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Urotensin Chatenet D et al: Update on the urotensinergic system: New trends in receptor localization buy celebrex toronto rheumatoid arthritis chemo, activation 100mg celebrex amex arthritis treatment legs, and drug design order celebrex from india rheumatoid arthritis organization. General Hoyer D buy 200 mg celebrex otc dog arthritis medication metacam, Bartfai T: Neuropeptides and neuropeptide receptors: Drug targets, and peptide and non-peptide ligands: A tribute to Prof. Since converting enzyme also inactivates bradykinin, enalapril increases bradykinin levels, and this is responsible for adverse side effects such as cough and angioedema. They are ubiquitous in the animal kingdom and are also found—together with their precursors—in a variety of plants. They constitute a very large family of compounds that are highly potent and display an extraordinarily wide spectrum of biologic activity. Because of their biologic activity, the eicosanoids, their specific receptor antagonists and enzyme inhibitors, and their plant and fish oil precursors have great therapeutic potential. Among factors determining the type of eicosanoid synthesized are (1) the substrate lipid species, (2) the type of cell, and (3) the manner in which the cell is stimulated. This shift in product formation is the basis for dietary manipulation of eicosanoid generation using fatty acids obtained from cold-water fish or from plants as nutritional supplements in humans. The hypothesis that dietary eicosapentaenoate substitution for arachidonate could reduce the incidence of cardiovascular disease and cancer remains controversial. This distinction is overly simplistic, however; there are both physiologic and pathophysiologic processes in which each enzyme is uniquely involved and others in which they function coordinately. These terminal enzymes are expressed in a relatively cell- specific fashion, such that most cells make one or two dominant prostanoids. The inactive metabolites are chemically stable and can be quantified in blood and urine by immunoassay or mass spectrometry as a measure of the in vivo synthesis of their parent compounds. This pathway is of great interest since it is associated with asthma, anaphylactic shock, and cardiovascular disease. Although these compounds can be formed from endogenous substrates in vitro and when synthesized may have potent biologic effects, the importance of the endogenous compounds in vivo in human biology remains ill defined. Proinflammatory effects of synthetic hepoxilins have been reported although their biologic relevance is unclear. Their biosynthesis can be altered by pharmacologic, nutritional, and genetic factors that affect P450 expression. This results in smooth muscle cell hyperpolarization and vasodilation, leading to reduced blood pressure. Because prostaglandins have many asymmetric centers, they have a large number of potential stereoisomers. They have potent vasoconstrictor effects when infused into renal and other vascular beds and may activate prostanoid receptors. They also may modulate other aspects of vascular function, including leukocyte and platelet adhesive interactions and angiogenesis. A particular difficulty in assessing the likely biologic functions of isoprostanes—several of which have been shown to serve as incidental ligands at prostaglandin receptors—is that while high concentrations of individual isoprostanes may be necessary to elicit a response, multiple compounds are formed coincidentally in vivo under conditions of oxidant stress. These ligands bind to receptors on the cell surface, and pharmacologic specificity is determined by receptor density and type on different cells (Figure 18–4). Receptor heterodimerization has been reported for a number of the eicosanoid receptors, providing for additional receptor subtypes from the currently identified gene products. All of these receptors are G protein- coupled; properties of the best-studied receptors are listed in Table 18–1. The terms “relaxant,” “contractile,” and “inhibitory” refer to the phylogenetic characterization of their primary effects. Specific receptors for isoprostanes have not been identified, and the biologic importance of their capacity to act as incidental ligands at prostaglandin receptors remains to be established. Effects of Prostaglandins & Thromboxanes The prostaglandins and thromboxanes have major effects on smooth muscle in the vasculature, airways, and gastrointestinal and reproductive tracts. Many of the eicosanoids’ contractile effects on smooth muscle can be inhibited by lowering extracellular calcium or by using calcium channel-blocking drugs. Other important targets include platelets and monocytes, kidneys, the central nervous system, autonomic presynaptic nerve terminals, sensory nerve endings, endocrine organs, adipose tissue, and the eye (the effects on the eye may involve smooth muscle). It is also a smooth muscle cell mitogen and is the only eicosanoid that has2 convincingly been shown to have this effect. Gastrointestinal tract—Most of the prostaglandins and thromboxanes activate gastrointestinal smooth muscle. They act principally on smooth muscle in peripheral airways and are a thousand times more potent than histamine, both in vitro and in vivo. Reproductive—The actions of prostaglandins on reproductive smooth muscle are discussed below under section D, Reproductive Organs. Activation of G2 12/G13 induces Rho/Rho-kinase– dependent regulation of myosin light chain phosphorylation leading to platelet shape change. Kidney Both the medulla and the cortex of the kidney synthesize prostaglandins, the medulla substantially more than the cortex. The kidney also synthesizes2 several hydroxy-eicosatetraenoic acids, leukotrienes, cytochrome P450 products, and epoxides. Prostaglandins play important roles in maintaining blood pressure and regulating renal function, particularly in marginally functioning kidneys and volume-contracted states. These prostaglandins also modulate systemic blood pressure through regulation of water and sodium excretion. This elevates glomerular filtration rate and contributes to enhanced sodium reabsorption and a rise in blood pressure. The effects of prostaglandins on uterine function are discussed below (see Clinical Pharmacology of Eicosanoids). Male reproductive organs—Despite the discovery of prostaglandins in seminal fluid, and their uterotropic effects, the role of prostaglandins in semen is still conjectural. The major source of these prostaglandins is the seminal vesicle; the prostate, despite the name “prostaglandin,” and the testes synthesize only small amounts. The factors that regulate the concentration of prostaglandins in human seminal plasma are not known in detail, but testosterone does promote prostaglandin production. Both markedly enhance edema formation2 2 and leukocyte infiltration by promoting blood flow in the inflamed region. These effects likely contribute to immune escape in tumors where infiltrating myeloid-derived cells predominantly display type 2 phenotypes. Bone Metabolism Prostaglandins are abundant in skeletal tissue and are produced by osteoblasts and adjacent hematopoietic cells. Prostaglandins may mediate the effects of mechanical forces on bones and changes in bone during inflammation. The mechanism of this action is unclear but probably involves increased outflow of aqueous humor from the anterior chamber via the uveoscleral pathway (see Clinical Pharmacology of Eicosanoids).
Kidney Stones Triamterene is only slightly soluble and may precipitate in the urine buy 200 mg celebrex visa arthritis relief using gelatin, causing kidney stones discount 100mg celebrex facet arthritis definition. Contraindications Potassium-sparing agents can cause severe buy cheap celebrex 200 mg on line zyrtec arthritis pain, even fatal discount celebrex 200 mg on line arthritis ear pain, hyperkalemia in susceptible patients. Patients with chronic renal + insufficiency are especially vulnerable and should rarely be treated with these diuretics. Patients with liver disease may have impaired metabolism of triamterene and spironolactone, so dosing must be carefully adjusted. Any osmotically active agent that is filtered by the glomerulus but not reabsorbed causes water to be retained in these segments and promotes a water diuresis. Such agents can be used to reduce intracranial pressure and to promote prompt removal of renal toxins. Glucose is not used clinically as a diuretic but frequently causes osmotic diuresis (glycosuria) in patients with hyperglycemia. Mannitol is not metabolized and is excreted by glomerular filtration within 30–60 minutes, without any important tubular reabsorption or secretion. Pharmacodynamics Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle’s loop. The presence of a nonreabsorbable solute such as mannitol prevents the normal absorption of water by interposing a countervailing osmotic force. The increase in urine flow decreases the contact time between fluid and the tubular epithelium, thus reducing Na as well as water reabsorption. The resulting natriuresis is of lesser magnitude than the water diuresis, leading eventually to excessive water loss and hypernatremia. Clinical Indications & Dosage Reduction of Intracranial and Intraocular Pressure Osmotic diuretics alter Starling forces so that water leaves cells and reduces intracellular volume. This effect is used to reduce intracranial pressure in neurologic conditions and to reduce intraocular pressure before ophthalmologic procedures. At times the rapid lowering of serum osmolality at initiation of dialysis (from removal of uremic toxins) results in symptoms. Many nephrologists also use mannitol to prevent adverse reactions when first starting patients on hemodialysis. Extracellular Volume Expansion Mannitol is rapidly distributed in the extracellular compartment and extracts water from cells. Dehydration, Hyperkalemia, and Hypernatremia Excessive use of mannitol without adequate water replacement can ultimately lead to severe dehydration, free water losses, + and hypernatremia. As water is extracted from cells, intracellular K concentration rises, leading to cellular losses and hyperkalemia. Hyponatremia When used in patients with severe renal impairment, parenterally administered mannitol cannot be excreted and is retained in the blood. Demeclocycline is used more often than lithium because of the many adverse effects of lithium administration. Pharmacokinetics The half-lives of conivaptan and demeclocycline are 5–10 hours, while that of tolvaptan is 12–24 hours. 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. 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. It is hypothesized that inhibition of V receptors in the kidney might delay the2 progression of polycystic kidney disease. In a large multicenter prospective trial, tolvaptan was able to reduce the increase in kidney size and slow progression of kidney failure over a three-year follow-up period. In this trial, however, the tolvaptan group experienced a 9% incidence of abnormal liver function test results compared with 2% in the placebo group. 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). 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. Since these + agents have a short half-life (2–6 hours), refractoriness may be due to an excessive interval between doses. 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. The combination of loop diuretics and + thiazides can therefore reduce 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. 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. When hypokalemia cannot be managed in this + + way, the addition of a K -sparing diuretic can significantly lower K excretion. 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. Therefore, the use of diuretics to mobilize edema requires careful monitoring of the patient’s hemodynamic status and an understanding of the pathophysiology of the underlying illness. This physiologic response initially increases intravascular volume and venous return to the heart and may partially restore the cardiac output toward normal (see Chapter 13).
Therefore buy cheap celebrex 100 mg online rheumatoid arthritis diet supplements, preparations have been developed with a range of durations of action from several hours (for daily administration) to 1 discount celebrex 100mg with mastercard arthritis pain formula commercial, 4 purchase celebrex 100 mg online arthritis for dogs symptoms, 6 purchase discount celebrex line arthritis diet prevention, or 12 months (depot forms). By the end of puberty, the system is well established so that menstrual cycles proceed at relatively constant intervals. During the first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females; this initial phase is referred to as a flare. When this approach is used, a portable battery-powered programmable pump and intravenous tubing deliver pulses of gonadorelin every 90 minutes. Male infertility—It is possible to use pulsatile gonadorelin for infertility in men with hypothalamic hypogonadotropic hypogonadism. This suppression is most commonly achieved by daily subcutaneous injections of leuprolide or daily nasal applications of nafarelin. For leuprolide, treatment is commonly initiated with 1 mg daily for about 10 days until menstrual bleeding occurs. For nafarelin, the beginning dosage is generally 400 mcg twice a day, which is decreased to 200 mcg when menstrual bleeding occurs. In women who respond poorly to the standard protocol, alternative protocols that use shorter courses may improve the follicular response to gonadotropins. Endometriosis—Endometriosis is defined as the presence of estrogen-sensitive endometrium outside the uterus that results in cyclical abdominal pain in premenopausal women. The pain of endometriosis is often reduced by abolishing exposure to the cyclical changes in the concentrations of estrogen and progesterone that are a normal part of the menstrual cycle. Uterine leiomyomata (uterine fibroids)—Uterine leiomyomata are benign, estrogen-sensitive, smooth muscle tumors in the uterus that can cause menorrhagia, with associated anemia and pelvic pain. The preferred formulation is one of the long-acting depot forms that provide 1, 3, 4, 6, or 12 months of active drug therapy. Such tumor flares can usually be avoided with the concomitant administration of an androgen receptor antagonist (flutamide, bicalutamide, or nilutamide) (see Chapter 40). Treatment is typically indicated in a child whose final height would be otherwise significantly compromised (as evidenced by a significantly advanced bone age) or in whom the early development of pubertal secondary sexual characteristics or menses causes significant emotional distress. Treatment is most commonly carried out with either a monthly or three-monthly intramuscular depot injection of leuprolide acetate or with a once-yearly implant of histrelin acetate. Ovarian cysts may develop within the first month of therapy due to its flare effect on gonadotropin secretion and generally resolve after an additional 6 weeks. Reduced bone mineral density and osteoporosis may occur with prolonged use, so patients should be monitored with bone densitometry before repeated treatment courses. However, temporary exacerbation of precocious puberty may occur during the first few weeks of therapy. Ganirelix and cetrorelix are approved for use in controlled ovarian stimulation procedures, whereas degarelix and abarelix are approved for men with advanced prostate cancer. The recommended dosage of abarelix is 100 mg administered intramuscularly every 2 weeks for three doses and every 4 weeks thereafter. They also appear to have a less suppressive effect on the ovarian response to gonadotropin stimulation, which permits a decrease in the total duration and dose of gonadotropin. On the other hand, because their antagonist effects reverse more quickly after their discontinuation, adherence to the treatment regimen is critical. Advanced Prostate Cancer Degarelix and abarelix are approved for the treatment of symptomatic advanced prostate cancer. During the treatment of men with prostate cancer, degarelix caused injection-site reactions and increases in liver enzymes. Milk production is stimulated by prolactin when appropriate circulating levels of estrogens, progestins, corticosteroids, and insulin are present. A deficiency of prolactin—which can occur in rare states of pituitary deficiency—is manifested by failure to lactate or by a luteal phase defect. In pituitary stalk section from surgery or head trauma, stalk compression due to a sellar mass, or rare cases of hypothalamic destruction, prolactin levels may be elevated as a result of impaired transport of dopamine (prolactin- inhibiting hormone) to the pituitary. These include antipsychotic and gastrointestinal motility drugs that are known dopamine receptor antagonists, estrogens, and opiates. Hyperprolactinemia causes hypogonadism, which manifests with infertility, oligomenorrhea or amenorrhea, and galactorrhea in premenopausal women, and with loss of libido, erectile dysfunction, and infertility in men. In the case of large tumors (macroadenomas), it can be associated with symptoms of a pituitary mass, including visual changes due to compression of the optic nerves. For patients with symptomatic hyperprolactinemia, inhibition of prolactin secretion can be achieved with dopamine agonists, which act in the pituitary to inhibit prolactin release. Bromocriptine and cabergoline are ergot derivatives (see Chapters 16 and 28) with a high affinity for dopamine D receptors. Bromocriptine has also been used in Parkinson’s disease to improve motor function and reduce levodopa requirements (see Chapter 28). Newer, nonergot D agonists used in2 Parkinson’s disease (pramipexole and ropinirole; see Chapter 28) have been reported to interfere with lactation, but they are not approved for use in hyperprolactinemia. Pharmacokinetics All available dopamine agonists are active as oral preparations, and all are eliminated by metabolism. Quinagolide has a half-life of about 20 hours, whereas the half-life of bromocriptine is about 7 hours. These drugs shrink pituitary prolactin- secreting tumors, lower circulating prolactin levels, and restore ovulation in approximately 70% of women with microadenomas and 30% of women with macroadenomas (Figure 37–4). It can be increased gradually, according to serum prolactin determinations, up to a maximum of 1 mg twice weekly. B: Complete success was defined as pregnancy or at least two consecutive menses with evidence of ovulation at least once. The most common reasons for withdrawal from the trial were nausea, headache, dizziness, abdominal pain, and fatigue. Physiologic Lactation Dopamine agonists were used in the past to prevent breast engorgement when breast-feeding was not desired. Their use for this purpose has been discouraged because of toxicity (see Toxicity & Contraindications). Acromegaly A dopamine agonist alone or in combination with pituitary surgery, radiation therapy, or octreotide administration can be used to treat acromegaly. Toxicity & Contraindications Dopamine agonists can cause nausea, headache, light-headedness, orthostatic hypotension, and fatigue. Cabergoline treatment at high doses for Parkinson’s disease is associated with higher risk of valvular heart disease, but probably not at the lower dose used for hyperprolactinemia. Dopamine agonist therapy during the early weeks of pregnancy has not been associated with an increased risk of spontaneous abortion or congenital malformations. Although there has been a longer experience with the safety of bromocriptine during early pregnancy, there is growing evidence that cabergoline is also safe in women with macroadenomas who must continue a dopamine agonist during pregnancy. In patients with small pituitary adenomas, dopamine agonist therapy is discontinued upon conception because growth of microadenomas during pregnancy is rare. Patients with very large adenomas require vigilance for tumor progression and often require a dopamine agonist throughout pregnancy. There have been rare reports of stroke or coronary thrombosis in postpartum women taking bromocriptine to suppress postpartum lactation.
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This case demonstrates the need for very close monitoring of patients after addition of thiazide diuretics to chronic loop diuretic therapy (particularly if they have preexisting chronic kidney disease) order celebrex in india rheumatoid arthritis in dogs symptoms. A short time later order celebrex 200mg with amex arthritis medication for dogs metacam, another physician at the table developed similar signs and symptoms with marked orthostatic hypotension generic celebrex 100 mg without a prescription arthritis in the knee cap. It has long been known that many tissues contain substances that discount celebrex 200 mg with amex can arthritis in dogs cause fever, when released by various stimuli, cause physiologic effects such as reddening of the skin, pain or itching, and bronchospasm. Later, it was discovered that many of these substances are also present in nervous tissue and have multiple functions. Together with endogenous peptides (see Chapter 17), prostaglandins and leukotrienes (see Chapter 18), and cytokines (see Chapter 55), they constitute the autacoid group of drugs. Because of their broad and largely undesirable peripheral effects, neither histamine nor serotonin has any clinical application in the treatment of disease. However, compounds that selectively activate certain receptor subtypes or selectively antagonize the actions of these amines are of considerable clinical value. This chapter therefore emphasizes the basic pharmacology of the agonist amines and the clinical pharmacology of the more selective agonist and antagonist drugs. The ergot alkaloids, compounds with partial agonist activity at serotonin and several other receptors, are discussed at the end of the chapter. Early hypotheses concerning the possible physiologic roles of tissue histamine were based on similarities between the effects of intravenously administered histamine and the symptoms of anaphylactic shock and tissue injury. Marked species variation is observed, but in humans histamine is an important mediator of immediate allergic (such as urticaria) and inflammatory reactions, although it plays only a modest role in anaphylaxis. Histamine plays an important role in gastric acid secretion (see Chapter 62) and functions as a neurotransmitter and neuromodulator (see Chapters 6 and 21). Newer evidence indicates that histamine also plays a role in immune functions and chemotaxis of white blood cells. Histamine is formed by decarboxylation of the amino acid L-histidine, a reaction catalyzed in mammalian tissues by the enzyme histidine decarboxylase. Certain neoplasms (systemic mastocytosis, urticaria pigmentosa, gastric carcinoid, and occasionally myelogenous leukemia) are associated with increased numbers of mast cells or basophils and with increased excretion of histamine and its metabolites. Most tissue histamine is sequestered and bound in granules (vesicles) in mast cells or basophils; the histamine content of many tissues is directly related to their mast cell content. The bound form of histamine is biologically inactive, but as noted below, many stimuli can trigger the release of mast cell histamine, allowing the free amine to exert its actions on surrounding tissues. Mast cells are especially rich at sites of potential tissue injury—nose, mouth, and feet; internal body surfaces; and blood vessels, particularly at pressure points and bifurcations. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Strong evidence implicates endogenous neurotransmitter histamine in many brain functions such as neuroendocrine control, cardiovascular regulation, thermal and body weight regulation, and sleep and arousal (see Chapter 21). Storage & Release of Histamine The stores of histamine in mast cells can be released through several mechanisms. Immunologic Release Immunologic processes account for the most important pathophysiologic mechanism of mast cell and basophil histamine release. These cells, if sensitized by IgE antibodies attached to their surface membranes, degranulate explosively when exposed to the appropriate antigen (see Figure 55–5, effector phase). Histamine released by this mechanism is a mediator in immediate (type I) allergic reactions, such as hay fever and acute urticaria. Substances released during IgG- or IgM-mediated immune reactions that activate the complement cascade also release histamine from mast cells and basophils. By a negative feedback control mechanism mediated by H receptors, histamine appears to modulate its own release2 and that of other mediators from sensitized mast cells in some tissues. In humans, mast cells in skin and basophils show this negative feedback mechanism; lung mast cells do not. Upon injury to a tissue, released histamine causes local vasodilation and leakage of plasma-containing mediators of acute inflammation (complement, C-reactive protein) and antibodies. Histamine has an active chemotactic attraction for inflammatory cells (neutrophils, eosinophils, basophils, monocytes, and lymphocytes). Release of peptides from2 4 nerves in response to inflammation is also probably modulated by histamine acting on presynaptic H receptors. Chemical and Mechanical Release Certain amines, including drugs such as morphine and tubocurarine, can displace histamine from its bound form within cells. This type of release does not require energy and is not associated with mast cell injury or degranulation. Loss of granules from the mast cell also releases histamine, because sodium ions in the extracellular fluid rapidly displace the amine from the complex. Compound 48/80, an experimental drug, selectively releases histamine from tissue mast cells by an exocytotic degranulation process requiring energy and calcium. Mechanism of Action Histamine exerts its biologic actions by combining with specific receptors located on the cell membrane. Four different histamine receptors have been characterized and are designated H –H ; they are described in1 4 Table 16–1. Unlike the other amine transmitter receptors discussed previously, no subfamilies have been found within these major types, although different splice variants of several receptor types have been described. The H receptor has about 40% homology with the H receptor but does not1 4 3 seem to be closely related to any other histamine receptor. All four histamine receptors have been shown to have constitutive activity in some systems; thus, some antihistamines previously considered to be traditional pharmacologic antagonists must now be considered to be inverse agonists (see Chapters 1 and 2). Furthermore, a single molecule may be an agonist at one histamine1 receptor and an antagonist or inverse agonist at another. For example, clobenpropit, an agonist at H receptors, is an4 antagonist or inverse agonist at H receptors (3 Table 16–1). In the brain, H and H receptors are located on postsynaptic membranes, whereas H receptors are predominantly1 2 3 presynaptic. Activation of H receptorsq 3 3 decreases transmitter release from histaminergic and other neurons, probably mediated by a decrease in calcium influx through N-type calcium channels in nerve endings. They may also modulate production of these cell types and they may mediate, in part, the previously recognized effects of histamine on cytokine production. Tissue and Organ System Effects of Histamine Histamine exerts powerful effects on smooth and cardiac muscle, on certain endothelial and nerve cells, on the secretory cells of the stomach, and on inflammatory cells. Guinea pigs are exquisitely sensitive; humans, dogs, and cats somewhat less so; and mice and rats very much less so. Nervous system—Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching. This H -mediated effect is an important component of the urticarial response and reactions to insect and nettle1 stings. Some evidence suggests that local high concentrations can also depolarize efferent (axonal) nerve endings (see Triple Response, item 8 in this list).
In addition to these pharmacokinetic factors discount celebrex 200 mg free shipping equate arthritis relief, it is generally believed that the elderly vary more in their sensitivity to the sedative-hypnotic drugs on a pharmacodynamic basis as well purchase line celebrex rheumatoid arthritis icd 10. Among the toxicities of these drugs cheap celebrex 200mg online rheumatoid arthritis and headaches, ataxia and other stability impairments lead to increased falls and fractures buy celebrex overnight delivery arthritis in the fingers. However, the elderly are often markedly more sensitive to the respiratory effects of these agents because of age-related changes in respiratory function. Therefore, this group of drugs should be used with caution until the sensitivity of the particular patient has been evaluated, and the patient should then be dosed appropriately for full effect. Unfortunately, studies show that opioids are consistently underutilized in patients who require strong analgesics for chronic painful conditions such as cancer. There is no justification for underutilization of these drugs, especially in the care of the elderly, and good pain management plans are readily available (see Morrison, 2006; Rabow, 2011). Antipsychotic & Antidepressant Drugs The traditional antipsychotic agents (phenothiazines and haloperidol) have been very heavily used (and probably misused) in the management of a variety of psychiatric conditions in the elderly. There is no doubt that they are useful in the management of schizophrenia in old age, and also in the treatment of some symptoms associated with delirium, dementia, agitation, combativeness, and a paranoid syndrome that occurs in some geriatric patients (see Chapter 29). However, they are not fully satisfactory in these geriatric conditions, and dosage should not be increased on the assumption that full control is possible. There is no evidence that these drugs have any beneficial effects in Alzheimer’s dementia, and on theoretical grounds the antimuscarinic effects of the phenothiazines might be expected to worsen memory impairment and intellectual dysfunction (see below). Much of the apparent improvement in agitated and combative patients may simply reflect the sedative effects of the drugs. Haloperidol has increased extrapyramidal toxicity, however, and should be avoided in patients with preexisting extrapyramidal disease. The phenothiazines, especially older drugs such as chlorpromazine, often induce orthostatic hypotension because of their α-adrenoceptor-blocking effects. The atypical antipsychotic agents (clozapine, olanzapine, quetiapine, risperidone, aripiprazole) do not appear to be significantly superior to the traditional agents although they have fewer autonomic adverse effects. Evidence supporting the benefits of olanzapine is somewhat stronger than that for the other atypical agents. Because it is cleared by the kidneys, dosages must be adjusted appropriately and blood levels monitored. Concurrent use of thiazide diuretics reduces the clearance of lithium and should be accompanied by further reduction in dosage and more frequent measurement of lithium blood levels. Unfortunately, the apathy, flat affect, and social withdrawal of major depression may be mistaken for senile dementia. Clinical evidence suggests that the elderly are as responsive to antidepressants (of all types) as younger patients but are more likely to experience adverse effects. This factor along with the reduced clearance of some of these drugs underlines the importance of careful dosing and strict attention to the appearance of toxic effects. If a tricyclic is to be used, a drug with reduced antimuscarinic effects should be selected, eg, nortriptyline or desipramine (see Table 30–2). Early onset of Alzheimer’s disease is associated with several gene defects, including trisomy 21 (chromosome 21), a mutation of the gene for presenilin-1 on chromosome 14, and an abnormal allele, ε4, for the lipid-associated protein, ApoE, on chromosome 19. Unlike the common forms (ApoE ε2 and ε3), the ε4 form strongly correlates with the formation of amyloid β deposits (see below). Pathologic changes include increased deposits of amyloid beta (Aβ) peptide in the cerebral cortex, which eventually forms extracellular plaques and cerebral vascular lesions, and intra- and interneuronal fibrillary tangles consisting of the tau protein (Figure 60–2). The loss of cholinergic neurons results in a marked decrease in choline acetyltransferase and other markers of cholinergic activity. Patients with Alzheimer’s disease are often exquisitely sensitive to the central nervous system toxicities of drugs with antimuscarinic effects. From the left: mitochondrial dysfunction, possibly involving glucose utilization; synthesis of protein tau and aggregation in filamentous tangles; synthesis of amyloid beta (Aβ) and secretion into the extracellular space, where it may interfere with synaptic signaling and accumulates in plaques. Much attention has been focused on the cholinomimetic drugs because of the evidence of loss of cholinergic neurons. Unfortunately, this drug may be associated with increased cardiovascular risk and its use has been restricted (see Chapter 41). Because of its hepatic toxicity, tacrine has been replaced in clinical use by newer cholinesterase inhibitors: donepezil, rivastigmine, and galantamine. These agents are orally active, have adequate penetration into the central nervous system, and are much less toxic than tacrine. Although evidence for the benefit of cholinesterase inhibitors (and memantine; see below) is statistically significant, the amount of benefit is modest and does not prevent the progression of the disease. The cholinesterase inhibitors cause significant adverse effects, including nausea and vomiting, and other peripheral cholinomimetic effects. These drugs should be used with caution in patients receiving other drugs that inhibit cytochrome P450 enzymes (eg, ketoconazole, quinidine; see Chapter 4). Its modest efficacy in Alzheimer’s disease is similar to or smaller than that of the cholinesterase inhibitors. Combination therapy with both memantine and one of the cholinesterase inhibitors has produced mixed results. Recent research has focussed on amyloid beta, because the characteristic plaques consist mostly of this peptide. Unfortunately, two anti-amyloid antibodies, solanezumab and bapineuzumab, both failed to improve cognition or slow progression in recent phase 2 clinical trials. Another effort suggests that the accumulation of filamentous tangles of tau protein is a critical component of neuronal damage in Alzheimer’s and several other neurodegenerative conditions. Accumulation of tau appears to be associated with dissociation from microtubules in neurons, which has stimulated interest in drugs that inhibit microtubule disassembly, such as epothilone-D. Although sometimes ignored in the past, most clinicians now believe that hypertension should be treated in the elderly. The basic principles of therapy are not different in the geriatric age group from those described in Chapter 11, but the usual cautions regarding altered pharmacokinetics and blunted compensatory mechanisms apply. Because of its safety, nondrug therapy (weight reduction in the obese and salt restriction) should be encouraged. The hypokalemia, hyperglycemia, and hyperuricemia caused by these agents are more relevant in the elderly because of the higher prevalence in these patients of arrhythmias, type 2 diabetes, and gout. Beta blockers are potentially hazardous in patients with obstructive airway disease and are considered less useful than calcium channel blockers in older patients unless chronic heart failure is present. Angiotensin-converting enzyme inhibitors are also considered less useful in the elderly unless heart failure or diabetes is present. Every patient receiving antihypertensive drugs should be checked regularly for orthostatic hypotension because of the danger of cerebral ischemia and falls. The toxic effects of digoxin are particularly dangerous in the geriatric population, since the elderly are more susceptible to arrhythmias. The clearance of digoxin is usually decreased in the older age group, and although the volume of distribution is often decreased as well, the half-life of this drug may be increased by 50% or more. Because the drug is cleared mostly by the kidneys, renal function must be considered in designing a dosage regimen. There is no evidence that there is any increase in pharmacodynamic sensitivity to the therapeutic effects of the cardiac glycosides; in fact, animal studies suggest a possible decrease in therapeutic sensitivity.