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Demeclocycline is used more often than lithium because of the many side effects of lithium administration menstruation vs ovulation purchase 50 mg danazol free shipping. However menstrual napkins generic danazol 200mg with visa, demeclocycline is now being rapidly replaced by several specific ADH receptor antagonists (vaptans) pregnancy ovulation cheap danazol online, which have yielded encouraging clinical results pregnancy 4th week purchase generic danazol from india. V1 receptors are expressed in the vasculature and CNS, while V2 receptors are expressed specifically in the kidney. Conivaptan (currently available only for intravenous use) exhibits activity against both V1a and V2 receptors (see below). The oral agents tolvaptan, lixivaptan, and satavaptan are selectively active against the V2 receptor. Lixivaptan and satavaptan are still under clinical investigation, but tolvaptan, which recently received Food and Drug Administration approval, is very effective in treatment of hyponatremia and as an adjunct to standard diuretic therapy in patients with CHF. Pharmacodynamics Antidiuretic hormone antagonists inhibit the effects of ADH in the collecting tubule. Conivaptan and tolvaptan are direct ADH receptor antagonists, while both lithium and demeclocycline reduce ADH-induced cAMP by mechanisms that are not yet completely clarified. This generally occurs in the outpatient setting, where water restriction cannot be enforced, but can occur in the hospital when large quantities of intravenous fluid are needed for other purposes. Appropriate plasma levels of demeclocycline (2 mcg/mL) should be maintained by monitoring, but tolvaptan levels are not routinely monitored. Unlike demeclocycline or tolvaptan, conivaptan is administered intravenously and is not suitable for chronic use in outpatients. Other Causes of Elevated Antidiuretic Hormone Antidiuretic hormone is also elevated in response to diminished effective circulating blood volume, as often occurs in heart failure. Their renal action appears to be mediated primarily via V2 ADH receptors, although V1a receptors may also be involved. In patients with heart failure, this approach is often unsuccessful in view of increased thirst and the large number of oral medications being used. For patients with heart failure, intravenous conivaptan may be particularly useful because it has been found that the blockade of V1a receptors by this drug leads to decreased peripheral vascular resistance and increased cardiac output. The combination of loop diuretics and thiazides can mobilize large amounts of fluid, even in patients who have not responded to single agents. Furthermore, + + K wasting is extremely common and may require parenteral K administration with careful monitoring of fluid and electrolyte status. Nephrogenic Diabetes Insipidus If serum Na+ is not monitored closely, any ADH antagonist can cause severe hypernatremia and nephrogenic diabetes insipidus. If lithium is being used for a psychiatric disorder, nephrogenic diabetes insipidus can be treated with a thiazide diuretic or amiloride (see Diabetes Insipidus, below). Renal Failure Both lithium and demeclocycline have been reported to cause acute renal failure. Multiple adverse effects associated with lithium therapy have been found and are discussed in Chapter 29. Demeclocycline should be avoided in patients with liver disease (see Chapter 44) and in children younger than 12 years. This can usually be managed by dietary NaCl restriction or by taking dietary KCl supplements. When hypokalemia cannot be managed in this way, the addition of a K+-sparing diuretic can significantly lower K+ excretion. Although this approach is generally safe, it should be avoided in patients with renal insufficiency and in those receiving angiotensin antagonists such as ACE inhibitors, in whom life-threatening hyperkalemia can develop in response to K+-sparing diuretics. It is not yet known whether adenosine receptor antagonists, which are K+-sparing diuretics (but which act primarily in the proximal tubule), will cause hyperkalemia. Renal Na+ retention may be greatly increased during the time period when the drug is no longer active. After the dosing interval for loop agents is minimized or the dose is maximized, the use of two drugs acting at different nephron sites may exhibit dramatic synergy. Loop agents and thiazides in combination often produce diuresis when neither agent acting alone is even minimally effective. First, salt reabsorption in either the TAL or the DCT can increase when the other is blocked. Second, thiazide diuretics often produce a mild natriuresis in the proximal tubule that is usually masked by increased reabsorption in the TAL. The + combination of loop diuretics and thiazides can therefore block Na reabsorption, to some extent, from all three segments. Metolazone is the thiazide-like drug usually used in patients refractory to loop agents alone, but it is likely that other thiazides would be as effective. Moreover, metolazone is available only in an oral preparation, whereas chlorothiazide can be given parenterally. This reduction is sensed as insufficient effective arterial blood volume and leads to salt and water retention, which expands blood volume and eventually causes edema formation. Judicious use of diuretics can mobilize this interstitial edema without significant reductions in plasma volume. However, excessive diuretic therapy may compromise the effective arterial blood volume and reduce the perfusion of vital organs. If the underlying disease causes cardiac output to deteriorate despite expansion of plasma volume, the kidney continues to retain salt and water, which then leaks from the vasculature and becomes interstitial or pulmonary edema. At this point, diuretic use becomes necessary to reduce the accumulation of edema, particularly in the lungs.

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Although cardioselectivity is not complete menstruation uterine lining cheap 100 mg danazol fast delivery, metoprolol causes less bronchial constriction than propranolol at doses that produce equal inhibition of 1-adrenoceptor responses menopause gifts 50mg danazol visa. Sustained-release metoprolol is effective in reducing mortality from heart failure and is particularly useful in patients with hypertension and heart failure pregnancy journal book purchase danazol master card. 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 menstruation blood cheap danazol master card. Recent studies have found atenolol 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. Dosing is generally started at 5 mg/d, with dose escalation as high as 40 mg, if necessary. The efficacy of nebivolol is similar to that of other antihypertensive agents, but several studies report fewer adverse effects. 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. 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. 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. Mechanism Release of nitric oxide from drug or endothelium Reduction of calcium influx Hyperpolarization of smooth muscle membrane through opening of potassium channels Activation of dopamine receptors 1 Toxicity the most common adverse effects of hydralazine are headache, nausea, anorexia, palpitations, sweating, and flushing. 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. Examples Nitroprusside, hydralazine, 1 nitrates, histamine, acetylcholine Verapamil, diltiazem, nifedipine Minoxidil, diazoxide Fenoldopam See Chapter 12. 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. The effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely. Because of its greater potential antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe hypertension, who do not respond well to hydralazine.

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Note that IL-1 stimulates the production of chemokines and other cytokines from a variety of cells menopause in men symptoms cheap danazol online master card. Acute arthritis is characterized by a dense neutrophilic infiltrate that permeates the synovium and synovial fluid womens health 012013 pl cheap generic danazol canada. Slender women's health center gainesville fl 100mg danazol visa, Calcium Pyrophosphate Crystal Deposition Disease (Pseudogout) Calcium pyrophosphate crystal deposition disease (CPPD) menstrual questionnaire generic danazol 200mg otc, also known as pseudogout, usually occurs in individuals older than 50 years of age and becomes more common 1206 C H A P T E R 26 Bones, Joints, and Soft Tissue Tumors with increasing age; up to 60% of those 85 years of age or older are affected. An autosomal dominant variant is caused by germline gain-of-function mutations in ANKH, an inorganic pyrophosphate transporter, that result in crystal deposition and osteoarthritis at relatively early ages. These mutations are distinct from those associated with craniometaphyseal dysplasia. Various disorders, including previous joint damage, hyperparathyroidism, hemochromatosis, hypomagnesemia, hypothyroidism, ochronosis, and diabetes predispose to secondary CPPD. Pathogenesis A the basis for crystal formation is not known, but studies suggest that degradation of articular cartilage proteoglycans, which normally inhibit mineralization, allows crystallization around chondrocytes. As in gout, inflammation is caused by activation of the inflammasome in macrophages. The crystals form chalky, white friable deposits, which are seen histologically in stained preparations as oval blue-purple aggregates. However, it may produce acute, subacute, or chronic arthritis that can be confused with osteoarthritis or rheumatoid arthritis clinically. Joint involvement may last from several days to weeks and may be monoarticular or polyarticular; the knees, followed by the wrists, elbows, shoulders, and ankles, are most commonly affected. Chondrocalcinosis, radiographically evident calcification of hyaline or fibrocartilage, is often present but is not synonymous with CPPD. Ultimately, approximately 50% of affected individuals experience significant joint damage. Inflammation is minimal and typically secondary, but locally produced cytokines may contribute to progression of joint degeneration. RA is caused by a cellular and humoral immune response against self antigens, particularly citrullinated proteins. A common location is around the joints of the wrist, where the cysts appear as firm, fluctuant, pea-sized translucent nodules. Ganglion cysts develop due to cystic or myxoid connective tissue degeneration; hence the cyst wall lacks a cell lining. Lesions may be multilocular and can enlarge through coalescence and degeneration of adjacent connective tissue. The fluid that fills ganglion cysts is similar to synovial fluid, but there is no communication with the joint space. Herniation of synovium through a joint capsule or massive enlargement of a bursa may produce a synovial cyst. A wellrecognized example is the popliteal synovial cyst, or Baker cyst, associated with rheumatoid arthritis. The cyst lining resembles the synovium, and both cyst and synovium may be hyperplastic. A Tenosynovial Giant Cell Tumor Tenosynovial giant cell tumor is a benign neoplasm that develops in the synovial lining of joints, tendon sheaths, and bursae. Tenosynovial giant cell tumor can be diffuse (previously known as pigmented villonodular synovitis) or localized. The diffuse type tends to involve large joints, while the localized type usually occurs as a discrete nodule attached to a tendon sheath, commonly in the hand. Both variants are most often diagnosed in the 20s to 40s and affect the sexes equally. Pathogenesis Both diffuse and localized tenosynovial giant cell tumors harbor a reciprocal somatic chromosomal translocation, t(1;2) (p13;q37), resulting in fusion of the type VI collagen -3 promoter upstream of the coding sequence of the MCSF gene. As a result, the tumor cells overexpress M-CSF, which, through autocrine and paracrine effects, stimulates proliferation of macrophages in a manner similar to giant cell tumor of bone (described earlier). Reactive arthritis is an uncommon immune-mediated disorder that develops after resolution of genitourinary or gastrointestinal infection. In diffuse tumors, the normally smooth joint synovium is converted into a tangled mat by red-brown folds, fingerlike projections, and nodules. The neoplastic cells, which are a minority of the cells in the mass, are polygonal, moderately sized, and resemble synoviocytes. In the diffuse variant, they spread along the surface and infiltrate the subsynovial tissue. Both diffuse and localized types are densely infiltrated by macrophages that may contain hemosiderin or foamy lipids and can be multinucleated. They usually result from trauma or degenerative processes and are much more common than neoplasms. Primary neoplasms are rare, usually benign, and tend to recapitulate the cells and tissue types (synovial 1208 C H A P T E R 26 Bones, Joints, and Soft Tissue Tumors A B Figure 26. Clinical Features Diffuse tenosynovial giant cell tumors present in the knee in 80% of cases. Affected individuals complain of pain, locking, and recurrent swelling, similar to monoarticular arthritis. Aggressive tumors erode into adjacent bones and soft tissues, causing confusion with other types of neoplasms. Localized tenosynovial giant cell tumors present as a solitary, slow-growing, painless mass that frequently involves the tendon sheaths along the wrists and fingers. Soft Tissue Tumors By convention, soft tissue refers to non-epithelial tissue excluding the skeleton, joints, central nervous system, and hematopoietic and lymphoid tissues.

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Remodeling is the term applied to dilation (other than that due to passive stretch) and other slow structural changes that occur in the stressed myocardium menstrual tracker app generic danazol 50mg. It may include proliferation of connective tissue cells as well as abnormal myocardial cells with some biochemical characteristics of fetal myocytes breast cancer walk in chicago discount 50 mg danazol with visa. Ultimately 5 menstrual weeks order danazol 200mg on line, myocytes in the failing heart die at an accelerated rate through apoptosis women's health clinic lansing mi buy cheapest danazol and danazol, leaving the remaining myocytes subject to even greater stress. The ascending limb (< 15 mm Hg filling pressure) represents the classic Frank-Starling relation described in physiology texts. As noted above, preload is usually increased in heart failure because of increased blood volume and venous tone. Because the function curve of the failing heart is lower, the plateau is reached at much lower values of stroke work or output. Increased fiber length or filling pressure increases oxygen demand in the myocardium, as described in Chapter 12. Reduction of high filling pressure is the goal of salt restriction and diuretic therapy in heart failure. Venodilator drugs (eg, nitroglycerin) also reduce preload by redistributing blood away from the chest into peripheral veins. Afterload: Afterload is the resistance against which the heart must pump blood and is represented by aortic impedance and systemic vascular resistance. This sets the stage for the use of drugs that reduce arteriolar tone in heart failure. Contractility: Heart muscle obtained by biopsy from patients with chronic low-output failure demonstrates a reduction in intrinsic contractility. However, the heart is usually still capable of some increase in all of these measures of contractility in response to inotropic drugs. In heart failure, function is shifted down and to the right, through points 1 and 2, finally reaching point B. A "pure" positive inotropic drug (+ Ino) would move the operating point upward by increasing cardiac stroke work. As the intrinsic function of the heart decreases in failure and stroke volume diminishes, an increase in heart rate- through sympathetic activation of adrenoceptors-is the first compensatory mechanism that comes into play to maintain cardiac output. Chemistry All of the cardiac glycosides, or cardenolides-of which digoxin is the prototype-combine a steroid nucleus linked to a lactone ring at the 17 position and a series of sugars at carbon 3 of the nucleus. Because they lack an easily ionizable group, their solubility is not pH-dependent. Digoxin is obtained from Digitalis lanata, the white foxglove, but many common plants (eg, oleander, lily of the valley, and milkweed) contain cardiac glycosides with similar properties. The fact that a receptor for cardiac glycosides exists on the sodium pump has prompted some investigators to propose that an endogenous digitalis-like steroid, possibly ouabain or marinobufagenin, must exist. Furthermore, additional functions of Na+/K+-ATPase have been postulated, involving apoptosis, cell growth and differentiation, immunity, and carbohydrate metabolism. Mechanical effects-Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free calcium concentration in the vicinity of the contractile proteins during systole. In isolated myocardial preparations, the rate of development of tension and of relaxation are both increased, with little or no change in time to peak tension. This effect occurs in both normal and failing myocardium, but in the intact patient the responses are modified by cardiovascular reflexes and the pathophysiology of heart failure. Electrical effects-The effects of digitalis on the electrical properties of the heart are a mixture of direct and autonomic actions. Direct actions on the membranes of cardiac cells follow a well-defined progression: an early, brief prolongation of the action potential, followed by shortening (especially the plateau phase). The decrease in action potential duration is probably the result of increased potassium conductance that is caused by increased intracellular calcium (see Chapter 14). At higher concentrations, resting membrane potential is reduced (made less negative) as a result of inhibition of the sodium pump and reduced intracellular potassium. The afterpotentials (also known as delayed after-depolarizations, DADs) are associated with overloading of the intracellular calcium stores and oscillations in the free intracellular calcium ion concentration. When afterpotentials reach threshold, they elicit action potentials (premature depolarizations, ectopic "beats") that are coupled to the preceding normal action potentials.

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