fever are other serious but uncommon adverse effects. The effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite.