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Opioid-Induced Hyperalgesia A paradoxical increase in pain states has been observed in response to acute (hours to days) and chronic opiate exposure menstrual or pregnancy cramps 100mg serophene otc. This increase may be reflected by unexplained increases in pain reports womens health specialist yuma az discount serophene 100mg on-line, increased levels of pain with increasing opiate dosages womens health magazine customer service buy cheap serophene 50 mg online, or a diffuse sensitivity unassociated with the original pain (Lee et al womens health weight loss pills order serophene australia. The mechanisms of this increased pain profile is not understood, although an enhanced excitability of central systems with chronic opiate exposure is considered relevant. Other avenues have pointed to the stimulatory effects of opioids on innate immune signaling through Toll-like receptor 4 activation, leading to central sensitization (Grace et al. These effects are most typically noted following initiation of opiate therapy or after dose incrementation. As with respiratory depression, the degree of drug effect can be enhanced by a variety of predisposing patient factors, including dementia, encephalopathies, brain tumors, and other depressant medications, including sleep aids, antihistamines, antidepressants, and anxiolytics (Cherny, 1996). Factors Exacerbating Opiate-Induced Respiratory Depression A number of factors can increase the risk of opiate-related respiratory depression even at therapeutic doses: Other medications. The combination of opiates with other depressant medications, such as general anesthetics, tranquilizers, alcohol, or sedative-hypnotics, produces additive depression of respiratory activity. Natural sleep produces a decrease in the sensitivity of the medullary center to CO2, and the depressant effects of morphine and sleep are at least additive. Obstructive sleep apnea is considered to be an important risk factor for increasing the likelihood of fatal respiratory depression. Elderly patients are at greater risk of depression because of reduced lung elasticity, chest wall stiffening, and decreased vital capacity. Opiates may cause a greater depressant action in patients with chronic cardiopulmonary or renal diseases because they can manifest a desensitization of their response to increased CO2. Enhanced depression can also be noted in patients with COPD and sleep apnea secondary to diminished hypoxic drive. Because pain stimulates respiration, removal of the painful condition (as with the analgesia resulting from the therapeutic use of the opiate) will reduce the ventilatory drive and lead to apparent respiratory depression. Neuroendocrine Effects the regulation of the release of hormones and factors from the pituitary is under complex regulation by opiate receptors in the HPA axis. Broadly considered, morphine-like opioids reduce the release of a large number of HPA hormones (Armario, 2010). Sex Hormones In males, acute opiate therapy reduces plasma cortisol, testosterone, and gonadotrophins. Inhibition of adrenal function is reflected by reduced cortisol production and reduced adrenal androgens (DHEA). In both males and females, chronic therapy can result in endocrinopathies, including hypogonadotrophic hypogonadism. In men, this may result in decreased libido and, with extended exposure, reduced secondary sex characteristics. Prolactin release from the anterior pituitary is under inhib- itory control by DA released from neurons of the arcuate nucleus. MOR agonists act presynaptically on these DA-releasing terminals to inhibit DA release and thereby increase plasma prolactin. The effects of opiates on ADH Comparative Respiratory Effects of Different Opiates Numerous studies have compared morphine and morphine-like opioids with respect to their ratios of analgesic to respiratory-depressant activities, and most have found that when equianalgesic doses are used, there is no significant difference. Maximal respiratory depressant effects occur more rapidly with more lipid-soluble agents. Agents that have persistent kinetics, such as methadone, must be carefully monitored, particularly after dose incrementation. Respiratory depression produced by any opiate agonist can be readily reversed by delivery of an opiate antagonist. Opiate antagonist reversal in the somnolent patient is considered to be indicative of an opiate-mediated depression. It is important to remember that most opiate antagonists have a relatively short duration of action compared to an agonist such as morphine or methadone, and fatal "renarcotization" can occur if vigilance is not exercised. These hormones are synthesized in the perikarya of the magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus and released from the posterior pituitary (Chapter 42). KOR agonists inhibit the release of oxytocin and ADH and cause prominent diuresis. Note, however, that agents such as morphine may yield a hypotension secondary to histamine release; this would, by itself, promote ADH release. Miosis the MOR agonists induce pupillary constriction (miosis) in the awake state and block pupillary reflex dilation during anesthesia. The parasympathetic outflow from the Edinger Westphal nucleus activates parasympathetic outflow through the ciliary ganglion to the pupil, producing constriction. Opiates block this GABAergic interneuron-mediated inhibition, leading to increased parasympathetic outflow (Larson, 2008). At high doses of agonists, the miosis is marked, and pinpoint pupils are pathognomonic; however, marked mydriasis will occur with the onset of asphyxia. While some tolerance to the miotic effect develops, addicts with high circulating concentrations of opioids continue to have constricted pupils. Therapeutic doses of morphine increase accommodative power and lower intraocular tension in normal and glaucomatous eyes (Larson, 2008). Seizures and Convulsions In older children and adults, moderately higher doses of opiates produce EEG slowing.
Because orthostatic hypotension may be a problem during long-term treatment with prazosin or its congeners pregnancy 2 generic 100 mg serophene with visa, it is essential to check standing as well as recumbent blood pressure breast cancer vs prostate cancer purchase generic serophene canada. Nonspecific adverse effects such as headache breast cancer 90 year old woman serophene 50mg line, dizziness women's health issues in peru 50 mg serophene with mastercard, and asthenia rarely limit treatment with prazosin. Prazosin and its congeners have been used successfully in the treatment of essential hypertension (Chapter 28). Pleotropic effects of these drugs improve lipid profiles and glucose-insulin metabolism in patients with hypertension who are at risk for atherosclerotic disease (Deano and Sorrentino, 2012). Catecholamines are also powerful stimulators of vascular smooth muscle hypertrophy, acting by 1 receptors. To what extent these effects of 1 antagonists have clinical significance in diminishing the risk of atherosclerosis is not known. Receptor antagonists have been used in the treatment of congestive heart failure but are not the drugs of choice. Shortterm effects of receptor blockade in these patients are due to dilation of both arteries and veins, resulting in a reduction of preload and afterload, which increases cardiac output and reduces pulmonary congestion. In contrast to results obtained with inhibitors of angiotensin-converting enzyme or a combination of hydralazine and an organic nitrate, prazosin has not been found to prolong life in patients with congestive heart failure. Although certain vascular beds contain 2 receptors that promote contraction of smooth muscle, it is thought that these receptors are preferentially stimulated by circulating catecholamines, whereas 1 receptors are activated by NE released from sympathetic nerve fibers. In other vascular beds, 2 receptors reportedly promote vasodilation by stimulating the release of NO from endothelial cells. The physiological role of vascular 2 receptors in the regulation of blood flow within various vascular beds is uncertain. The 2 receptors contribute to smooth muscle contraction in the human saphenous vein, whereas 1 receptors are more prominent in dorsal hand veins. The effects of 2 receptor antagonists on the cardiovascular system are dominated by actions in the CNS and on sympathetic nerve endings. The compound is an indolealkylamine alkaloid and is found in the bark of the tree Pausinystalia yohimbe and in Rauwolfia root; its structure resembles that of reserpine. Yohimbine readily enters the CNS, where it acts to increase blood pressure and heart rate; it also enhances motor activity and produces tremors. Some studies suggested that yohimbine may be useful for diabetic neuropathy and in the treatment of postural hypotension. Yohimbine is approved in veterinary medicine for the reversal of xylazine anesthesia. In a significant percentage of older men, BPH produces symptomatic urethral obstruction that leads to weak stream, increased urinary frequency, and nocturia. Prazosin reduces this resistance in some patients with impaired bladder emptying caused by prostatic obstruction or parasympathetic decentralization from spinal injury. Finasteride and dutasteride, two drugs that inhibit conversion of testosterone to dihydrotestosterone (Chapter 45) and can reduce prostate volume in some patients, are approved as monotherapy and in combination with receptor antagonists. Combination therapy with doxazosin and finasteride reduces the risk of overall clinical progression of BPH significantly more than treatment with either drug alone (McConnell et al. The predominant 1 subtype expressed in the human prostate is the 1A receptor (Michel and Vrydag, 2006). Developments in this area will provide the basis for the selection of receptor antagonists with specificity for the relevant subtype of 1 receptor. However, the possibility remains that some of the symptoms of BPH are due to 1 receptors in other sites, such as bladder, spinal cord, or brain. Some studies indicated that prazosin can decrease the incidence of digital vasospasm in patients with Raynaud disease; however, its relative efficacy as compared with Ca2+ channel blockers is not known. Prazosin may be useful for the treatment of patients with mitral or aortic valvular insufficiency, presumably by reducing afterload. Nonselective Adrenergic Antagonists Phenoxybenzamine and Phentolamine Phenoxybenzamine and phentolamine are nonselective receptor antagonists. Phenoxybenzamine, a haloalkylamine compound, produces an irreversible antagonism, while phentolamine, an imidazaline, produces a competitive antagonism. Phenoxybenzamine and phentolamine cause a progressive decrease in peripheral resistance due to antagonism of receptors in the vasculature and an increase in cardiac output that is due in part to reflex sympathetic nerve stimulation. The cardiac stimulation is accentuated by enhanced release of NE from cardiac sympathetic nerve due to antagonism of presynaptic 2 receptors by these nonselective blockers. Postural hypotension is a prominent feature with these drugs, and this, accompanied by reflex tachycardia that can precipitate cardiac arrhythmias, severely limits the use of these drugs to treat essential hypertension. The 1-selective antagonists, such as prazosin, have replaced the "classical" -blockers in the management of essential hypertension. Phenoxybenzamine and phentolamine are still marketed for several specialized uses. Activation of presynaptic 2 receptors inhibits the release of NE and other cotransmitters from peripheral sympathetic nerve endings. Activation of 2 receptors in the pontomedullary region of the CNS inhibits sympathetic nervous system activity and leads to a fall in blood pressure; these receptors are a site of action for drugs such as clonidine. Blockade of 2 receptors with selective antagonists such as yohimbine thus can increase sympathetic outflow and potentiate the release of NE from nerve endings, leading to activation of 1 and 1 receptors in the heart and peripheral vasculature with a consequent rise in blood pressure.
PRR functions as an accessory protein essential for V-ATPase activity pregnancy acne discount serophene 100 mg otc, which is required for intracellular acidity pregnancy exercise generic serophene 100mg amex, receptormediated endocytosis women's health center allentown pa order serophene 25mg with mastercard, and activation of lysosomal and autophagosomal enzymes (Oshima et al womens health exercise book generic 50 mg serophene free shipping. Cardiomyocyte-specific PRR knockout mice and podocyte-specific PRR knockout mice develop lethal organ-specific failure due loss of V-ATPase and the dysregulation of intracellular acidification and autophagic functions (Binger and Muller, 2013). PRR also participates in the activation of Wnt/-catenin and Wnt/planar cell polarity signaling pathways that are important in cell polarization in the plane of tissue (Nguyen, 2011). In hepatocytes, silencing PRR expression decreased cellular LDL uptake by decreasing expression of LDL receptor and sortelin 1 protein, a regulator of LDL uptake and metabolism and a PRR-interacting protein (Lu et al. Modest increases in plasma concentrations of AngII acutely raise blood pressure; on a molar basis, AngII is about 40 times more potent than NE; the EC50 of AngII for acutely raising arterial blood pressure is about 0. This rapid pressor response to AngII is due to a swift increase in TPR-a response that helps to maintain arterial blood pressure in the face of an acute hypotensive challenge. Although AngII increases cardiac contractility directly (via opening voltage-gated Ca2+ channels in cardiac myocytes) and increases heart rate indirectly (via facilitation of sympathetic tone, enhancing adrenergic neurotransmission, and provoking adrenal catecholamine release), the rapid increase in arterial blood pressure activates a baroreceptor reflex that decreases sympathetic tone and increases vagal tone. Thus, depending on the physiological state, AngII may increase, decrease, or not change cardiac contractility, heart rate, and cardiac output. Changes in cardiac output therefore contribute little, if at all, to the rapid pressor response induced by AngII. AngII also causes a slow pressor response that helps to stabilize arterial blood pressure over the long term. Release of aldosterone from adrenal cortex (increased Na+ reabsorption and increased K+ excretion in distal nephron) III. Slow Pressor Response Vascular and Cardiac Hypertrophy and Remodeling the maximum effect requiring days to achieve. AngII stimulates the synthesis of endothelin 1 and superoxide anion, which may contribute to the slow pressor response. In addition to its effects on arterial blood pressure, AngII stimulates remodeling of the cardiovascular system, causing hypertrophy of vascular and cardiac cells and increased synthesis and deposition of collagen by cardiac fibroblasts. Circulating AngII also attenuates baroreceptor-mediated reductions in sympathetic discharge, thereby increasing arterial pressure. The CNS is affected both by blood-borne AngII and by AngII formed within the brain. AngII also causes a centrally mediated dipsogenic (thirst) effect and enhances the release of vasopressin from the neurohypophysis. Angiotensin II stimulates the release of catecholamines from the adrenal medulla by promoting Ca2+ entry secondary to depolarization of chromaffin cells. Mechanisms by Which Angiotensin II Regulates Renal Function Angiotensin II has pronounced effects on renal function, reducing the urinary excretion of Na+ and water while increasing the excretion of K+. Direct Vasoconstriction Angiotensin II constricts precapillary arterioles and, to a lesser extent, postcapillary venules by activating AT1 receptors located on vascular smooth muscle cells and stimulating the Gq-PLC-IP3-Ca2+ pathway. AngIIinduced vasoconstriction is much less in vessels of the brain and still weaker in those of the lung and skeletal muscle. Nevertheless, high circulating concentrations of AngII may decrease cerebral and coronary blood flow. Enhancement of Peripheral Noradrenergic Neurotransmission Angiotensin II, binding to AT1 receptors, augments NE release from sympathetic nerve terminals by inhibiting the reuptake of NE into nerve terminals and by enhancing the vascular response to NE in model systems (see Chapter 12). Effects on the CNS Very low concentrations of AngII stimulate Na+/H+ exchange in the proximal tubule-an effect that increases Na+, Cl-, and bicarbonate reabsorption. Paradoxically, at high concentrations, AngII may inhibit Na+ transport in the proximal tubule. AngII also directly stimulates the Na+-K+-2Cl- symporter in the thick ascending limb. The proximal tubule secretes angiotensinogen, and the connecting tubule releases renin, so a paracrine tubular RAS may contribute to Na+ reabsorption. Direct Effects of AngII on Na+ Reabsorption in the Renal Tubules Angiotensin II increases sympathetic tone. Small amounts of AngII infused into the vertebral arteries cause an increase in arterial blood pressure. This response reflects effects of the hormone on circumventricular nuclei that are not protected by a blood-brain barrier.
These drugs also are used frequently in the treatment of supraventricular and ventricular arrhythmias (Chapter 30) menstrual cycle 7 days buy serophene 50mg. Receptor antagonists are used in the treatment of hypertrophic obstructive cardiomyopathy menstruation 3 weeks straight 100mg serophene fast delivery, relieving angina breast cancer 74 order cheapest serophene and serophene, palpitations women's health center peterborough discount 50mg serophene visa, and syncope in patients with this disorder. Efficacy probably is related to partial relief of the pressure gradient along the outflow tract. Blockers also may attenuate catecholamine-induced cardiomyopathy in pheochromocytoma. Blockers are used frequently in the medical management of acute dissecting aortic aneurysm; their usefulness comes from reduction in the force of myocardial contraction and the rate of development of such force. Nitroprusside is an alternative, but when given in the absence of receptor blockade, it causes an undesirable reflex tachycardia. Chronic treatment with antagonists may be efficacious in slowing the progression of aortic dilation and its complications in patients with Marfan syndrome, although surgical aortic repair is still warranted as aortic diameter expands; losartan, an ACEI, is showing promise as a more effective treatment (Hiratzka et al. The receptor antagonists are used in the treatment of chronic open-angle glaucoma (see Chapter 69). These agents decrease the production of aqueous humor, which appears to be the mechanism for their clinical effectiveness. Many of the signs and symptoms of hyperthyroidism are reminiscent of the manifestations of increased sympathetic nervous system activity. Receptor antagonists control many of the cardiovascular signs and symptoms of hyperthyroidism and are useful adjuncts to more definitive therapy. In addition, propranolol inhibits the peripheral conversion of thyroxine to triiodothyronine, an effect that may be independent of receptor blockade (see Chapter 43). Propranolol, timolol, and metoprolol are effective for the prophylaxis of migraine; these drugs are not useful for treatment of acute attacks of migraine. Propranolol and other blockers are effective in controlling acute panic symptoms in individuals who are required to perform in public or in other anxiety-provoking situations. Tachycardia, muscle tremors, and other evidence of increased sympathetic activity are reduced. Blockers may be of some value in the treatment of patients undergoing withdrawal from alcohol or those with akathisia. Propranolol and nadolol are efficacious in the primary prevention of variceal ADME. Propranolol is highly lipophilic and almost completely absorbed after oral administration. Much of the drug is metabolized by the liver during its first passage through the portal circulation; only about 25% reaches the systemic circulation. In addition, there is great interindividual variation in the presystemic clearance of propranolol by the liver; this contributes to enormous variability in plasma concentrations (~20-fold) after oral administration of the drug and to the wide dosage range for clinical efficacy. The degree of hepatic extraction of propranolol declines as the dose is increased. The bioavailability of propranolol may be increased by the concomitant ingestion of food and during long-term administration of the drug. One product of hepatic metabolism is 4-hydroxypropranolol, which has some adrenergic antagonist activity. Analysis of the distribution of propranolol, its clearance by the liver, and its activity is complicated by the stereospecificity of these processes (Walle et al. The clearance of propranolol may vary with hepatic blood flow and liver disease and also may change during the administration of other drugs that affect hepatic metabolism. Despite its short t1/2 in plasma (~4 h), twice-daily administration suffices to produce the antihypertensive effect in some patients. Sustained-release formulations of propranolol maintain therapeutic concentrations of propranolol in plasma throughout a 24-h period. For the treatment of angina, the dose may be increased at intervals of less than 1 week, as indicated clinically. In hypertension, the full blood pressure response may not develop for several weeks. If propranolol is taken twice daily for hypertension, blood pressure should be measured just prior to a dose to ensure that the duration of effect is sufficiently prolonged. Propranolol may be administered intravenously for the management of life-threatening arrhythmias or to patients under anesthesia. If an adequate response is not obtained, a second dose may be given after several minutes. If bradycardia is excessive, atropine should be administered to increase heart rate. Unlabeled uses have included migraine prophylaxis, parkinsonian tremors, and variceal bleeding in portal hypertension.
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