By O. Grim. Converse College. 2019.
As a result fluticasone 250 mcg on line, research of anxiety in humans has concentrated on drugs with a known pharmacological target (usually a neurotransmitter receptor) and has compared their effects in anxious patients and normal subjects discount fluticasone 100mcg overnight delivery. The apparent delay in the increase in punished responses is due to the reduction in all responses (including unpunished ones) at the start of drug administration purchase fluticasone 500 mcg. The progressive recovery of unpunished responses reflects the development of tolerance to the sedative effects of the test compound discount fluticasone 500 mcg without a prescription. Note the immediate increase in punished responses and the lack of a decline in unpunished responses, indicating pre-existing tolerance to the sedative effects of the test compound. A full appraisal of this topic is beyond the scope of this chapter but the links between drugs that affect central monoamine transmission and anxiety are discussed in later sections. Details of findings from research in humans can be found in Ballenger (1990) and Coupland, Glue and Nutt (1992). Alternative treatments, such as paraldehyde and chloral hydrate, were also widely used but these too had adverse effects; the former can cause psychosis but the latter is still used as a sedative and anaesthetic agent. It was not until the 1930s that it was recognised that this adverse behavioural effect of barbiturates in fact represented a drug-withdrawal syndrome (Seevers and Tatum 1931). This, together with the overt sedation caused by barbiturates, their narrow therapeutic index and their lethal toxicity in overdose, motivated the search for non- sedative anti-anxiety agents. However, the initial enthusiasm over the use of this compound as a treatment for anxiety rapidly abated because it too proved to be a potent sedative and, of even more concern, it induced dependence and was widely abused. Like their predecessors, but with greater justification, these drugs were claimed to relieve anxiety at non-sedative doses (see Sternbach, Randall and Gustafson 1964). However, the benzodiazepines are members of the sedative/hypnotic group of anti-anxiety drugs, which also include alcohol, meprobamate and the barbi- turates. This means that the liability of all these compounds to induce sedation, or even hypnosis (sleep), is largely a question of dose (Fig. This action is thought to play a crucial role in the anti-anxiety effects of these drugs. Barbiturates bind non-competitively to yet another, functionally distinct, domain on the receptor which is thought to be directly associated with the Cl7 channel itself. In contrast, in the cerebellum, the curve was steep with a Hill coefficient of 1 (Duggan and Stephenson 1988). In this technique [3H]flunitrazepam binding is carried out under ultra-violet light which renders most of the ligand binding irreversible. The discovery of these receptor subtypes kindled the hope that it would be possible to develop subtype-selective drugs with specific clinical actions: i. Notwithstanding this selectivity, zolpidem turns out to be a potent hypnotic agent. Indeed, there are reports of their anti-anxiety effects in patients receiving these treatments for relief of epilepsy. There is also some supporting evidence from preclinical studies but the behavioural effects of these drugs in animal models are less robust than are those of the benzodiazepines. It remains to be seen whether this is because they are just less effective anti-anxiety agents than the benzodiazepines or whether existing preclinical models show a bias that detects preferentially the anti-anxiety effects of benzodiazepines. This is regrettably confusing because this receptor has now been found in the brain also (Awad and Gavish 1987). Another difference is that these peripheral benzodiazepine receptors are located mainly intraneuronally, on mitochondrial outer membranes, rather than on the plasma membrane. In the brain, they are associated with glial cells but in the periphery they are found in a range of tissues, including mast cells and platelets. Their function is still a matter of intense debate but one possibility is that they regulate cholesterol uptake and, secondary to this, the synthesis of neurosteroids (Do Rego et al. Other possible, albeit controversial, functions of these receptors are reviewed in Doble and Martin (1996). However, not all turned out to share the properties of the protypical benzodiazepines (anti-anxiety, anticonvulsant, etc. However, all these groups of compounds, including the benzodiazepines themselves, span the activity spectrum: from full inverse agonist to full agonist. In between these extremes are compounds which have either partial agonist or partial inverse agonist activity and some are antagonists (Fig. This spectrum of actions reflects the overall effects of these drugs on native receptors and is usually assessed in whole animals. However, the synthesis of receptors comprising different combinations of subunits has shown that the activity of these drugs depends greatly on subunit composition. Apparent effects of the antagonist in vivo could also depend on whether there is any tonic activation of the benzodiazepine receptor by an endogenous ligand. Flumazenil is available in the clinic for intravenous infusion to reverse benzodiazepine-induced sedation (e. However, because it has a half-life of only 1 h in humans, it is only of realistic benefit in reversing the actions of agonist benzodiazepines with a short half-life, such as midazolam. The potential benefits of benzodiazepine partial agonists are as non-sedative, anti- anxiety agents. Because of their low efficacy, it was predicted that a partial agonist should not induce sedation even if their receptor occupancy exceeds that normally required for an anti-anxiety effect when using a full agonist. One such compound, bretazenil, has been developed but failed to reach the clinic because it displayed some sedative activity and, more problematic, there were end-of-dose rebound effects that were undoubtedly exacerbated by its short half-life. Currently, the partial agonist, abecarnil (a b-carboline), is undergoing clinical trials. For the current status of the development of partial agonists and other promising benzodiazepine receptor ligands see Cheetham and Heal (2000). Even benzodiazepine inverse agonists might yet find some useful applications such as in the relief of cognitive deficits (which are increased by benzodiazepine full agonists) (Abe, Takeyama and Yoshimura 1998). However, three candidates have been given prominent attention, albeit for different reasons, and are worthy of mention. Although subsequently found to be an artefact of the extraction process, this compound turned out to be a ligand for the benzodiazepine receptor, nonetheless, and was the first inverse agonist to be identified. Finally, the presence in human post-mortem brain tissue of the active metabolite of diazepam, desmethyldiazepam, raised some curiosity and frank alarm (Sangameswaran et al. At the time of its discovery in the brain it was thought that there was no enzyme system capable of producing such halogenated compounds and that its presence in the brain reflected dietary intake from an environment contaminated by overuse of its parent compound. However, its discovery in stored brain tissue which had been obtained before the synthesis of the benzodiazepines allayed these fears. It is now thought possible that some benzodiazepines, including desmethyl- diazepam, occur naturally and that they are taken in as part of a normal diet (Table 19. Although, by analogy with the opioids, one would expect there to be an endogenous ligand for the widely distributed benzodiazepine receptor, its existence remains uncertain and we must be alert to the possibility that any such ligand(s) could have either agonist or inverse agonist activity. An important study, aimed at distinguishing between these possibilities, has been carried out in humans (Nutt et al. In this case, the administration of the antagonist, flumazenil, should induce anxiety in normal subjects and exacerbate anxiety in anxious patients.
This type of device is implanted subcutaneously and connected via a special lead which is inserted via the cephalic or subclavian vein and advanced to the right ventricle cheap fluticasone 100mcg with mastercard. The device automatically monitors the heart rate using this lead and when a programmed is achieved order 500mcg fluticasone, the device will deliver a synchronized electrical shock to the lead in the right ventricle (and possibly right atrium or superior vena cava) which will reuslt in conversion of the ventricular tachycardia or ventricular fibrillation cheap fluticasone 500 mcg with mastercard. For some reentrant ventricular tachycardias fluticasone 100 mcg line, the implantable defibrillator may pace in the heart at rates faster than the ventricular tachycardia, resulting in termination of the arrhythmia without the need for an electrical shock. For the acute treatment of ventricular arrhythmias, intravenous lidocaine and amiodarone and less commonly procainamide may be administered. Catheter ablation techniques for ventricular tachycardia may be used but are more complex than for supraventricular tachycardias. Such a device may be used to quantitate frequency symptomatic or asymptomatic arrhythmias. Patients with less frequent but prolonged (> 1 minute) episodes of arrhythmias without syncope may use an event monitor which is carried with the patient and connected only in the event of an arrhythmia. Patients with episodes of syncope or very brief episodes of arrhythmias may use a “loop” monitor which is connected to the patient for several weeks to several months. The recorder saves the preceding several minutes and may be transmitted via a telephone hookup Autonomic Drugs (Sympathomimetics 1) - James Whitlock, M. Understand the differences between direct-acting and indirect acting sympathomimetic drugs. Become familiar with the major structure-activity relationships among sympathomimetic drugs. Continue to learn the tissue distribution of adrenergic receptor subtypes and their responses following agonist administration. The primary role of each atrium is to act as a reservoir and "booster pump" for venous blood entering the ventricles. Recently, with the discovery of atrial naturetic hormone, other homeostatic roles of the atrium have been proposed. The primary physiologic function of each ventricle is to maintain circulation of blood to the organs of the body. The left heart receives oxygenated blood from the pulmonary circulation, and contraction of the muscles of the left ventricle provide energy to propel that blood through the systemic arterial network. The right ventricle receives blood from the systemic venous system and propels it through the lungs and onward to the left ventricle. The reason that blood flows through the system is because of the pressure gradients set up by the ventricles between the various parts of the circulatory system. In order to understand how the heart performs its task, one must have an appreciation of the force-generating properties of cardiac muscle, the factors which regulate the transformation of muscle force into intraventricular pressure, the functioning of the cardiac valves, and something about the load against which the ventricles contract, i. You have learned about the properties of cardiac muscle and vascular systems in previous lectures. This session will focus on a description of the pump function of the ventricles with particular attention to a description of those properties as represented on the pressure-volume diagram. The ventricles are chambers whose walls are composed predominantly of cardiac muscle. Therefore, when considering the properties of the ventricle as a mechanical pump, one should keep in mind the underlying force-generating properties of cardiac muscle and the structural features of the ventricle which determine how muscle force translates into pressure inside the ventricle. The force generated by a muscle is directly influenced by the initial (or "diastolic") length of the muscle -- increased diastolic length results in greater force production. When the volume of the heart is changed, so too is the length of the muscles in the wall of the heart. There are at least four factors that contribute to determining the relationship between muscle properties (length and force) and ventricular properties (volume and pressure): 1. Muscle Mass It is intuitively obvious that the more muscle that comprises the chamber wall the stronger the ventricle will be. As one example of this, compare the functioning of the right and left ventricles of the same heart. The left ventricle generates about 4 to 5 times the pressure of the right ventricle when the wall stress (stress = force/unit area of muscle) is the same. There are several factors which contribute to this difference, but the predominant one is that left ventricular weight (the amount of muscle) is roughly 3 to 4 times that of the right. Ventricular Geometry Compare a chamber with a circular cross-section to one with an elliptical cross-section. The mathematical equations relating wall stress and chamber pressure will be different. Thus for the same muscle mass and wall stress, the pressure inside these two chambers would be different. Architecture of the wall This refers to the how the fibers are put together to form the ventricular wall. Histologic studies have shown that the fiber bundles wrap around the ventricular chamber in a standard way. If one cuts out a small piece of the ventricular wall and examines the fibers, one finds that the angle at which the fibers run relative to the axis of the chamber varies with the depth of the layer within the wall. The muscles are activated by the specialized Purkinje network which conducts electrical impulses an order of magnitude faster than ventricular muscle. In the normal human heart, it takes about 80 ms for all the muscle to become activated and start contracting. This can be greatly prolonged if activation is initiated from outside the normal pathways or when the Purkinje network is diseased. When the activation time is increased, there is greater dispersion in the onset of mechanical contraction of the muscles and the strength of the chamber is reduced an amount proportional to the increase in the dispersion time. When the pressure P1 is greater than P2, as in the left side of the figure, flow tends towards the right and fluid pushes on the convex surfaces of the leaflets, opening the valve. In contrast if P2 is greater than P1, as in the right side of the figure, flow tends towards the left and fluid is caught in the concave portion of the leaflets, Ventricular Physiology - Robert Turcott, M. Thus, the main (though not exclusive) determinant of whether the valve is open or closed is the pressure gradient across it. The heart valves are responsible for enabling the heart to propel blood in only one direction. The cardiac cycle (the period of time required for one heart beat) is divided into two parts: systole and diastole. Systole (from Greek, meaning "contracting") is the period of time during which the muscle transforms from its rested state to the instant of maximal mechanical activation; this period of time includes the electrical events responsible for initiating the contraction. Diastole (from Greek, meaning "dilation") is the period of time during which the muscle relaxes from the end-systolic (maximally activated) state back towards its resting state. These "physiologic" definitions of onsets of systole and diastole differ from the "clinical" definitions which use the first and second heart sounds to define these events. The mechanical events occurring during the cardiac cycle consist of changes in pressure in the ventricular chamber which cause blood to move in and out of the ventricle. Thus, we can characterize the cardiac cycle by tracking changes in pressures and volumes in the ventricle as shown in the Fig. During this time the heart is in its relaxed (diastolic) state; AoP falls as the blood ejected into the arterial system on the previous beat gradually moves from the large arteries to the capillary bed. Since both valves are closed, no blood can enter or leave the ventricle during this time, and therefore the ventricle is contracting "isovolumically" (at a constant volume).
Genetic testing is becoming increasingly easier order 100mcg fluticasone mastercard, but tests for these genetic problems associated with the thyroid are still not widely available buy fluticasone 100 mcg free shipping. Goitrogens are compounds (found in soy 100mcg fluticasone free shipping, millet generic fluticasone 500mcg visa, and certain vegetables such as broccoli and Brussels sprouts) that suppress the thyroid by interfering with the cells’ uptake of iodine, which is key to normal thyroid production. Several drugs prescribed in cases of excess thyroid, or hyperthyroidism, are designed to block the thyroid; two examples are propylthiouracil and lithium (used to treat bipolar disorder). You need not avoid goitrogens; just make sure you are getting the right amount of iodine and track your thyroid levels. Low thyroid function is increasingly recognized to be a consequence of cancer therapy, particularly with newer anticancer therapies. We know that vitamin D deficiency is more common in folks with autoimmune thyroiditis, as well as in people who harbor antithyroid antibodies. Celiac disease is a permanent intolerance to eating gluten, and it triples your risk of problems with low thyroid function. In people genetically predisposed to this disease, eating gluten results in inflammation and damage to the lining of the small intestine, preventing this twenty-foot section of the gut from absorbing nutrients crucial to your health. One percent of Americans have celiac disease, although many more—an estimated six out of one hundred—suffer from gluten sensitivity. Many struggle for years with “irritable bowel syndrome,” until a good medical detective helps them figure out the root cause of their long-standing bowel problems. Many people don’t know they suffer from gluten intolerance because they have no symptoms at all. They don’t know they aren’t absorbing crucial nutrients until they start to develop symptoms of hypothyroidism, or perhaps signs of osteoporosis, such as bone fractures. Too often, doctors don’t think of celiac as a root cause for such vague and nonspecific symptoms as fatigue and bloating. Fortunately, knowledge is spreading, and more people are getting diagnosed prior to the onset of symptoms. If you have celiac disease, you may be missing out on key nutrients, such as the fat- soluble vitamins A, D, E, and K; you may not be absorbing iron, vitamin B12, and folate, and some of these nutrients impact your thyroid function as well. If left untreated, celiac disease can cause ulcers in your small intestine, or intestinal stricturing, which is when the internal opening narrows as a result of inflammation and scarring. Celiac disease increases the risk of bacterial overgrowth of the small intestine—an imbalance between the good and bad bacteria in the gut that favors the bad. Even worse, celiac disease puts you at greater risk for cancer of the small bowel, including adenocarcinoma and lymphoma. People with a sensitivity to gluten develop something known as leaky-gut syndrome, or increased intestinal permeability, when the tight junctions between the cells lining the small intestine become disrupted. If you have autoimmune thyroiditis, consider testing for leaky-gut syndrome with a blood or urine test ordered through your doctor. Some of my patients initially have hyperthyroidism, or excess thyroid, when the thyroid produces too many hormones. Symptoms include palpitations, shortness of breath, weight loss, tremulousness or shakiness, and proptosis (eyes bugging out). Untreated, hyperthyroidism can lead to cardiovascular problems such as a potentially dangerous type of arrhythmia called atrial fibrillation, cardiomyopathy (a disease of the heart), and congestive heart failure. When you have hyperthyroidism, you are more likely to have increased bone turnover, which over time may lead to bone loss and fracture. Another serious consequence is thyrotoxicosis, also known as thyroid storm, which has a significant risk of mortality. Surgeon General suggested that Americans have some on hand, in case nuclear radiation came our way in significant amounts. Nuclear accidents release radioactive iodine (I- 131), which your body can’t distinguish from the iodine you get in seafood and iodized salt. This is bad, because the thyroid absorbs and concentrates iodine, and a relatively small dose of radiation can increase your risk for developing thyroid cancer even ten or twenty years later. Potassium iodine can come to the rescue by saturating the thyroid gland, crowding out the radioactive iodine, and preventing it from being absorbed for up to twenty-four hours. It may be dangerous to take it prior to exposure, particularly if you have Hashimoto’s thyroiditis. In addition to thinning and shedding, your hair can become coarse, dry, and easily tangled. If the cause of your hair-loss woes is low thyroid, it’s likely this kind of general hair loss will slow and eventually stop once your hormone levels are stabilized. But sometimes the problem continues even after treatment, especially if you’re taking levothyroxine, a synthetic hormone often used to treat hypothyroidism. You’ll want to look into this if you’re still losing hair despite what your doctor calls sufficient treatment. Some people find their hair loss diminishes if they take Thyrolar, a synthetic combination of both thyroid hormones, T4 and T3. Sometimes the problem is male-pattern hair loss, on the temples and top of the head, seen in women with high testosterone. The problem may be exacerbated in some patients treated with drugs for thyroid problems. The nutritional supplement evening primrose oil inhibits the conversion of testosterone to dihydrotestosterone. And it is a good source of essential fatty acids—the symptoms of hypothyroidism are quite similar to those for insufficient essential fatty acids. In one study, 90 percent of women with thinning hair were deficient in iron and the amino acid 25 lysine. Good sources of lysine are foods rich in protein, such as meat and poultry, eggs, and some fish (cod, sardines). Because grains contain small quantities of lysine but legumes contain lots, meals that combine the two—Indian dal with rice, beans with rice and tortilla, falafel and hummus with pita bread—are a good way to get complete protein in your diet and keep hair on your head. The Solution: The Gottfried Protocol for Low Thyroid Step 1: Targeted Lifestyle Changes and Nutraceuticals Several micronutrients, required by your body in small quantities for optimal physiological function, can alter your thyroid balance. Additionally, certain heavy metals and endocrine disruptors from the environment can harm your thyroid function. The thyroid gland is quite sensitive to copper and zinc, which must remain in proportion; an imbalance in these two elements can result in hypothyroidism. Additionally, thyroid hormone regulates blood levels of copper by adjusting the copper transport protein ceruloplasmin, and thereby changing the level of copper inside and outside of cells. Meats, poultry, and eggs are the best dietary sources of copper, which means vegans need to supplement their diets with an abundance of nuts, seeds, and grains, other good sources of copper. Even with sufficient copper in your diet, you may be like me: I have trouble absorbing copper and consistently measure low on blood tests.
We will analyze the forces involved when the trunk is bent at 60◦ from the vertical with the arms hanging freely buy 100mcg fluticasone fast delivery. The weight of the trunk W1 is uniformly distributed along the back; its eﬀect can be represented by a weight suspended in the middle discount 250mcg fluticasone overnight delivery. The weight of the head and arms is represented by W2 suspended at the end of the lever arm fluticasone 100mcg overnight delivery. The erector spinalis muscle discount 500 mcg fluticasone, shown as the connection D-C attached at a point two-thirds up the spine, maintains the position of the back. For a 70-kg man, W and W 1 2 are typically 320 N (72 lb) and 160 N (36 lb), respectively. If, in addition, the person holds a 20-kg weight in his hand, the force on the muscle is 3220 N (725 lb), and the compression of the vertebra is 3490 N (785 lb) (see Exercise 1-12). It is evident too that the position shown in the ﬁgure is not the recom- mended way of lifting a weight. The balancing force is provided by the muscle connected to the heel by the Achilles tendon. Calculations show that while standing tiptoe on one foot the compressional force on the tibia is 3. In fact, the human body (and bodies of all animals) is a dynamic system continually responding to stimuli generated internally and by the external environment. Because the center of gravity while standing erect is about half the height above the soles of the feet, even a slight displacement tends to topple the body. As has been demonstrated experimentally the simple act of standing upright requires the body to be in a continual back and forth, left right, swaying motion to maintain the center of gravity over the base of support. In a typical experi- ment designed to study this aspect of posture, the person is instructed to stand, feet together, as still as possible, on a platform that registers the forces applied by the soles of the feet (center of pressure). To compensate for the shifting center of gravity this center of pressure is continually shifting by several cen- timeters over the area of the soles of the feet on a time scale of about half a second. Small back-and-forth perturbations of the center of mass (displace- ments less than about 1. Hip movements are required to compensate for larger displacements as well as for left right perturbations. The maintaining of balance in the process of walking requires a yet more complex series of compensating movements as the support for the center of gravity shifts from one foot to the other. The performance of this task is most remarkable when accidentally we slip and the center of gravity is momentar- ily displaced from the base of support. As is shown in Chapter 4, Exercise 4-9, Chapter 1 Exercises 21 without compensating movements an erect human body that looses its balance will hit the ﬂoor in about 1 sec. During this short time interval, the whole mus- cular system is called into action by the “righting reﬂex” to mobilize various parts of the body into motion so as to shift the center of mass back over the base of support. The nervous system obtains information required to maintain balance prin- cipally from three sources: vision, the vestibular system situated in the inner ear that monitors movement and position of the head, and somatosensory sys- tem that monitors position and orientation of the various parts of the body. With age, the eﬃciency of the functions required to keep a person upright decreases resulting in an increasing number of injuries due to falls. In the United States, the number of accidental deaths per capita due to falls for persons above the age of 80 is about 60 times higher than for people below the age of 70. Another aspect of the body dynamics is the interconnectedness of the musculoskeletal system. Through one path or another, all muscles and bones are connected to one another, and a change in muscle tension or limb posi- tion in one part of the body must be accompanied by a compensating change elsewhere. The bones act as the tent poles and the muscles as the ropes bringing into and balancing the body in the desired posture. The proper functioning of this type of a structure requires that the forces be appropriately distributed over all the bones and muscles. In a tent, when the forward-pulling ropes are tightened, the tension in the back ropes must be correspondingly increased; otherwise, the tent collapses in the forward direction. For example, excessive tightness, perhaps through overexertion, of the large muscles at the front of our legs will tend to pull the torso forward. To compensate for this forward pull, the muscles in the back must also tighten, often exerting excess force on the more delicate structures of the lower back. In this way, excess tension in one set of muscles may be reﬂected as pain in an entirely diﬀerent part of the body. Assume the person does not slide and the weight of the person is equally distributed on both feet. Using the data provided in the text, calculate the maximum weight that the arm can support in the position shown in Fig. Calculate the force applied by the biceps and the reaction force (Fr) at the joint as a result of a 14-kg weight held in hand when the elbow is at (a) 160◦ and (b) 60◦. Note that under these conditions the lower part of the arm is no longer horizontal. Now let the 14-kg weight hang from the mid- dle of the lower arm (20 cm from the fulcrum). Assume that the lower part of the arm has a mass of 2 kg and that its total weight can be considered to act at the middle of the lower arm, as in Exercise 1-6. Estimate the dimensions of your own arm, and draw a lever model for the extension of the elbow by the triceps. Calculate the force of the tri- ceps in a one arm push-up in a hold position at an elbow angle of 100◦. Suppose that the muscle contraction is uni- form in time and occurs in an interval of 0. Compute the velocity of the point of attachment of the tendon to the bone and the velocity of the weight. Chapter 2 F riction If we examine the surface of any object, we observe that it is irregular. Even surfaces that appear smooth to the eye show such irregularities under microscopic examination. When two surfaces are in contact, their irregularities intermesh, and as a result there is a resistance to the sliding or moving of one surface on the other. If one surface is to be moved with respect to another, a force has to be applied to overcome friction. But the intermeshing of surfaces produces a frictional reaction force Ff that opposes motion. In order to move the object along the surface, the applied force must overcome the frictional force. The magnitude of the frictional force depends on the nature of the surfaces; clearly, the rougher the surfaces, the greater is the frictional force. The frictional property of the surfaces is represented by the coeﬃcient of friction μ. The magnitude of the frictional force depends also on the force Fn perpendicular to the surfaces that presses the surfaces together. The magnitude of the force that presses the surfaces together determines to what extent the irregularities are intermeshed. In general, it takes a larger force to get the object moving against a frictional force than to keep it in motion.