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Synthesis of bile; serum albumin and globulin; pro- thrombin; fibrinogen; blood coagulation factors V cheap 160 mg kamagra super free shipping erectile dysfunction juice, VII purchase 160 mg kamagra super visa erectile dysfunction lack of desire, the liver is a vital organ that performs numerous functions purchase kamagra super 160mg visa erectile dysfunction 21 years old. Formation of urea re- It receives about 1500 mL of blood per minute, or 25% to moves ammonia from body fluids. About three fourths of the ammonia are formed by intestinal bacteria and ab- blood flow is venous blood from the stomach, intestines, sorbed into the blood. If the ammonia is not converted spleen, and pancreas (portal circulation); the remainder is ar- to urea by the liver, plasma ammonia concentrations terial blood through the hepatic artery. The hepatic artery car- rise to toxic levels and cause hepatic coma and death. Production of body heat by continuous cellular me- then empties into the hepatic sinuses. The liver is the body organ with the highest with blood from the portal circulation. Venous blood from rate of chemical activity during basal conditions, and it the liver flows into the inferior vena cava for return to the sys- produces about 20% of total body heat. The hormone cholecystokinin causes Mucus is secreted by mucous glands in every part of the the gallbladder to contract and release bile into the small in- gastrointestinal (GI) tract. The functions of mucus are to pro- testine when fats are present in intestinal contents. The liver tect the lining of the tract from digestive juices, lubricate the secretes about 600 mL of bile daily. This amount is concen- food bolus for easier passage, promote adherence of the fecal trated to the 50- to 60-mL capacity of the gallbladder. Bile salts are required for digestion and absorption of fats, including fat-soluble vitamins. Most of the bile salts are reabsorbed and reused by the liver (enterohepatic Saliva recirculation); some are excreted in feces. Saliva EFFECTS OF DRUGS ON THE has a slightly acidic to neutral pH (6 to 7); it lubricates the DIGESTIVE SYSTEM food bolus and starts starch digestion. Many common symptoms (ie, nausea, vomiting, con- Gastric Juice stipation, diarrhea, abdominal pain) relate to GI dysfunction. These symptoms may result from a disorder in the digestive Gastric juice consists of mucus, digestive enzymes, hydro- system, disorders in other body systems, or drug therapy. The gastric glands secrete about Many GI symptoms and disorders alter the ingestion, dissolu- 2000 mL of highly acidic (pH of 1 to 3) gastric juice daily. Drugs may be ad- Secretion varies according to time of day, the time and type ministered to relieve these symptoms and disorders, but drugs of food intake, psychological states, and other metabolic administered for conditions unrelated to the digestive system activities of the body. It is highest in the evening and lowest may cause such symptoms and disorders. Secretion is stimulated by the parasym- alter responses to drug therapy. The drug groups included in this sec- tion are drugs used for acid-peptic disorders, laxatives, an- the major digestive enzyme in gastric juice is pepsin, a pro- tidiarrheals, and antiemetics. Other drug groups used in GI teolytic enzyme (named before the ase system of naming en- disorders include cholinergics (see Chap. There is also a weak action on fats by gastric lipase and on car- bohydrates by gastric amylase. A large amount of mucus is se- creted in the stomach to protect the stomach wall from the Review and Application Exercises proteolytic action of pepsin. Pancreatic juices are alkaline (pH 8 or above) secretions that contain amylase for carbohydrate digestion, lipase for fat di- 5. This protects the mu- SELECTED REFERENCES cosa of the small intestine from the digestive properties of Guyton, A. Pathophysiology: Concepts of altered health cretion of pancreatic juices. Discuss significant drug–drug interactions with disease and gastroesophageal reflux disease. Describe characteristics, uses, and effects of peptic ulcers and acid reflux disorders. Teach clients nonpharmacologic measures to the-counter uses of histamine-2 receptor manage peptic ulcers and gastroesophageal blocking agents. Greenspan, a 26-year-old homemaker, has rheumatoid arthritis that has been treated with aspirin, nonsteroidal anti-inflammatory drugs, and prednisone for the last 10 years. She is dizzy when getting up and has had one episode of syncope (fainting). How symptoms of weakness, dizziness, and syncope are associated with a peptic ulcer. What therapies (drugs and nondrugs) can be used to prevent a recurrence of her ulcer. OVERVIEW intestinal (GI) mucosa that are exposed to gastric acid and pepsin. Gastric and duodenal ulcers are more common then Drugs to prevent or treat peptic ulcer and acid reflux dis- esophageal ulcers. To aid understanding structive mechanisms or decreased protective mechanisms). Gastric acid, a strong acid that can digest the stom- ach wall, is secreted by parietal cells in the mucosa of the PEPTIC ULCER DISEASE stomach antrum, near the pylorus. The parietal cells contain re- ceptors for acetylcholine, gastrin, and histamine, substances Peptic ulcer disease is characterized by ulcer formation that stimulate gastric acid production. Acetylcholine is released in the esophagus, stomach, or duodenum, areas of the gastro- by vagus nerve endings in response to stimuli, such as thinking 867 868 SECTION 10 DRUGS AFFECTING THE DIGESTIVE SYSTEM BOX 60–1 SELECTED UPPER GASTROINTESTINAL DISORDERS Gastritis sis, burns, acute respiratory distress syndrome, major surgical pro- Gastritis, a common disorder, is an acute or chronic inflammatory cedures, or other severe illnesses. Stress ulcers are usually manifested by cers usually also have gastritis. Acute gastritis (also called gas- painless upper gastrointestinal (GI) bleeding. The frequency of oc- tropathy) usually results from irritation of the gastric mucosa by currence has decreased, possibly because of prophylactic use of such substances as alcohol, aspirin or other nonsteroidal anti- antacids and antisecretory drugs and improved management of inflammatory drugs (NSAIDs), and others. Chronic gastritis is sepsis, hypovolemia, and other disorders associated with critical usually caused by H. Acidosis increases severity Nonsteroidal Anti-inflammatory Drug Gastropathy of lesions, and correction of acidosis decreases their formation. In NSAID gastropathy indicates damage to gastroduodenal mucosa addition, lesions do not form if the pH of gastric fluids is kept by aspirin and other NSAIDs. Many people take NSAIDs daily for Zollinger-Ellison Syndrome pain, arthritis, and other conditions. Chronic ingestion of NSAIDs Zollinger-Ellison syndrome is a rare condition characterized by causes local irritation of gastroduodenal mucosa, inhibits the syn- excessive secretion of gastric acid and a high incidence of ulcers. Approximately two thirds of the gastrinomas are and mucus, and maintaining mucosal blood flow), and increases malignant. Symptoms are those of peptic ulcer disease, and diag- the synthesis of leukotrienes and possibly other inflammatory sub- nosis is based on high levels of serum gastrin and gastric acid. Treatment may involve long-term use of a proton pump inhibitor to diminish gastric acid, or surgical excision.

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Progesterone also may help maintain triphasic preparations mimic normal variations of hor- pregnancy by decreasing uterine contractility purchase generic kamagra super on-line erectile dysfunction in young age. This cheap kamagra super 160mg amex erectile dysfunction pill identifier, in turn best purchase kamagra super impotence 25 years old, mone secretion, decrease the total dosage of hormones, decreases the risk of spontaneous abortion. Progesterone, in general, has opposite effects on lipid me- These contraceptives are dispensed in containers with tabolism compared with estrogen. That is, progestins decrease color-coded tablets that must be taken in the correct se- high-density lipoprotein (HDL) cholesterol and increase low- quence. Dispensers with 28 tablets contain seven inactive density lipoprotein (LDL) cholesterol, both of which increase or placebo tablets of a third color. These are not widely creases insulin levels but does not usually impair glucose tol- used because they are less effective in preventing preg- erance. However, long-term administration of potent synthetic nancy and are more likely to cause vaginal bleeding, progestins, such as norgestrel, may decrease glucose tolerance which makes them less acceptable to many women. Like • Several combination products and alternative dosage estrogen, progesterone is metabolized in the liver. For example, several noncontra- ceptive combination oral tablets are available for treat- ESTROGENS AND PROGESTINS ment of menopausal symptoms and osteoporosis. Two USED AS DRUGS combination products (Combi-Patch and Ortho Evra) are available in transdermal patches for topical applica- • When exogenous estrogens and progestins are adminis- tion. Also, along with several cream formulations, a tered for therapeutic purposes, they produce the same vaginal tablet (Vagifem) and a vaginal ring (Estring) of effects as endogenous (naturally occurring) hormones. Estrogens circulate in estrogens and oil solutions of both estrogens and pro- the bloodstream to target cells, where they enter the cells gesterone prolong drug action by slowing absorption. The • Conjugated estrogens (eg, Premarin) and some syn- estrogen–receptor complex is then transported to the cell thetic derivatives of natural estrogens (eg, ethinyl estra- nucleus where it interacts with deoxyribonucleic acid (DNA) diol) and natural progesterone (eg, norethindrone) are to produce ribonucleic acid (RNA) and new DNA. These chemically modified to be effective with oral adminis- substances stimulate cell reproduction and production of tration. Progestins also diffuse freely into cells, trogen is ethinyl estradiol, which is used in hormonal where they bind to progesterone receptors. Ethinyl estradiol is well absorbed with Hormonal contraceptives act by several mechanisms. It is 98% bound to plasma proteins and releasing hormone, which inhibits pituitary secretion of FSH its half-life varies from 6 to 20 hours. When these gonadotropic hormones are absent, ovu- undergoes extensive first-pass hepatic metabolism and lation and, therefore, conception cannot occur. Second, the is further metabolized and conjugated in the liver; the drugs produce cervical mucus that resists penetration of sper- conjugates are then excreted in bile and urine. Third, the drugs in- • Nonsteroidal, synthetic preparations are usually terfere with endometrial maturation and reception of ova that administered orally or topically. These overlapping mechanisms cally altered to slow their metabolism in the liver. They are also less bound to serum proteins than nat- urally occurring hormones. Norethindrone undergoes first-pass Estrogens metabolism so that it is only 65% bioavailable. It is metabolized in the liver and excreted in ciency states usually result from hypofunction of the urine and feces. Monophasic contraceptives contain fixed pituitary gland or the ovaries and may occur anytime amounts of both estrogen and progestin components. For example, in the adolescent girl Biphasics and triphasics contain either fixed amounts of with delayed sexual development, estrogen can be given estrogen and varied amounts of progestin or varied to produce the changes that normally occur at puberty. Biphasic and In the woman of reproductive age (approximately 12 to 412 SECTION 4 DRUGS AFFECTING THE ENDOCRINE SYSTEM 45 years of age), estrogens are occasionally used in the drugs decreased myocardial infarctions and deaths menstrual disorders, including amenorrhea and abnor- from cardiovascular disease. The difference was with a progestin, is used widely in the 12- to 45-year age attributed to decreased hormone production at meno- group to control fertility. The drugs are now recommended for short-term trogens are contraindicated because their use during use (eg, 2 years) to relieve menopausal symptoms, but not pregnancy has been associated with the occurrence of for long-term use for cardioprotective effects. A recent vaginal cancer in female offspring and possible harmful well-done study indicated that risks are greater than ben- effects on male offspring. Estrogens are prescribed to relieve symp- the part of the study concerned with estrogen replace- toms of estrogen deficiency (eg, atrophic vaginitis and ment only is scheduled to be completed in 2005. The early vasomotor instability, which produces hot flashes) part of the study did not indicate significantly increased and to prevent or treat osteoporosis. Such usage is usu- Progestins ally called estrogen replacement therapy (ERT) or HRT. In addition, ERT and HRT have been used long-term Progestins are most often used in combination with an estro- for cardioprotective effects because it was believed that gen in contraceptive products. They also are used to suppress BOX 28–2 HORMONE REPLACEMENT THERAPY IN POSTMENOPAUSAL WOMEN Background atively small, the investigators concluded that the drug combination For many years, postmenopausal women have been treated with produced more harm than benefit and should not be started or con- estrogen replacement therapy (ERT) to manage symptoms of tinued to prevent coronary heart disease (CHD) in healthy women. In addition, estrogen was thought to have cardio- the WHI study was done with healthy women, to see if the drugs protective effects, partly because the incidence of heart attacks in would prevent CHD from developing. The Heart and Estrogen/ women increased substantially after menopause and became sim- Progestin Replacement Studies, HERS and HERS II, involved ilar to the incidence in men. Several studies also indicated benefi- postmenopausal women with intact uteri who already had CHD. Because estrogen alone increases conclusion was that the hormones should not be started or contin- risks of endometrial cancer in women with an intact uterus, a pro- ued in women with CHD for preventive purposes. For individual women, the benefits in reducing symptoms of menopause, fractures from osteoporosis, and colon cancer must be Estrogen-Progestin Combinations weighed against the increased risks of CHD, thromboembolic Combined estrogen/progestin hormone replacement therapy be- stroke, venous thromboembolism, breast cancer, and cholecysti- came the standard of care for women with an intact uterus and was this. In 2002, the prevailing opinion changed dramatically to disease increase with the duration of drug use. If the combined indicate that combined estrogen/progestin therapy should not be drugs are prescribed to relieve menopausal symptoms in women used to prevent cardiovascular disease in healthy postmenopausal who have not had a hysterectomy, they should probably be used women, because risks were greater than benefits. This part of the study was stopped after an tion, estrogen is generally thought to have beneficial effects on average follow-up period of 5 years (8 years planned), because of a serum cholesterol and bone density. However, there has been con- higher incidence of invasive breast cancer. Results also indicated in- siderable debate about possible increases in breast cancer risks. To date, no alarming results have combination, there would be seven more coronary heart disease developed; the study is scheduled for completion in 2005. There are events, eight more strokes, eight more pulmonary emboli, eight more currently no new recommendations for or against the use of estrogen invasive breast cancers, six fewer colorectal cancers, and five fewer alone in women who have had a hysterectomy. Although these numbers are not large and the risk is rel- and their health care providers must weigh risks versus benefits.

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The Network of Purkinje Units Let us now consider the hierarchical network of Purkinje units in which each unit is itself a neural network as defined earlier buy cheap kamagra super 160mg on line erectile dysfunction pump hcpcs. The interactions among the Purkinje units lead to new learning rules governing the co- ordination of movement on the basis of the external context order kamagra super 160 mg mastercard erectile dysfunction treatment in lahore. Here we refer to the learning mechanisms associated with circuits adjacent to the local circuit correspond- ing to the individual Purkinje unit discount kamagra super 160 mg line low libido erectile dysfunction treatment. Basically, the dynamics of the coordination may be explained by the hierarchy of the system of Purkinje units and by the granular Mathematical Modeling of Neuromimetic Circuits 145 cell subsystem associated with a Golgi cell. The learning rules then emerge at a higher level of Purkinje units, if certain conditions are satisfied [see Eqs. Applied to Purkinje units, these learning rules give the model a predictive value, at least from a qualitative point of view. For example, it is su‰cient to know the sense of the variation in cerebellar inputs to be able to determine the sense of the varia- tion in the synaptic e‰cacies and the outputs. In the learning phase, the outputs and the modifiable synaptic weights are given by the solutions of algebraic nonlinear equations coupled with integral-di¤erential nonlinear equations. The Purkinje network, because of its hierarchical nature, may thus be conveniently investigated on a mathematical basis. This is the preliminary condition necessary to implement the coordination of movement on a computer. The mathematical conditions for the stability of the network have been determined by means of a Lyapunov function (P. Using the properties of inter- connected neurons described earlier, the equations for coupled units, indexed ðlÞ,are given by: ðlÞ ðlÞ ðlÞ ðlÞ ðlÞ ðlÞ ðlÞ ðlÞ X ðtÞ¼ÀG X ðt À TGÞþX0 þ S U À hc V À XextðtÞ ð7:9Þ ðlÞ ðlÞ t ðlÞ ðlÞ t ðlÞ ðlÞ ðlÞ ðlÞ ðlÞ Y ðtÞ¼Y0 þ mp X ðtÞÀ gp X ðt À TpÞþmc V þ YextðtÞ ðlÞ in which the notations [e. The hierarchical approach thus leads to the emergence of new properties at the higher level. It should be noted that the learning rules have been mathematically deduced from the natural rules operating at the neuronal level. In this approach, intelligence of movement corresponds to the combination of the activities of a set of Purkinje units. Defined on the basis of the contexts created by functional units, coordination of movement is clearly a physiological function that can be im- plemented on a computer. The n-level field theory also may be used to better charac- terize these results because of the delays involved in the propagation between any two neurons (Daya and Chauvet, 1999). The Hippocampus and Learning and Memory the properties of the hippocampus have been mainly explored through experiments with synaptically evoked population activity. Presynaptic neurons were stimulated for various intensities and the extracellular field potential (EFP) recorded at various 146 G. Berger Time scale: sec Learning coordinated CC Time scale: msec movement SMS Derivative Activity CN (VLR) PU CC Synapses LT (Hebb) PCS, GCS Activity PU Current Channels Meta Cytoplasm Activity PCS, GCS Potentiel Coordinated Neurons Current ST-synapses activity Current Channels Functional organization Instantaneous activity Figure 7. These EFPs are the images of the variation in time of the fields at the corresponding points in the space. The extracellular wave form can be viewed as the image of the number of synapses that create an extracellular potential at a given time, that is, in relation to the number of micropotentials created by the corresponding synapses at one point of the extra- cellular space. Specifically, we may interpret an EFP wave form as resulting from two processes: firing of stimulated neurons when the membrane potential c (the value of the field variable) is over threshold, and synaptic activation that results from all the ionic current variations in the recorded volume of granule cells. The first process is completely determined by the resolution of the field equation [Eqs. The second process reflects the time distribution of the summed excitatory post- synaptic potential (EPSP) in this volume, owing to the large number of causes, such as the orientation of currents in space, the location of dendrites and synapses, and the distance between the synapse and the recording electrode. Because of these inde- pendent influences on the extracellular potential measured at a distance, the central limit theorem in the theory of probability establishes that this sum is a Gaussian Mathematical Modeling of Neuromimetic Circuits 147 variable. Thus, we have a statistical interpretation of the extracellular wave form, confirmed by the observed wave forms (G. Appendix D summarizes the specific statistical method based on the meaning of the field vari- ables that allows the deduction of the EFP behavior of a population of neurons from the fields at all levels. Because the state of a synapse is defined by two field variables, the postsynaptic potential f (short time scale) and the synaptic e‰cacy m (long time scale), the theo- retical results shown in appendix D apply. We have considered the distribution function of the state variables f as the new time distribution function defined by Fðt; c; mÞ¼N ÃðtÞ=NðtÞ where N ÃðtÞ is the sum of the micropotentials created by the activated synapses at time t [NðtÞ is the number of synapses in the considered volume]. Therefore, Fðc; m; tÞ will be interpreted as the time distribution of the micropotentials ne created by the activated synapses. This method provides a means to define the relation between the intracellular and the extracellular potentials us- ing new parameters at the level of the neuronal population having a physiological interpretation. Conclusion the models described here are based on a general theory incorporating new con- cepts: Any biological system may be represented as a combinatorial set of nonsym- metric and nonlocal functional interactions in a specific, hierarchical representation, in which the structures are distributed along space scales, and functions along time scales. Mathematical Modeling of Neuromimetic Circuits 149 Applied to the nervous tissue, elementary physiological mechanisms, such as syn- aptic molecular mechanisms, can be integrated at the level of a neuron, and neuronal mechanisms at the level of the neural network. The crucial point is that the integra- tion leads to new functional laws that can be simulated with a computer, using the techniques of numerical analysis, and tested through specific experiments. This kind of approach seems to be a necessary condition for the mimesis of a physiological function by a neural prosthesis. The theory proposed has been illustrated here by two examples: the cerebellum and the hippocampus. First, the hierarchical organization of the cerebellum, proved mathematically from the functional point of view, has led to the concept of the func- tional unit. New learning rules have been shown to appear at the higher levels of functional organization [Eqs. We thus have, on one hand, the functional hierarchy created by time scales [conditions (B. Since the conditions of stability originate in the nature of the hierarchy, the functional unit, that is, the structure that has the desired function at a higher level, may be derived. Thus, the mathematical model appears to reveal properties that would not be ap- parent without formalization (G. This approach, which consists of making a profound mathematical study before using numerical computation, is very di¤erent from the usual computational approach, which to a certain extent could be considered as being analogical. In the case of neural prostheses, the implant must simulate the physiological func- tion of the neural network it replaces. Thus, functional integration must result from the working of the implant, given that the neural network, which is hierarchical, inte- grates the function of a large number of elements, for example, activity (P. Moreover, the input of the system is a spatiotemporal pattern, as is its output. The model must therefore be able to realize the spatiotemporal func- tion that results in collective activity. This is the case of the cerebellar cortex, where each element is itself a neural network. We have shown that the functional unit is the Purkinje domain, an ensemble of Purkinje units associated with neurons of the deep cerebellar nucleus. We now know how to simulate, by means of a mathematical algorithm, the learning and memorization of the coordination of movements by an ensemble of Purkinje domains. In the same way, the cognitive function of the hippocampus must be a product of the collective activity of its intrinsic neurons. The information represented in this col- lective activity can only be understood if we consider the spatiotemporal distribution of active cells, given the complexity of the representations for any one set of condi- tions and the fact that the information represented in the activity of hippocampal 150 G.

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