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From Adrenal Health to Adrenal Dysregulation Adrenal health is the key difference between my approach to wellness and that of the traditional medical establishment cheap 50mg azathioprine with mastercard muscle relaxant yoga, which holds that the adrenals are unimportant unless they completely fail cheap azathioprine 50mg free shipping spasms during bowel movement, or are extremely overactive (that is buy cheap azathioprine 50mg online spasms due to redundant colon, you have Cushing’s Disease). I regard stress resilience and adrenal wellness as the foundation of health and vitality, and I believe that it is largely unrecognized and under-addressed in conventional medicine. Time and again I have seen that the healthiest, most vibrant individuals cope successfully with stress and have found ways to keep their adrenals in top form. Those are the ideal hormonal specimens who experience the smart function of their glucocorticoids. That is, they experience an external stressor—a true physical threat—such as a car accident or robbery, and stress hormones such as cortisol help them focus and problem solve, and shunt blood to their legs and away from nonessential activities such as getting pregnant and digestion. They adapt to the stressor, recover swiftly, and then blood and energy can be directed once again to digesting lunch, reproduction, growth, and repair. Their cavewoman tendencies to constantly scan the environment for threats are contained and mostly dismissed. Most women I know respond the same way almost daily to the emotional stress of financial worries or traffic tie-ups or the state of their marriage as they would to an immediate physical stress. When psychosocial stress is incessant, or when you perceive that life is incessantly stressful, you move progressively from healthy adaptation to toxic, stress-related harm to your body. You run low on certain amino acids, and it’s harder for your brain to make serotonin, norepinephrine, and dopamine. Over time, your problem may evolve beyond a minor issue to a serious health threat— you start to experience blood pressure problems or unstable blood sugar—and you need to intervene, even though your mainstream doctor may not agree. Ultimately, when mired in habitual psychosocial stress, your body starts to show signs of maladaptation. Perhaps your cortisol slope, which should show a daily downhill pattern—high in the morning and low at night— becomes flattened. Stress-induced secretion of glucocorticoids such as cortisol evolved to help us respond to physical threats in our external environment. Ironically, the same stress response is mostly triggered in our modern lives by emotional stress and causes damage. Understanding what happens during adrenal dysregulation is helpful when you’re exploring what integrative treatments may be most appropriate and effective, as described later in The Solution section for high and low cortisol. Low sodium and potassium may occur if production of aldosterone, another hormone made in the outer shell or cortex of the adrenal gland, is low from adrenal dysregulation. Aldosterone controls the level of electrolytes in your blood and urine, mediating water retention and blood pressure. Symptoms include a fast pulse, palpitations, light- headedness, fatigue, frequent urination, thirst, and salt cravings. Symptoms of this medical disorder include widespread and protracted pain, a heightened sensitivity to pressure, joint stiffness, debilitating fatigue, and difficulty sleeping. Symptoms may include weakness, muscle pain, sleep problems, and impaired memory and concentration, and they may result in reduced participation in daily activities. When allostatic load is more than you can tolerate, you are at significant risk for burnout. She started taking licorice, which helps the adrenals produce more cortisol, and got on her proper dose of thyroid medicine. Common symptoms include fatigue, headache, disturbed sleep, pain, attention deficit disorder, feelings of apathy and meaninglessness, and detachment from work. The International Labor Organization estimates that 10 percent of the workforce in North America and Europe experiences burnout. Allostatic load is a measure of biological strain on your body from poor stress response, and imbalanced cortisol is the primary marker. Recently, fifteen biological markers of stress reactivity were consolidated into an allostatic load index and shown to predict burnout. Burnout can happen to anyone, but it’s seen frequently in teachers, caregivers, nurses, doctors, and social service staff— professions in which people care directly for others and in which women predominate. A study of female teachers showed higher cortisol levels while they were teaching and lower to normal levels when not 35 teaching. Some of my patients exit adrenal overdrive only when they go on vacation, and even then they take their cell phones and laptops. The parasympathetic nervous system never has a chance to calm their systems back to normal. Our penchant for smartphones and our endless availability, overwork, multitasking, and perhaps our addiction to excess have led to an allostatic load that’s often more than we can bear. Many mainstream doctors take the easy way and prescribe an antidepressant, yet here’s what concerns me: few women are tested for hormonal causes of their ennui (for instance, 20 percent are known to have thyroid problems associated with depression), and even fewer are informed about the increased risk of stroke, breast and ovarian cancer, low libido, preterm birth, infant convulsions, and weight gain associated with taking antidepressants. Even worse, very few of these women are told that antidepressants help only the most 36 severe cases. Given the list of adverse effects, antidepressants are worse than placebo if depression is mild to moderate. Don’t get me wrong: I’m not suggesting that we discard antidepressants any time soon. I simply believe that they’re overused, few patients get full informed consent, and the root cause—often neuroendocrine imbalance—is sometimes overlooked. We want to avoid the either/or thinking that polarizes women—that makes women feel damned if they do take an antidepressant given the risks and loss of sexual interest, and damned if they don’t. Women need more choices, preferably choices that are natural and address the root cause of their discontent. Some conventional clinicians might even be resistant to considering any other options, such as looking at your cortisol levels, despite the documentation I’ve provided in this chapter (and on my webpage specifically for practitioners: http://thehormonecurebook. I believe that with a closer look, many burned-out women would show adrenal dysregulation, given the telltale signs of insulin resistance, decreased immunity, midsection weight gain, fatigue, tension, and low mood. This is when you need to find a doctor who will work with you, in a partnership that feels aligned with your goals and belief system. It’s also important to develop tools to dance with stress and to deal with a frantic lifestyle.

Monitor and correct urine and electrolytes order azathioprine 50 mg infantile spasms 6 months old, arterial blood gases and pH order azathioprine 50 mg mastercard muscle relaxant home remedy, blood sugar generic 50 mg azathioprine with amex spasms in legs, prothrombin time. Urinary alkalinisation For salicylate level 500–700 mg/L in adults or salicylate level 350–600 mg/L in children/elderly where patients have moderate clinical effects. An estimated 8 h after maternal ingestion of 5 g of naproxen at 35 weeks of gestation, nonspecific and supportive antidote therapy was initiated because no specific antidote is available. The mother recovered with no evidence of hepatotoxicity or other adverse effects (Alon-Jones and Williams, 1986). In contrast to the pharmacokinetics of salicylate elimination, high doses of naproxen (1–4 g) result in a disproportionate increase in renal excretion of the drug without apparent saturation of the excretory mechanism or metabolic pathway (Erling and Strand, 1977; Runkel et al. Increase in renal elimination may contribute to a lower incidence of acute toxicity compared with salicylate overdose. Ibuprofen Ibuprofen overdose during pregnancy has not been described in case studies and no spe- cific antidote exists. Symptoms of ibuprofen toxicity include nausea, epigastric pain, diarrhea, vomit- ing, dizziness, blurred vision, and edema. Fifty reports of ibuprofen overdose during pregnancy have been reported, with mothers and infants suffering no untoward effects (i. Since there is no specific antidote to prenatal vitamins, nonspecific and supportive antidote therapy should be given. It is reasonable to think that most cases of vitamin overdose would probably result in little, if any, risk to either mother or fetus. However, the retinoic acid content of the vitamins should be determined to esti- mate the total exposure. It is possible that megadose vitamin A may be involved, in which case Chapter 13, Use of dermatologics during pregnancy, should be consulted. Iron The clinical course following iron overdose during pregnancy has been reported for six cases (Table 14. Iron poison- ing is associated with gastrointestinal hemorrhage, physiological shock, acidosis, hepatic failure, and coagulopathies (Table 14. The highest serum iron concentrations are likely to occur within 4 h of ingestion, with serum levels in excess of 500 µg/100 mL being more likely to be associ- ated with severe poisoning (James, 1970). From clinical experience, it is clear that early administration of the antidote is essential if therapy is to be efficacious. Total iron-binding capacity and liver function should be routinely monitored in the patient with an iron overdose, as should thrombin and prothrombin times. Essentially, the gravida with an iron overdose should be managed similarly to the nonpregnant adult, as is described in detail elsewhere (Friedman, 1987). Guidelines for treatment according to ingested dose (if known) are given in Table 14. In a report of 49 preg- nancies in which iron overdose occurred, there were 43 live births. Three infants had congenital anomalies, but they were exposed to the iron overdose and deferoxamine after the first trimester. The authors urge aggressive treatment of iron overdose with the specific antidote to prevent mater- nal death or organ toxicity (McElhatton et al. Review of 61 pregnancies indi- cated that in iron poisoning during pregnancy (1) peak maternal serum iron levels are associated with iron toxicity, and (2) deferoxamine should be administered without hes- itation (Tran et al. Following unpublished animal studies that suggest deferoxamine may cause signifi- cant fetal effects in animals, clinical experience has not shown this to be true in the human. Iron-overdose-associated pathophysiological effects on the mother seem to be the cause of adverse fetal outcomes, and not the direct result of iron overdose or anti- dote. No abnormalities have been reported among infants whose mothers consumed high doses of iron during pregnancy (Lacoste et al. It appears as though the placenta acts as a partial barrier to iron (Olenmark et al. Chemical properties of the deferoxamine mol- ecule strongly suggest that it would not cross the placenta in large amounts because it is a large molecule (molecular weight, 657) and is highly polarized. Several investigators have shown the efficacy of flumazenil in revers- ing the clinical signs and symptoms of a benzodiazepine overdose (Krisanda, 1993; L’Heureux et al. One case study reported on the reversal of fetal benzodiazepine intoxica- tion using flumazenil (Stahl et al. A 36-weeks, 22-year-old primipara ingested between 50 and 60 5 mg diazepam tablets. No adverse effects or withdrawal symptoms were noted in the patient or in the infant, who was born spontaneously 2 weeks later. The ‘floppy infant syndrome’ has been described, showing that benzodiazepines (1) cross the placenta and (2) have a depressive effect on the fetus. Warnings signs of complications in benzodiazepine overdoses in pregnancy are bradycardia and other symptoms of the drugs’ depressive physiologic effects on mother and fetus. Hydroxyzine The clinical courses of pregnancies after hydroxyzine overdoses have not been pub- lished. Hypersedation and hypotension are the most frequently observed abnormalities with hydroxyzine overdose in nonpregnant adults. Therefore, hydroxyzine overdose-associated hypotension should not be treated with epinephrine. Intravenous fluids and other pressor agents (levarterenol or metaraminol) should be used instead to treat hypotension. Between 1 and 2 g of hydroxyzine pamoate commonly produces drowsiness and lethargy that may progress to a coma (Magera et al. Barbituric acids cross the pla- centa and these drugs may induce fetal hepatic enzymes. Half-lives of phenobarbital and secobarbital range from 2 to 6 days and 22 to 29 h, respectively (Baselt, 1978). Five clinical stages of intoxication have been described in adults with acutely toxic (i. Pyrilamine No reports of pregnancy following pyrilamine overdoses have been published. Approximately 6 percent of suicide gestures in one study involved opioid anal- gesic preparations (Rayburn et al. It competitively binds to opioid recep- tors and opioid analgesics and blocks uptake. If the patient is addicted to opioids, naloxone will cause an almost immediate onset of withdrawal symptoms.

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These knots are often painful to the touch and buy azathioprine 50mg without prescription infantile spasms 2013, in some cases buy cheap azathioprine 50 mg on line muscle relaxant addiction, can cause muscles to spasm or “lock up discount azathioprine 50mg overnight delivery quad spasms,” which can pull your spinal column out of alignment— pinching nerves and causing nerve-based back pain. And if you doubt the effects the mind can have on the body, let me tell you about a study that was done in Finland. Autopsies were performed on people who had died from non- back-pain-related causes but had reported suffering from back 47 The 7-Day Back Pain Cure The Mind: How Emotions Cause Physical Pain 48 physical conditions in your body that make it highly pain while alive. Researchers were shocked to find that the susceptible to pain—especially back pain. And remember, without fresh blood University on more than 3,000 employees at the Boeing supplying oxygen and nutrients, it’s nearly impossible to heal. Corporation found that emotions and psychological factors Stress also alters your breathing. Oxygen and nutrients don’t How Emotions Act on the Body circulate at optimum levels, again contributing to the buildup of toxins. Stress also can release hormones, such as adrenaline, The mind is inextricably connected to the body. You have which can trigger chronic tension and inflammation in your only to imagine stepping off a bridge to feel your stomach fly muscles, ligaments, and tendons. This mental flow to remove these hormones from the body, they can thought can trigger a chain of physical reactions, including linger longer than usual and create more damage. Which muscles do you tend to tense most Just thinking about a stressful event can cause all this! Shoulders usually come first, directly So you can see the effect your mind can have on your affecting the spine. The jaw, stomach, and lower back also are body, particularly if you’re thinking stressful thoughts many very common areas. Your muscles tighten and, if you some of the first parts of the body to suffer from stress. They inhibit circulation, constricting blood vessels Other Ways Emotions Affect Health so the blood doesn’t flow through your body like it should and creating muscle imbalances. Negative emotions can have other detrimental effects on Without adequate blood flow, the cells in your body our health—effects that can make back pain worse. Toxins and waste aren’t Think about an emotionally distressing episode in your cleaned out as efficiently as they should be and can build up life. You probably slept too little, depriving your body of its in certain parts of your body, creating or reactivating trigger primary healing time. These knots are often painful to the touch somehow, so that you either lost your appetite and ate too and, in some cases, can cause muscles to spasm or “lock up,” little or reverted to eating too many highly processed, low- which can pull your spinal column out of alignment— nutrient foods. You might have skipped your usual exercise pinching nerves and causing nerve-based back pain. And if you doubt the effects the mind can have on the People around you may have commented on your increased body, let me tell you about a study that was done in Finland. Too little sleep, exercise, and calm, along with too much anxiety, bad foods, and inactivity all can have profound effects on your body. Back pain, neck pain, headaches, jaw pain, and joint soreness all are just around the corner. What makes this especially difficult is that the emotional component of any painful condition often is ignored. Somehow we’re conditioned to believe that any physical manifestation of our feelings is a sign of weakness or some mental problem. On the contrary, it’s quite typical to have a mental burden impact your physical body. As a society, we accept that being diagnosed with cancer or suffering a heart attack—even having a baby—can cause emotions like depression, anger, and even guilt. What we don’t recognize as easily is that the communication works both ways—from mind to body and from body to mind. Science has proven that the brain’s messengers (neurotransmitters) communicate information in the brain and throughout the body. Since the mind itself operates on physical and chemical reactions, why wouldn’t emotions, which are communicated in physical ways inside the body, have very physical outcomes? The truth is that our thoughts and emotions, and how we handle them, all have a very large effect on our everyday health and well-being. During periods of stress, they certainly cause or exacerbate physical discomfort or injury. It’s an unfortunate thing that as children 49 The 7-Day Back Pain Cure The Mind: How Emotions Cause Physical Pain 50 All these occasions are like dominoes stacked up against we’re rarely taught how to deal with our feelings. Too little sleep, exercise, and were learning all about reading, writing, math, and science— calm, along with too much anxiety, bad foods, and inactivity unless our parents were especially gifted in teaching us—we all can have profound effects on your body. Back pain, neck learned very little about the art of mastering our own pain, headaches, jaw pain, and joint soreness all are just emotions. If we were angry and blew up, most likely we were sent to What makes this especially difficult is that the emotional our rooms, or if we were in school, to the principal’s office. On the contrary, it’s quite typical to have a mental instruction along the way may have avoided the aches and burden impact your physical body. As a society, we accept that being diagnosed with cancer or But for many of us, we never learned the art of expressing suffering a heart attack—even having a baby—can cause ourselves without hurting others, or how journaling, emotions like depression, anger, and even guilt. Science has proven that the brain’s Some of us may not even realize when a powerful emotion messengers (neurotransmitters) communicate information in has taken hold of us. Since the mind itself or turning to self-destructive habits like alcohol or drug use. The truth is that our thoughts and emotions, and how we Psychology has shown us that, by far, the most dangerous handle them, all have a very large effect on our everyday way to handle emotions is to deny or repress them. During periods of stress, they certainly don’t learn to express them (in healthy ways), they stay in our cause or exacerbate physical discomfort or injury. Learning to properly express and deal with our emotions is one of the best things we can do for our overall health, and How we handle our emotions determines how they will especially for back pain.

On investigation order azathioprine 50 mg visa muscle relaxant liver disease, it was found that phenylbutazone not only markedly inhibits many of the metabolic pathways responsible for warfarin elimination generic azathioprine 50mg line muscle relaxant examples, but also displaces warfarin from its major binding protein purchase azathioprine 50mg overnight delivery spasms pancreas, albumin, making interpretation of the pharmacokinetic events based on total plasma concentration problematic (13,14). In such sit- uations, and indeed whenever possible, interpretation should be based on the more relevant unbound drug. For example, increasing evidence points to the small intestine, in addition to the liver, having sufficient metabolic activity to cause appreciable loss in the oral bioavailability of some drugs. Then unambiguous quantitation of the degree of involvement of each organ in an interaction in vivo becomes difficult, unless one has a way of separating them physically, such as by sampling the hepatic portal vein, which drains the intestine, to assess the amount passing across the intestinal wall, as well as the systemic circulation to assess the loss of the drug on passage through the liver. Still another is the metabolites themselves, which may possess pharma- cological and toxicological activity in their own right. Each metabolite has its Introducing Pharmacokinetic and Pharmacodynamic Concepts 25 own kinetic profile, which is often altered during an interaction, through a change either in its formation or occasionally in its elimination and distribution. Despite these complexities, however, measurement of both a drug and its metabolites can often be very informative and provide more definitive insights into an interaction than gained from measurement of the drug alone (5). The last complexity mentioned here is the pharmacokinetics of the inter- acting drug itself, be it an inhibitor, an inducer, or a displacer. Given that drug interactions are graded and recognizing that individuals vary widely in their degree of interaction for a given dosage regimen of each drug, it would seem sensible to measure both of them when characterizing an interaction. Even in vitro, all too often it is assumed that the concentration of the interactant is that added, without any regard to the possi- bility that it may bind extensively to components in the system or be metabol- ically degraded. In both cases, the unbound compound of the interacting drug is lower than assumed and if ignored may give a false sense of comfort, suggesting that higher (unbound) concentrations are needed to produce a given degree of interaction than is actually the case. When measured in vivo, it is usually the interacting drug in the circulating plasma rather than at the site of the interaction, such as the hepatocyte, that is inaccessible. In addition, the liver receives the drug primarily from the portal blood, where the concentration may be much higher than in plasma during the absorption phase of the interactant, making any attempt to generate a meaningful concentration-response relationship difficult. Finally, because many drug interactions involve competitive processes, the possibility always exists that the interaction is mutual, with both drugs affecting each other, the degree of effect exerted by each on the other depending on the relative concentrations of the two compounds. Through careful planning and subsequent analysis of both in vitro and in vivo data, progress is being made in our understanding of the mechanisms and pharmacokinetic aspects of drug interactions. In the former case, the change in response is caused by a change in the concentration of the affected drug, together perhaps with one or more metabolites. One feature commonly experienced in pharmacodynamics but much less in pharmacokinetics is saturability, giving rise to nonlinearity. The increase in toxicity for a drug with a wide therapeutic window is minimal (left panel). This relationship is of the same hyperbolic form as that used to describe the Michaelis-Menten enzyme kinetics. Accordingly, the concen- trations needed to produce the often-desired 50 –80% of Emax, which are already in the saturable part of the concentration-response relationship, are well below the Km of the metabolic enzyme systems. It also follows that quite large dif- ferences in the plasma concentration of drugs when operating in the 50–80% Emax range will produce relatively small changes in response. The answer is complex, but one reason is that as one pushes further toward the maximum possible response, Emax, the body sometimes goes into a hazardous state, putting the patient at risk. An example of this is seen with warfarin, which is used to lower the concen- trations of the clotting factors, thereby decreasing the tendency to form clots, through inhibition of the production of these clotting factors. However, if it is too severe, the clotting factors fall to such low con- centrations that internal hemorrhage may occur, with potential fatal Introducing Pharmacokinetic and Pharmacodynamic Concepts 27 Figure 17 When two drugs, drug A and drug B, are full competitive agonists (or antagonists), the effect of drug B on drug A depends on the fraction of the maximum effect achieved by drug A in the absence of drug B. As can readily be seen, the closer to Emax achieved by drug A alone, the smaller the impact of drug B. This condition is clearly an example of the adverse effect being the direct extension of the pharmacological properties of the drug. In many other cases, the limiting toxicity is not an extension of its desired effect but rather arises from a different effect of the drug, such as excessive intestinal bleeding associated with some anti-inflammatory agents. The wider the window, the bigger the increase in plasma concentration of a drug needed to produce a significant interaction. Pharmacodynamic interactions occur when one drug modifies the phar- macodynamic response to the same concentration of another. In most cases the mechanism of the effect of each is known, so the outcome is predictable and the combination is either used in therapy to benefit or is contraindicated if it is anticipated to produce undesirable effects. The interaction can result in addi- tivity, but also sometimes in synergism or antagonism, when the response is either greater or less than expected for additivity (16–19). Additivity occurs when the increase in response produced by the addition of the second drug is that expected from the concentration-response curve for each substance. A common example of additivity is seen with full agonists and antagonisms competing for 28 Rowland the same receptor. Accordingly, in terms of drug interactions, as shown in Figure 17, however much drug B is added to drug A, one cannot exceed Emax. The nearer the effect is to Emax, with one drug alone, the lower the impact of the addition of the other. In summary, a sound understanding of pharmacokinetic and pharmacodynamic concepts not only enables one to place in vitro information into an in vivo framework, but also helps in both the design and the interpretation of in vitro and in vivo drug interaction studies. Kinetics of drug metabolism inhibition: use of metabolite concentration-time profiles. Influence of hepatic blood flow, plasma and blood cell binding, and hepatocellular enzymatic activity on hepatic drug clearance. Models of hepatic elimination: a com- parison of stochastic models to describe residence time distributions and to predict the influence of drug distribution, enzyme heterogeneity, and systemic recycling on hepatic elimination. Phenylbutazone-warfarin interaction in man: further stereochemical and metabolic considerations. Stereochemical aspects of warfarin drug interactions: use of a combined pharmacokinetic-pharmacodynamic model. Most of this infor- mation is obtained from (1) animal studies, (2) human tissue preparations in conjunction with chemical inhibitors or antibodies, and (3) expressed enzymes. This chapter will focus on the techniques used to characterize the in vitro metabolism of drugs.

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