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Magnetic resonance imaging is weight-bearing loading blood pressure chart over 65 cheap labetalol 100 mg on line, including muscle resistance wide pulse pressure in young adults 100 mg labetalol purchase with amex. It often helpful in excluding other causes of pathologic frac- should be performed two to three times per week heart attack grill arizona buy labetalol cheap online, exceed- ture and in distinguishing fresh from older fractures. Interventional treatment options High-risk patients need special attention. Patients with one or more vertebral fractures are five times more likely With failure of conservative treatment, operative stabilisa- to have an additional VCF within the next year [22]. As vertebral fractures are bio- patients with secondary osteoporosis have multiple risk mechanically complex and surgical strategies vary ac- factors. In patients with rheumatoid arthritis, the inflam- cording to the fracture type [24], the evaluation of the pa- matory process itself, the physical inactivity and the nec- tient for surgery is ideally done in an interdisciplinary essary treatment with glucocorticoids also enhances the manner together with a spine surgeon. Con- ther aggravated by microarchitectural deterioration stress- ventional reconstructive procedures involving implants ing the severe osteoporosis associated with the disease. Vertebroplasty and kyphoplasty creased risk of osteoporotic fractures [25]. Both techniques may be performed under general or local anaesthesia using CT or biplanar Treatment options fluoroscopy. The technique of vertebroplasty is well de- scribed in the literature [17]. Briefly, a needle (usually a An interdisciplinary approach is substantial not only in di- bone biopsy needle) is percutaneously introduced into the agnostic, but also in therapeutic strategies. The aim of treat- affected vertebral body via a transpedicular or extrapedic- ment of osteoporosis is to halt bone loss, to reduce pain ular approach. Bone cement, polymethylmethacrylate and to prevent the occurrence of future fractures through (PMMA), is then injected directly into the vertebral body osteoinduction. Pharmacological treatments for bone loss at moderate to high pressure at low viscosity in order to include the bisphosphonates, hormone replacement ther- achieve trabecular filling. The fracture is stabilised once apy, selective oestrogen receptor modulators, calcitonin, the PMMA is cured. Kyphoplasty employs the same ap- the 1–34 fragment of parathyroid hormone, calcium and proaches as vertebroplasty; however, working cannulae vitamin D supplements, and calcitriol. Long acting strate- are bilaterally passed over initially placed guide pins and gies for patients with secondary osteoporosis must include obturators, which allows inflatable balloons to be placed effective treatment of the primary disease. In rheumatoid in the vertebral body (for detailed technique see Garfin et arthritis, this aims to reduce risk factors by inhibiting in- al. The balloon is slowly inflated under fluoroscopic flammatory activities of the disease by avoiding glucocor- guidance while carefully monitoring the balloon position- ticoids and applying physical therapy. Once maximum fracture re- However, these medications for osteoporosis alone duction and height restoration are achieved, both balloons cannot inhibit or reduce pain instantly or completely. Con- are deflated and removed, leaving behind a defined cavity, sequently, a conventional treatment for pain reduction in- which is then manually filled under low pressure with cluding the WHO recommendations of staged pain treat- highly viscous, radiopaque PMMA cement. Drugs for the treatment of pain should regulated according to the end volume of the inflated bal- be prescribed cautiously if the drugs have side effects on loon as noted on the inflation syringe. Biomechanically, the central nervous system that could potentially lead to both procedures are very efficient in restoring vertebral falls. As pain re- analgesics and bracing, all of which are aimed toward lief is similarly efficient for both procedures [11, 17], the pain management and remobilisation; however, none of choice of technique involves several factors. Here, kyphoplasty in- a vertebral deformity model, kyphotic deformity in excess creases operative safety, as PMMA is injected at high vis- of 10° at T7 and T8 produces 15. Although minor leakage does not usually pressive force and 40% increase in paraspinal extensor result in neurological impairment, several cases of severe muscle force at these levels. While vertebroplasty essen- neurological deficit and systemic embolism following tially freezes the deformity, kyphoplasty has been found vertebroplasty have been documented [2, 6, 15, 18, 21, to reduce segmental kyphosis on average by 6–18° [11]. In fresh fractures, reduction reaches an average of 14° the potential for serious complications, however rare, [11], with the possibility of near complete height restora- require scrutinous intraoperative fluoroscopic monitoring tion in the acute setting [4].

The ligand that binds the receptor is the so-called first Norepinephrine also functions as a hormone blood pressure medication for preeclampsia labetalol 100 mg purchase, along with messenger blood pressure medication and breastfeeding cheap labetalol 100 mg buy on line. In response to adrenergic nerve stimulation heart arrhythmia 4 year old purchase genuine labetalol, nor- tivates a cell membrane-bound G protein and an effector en- epinephrine and epinephrine are secreted into the bloodstream zyme that then activate a molecule inside the cell called a by the adrenal medullae and transported to all body tissues. This second messenger is the link be- They are continually present in arterial blood in amounts that tween events that are occurring outside the cell (ie, receptor vary according to the degree of stress present and the ability activation by the ligand) and resulting events that will occur of the adrenal medullae to respond to stimuli. The larger pro- inside the cell, such as opening ion channels, stimulating portion of the circulating hormones (approximately 80%) is other enzymes, and increasing intracellular calcium levels. These catecholamines exert the same effects as These intracellular events ultimately produce the physiologic those caused by direct stimulation of the SNS. However, the responses to neurotransmitter and hormone release or drug effects last longer because the hormones are removed from the administration. These hormones are metabolized mainly of signal transduction that occur when an adrenergic beta re- in the liver by the enzymes MAO and COMT. The SNS is stimulated by physical or emotional stress, such Adrenergic Receptors as strenuous exercise or work, pain, hemorrhage, intense emotions, and temperature extremes. Increased capacity for When norepinephrine and epinephrine act on body cells that vigorous muscle activity in response to a perceived threat, respond to sympathetic nerve or catecholamine stimulation, whether real or imaginary, is often called the fight-or-flight they interact with two distinct adrenergic receptors, alpha and reaction. Increased arterial blood pressure and cardiac output nephrine acts on both alpha and beta receptors. Increased blood flow to the brain, heart, and skeletal tors have been further subdivided into alpha1, alpha2, beta1, muscles; decreased blood flow to viscera, skin, and and beta2 receptors. A beta3 receptor has been identified, and other organs not needed for fight-or-flight animal studies suggest that drugs targeted to this receptor 3. Increased rate of cellular metabolism—increased oxy- may augment heat production, produce lipolysis (thermoge- gen consumption and carbon dioxide production nesis), and increase energy expenditure. Increased breakdown of muscle glycogen for energy are being tested to treat obesity, hyperglycemia, and the prob- 5. Increased mental activity and ability to think clearly compounds approved by the Food and Drug Administration 7. Increased rate of blood coagulation When dopamine acts on body cells that respond to adren- 9. Increased rate and depth of respiration ergic stimulation, it can activate alpha1 and beta1 receptors as 10. Only dopamine can activate 264 SECTION 3 DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM (1) Epinephrine ("first messenger") Outside cell (2) (3) Beta Plasma receptor membrane of cell ATP (4) Inside cell GTP cAMP "second messenger" (5) Phosphorylates (activates) enzymes in target tissue (6) Produces physiologic responses to epinephrine Liver Heart Smooth Fatty muscle tissue Increased heart rate Glycogenolysis Increased force Gluconeogenesis Relaxation Lipolysis of contraction Increased automaticity Increased AV conduction Figure 17–3 Signal transduction mechanism for an adrenergic beta receptor. Epinephrine (1), the first mes- senger, interacts with a beta receptor (2). This hormone-receptor complex activates a G protein, which reacts with a guanosine triphosphate (GTP) (3). The activated G protein then activates the enzyme adenyl cyclase, which (4) catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), the sec- ond messenger. Dopamine receptors are located in • Alpha1 receptors: the binding of adrenergic substances the brain, in blood vessels of the kidneys and other viscera, and to receptor proteins in the cell membrane of smooth probably in presynaptic sympathetic nerve terminals. Activa- muscle cells is thought to open ion channels, allow cal- tion (agonism) of these receptors may result in stimulation or cium ions to move into the cell, and produce muscle inhibition of cellular function. Like alpha and beta receptors, contraction (eg, vasoconstriction, gastrointestinal and dopamine receptors are divided into several subtypes (D1 to bladder sphincter contraction). D5), and specific effects depend on which subtype of receptor • Alpha2 receptors: In the brain, some of the norepineph- is activated. Table 17–1 describes the location of adrenergic rine released into the synaptic cleft between neurons re- receptors in the body and the response that occurs when each turns to the nerve endings from which it was released receptor is stimulated. This nega- the intracellular events (of signal transduction) after stim- tive feedback causes less norepinephrine to be released ulation of adrenergic receptors are thought to include the fol- by subsequent nerve impulses. The result is decreased lowing mechanisms: sympathetic outflow and an antiadrenergic effect. The CHAPTER 17 PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM 265 the number and the binding activity of receptors is dy- TABLE 17–1 Adrenergic Receptors namic and may be altered. These phenomena are most clearly Type Location Effects of Stimulation understood with beta receptors. For example, when chroni- cally exposed to high concentrations of substances that stim- Alpha1 Blood vessels Vasoconstriction Kidney Decreased renin ulate their function, the receptors decrease in number and secretion become less efficient in stimulating adenyl cyclase. The re- Intestinal smooth muscle Relaxation sulting decrease in beta-adrenergic responsiveness is called Liver Glycogenolysis, gluco- desensitization or down-regulation of receptors.

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Another leads to osmotic diuresis and resultant thirst blood pressure medication restless leg syndrome purchase discount labetalol on-line, polyuria heart attack film labetalol 100 mg purchase visa, dehydra- attempt to remove excess acid involves the lungs pulse pressure pediatrics 100 mg labetalol order mastercard. Deep, labored tion, and electrolyte losses, as well as neurologic signs ranging respirations, called Kussmaul respirations, eliminate more carbon from drowsiness to stupor to coma. Additional clinical problems dioxide and prevent formation of carbonic acid. A third attempt to may include hypovolemic shock, thrombosis, renal problems, or regain homeostasis involves the kidneys, which excrete some of stroke. In contrast to DKA, hyperosmolar coma occurs in people the ketones, thereby producing acetone in the urine. Clinical occurs in hyperglycemic conditions other than diabetes (eg, severe signs and symptoms become progressively more severe. Pork insulin is contraindicated in clients given only parenterally, most often SC. They are Pork insulin differs from human insulin by one amino usually categorized as short, intermediate, or long act- acid. Short-acting insulins have a rapid onset and a with recombinant DNA techniques using strains of short duration of action. Intermediate- and long-acting Escherichia coli or by modifying pork insulin to replace insulins (except for insulin glargine) are modified by the single different amino acid. The name human insulin adding protamine (a large, insoluble protein), zinc, or means that the synthetic product is identical to endoge- both to slow absorption and prolong drug action. Sev- nous insulin (ie, has the same number and sequence of eral mixtures of an intermediate- and a short-acting in- amino acids). Insulin analogs are synthesized in the laboratory by • U-100, the main insulin concentration in the United altering the type or sequence of amino acids in insulin States, contains 100 units of insulin per milliliter of so- molecules. It can be accurately measured only in a syringe (Novolog) are short-acting products. Absorption is delayed or decreased half-life after subcutaneous (SC) injection than regular by injection into SC tissue with lipodystrophy or other human insulin. As a result, it is similar to physiologic lesions, by circulatory problems such as edema or hypo- insulin secretion after a meal, more effective at de- tension, by insulin-binding antibodies (which develop creasing postprandial hyperglycemia, and less likely to after 2 or 3 months of insulin administration), and by in- cause hypoglycemia before the next meal. In- those of an injection of conventional regular insulin sulin retains potency up to 36 months under refrigera- given 30 minutes before a meal. If frozen, insulin clumps or to provide a basal amount of insulin through 24 hours, precipitates, cannot be measured accurately, and should similar to normal, endogenous insulin secretion. CHAPTER 27 ANTIDIABETIC DRUGS 387 Drugs at a Glance: Insulins Action (h) Routes and Generic/Trade Name Characteristics Dosage Ranges Onset Peak Duration Short-acting Insulin Insulin injection 1. A clear liquid solution with the SC, dosage individualized according to 1⁄ –1 2–3 5–7 2 (Regular Iletin II, appearance of water blood glucose levels. The hypoglycemic drug of choice for scale, 5–20 units before meals and diabetics experiencing acute or bedtime, depending on blood glu- emergency situations, diabetic cose levels ketoacidosis, hyperosmolar non- IV, dosage individualized. For ketoaci- ketotic coma, severe infections or dosis, regular insulin may be given other illnesses, major surgery, and by direct injection, intermittent infu- pregnancy sion, or continuous infusion. The only insulin preparation that regimen involves an initial bolus in- can be given IV jection of 10–20 units followed by a continuous low-dose infusion of 2–10 units/h, based on hourly blood and urine glucose levels Intermediate-acting Insulins Isophane insulin 1. Initially, 1–11⁄ 8–12 18–24 2 suspension administration 7–26 units may be given once or (NPH, NPH Iletin II, 2. A suspension with a cloudy appear- ance when correctly mixed in the drug vial 4. Hypoglycemic reactions are more likely to occur during mid-to-late afternoon Insulin zinc suspension 1. May be used interchangeably with 7–26 units may be given once or Humulin L, Novolin L) NPH insulin twice daily. A suspension with a cloudy appear- ance when correctly mixed in the drug vial 4. Initially, 4–8 10–30 36 plus suspension mation of large crystals, which are 7–26 units may be given once daily (Humulin U, Ultralente) slowly absorbed 2. Onset, peak, and duration of action 70/30, Novolin 70/30) same as individual components NPH 50% See Humulin 70/30, above SC, dosage individualized Regular 50% (Humulin 50/50) Insulin Analogs Insulin lispro (Humalog) 1. A synthetic insulin of recombinant SC, dosage individualized, 15 min 1⁄ 1⁄ –11⁄ 6–8 4 2 2 DNA origin, created by reversing two before meals amino acids 2. Has a faster onset and a shorter duration of action than human regu- lar insulin 3.

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Deficient hormone in adults (less than expected for age) can Posterior Pituitary Hormones cause increased fat blood pressure chart for male and female purchase labetalol 100 mg with mastercard, reduced skeletal and heart muscle mass blood pressure chart lower number buy line labetalol, re- duced strength pulmonary hypertension xanax order genuine labetalol online, reduced ability to exercise, and worsened cho- the posterior pituitary gland stores and releases two hormones lesterol levels (ie, increased low-density lipoprotein [LDL] that are synthesized by nerve cells in the hypothalamus. When ADH is secreted, Excessive growth hormone in preadolescent children pro- it makes renal tubules more permeable to water. This allows duces gigantism, resulting in heights of 8 or 9 feet if untreated. In the absence of ADH, little water is which distorts facial features and is associated with an in- reabsorbed, and large amounts are lost in the urine. Antidiuretic hormone is secreted when body fluids become Thyrotropin (also called TSH) regulates secretion of thy- concentrated (high amounts of electrolytes in proportion to the roid hormones. Thyrotropin secretion is controlled by a neg- amount of water) and when blood volume is low. FSH, one of the gonadotropins, stimulates functions of sex Oxytocin functions in childbirth and lactation. It is produced by the anterior pituitary gland of both uterine contractions at the end of gestation to induce child- sexes, beginning at puberty. FSH acts on the ovaries in a cycli- birth, and it causes milk to move from breast glands to nipples cal fashion during the reproductive years, stimulating growth so the infant can obtain the milk by suckling. These follicles then produce estrogen, which prepares the endometrium for implantation of a fertil- ized ovum. FSH acts on the testes to stimulate the production THERAPEUTIC LIMITATIONS and growth of sperm (spermatogenesis), but it does not stimu- late secretion of male sex hormones. Drug preparations of FSH There are few therapeutic uses for hypothalamic hormones include urofollitropin (Fertinex), follitropin alfa (Gonal-F), and pituitary hormones. Pituitary hormones late ovarian function in the treatment of infertility. In women, LH is important in the mones (eg, corticosteroids, thyroid hormones, male or female maturation and rupture of the ovarian follicle (ovulation). However, the hormones perform impor- during the last half of the menstrual cycle. When blood pro- tant functions when used in particular circumstances, and gesterone levels rise, a negative feedback effect is exerted on drug formulations of most hormones have been synthesized hypothalamic and anterior pituitary secretion of gonadotropins. Indications for use, Growth hormone is synthesized from bacteria by recom- routes, and dosage ranges are listed in Drugs at a Glance: binant DNA technology. The main clinical use of the drugs is for children whose growth is im- Hypothalamic Hormones paired by a deficiency of endogenous hormone. The drugs are ineffective when impaired growth results from other causes or Gonadorelin (Factrel), goserelin (Zoladex), histrelin (Sup- after puberty, when epiphyses of the long bones have closed. After initial stimulation of LH and FSH secretion, (a genetic disorder that occurs in girls). In adults, the drugs chronic administration of therapeutic doses inhibits gona- may be used to treat deficiency states (eg, those caused by dotropin secretion. This action results in decreased produc- disease, surgery, or radiation of the pituitary gland) or the tis- tion of testosterone and estrogen, which is reversible when sue wasting associated with acquired immunodeficiency syn- drug administration is stopped. In general, dosage should be individualized according duced to castrate levels. Excessive administration can cause excessive are reduced to postmenopausal levels. In children Human chorionic gonadotropin (HCG; Chorex, others) with central precocious puberty (CPP), gonadotropins (testos- produces physiologic effects similar to those of the naturally terone in males, estrogen in females) are reduced to prepu- occurring LH. In women, HCG is jection and are available in depot preparations that can be used in combination with menotropins to induce ovulation in given once monthly or less often. Excessive doses or prolonged ad- cally those of testosterone or estrogen deficiency. When ministration can lead to sexual precocity, edema, and breast en- given for prostate cancer, the drugs may cause increased largement caused by oversecretion of testosterone and estrogen.

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Stud- volumetric bone mineral density of trabecular bone [32 blood pressure chart jnc labetalol 100 mg purchase without a prescription, ies have reported good correlation between bone mineral 46] blood pressure 8855 labetalol 100 mg low price, but has poor precision due to increasing fat content in density blood pressure 7545 100 mg labetalol buy mastercard, as measured by DXA, and vertebral body failure the marrow of older patients. There is a higher risk factor of fracture for a sim- nologist-dependent, with high variability depending on the ilar load as the bone density decreases. It has twenty times the radiation studies have demonstrated that low bone mineral density of a DXA scan, and its current use is mainly in the re- is associated with increased fracture rates for the spine [66]. Consequently, raloxifene has been shown to be an ef- fective anti-resorptive agent in the treatment of osteoporo- Laboratory studies used to assess quality and quantity of sis [24]. Post-menopausal use decreases vertebral frac- bone tissue in the spine are centered on bone marrow ab- tures by approximately 40% and increases spinal bone normalities (complete blood count, sedimentation rate, mass [92]. Unfortunately, similar protective effects have serum and urine immunoelectrophoresis); endocrinopathies not been demonstrated in preventing hip fractures [20, (hyperthyroidism, hyperparathyroidism, type I diabetes mel- 24]. However, by stimulating estrogen hormone, serum calcium and serum phosphate) [4, 94]. In light of the tide, pyridinoline peptide, dehydroxypyridinoline peptide, fact that it has no protection against hip fractures, raloxifene or serum c-terminal peptide. These markers identify ele- is not considered a primary treatment for osteoporosis. There are some controversial data suggesting that calcitonin may relieve bone pain through an unknown mechanism. Its current Treatment modalities use is in alleviating painful vertebral fractures as a conse- quence of osteoporosis, and only as a secondary antiresorp- Osteoporosis has been divided into high-turnover and low- tive agent. The most common form is high- controlled, as other agents are much more successful. Bone formation is compromised both oral agents, and zolendronic acid and pamidronate, in low-turnover osteoporosis. These agents have been shown to be have been suggested and developed to address the high- extremely efficacious in high-turnover osteoporosis [43]. Although calcium and vitamin D They increase bone mass at all measurable sites and de- are not considered anti-resorptive agents, approximately crease fracture incidence by 50%, including in the spine half of patients presenting at hospitals with hip fractures and the hip [7, 18, 57]. Reported side effects of oral bis- in the elderly population, primarily by reversing secondary phosphonates include esophagitis and indigestion, but the hyperparathyroidism [19. Intravenous shown to increase bone mass while effecting a decrease of therapies, while not tested specifically for treatment in os- vertebral fracture incidence by approximately 50% [54, teoporosis, appear to be efficacious, and once yearly zole- 60]. Unfortunately, estrogen in combination with proges- dronate (Zometa) infusions appear to be just as effective terone therapy is associated with increased cardiovascular as the oral dose of alendronate regarding bone mass [22]. As a consequence, estrogen is mainly Bisphosphonates decrease bone turnover, and in very used in the early post-menopausal period to treat post- high dosages in canine models have been shown to cause menopausal symptomatology, and then lowered to the least fatigue fractures that are not actively repaired. It is no indicate that patients on alendronate for 10 years have an longer recommended by the US Federal Government for 8. Patients stopping alendronate therapy after agents which have a significant anti-estrogen effect on 5 years retain the decreased fracture risk. However, osteoblasts are preferentially stim- that bisphosphonates remain active for extended periods ulated by SERMs and upregulate the rate of bone forma- once the bone surface has been coated. The half-lives of 68 alendronate and risedronate are at least 10 years and 1. Therapeu- somewhat delayed, the ultimate mechanical strength of the tic medications do not completely eliminate fractures, and repaired bone was unchanged compared to the controls [84]. Overall, bisphosphonates are critical factor in fracture prevention [81, 98]. Fall history extremely effective in the prevention of osteoporotic fragility can be determined through a complete patient interview, fractures. In addition, bisphosphonates are just as efficacious as can the inability to rise from a chair without using the in men as in women [1, 35, 78], and are particularly effec- hands, poor eye sight and neuromuscular impairment. Another easily administered and highly informative protection is afforded by the avoidance of significant bone test is the heel-toe straight line walk. However, in low-turnover osteoporosis, the pri- the etiology for increased falls, a wide variety of factors mary disturbance is ineffective osteoblast activity. Anabolic must be considered, including neurologic, metabolic, oph- agents lead to bone mass accretion at a high rate.

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