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The ability to ac- curately characterize nonstationarities provides the opportunity to extend the appli- cability of this approach to modeling adaptive properties of hippocampal and other cortical neural systems as well purchase bactrim paypal virus not alive. In total purchase bactrim with visa antibiotic beads for osteomyelitis, the kernel functions represent an experimentally based model that is highly accurate in describing the functional dynamics of the neuron in terms of the probability of neuron output as a function of the recent history of the input 480 mg bactrim overnight delivery virus 8 month old baby. In addi- tion order bactrim 960 mg with visa virus in michigan, because of the broadband nature of the test stimulus, the model generalizes to a wide range of input conditions, even to input patterns that are not explicitly included in the random impulse train. As such, the kernels not only provide the basis for a biologically realistic neural network model, but also perhaps an ideal basis for an implantable neural prosthesis. An input-output model can be sub- stituted for a neuron on which the model is experimentally based, without regard to the variability in neural representations that must exist from individual to individ- ual, or the nearly infinite range of environmental stimuli that would give rise to those representations. Neural Network Models with Biologically Realistic Dynamics Conventional, Artificial Neural Networks Brainlike processing is often modeled mathematically as artificial neural networks, or networks of processing elements that interact through connections. In artificial neural network models, a connection between processing elements—despite the com- plexity of the synaptic nonlinear dynamics described earlier—is represented as a sin- gle number to scale the amplitude of the output signal of a processing element. Berger and colleagues parameters of an artificial neural network can be optimized to perform a desired task by changing the strengths of connections according to what are termed learning rules, that is, algorithms for when and by how much the connection strengths are changed during optimization. This simplification of a synapse as a number results in two fundamental limitations. First, although a processing element can be connected to a large number of other processing elements, it can transmit only one, identical signal to all other elements. Second, only the connection strength can be changed during the optimization process, which amounts to merely changing the gain of the output signal of a processing element. In this scheme, processing elements are assumed to transmit information by variation in a series of point-process (i. By including these dynamic processes, each network connection transforms a sequence of input events into another sequence of output events. In the brain, it has been demonstrated that the functional properties of multiple synaptic outputs that arise from a given neuron are not identical. This characteristic of the brain also has been incorporated as a second fundamental property of dynamic synapse neural net- works. Although the same essential dynamics are included in each synapse originat- ing from a given processing unit, the precise values of time constants governing those dynamics are varied. The consequence arising from this second property is that each processing element transmits a spatiotemporal output signal, which, in principle, gives rise to an exponential growth in coding capacity. Like the nonlinear dynamics described earlier and included in the dynamic synapse network models, this learning algorithm also is based on experimentally determined, adaptive properties of hippocampal cor- tical neurons (which cannot be reviewed here; see Xie et al. The combination of nonlinear dynamics and dynamic learning algorithm provides a high degree of robustness against noise, which is a major issue in processing real biological signals in the brain, as well as real-world A Neural Prosthesis for Hippocampal Memory Function 251 Figure 12. Berger and colleagues signals, as demonstrated in our case studies of speaker-independent speech recogni- tion described in the following paragraphs. Application to Speech Recognition Current state-of-the-art speech recognition technology is based on complex, multi- stage processing that is not biologically based. Although commercial systems can demonstrate impressive performance, they are still far from performing at the level of human listeners. To test the computational capability of the dynamic synapse neu- ral network, two strong constraints were imposed: the network must be simple and small, and it must accomplish speech recognition in a single step, that is, with no pre- processing stages. Our system not only achieved this goal, but as will be described later, also performed better than human listeners when tested with speech signals cor- rupted by noise, marking the first time ever that a physical device has outperformed humans in a speech recognition task (Liaw and Berger, 1997, 1998, 1999). Invariant Feature Extraction Two characteristics of speech signals, variability and noise, make its recognition a di‰cult task. Variability refers to the fact that the same word is spoken in di¤erent ways by di¤erent speakers. Yet there exist invariant features in the speech signal, allowing the constant perception of a given word, re- gardless of the speaker or the manner of speaking. The variability of two signals can be measured by how well they correlate with each other. However, the dynamic synapse neu- ral network can be trained to produce highly correlated signals for a given word (figure 12. Thus, the dynamic synapse neural network can extract invariant features embedded in speech signals that are inherently very di‰cult to dis- criminate, and can do so with no preprocessing of the data (only the output from a microphone was used) using a core signal-processing system that is extremely small and compact. We then evaluated the performance of the model when the speech signals not used during training were corrupted with progressively increasing amount of white noise [measured by the A Neural Prosthesis for Hippocampal Memory Function 253 Figure 12. Inputs to the network are digitized speech wave forms from di¤erent speakers for the same word, which have little similarity (low cross-correlation) because of di¤erences in speaker vocaliza- tion. The two networks shown are intended to represent the same network on two di¤erent training or test- ing trials; in a real case, one network is trained with both (or more) speech wave forms. On any given trial, each speech wave form constitutes the input for all five of the input units shown in the first layer. The output of each synapse (arrows) to the second layer of the network is governed by four dynamic processes (see figure 12. A dynamic learning rule modifies the relative contribution of each dy- namic process until the output neurons converge on a common temporal pattern in response to di¤erent input speech signals (i. The results showed that our model is ex- tremely robust against noise, performing better than human listeners tested with the same speech dataset (figure 12. This is first time ever that a speech recognition sys- tem has outperformed human listeners, and the dynamic synapse system did so by a considerable margin. Comparison with a State-of-the-Art Commercial Product and Robustness with Respect to Conversational Noise the objective of this study was to compare the perfor- mance of the dynamic synapse neural network and one of the best state-of-the-art, A Neural Prosthesis for Hippocampal Memory Function 255 commercially available systems, namely, the Dragon Naturally Speaking speech rec- ognition system. In the first stage, the system was fully trained using the mate- rial provided by the manufacturer. In the second stage, it was further trained using the four target words. Once the training was complete, both the dynamic synapse neural network and the Dragon system were tested with noise-added speech signals at various SNRs. The same noise-added speech signals were used to test human performance (average of five subjects). Its performance degraded to 50% correct when the SNR was þ20 dB, whereas both the dynamic synapse neural network and human listeners retained a 100% recognition rate. The Dragon system failed to recognize any word when the SNR was þ10 dB, whereas the dynamic synapse neural network and human listeners performed at 100 and 90% recognition rates, respectively. Furthermore, the dynamic synapse neural network was highly robust and performed significantly better than human listeners when the SNR dropped below þ2. For example, for an SNR ranging from 0 to À5 dB, human performance varied from a 30 to 15% correct rate, while the dynamic synapse neural network retained a 75% correct rate. These find- ings show that human listeners perform far better than the Dragon system in terms of robustness against noise. Performance degradation under noisy conditions is well documented for all speech recognition systems based on conventional technology, like that used in the Dragon system. In contrast, the dynamic synapse neural network significantly outperformed the Dragon system, demonstrating a robustness superior to human listeners under highly noisy conditions. The significance of these findings with respect to developing a neural prosthesis for replacing cognitive functions is severalfold. First, the dynamic synapse neural net- work used in the studies described here is remarkably small: only eleven processing units and thirty synapses.

While somatosensory evoked po- ever buy 480 mg bactrim with visa antibiotics for acne birth control, bladder or bowel dysfunction is caused primarily by tentials (SEPs) and motor evoked potentials (MEPs) are a bilateral upper motor neuron lesion buy bactrim 480mg low price treatment for dogs ear infection. Cervical myelopa- most helpful in the investigation of the central nervous sys- thy is generally due to degenerative changes of the middle tem pathways buy bactrim with amex antibiotic resistance definition biology, electromyography purchase bactrim 480mg with visa bacteria eating flesh, conventional neurogra- and lower cervical spine. Therefore, impairment of hand phy and F-wave studies are more useful for evaluation of function can be attributed mainly to lower motor neuron the peripheral segments of the sensory and motor path- function (4 points), although similar disturbances of preci- ways. Proprioception and coordination depend on posterior column function (3 points). Posterior Somatosensory evoked potentials column function was included in the European Myelopa- thy Score instead of the JOA subscores for sensory function For spinal cord evaluation, SEPs are relevant. These are – a disturbance which is very difficult to classify into cat- potentials recorded from the lumbar and cervical spine as egories. Pain is not a major symptom in cervical myelopa- well as the first components of scalp recordings. Nevertheless, unpleasant sensations such as paresthe- SEPs are generally recorded after electrical stimulation sia or dysesthesia are often reported, and are mostly caused of peripheral nerves or skin. The nerves used are: the pos- by a mechanical irritation of the afferent posterior cervical terior tibial, sural, or common peroneal nerves of the roots (3 points). The maximum number of points a normal lower limbs, and the median radial and the ulnar nerve for subject can reach is 18. In radicular and spinal disease, several Borrowing from the Glasgow Coma Scale, the worst nerves, supplied by different segments, must be stimulated result is rated with 1 point for each subscore. Depending on the sum reached in the mended for the diagnosis of cervical myelopathy [41]. Subjects with 17 or 18 points are consid- Motor evoked potentials ered free of signs of cervical myelopathy. The functional character of the criteria used in the Eu- Somatosensory evoked potentials are delayed in cervical ropean Myelopathy Score allows a critical evaluation of spondylosis and the latency of N11 is significantly delayed cervical myelopathy from different centers and different statistically. The European Myelopathy Score helps to judge previously in electrical cortical stimulation studies [1, 12]. It also allows a more objective control of stimulation of the cerebral cortex was introduced in 1985 postoperative outcome. They applied short magnetic pulses, is a valuable tool for the evaluation of all conditions involv- designed to stimulate peripheral nerves, to the scalp, and 102 recorded muscle action potentials from upper and lower However, as the excitability of the spinal motor neuron limb muscles. In spite of ulate the motor cortex, the cervical nerve roots, and the these limitations, F-waves have a diagnostic value for an- lumbar nerve roots. When F-waves are recorded in a chronic following muscles: abductor pollicis, adductor minimi, neuropathic process, axonal reflexes must be differenti- quadriceps, tibialis anterior, gastrocnemius, extensor hal- ated [18, 33]. The segmental innerva- tion of these muscles is used for a level diagnosis in anal- ogy to the segmental distribution of the afferent nerves Electromyography (EMG) stimulated for SEPs. Needle electromyography examines segmentally affected For motor root stimulation over the cervical and lum- muscles, chosen based upon the clinical investigation. Increased inser- With this, the onset latency is not critically dependent on tional activity, spontaneous activity (involuntary) such as the positioning of the coil or the stimulation strength [6]. In patients diagnosed as In normal muscles, motor unit action potentials having a lateral compression of the nerve root, the periph- (MUAPs) are elicited only in response to neural discharges. These signs of denervation in EMG can be spotted at the earliest about 8 days after the nerve lesion, and are termed acute signs of M-wave and F-wave evaluation denervation. In order to judge the MEP waveform it is also necessary to obtain an M-wave recording by means of conventional neurography. The M-wave is the response to a supramax- Diagnostic reliability imal stimulus of the peripheral nerve, and therefore an electric measure of muscle size [32]. It is used as a ref- EMG is important in the differential diagnosis of cervical erence signal with which post transcranial stimulation spondylosis. It shows degrees of denervation and the num- MEP amplitude and duration are compared, i. The increased CML can be found in not only degenerative but also inflammatory dis- eases of the central nervous system, such as multiple scle- F-wave rosis. Kameyama examined 67 patients with clinically rel- evant cervical myelopathy, and 24 patients with cervical F-wave recordings allow for the determination of a total canal stenosis without myelopathy [15]. A positive corre- peripheral conduction time (peripheral latency: PL) from lation was found for the group of myelopathy patients. De the anterior horn cell to the muscle, which thus includes Mattei found sensitivity of MEPs in patients with cervical the conduction over the motor root to its exit from the in- compression myelopathy to be 70% for upper extremity tervertebral foramen. Distinct delay of the F-wave or a reduced number clinically relevant cervical myelopathy who underwent of clearly distinguishable F-waves after a given number of decompressive surgery. Patients who presented a CML supramaximal peripheral stimuli, in association with nor- longer than 15 ms and/or polyphasic wave pattern of the mal distal motor conduction, is a sign of a proximal le- potential had worse surgical results than the remaining pa- sion. The trophic lateral sclerosis, while in 19 out of 20 patients with authors of this excellent study, which is the only RCT to cervical myelopathy, a pathological finding was observed. The spondylotic cervical myelopathy has been prospectively problem is to find the predictive factors for a satisfac- examined by Bednarik et al. The group changes of tory outcome either for the surgical or the nonsurgical some SEP and MEP parameters correlated with the changes approach. It would be desirable to arrange a multicen- in clinical score, which means they could be used as an ter study aimed at addressing these questions, as has objective tool for the assessment of the results of therapy. First, however, it would In clinical silent cervical cord compression, abnormali- be necessary to validate the scoring systems carefully, ties were found in half the subjects (n=91) and predicted probably replacing those currently used to obtain more clinical manifestation of myelopathy in one-third of them reliable and reproducible data. The most promising candidates for highly predicted Guidelines for treatment procedures, either conservative good results from either conservative treatment or sur- or surgical, in patients with cervical myelopathy do not gery could be the transverse area of the stenotic cord, exist. The literature in this respect presents controversial duration of the disease [44], osseous or cartilaginous results. Increasing age, clinical, neurophysiological signs, compression, developmental diameter of the canal, pos- and the general health condition are relevant factors in the itivity of electrophysiologic findings, low-signal inten- decision-making process. Only 43 pa- As the indications for surgical decompression of cervi- tients (69%! Neither ISI nor spinal cord area was signifi- – Conduct a neurological assessment and diagnostic work cantly associated with outcome. The authors conclude out to exclude other systemic diseases that early decompression for mild cervical myelopathy is – If in doubt, wait and see, but carry out regular con- not warranted either by ISI or reduced spinal cord area. Factors that – Surgery is indicated in progressive and/or severe forms are unchangeable by nature, such as developmental steno- of cervical myelopathy sis or progressive degenerative changes of the cervical – Multimodal intraoperative monitoring (MIOM) is re- spine, are parameters to consider or indicate surgical de- quired for demanding decompressive surgery, to opti- compression. Negrin P, Lelli S, Fardin P (1991) M, Simonetti S, Spadavecchia L, Se- Dvorak J, Bock WJ (1994) the Euro- Contribution of electromyography to veri P, Andrioli GC, Favale E (1988) pean Myelopathy Score. In: Bauer BL, the diagnosis, treatment and prognosis Electrical stimulation of the motor Brock M, Klinger M (eds) Advances in of cervical disc disease: a study of tracts in cervical spondylosis. Electromyogr Clin Neu- Neurosurg Psychiatry 51:796–802 berg, pp 266–268 rophysiol 31:173–179 2. Neuhuber WL, Zenker W (1989) Cen- Merton PA, Morton HB (1985) Mag- Smrcka V, Krbec M, Stejskal L, tral distribution of cervical primary af- netic stimulation of the human brain. Chaloupka R, Surelova D, Novotny O, ferents in the rat, with emphasis on J Physiol 369:3 Urbanek I, Dusek L (2002) Approaches proprioceptive projections to vestibu- 3.

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Note Research and clinical observations indicate the following: that sustained-release forms of nifedipine cheap bactrim 480 mg overnight delivery antibiotic impetigo, diltiazem generic bactrim 960mg with visa antibiotics for sinus infection augmentin, and 1 generic 480 mg bactrim overnight delivery antibiotics for sinus staph infection. Sodium restriction potentiates the antihypertensive ac- felodipine) are recommended generic 960mg bactrim with mastercard bacteria 5 letters. Diuretics are preferred for initial therapy in older clients Conversely, excessive sodium intake decreases the and African-American hypertensive clients. Thiazide and related diuretics are equally thiazides may lose excessive potassium and become effective. Sodium restriction may decrease dosage requirements and a diuretic to prevent hypotension-induced compen- of antihypertensive drugs, thereby decreasing the inci- satory mechanisms (stimulation of the SNS and fluid dence and severity of adverse effects. Combination products usually combine two drugs with different mechanisms of action (eg, a thiazide or Genetic/Ethnic Considerations related diuretic plus a beta blocker or other antiadren- ergic, an ACE inhibitor, an ARB, or a calcium channel For most antihypertensive drugs, there have been few re- blocker). Most are available in various formulations search studies comparing their effects in different genetic or CHAPTER 55 ANTIHYPERTENSIVE DRUGS 811 ethnic groups. However, several studies indicate that beta body size (height and weight), and sex. Normal blood blockers have greater effects in people of Asian heritage pressure is defined as systolic and diastolic values less compared with their effects in Caucasians. For hypertension, than the 90th percentile; hypertension is defined as an Asians in general need much smaller doses because they me- average of systolic or diastolic pressures that equals or tabolize and excrete beta blockers slowly. Other populations exceeds the 95th percentile on three or more occasions. In cent should be compared with the norms and recorded African Americans, diuretics are effective and recommended in permanent health care records. Multiple accurate as initial drug therapy; calcium channel blockers, alpha1 re- measurements are especially important in diagnosing ceptor blockers, and the alpha–beta blocker labetalol are hypertension because blood pressure may be more la- reportedly equally effective in African Americans and Cau- bile in children and adolescents. Children have a greater incidence of secondary hyper- tan), and beta blockers are less effective as monotherapy in tension than adults. When beta blockers are used, they are usu- sure and the younger the child, the greater the likelihood ally one component of a multidrug regimen, and higher doses of secondary hypertension. Overall, African Americans are more likely needed to rule out renovascular disease or coarctation of to have severe hypertension and require multiple drugs. The goals of management are to reduce blood pressure Treatment of High Blood Pressure recommends that drug to below the 95th percentile and prevent the long-term therapy be continued until surgery and restarted as soon as effects of persistent hypertension. If clients cannot take drugs orally, par- vention of obesity, avoiding excessive sodium intake, enteral diuretics, antiadrenergic agents, ACE inhibitors, cal- and exercise are important nonpharmacologic mea- cium blockers, or vasodilators may be given to avoid the sures. Obese adolescents who lose weight may lower rebound hypertension associated with abrupt discontinuance their blood pressure, especially when they also increase of some antiadrenergic antihypertensive agents. Drug therapy should be cau- tious and conservative because few studies have been done in children and long-term effects are unknown. Thus, if an initial drug is ineffective, it may be better to Most principles of managing adult hypertension apply to give a different single drug than to add a second drug managing childhood and adolescent hypertension; some ad- to the regimen. Children may have primary or secondary hypertension, lowing: but the incidence is unknown and treatment is not well a. In recent years, increased blood pressure should probably be avoided in children with resting measurements during routine pediatric examinations pulse rates under 60. Thiazide diuretics may be used, and they do not com- hypertension and the realization that mild elevations in monly produce hyperglycemia, hyperuricemia, or blood pressure are more common during childhood, hypercalcemia in children as they do in adults. Angiotensin II receptor blockers have not been es- Hypertension in children and adolescents may indicate tablished as safe and effective for use in children underlying disease processes (eg, cardiac, endocrine, younger than 18 years of age. Although ACE inhibitors have been used to treat early onset of primary hypertension. Routine blood hypertension in children, their safety and efficacy pressure measurement is especially important for chil- have not been established. Most clinical experience dren who are overweight or who have a hypertensive has been with captopril, with which hemodynamic parent. Increased blood pressure in children often cor- effects are stronger and last longer in newborns and relates with hypertension in young adults. National norms have been established for blood pres- sive and prolonged hypotension, with oliguria and sure in children and adolescents of comparable age, seizures, has occurred. In general, captopril should 812 SECTION 9 DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM be used in children only when other measures for clients to meet because it requires rather stringent controlling blood pressure are ineffective. Also, be- lifestyle restrictions and may require two or more cause of teratogenic effects, these drugs should be antihypertensive drugs. Older adults may be especially susceptible to the who may be sexually active. Calcium channel blockers are used in treating acute their homeostatic mechanisms are less efficient. With chronic example, if hypotension occurs, the mechanisms hypertension, immediate-release forms have a short that raise blood pressure are less efficient and syn- duration of action and require frequent administra- cope may occur. In addition, renal and liver func- tion, and long-acting forms contain dosages that are tion may be reduced, making accumulation of drugs not suitable for young children. Initial drug doses should be approximately half of the and adolescent hypertension than in adult disease. Although all clients with primary hypertension need reg- should be smaller and spaced at longer intervals. Blood pressure should be reduced slowly to facilitate adequate blood flow through arteriosclerotic vessels. Use in Older Adults Rapid lowering of blood pressure may produce cere- bral insufficiency (syncope, transient ischemic at- Most principles of managing hypertension in other popula- tacks, stroke). A further incentive for successful management of lowing factors require consideration: hypertension in older clients is the benefit of reduc- 1. There are basically two types of hypertension in older ing the incidence of dementia with antihypertensives. If blood pressure control is achieved and maintained blood pressure is above 160 mm Hg, but diastolic for approximately 6 to 12 months, drug dosage should pressure is below 95 mm Hg or normal. Both types increase cardiovascular morbidity and Use in Renal Impairment mortality, especially heart failure and stroke, and should be treated. Nonpharmacologic management should be tried alone with renal impairment ranging from mild insufficiency to or with drug therapy. A temporary decrease in renal function and moderate sodium restriction may be the initial may occur in these clients when the blood pressure is initially management of choice if the client is hypertensive and lowered. If antihypertensive drug therapy is required, drugs used diabetic nephropathy, drug therapy may slow progres- for younger adults may be used alone or in combina- sion of renal impairment. Diuretics are usually required because sodium retention older adults and may be effective alone. Some ACE inhibitors ever, metolazone, a thiazide-related drug, may be used (eg, lisinopril, ramipril, quinapril, moexipril) or their and relatively large doses may be required. Loop di- active metabolites produce higher plasma concentra- uretics, such as furosemide, are more often used, and tions in older adults than in younger ones. Additional guidelines include: effective in clients with renal impairment, but responses a. The goal of drug therapy for systolic-diastolic may vary and the following factors should be considered.

The body normally muscle cells cheap bactrim 960 mg amex antibiotics for uti for elderly, where the enzyme lipoprotein lipase breaks down the attempts to compensate for high serum levels by inhibiting he- molecule and releases fatty acids to be used for energy or stored patic synthesis of cholesterol and cellular synthesis of new LDL as fat discount bactrim online american express antimicrobial pens. Thus order bactrim 960 mg line commonly used antibiotics for acne, chylomicrons transport Very–low-density lipoprotein (VLDL) contains approxi- triglycerides to peripheral tissues and cholesterol to the liver purchase cheapest bactrim and bactrim virus in jamaica. It transports en- Low-density lipoprotein (LDL) cholesterol, sometimes dogenous triglycerides (those synthesized in the liver and intestine, called bad cholesterol, transports approximately 75% of serum not those derived exogenously, from food) to fat and muscle cells. LDL There, as with chylomicrons, lipoprotein lipase breaks down the cholesterol is removed from the circulation by receptor and non- molecule and releases fatty acids to be used for energy or stored as receptor mechanisms. The removal of triglycerides from VLDL leaves a cholesterol- ing of LDL cholesterol to receptors on cell surface membranes. Then the cholesterol is se- the bound LDL molecule is then engulfed into the cell, where it creted into the intestine, mostly as bile acids, or it is used to form is broken down by enzymes and releases free cholesterol into the more VLDL and recirculated. High-density lipoprotein (HDL) cholesterol, often referred to Most LDL cholesterol receptors are located in the liver. It ever, nonhepatic tissues (eg, adrenal glands, smooth muscle cells, is synthesized in the liver and intestine and some is derived from endothelial cells, and lymphoid cells) also have receptors by which the enzymatic breakdown of chylomicrons and VLDL. It contains they obtain the cholesterol needed for building cell membranes moderate amounts of cholesterol. These cells can regulate their choles- transported from blood vessel walls to the liver for catabolism and terol intake by adding or removing LDL receptors. This reverse transport of cholesterol has protective Approximately two thirds of the LDL cholesterol is removed effects against coronary heart disease. The the mechanisms by which HDL cholesterol exerts protective number of LDL receptors on cell membranes determines the amount effects are unknown. Possible mechanisms include clearing choles- of LDL degradation (ie, the more receptors on cells, the more LDL terol from atheromatous plaque; increasing excretion of cholesterol is broken down). Conditions that decrease the number or function so less is available for reuse in the formation of LDL cholesterol; of receptors (eg, high dietary intake of cholesterol, saturated fat, or and inhibiting cellular uptake of LDL cholesterol. Nonreceptor uptake occurs in various cells, es- tors, smoking, and some medications (eg, steroids and beta block- pecially when levels of circulating LDL cholesterol are high. HDL cholesterol levels are example, macrophage cells in arterial walls can attach LDL, not directly affected by diet. CHAPTER 58 DRUGS FOR DYSLIPIDEMIA 853 Total serum cholesterol (mg/dL) excessive caloric intake (excessive dietary fats are stored Normal or desirable = less than 200 in adipose tissue; excessive proteins and carbohydrates Borderline high = 200 to 239 are converted to triglycerides and also stored in adipose tis- High = 240 or above sue) and obesity. High caloric intake also increases the LDL cholesterol (mg/dL) conversion of VLDL to LDL cholesterol, and high dietary Optimal = less than 100 intake of triglycerides and saturated fat decreases the ac- Near or above optimal = 100–129 tivity of LDL receptors and increases synthesis of choles- Borderline high = 130 to 159 terol. Very high triglyceride levels are associated with High = 160 to 189 acute pancreatitis. Very high = 190 or above Dyslipidemia may be primary (ie, genetic or familial) or HDL cholesterol (mg/dL) secondary to dietary habits, other diseases (eg, diabetes mel- High = more than 60 litus, alcoholism, hypothyroidism, obesity, obstructive liver Low = less than 40 disease), and medications (eg, beta blockers, cyclosporine, Triglycerides (mg/dL) oral estrogens, glucocorticoids, sertraline, thiazide diuretics, Normal or desirable = less than 150 anti–human immunodeficiency virus protease inhibitors). Borderline high = 150 to 199 Types of dyslipidemias (also called hyperlipoproteinemias High = 200 to 499 because increased blood levels of lipoproteins accompany Very high = 500 or above increased blood lipid levels) are described in Box 58–2. Overall, the most effective blood lipid profile for preven- Although hypercholesterolemia is usually emphasized, tion or management of atherosclerosis and its sequelae is high hypertriglyceridemia is also associated with most types of HDL cholesterol, low LDL cholesterol, and low total choles- hyperlipoproteinemia. The National Cholesterol Education Program recommends management of clients according to their blood levels of total DYSLIPIDEMIA and LDL cholesterol and their risk factors for cardiovascular disease (Table 58–1). Note that both dietary and drug therapy Dyslipidemia (also called hyperlipidemia) is associated are recommended at lower serum cholesterol levels in clients with atherosclerosis and its many pathophysiologic effects who already have cardiovascular disease or diabetes mellitus. Ischemic heart disease has a Guidelines include the following: high rate of morbidity and mortality. Elevated total choles- • Assess for, and treat, if present, conditions known to terol and LDL cholesterol and reduced HDL cholesterol are increase blood lipids (eg, diabetes mellitus, hypo- the abnormalities that are major risk factors for coronary thyroidism). Elevated triglycerides also play a role in car- • Stop medications known to increase blood lipids, if diovascular disease. BOX 58–2 TYPES OF DYSLIPIDEMIAS Type I is characterized by elevated or normal serum cholesterol, usually occurs in middle-aged adults (40 to 60 years) and is elevated triglycerides, and chylomicronemia. This rare condition associated with accelerated coronary and peripheral vascular may occur in infancy and childhood. Type IIa (familial hypercholesterolemia) is characterized by a Type IV is characterized by normal or elevated cholesterol lev- high level of low-density lipoprotein (LDL) cholesterol, a normal els, elevated triglycerides, and increased levels of VLDL. This level of very–low-density lipoprotein (VLDL), and a normal or type usually occurs in adults and may be the most common form slightly increased level of triglycerides. Type IV is often secondary to obesity, is a definite risk factor for development of atherosclerosis and excessive intake of alcohol, or other diseases. Type IIb (combined familial hyperlipoproteinemia) is charac- Type V is characterized by elevated cholesterol and triglyc- terized by increased levels of LDL, VLDL, cholesterol, and eride levels with an increased level of VLDL and chylomicrone- triglycerides and lipid deposits (xanthomas) in the feet, knees, and mia. Instead, it is associated Type III is characterized by elevations of cholesterol and with fat and carbohydrate intolerance, abdominal pain, and pan- triglycerides plus abnormal levels of LDL and VLDL. This type creatitis, which are relieved by lowering triglyceride levels. It is essential that diet therapy continue as the 30% of calories from fat, less than 10% of calories from benefits of diet and drug therapy are additive. A Step II diet contains no more than 30% of calories from fat, less than 7% of calo- DRUG THERAPY OF DYSLIPIDEMIA ries from saturated fat, and less than 200 mg of choles- terol per day. The Step II diet is more stringent and may Dyslipidemic drugs are used to decrease blood lipids, to pre- be used initially in clients with more severe dyslipidemia, vent or delay the development of atherosclerotic plaque, pro- cardiovascular disease, or diabetes mellitus. It can de- mote the regression of existing atherosclerotic plaque, and crease LDL cholesterol levels by 8% to 15%. The drugs act by altering the production, metabo- levels, and they lower HDL cholesterol concentrations. Drug therapy is • Use the Mediterranean diet, which includes moderate recommended when approximately 6 months of dietary and amounts of monounsaturated fats (eg, canola and olive other lifestyle changes fail to decrease dyslipidemia to an ac- oils) and polyunsaturated fats (eg, safflower, corn, cot- ceptable level. It is also recommended for clients with signs tonseed, sesame, soybean, sunflower oils), to also de- and symptoms of coronary heart disease, a strong family his- crease risks of cardiovascular disease. Categories of drugs are described in this sec- lowering margarines (eg, Benecol and Take Control) tion; individual drugs are listed in Drugs at a Glance: Dys- can help reduce cholesterol levels. This increases blood levels decreasing production of cholesterol, these drugs decrease total of HDL. They reduce LDL cholesterol within 2 weeks and In addition to numerous other benefits, HDL levels are reach maximal effects in approximately 4 to 6 weeks. Studies indicate that these drugs can reduce management includes efforts to achieve desirable body the blood levels of C-reactive protein (CRP) that is associated weight, ingest low amounts of saturated fat and choles- with severe arterial inflammation that leads to heart attacks terol, exercise regularly, stop smoking, and reduce al- and strokes. The incidence of coronary artery disease is re- cohol intake, if indicated. The goal is to reduce serum duced by 25% to 60% and the risk of death from any cause triglyceride levels to 200 mg/dL or less. They also reduce the risk of angina • Unless lipid levels are severely elevated, a minimum of pectoris and peripheral arterial disease as well as the need for 6 months of intensive diet therapy and lifestyle modifi- angioplasty and coronary artery grafting to increase or restore cation should be undertaken before drug therapy is con- blood flow to the myocardium. CHAPTER 58 DRUGS FOR DYSLIPIDEMIA 855 Drugs at a Glance: Dyslipidemic Agents Routes and Dosage Ranges Clinical Indications Generic/Trade Name (Type of Dyslipidemia) Adults Children HMG-CoA Reductase Inhibitors (Statins) Atorvastatin (Lipitor) Types IIa and IIb PO 10–80 mg daily in a single dose Fluvastatin (Lescol, Types IIa and IIb PO 40–80 mg daily in 1 or 2 doses Lescol XL) Lovastatin (Mevacor, Types IIa and IIb PO 10–80 mg daily in 1 or 2 doses <10 y: not recommended Altocor) 10–17 y: 10–40 mg daily Pravastatin (Pravachol) Types IIa and IIb PO 40–80 mg once daily Elderly, PO 10 mg once daily Simvastatin (Zocor) Types IV and V (hyper- PO 5–80 mg once daily in the evening triglyceridemia) Elderly, PO 5–20 mg once daily in the evening Fibrates Fenofibrate (Tricor) Types IV, V (hyper- PO 67 mg daily, increased if necessary triglyceridemia) to a maximum dose of 201 mg daily Gemfibrozil (Lopid) Types IV, V (hyper- PO 900–1500 mg daily, usually 1200 mg triglyceridemia) in 2 divided doses, 30 min before morning and evening meals Bile Acid Sequestrants Cholestyramine (Questran) Type IIa PO tablets 4 g once or twice daily ini- 240 mg/kg/d in 3 divided doses tially, gradually increased at monthly intervals to 8–16 g daily in 2 divided doses. LDL cholesterol levels de- extensive first-past metabolism by the liver, which results in crease within a week of starting these drugs and reach maxi- low levels of drug available for general circulation.

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