V. Hassan. Michigan State University.
Under steady-state conditions purchase extra super levitra 100 mg line xyzal erectile dysfunction, the velocity of the simple reaction shown in Figure 1B can be described by the Michaelis-Menten equation: v Vm½S ¼ ð2Þ Et Km þ½S In this equation order extra super levitra toronto erectile dysfunction at age 17, a hyperbolic saturation curve is described by two constants order extra super levitra with paypal erectile dysfunction doctor san jose, Vm and Km buy cheapest extra super levitra and extra super levitra impotence in a sentence. In the simple example in Figure 1B, v is velocity, Vm is simply k23[E ]t and Km is (k21þ k23)/k12. Vmax (or Vm) is the reaction velocity at saturating con- centrations of substrate, and Km is the concentration of the substrate that achieves half the maximum velocity. Although the constant Km is the most useful descriptor of the affinity of the substrate for the enzyme, it is important to note the difference between Km and Kb. More complex enzymatic reactions usually display Michaelis-Menten kinetics and can be described by Eq. However, the forms of constants Km and Vm can be very complicated, consisting of many individual rate constants. King and Altman (7) have provided a method to readily derive the steady-state equations for enzymatic reactions, including the forms that describe Km and Vm. The advent of symbolic mathematics programs makes the implementation of these methods routine, even for very complex reaction schemes. However, most P450-mediated reactions display standard hyperbolic saturation kinetics. Therefore, although the rate constants that determine Km and Vm are 34 Korzekwa Figure 2 P450 catalytic cycle. Another constant that has important implications in drug metabolism is the ratio of Vm to Km,orV/K. This ratio is the slope of the hyperbolic saturation curve at low substrate concentrations. Since most P450-mediated reactions have relatively high Km values, most drug metabolism occurs in the linear or V/K region of the saturation curve. P450 Enzyme Preparations The P450 enzymes are found primarily in the outer membrane of the endo- plasmic reticulum. Enzyme activity requires that the enzyme be integrated into a membrane that contains P450 reductase and, for some reactions, cytochrome b5. Characterization of the saturation kinetics for the P450 enzymes can be deter- mined using a variety of enzyme preparations, including tissue slices, whole cells, microsomes, and reconstituted, purified enzymes. The more intact the in vitro preparation, the more it is likely that the environment of the enzyme will represent the in vivo environment. However, intact cell preparations do not In Vitro Enzyme Kinetics Applied to Drug-Metabolizing Enzymes 35 generally give kinetic parameters that are observed with microsomal preparations. This could be due to factors such as limiting diffusion into the cells, binding to intracellular proteins, or differences in membrane partitioning. Therefore, when whole-cell preparations are used, observed kinetic characteristics may not provide the true kinetic constants for the enzyme being studied. Microsomal preparations generally provide reproducible kinetic analyses when only one enzyme is involved in the reaction. However, microsomal prep- arations (and other intact preparations) contain many different P450 enzymes. Although this characteristic is useful when trying to mimic the metabolic char- acteristics of an organ, it is a drawback when trying to characterize the kinetic constants of an individual P450 enzyme or when trying to determine which enzyme is involved in the metabolism of a particular drug. Because of the generally broad substrate selectivities of the P450 enzymes, most observed metabolic reactions can be catalyzed by more than one enzyme. Interindividual variability in the content of the different P450s makes it even more difficult to determine the different kinetic parameters when more than one enzyme is involved in a given reaction. Preparations containing a single P450 isozyme are available as either expression systems or purified, reconstituted enzymes. The P450s have been expressed in bacterial, yeast, insect, and mammalian cells (8). However, in order to obtain adequate enzyme activity for most expression systems, it is necessary to supplement the membranes with reductase and in some cases cytochrome b5. This is accomplished by either supplementing the membranes with purified coenzymes or by coexpression of the coenzymes. Alternatively, the P450 enzymes can be purified and reconstituted with coenzymes into artificial membranes. Micro- somes may more closely represent the in vivo activity of a particular organ, but kinetic analyses are complicated by the presence of multiple enzymes. It is not possible to spectrally quantitate the content of any individual enzyme when a mixture of enzymes is present. Expression systems provide isozymically pure preparations, but they also have their disadvantages. The P450 enzymes are membrane bound, and for the nonmammalian expression systems the membranes may have different interactions with the P450 proteins. Although expression levels in most of the systems are adequate for spectral quantitation, coexpression of the coenzymes adds variability to different batches. However, the membranes are artificial and can have an influence on enzyme activity. Finally, these differences are further complicated by unpredictable influences of ionic strength, pH, etc. Incubation Conditions Enzyme kinetics are normally determined under steady-state, initial-rate con- ditions, which place several constraints on the incubation conditions. First, the amount of substrate should greatly exceed the enzyme concentration, and the consumption of substrate should be held to a minimum. This constraint ensures that accurate substrate concentration data are available for the kinetic analyses and minimizes the probability that product inhibition of the reaction will occur. This constraint can be problematic when the Km of the reaction is low, since the amount of product (10% of a low substrate concentration) may be below that needed for accurate product quantitation. One method to increase the substrate amount available is to use larger incubation volumes. For example, a 10-mL incubation has 10 times more substrate available than a 1-mL incubation. When more than 10% of the substrate is con- sumed, the substrate concentration can be corrected via the integrated form of the rate equation (Dr. James Gillette, personal communication): v Vm½S ¼ ð3Þ Et Km þ½S 0 ½S0 À½Sf S ¼ ð4Þ ln½S0/½Sf In Eq. S0 0 f approaches [S] when substrate consumption is minimal, and S0 is substituted for [S] to correct for excess substrate consumption. In these analyses, however, substrate inhibition can be a problem if the product has a similar affinity to the substrate. Fortunately, most P450 oxidations produce products that are less hydrophobic than the substrates, resulting in lower affinities to the enzymes. There are exceptions, including desaturation reactions that produce alkenes from alkanes (10) and carbonyl compounds from alcohols. These products have hydrophobicities that are similar or increased relative to their substrates. In the presence of reducing equivalents, the P450 enzymes will generally lose activity over time. Provided that the loss of enzyme is not dependent on substrate con- centration, the Vm of the enzyme will change, but not the Km. For P450 reactions, the presence of substrate in the active site can either protect the enzyme or increase its rate of deactivation. Enzyme stabilization can result in a sigmoidal saturation curve for an enzyme showing hyperbolic saturation kinetics, and enzyme destabilization can show substrate inhibition if the enzyme content varies over the incubation time. The reaction should also be linear with enzyme In Vitro Enzyme Kinetics Applied to Drug-Metabolizing Enzymes 37 concentration to ensure that other processes, such as saturable, nonspecific binding, do not alter the enzyme saturation profile. Analysis of Michaelis-Menten Kinetic Data By far, the best method of determining kinetic parameters is to perform an appropriately weighted least-squares fit to the relevant rate equation (11). Although reciprocal plots are useful for determining initial parameters for the regression and for plotting the results, initial parameters for a single enzyme showing hyperbolic saturation kinetics can be obtained by inspection of the data. Reaction Conditions In addition to the preceding complexities, the P450 enzymes have some unique characteristics that complicate the design of experimental protocols. Because of the broad substrate selectivities for these enzymes, the enzymes are not opti- mized for the metabolism of a particular substrate. To further complicate matters, the velocities for these enzymes tend to vary greatly with changes in these reaction conditions. This variation may well be due to the dependence of the reaction velocity on several pathways in the catalytic cycle. However, the actual rates of substrate oxidation are probably dependent on three additional rates: the rate of substrate oxidation and the rates of the decoupling pathways (hydrogen peroxide formation and excess water formation). Thus, the efficiency of the reaction plays a major role in determining the velocity of a P450 oxidation (16,17). The sensitivity of the reaction velocities to incubation con- ditions may be due to changes in the reduction rate as well as to changes in the enzyme efficiency. Although many P450 reactions show optimal activity in the pH range of 7 to 8, both chlorobenzene and octane metabolism show optimum activity at pH 8. This is also the pH at which P450 38 Korzekwa oxidoreductase optimally reduces cytochrome c. In addition, whereas essentially all in vitro metabolism studies are carried out at 378C, both these reactions occur much faster at 258C. Even the optimum ratio of reductase to P450 depends on the substrate and the enzyme.
The host response is integral to the clinical presentation of periodontitis and other diseases have been postulated to upregulate this inflammatory response purchase extra super levitra american express experimental erectile dysfunction treatment. It has been observed that obesity and malnutrition have significant effects on immune purchase 100mg extra super levitra overnight delivery erectile dysfunction recovery stories, inflammatory and metabolic processes (Fantuzzi et al buy discount extra super levitra line erectile dysfunction age 29. Periodontitis may be exacerbated by the increase in systemic inflammatory burden caused by either of these two maladies purchase 100mg extra super levitra otc finasteride erectile dysfunction treatment. Obesity and nutritional habits are usually formed in childhood, and concomitant inflammatory burden early on may have detrimental effects on periodontal progression. The aim of this review is to discuss the association between obesity and nutrition with periodontal disease and to highlight some avenues for future research. It is routinely used in doctors’ offices as well as in epidemiological and clinical studies to assess obesity status. Childhood obesity is defined as a body mass index for age and gender that is greater than the 95th percentile (Fig. It is generally agreed that men with more than 25% body fat and women with more than 33% body fat are obese (Haslam, 2000) Prevalence and Causes The prevalence of obesity and diabetes is increasing in the United States and around the world not only in adults but also in children and adolescents as well. For the United States, prevalence of obesity among adults has doubled, and the prevalence of overweight among children and adolescents has tripled over the last 20 years. Approximately 31% (59 million) of adults in America are now classified as obese and 15. In 1990, four states had obesity prevalence rates of 15–19% and no states had rates at or above 20%. In 2005, only four states had obesity prevalence rates less than 20%, while 17 states had prevalence rates of 25% or greater (fig. In recent years, the trend for increasing obesity has been linked to larger portion sizes, processed foods, diets high in fat and increased consumption of sweetened drinks (Harnack et al. In children the reduced participation in physical exercise due to health and safety issues at school and the increased watching of television and video games have also added to the problem (Dollman et al. Genetic variability as well as metabolic rate although minor have been implicated in the current obesity epidemic (Haslam et al. Mortality risks appear to be directly related to body mass index, but only in younger and middle-aged, but not older, males and females (Freedman et al. This observation may reflect weight loss associated with illness in later stages of life. Therefore, death rates are higher in thinner people, a phenomenon known as reverse causation. According to the Framingham Study, a 2% increase in the death rate occurred with each extra pound of weight gained between ages of 50 to 62 years (Hubert et al. The risk of developing type 2 diabetes is increased 10-fold for obese women and 11. Compared with women with stable weight the relative risk for diabetes mellitus among women who had a weight gain of 5. Abdominal obesity appears to represent an increased diabetic risk with waist circumference over 40 inches producing a 3. Obesity is also associated with “metabolic syndrome”, a combination of maladies including hypertension, insulin resistance, dyslipemia and atherosclerosis which are all risk factors for cardiovascular disease. Accordingly, obesity may cause up to 12% of heart failure cases in North America (Kenchaiah et al. It is only in recent years that adipose tissue has been recognized as a complex secretory organ participating in physiologic and pathologic processes, including immunity and inflammation. Of the cells in adipose tissue, adipocytes are the most abundant and secrete a variety of bioactive molecules, known collectively as “adipokines”. These protein molecules either act locally or are released systemically where they function as signaling molecules to other tissues and organs (Trayhurn & Wood, 2004). The most studied adipokines, leptin and adiponectin have a number of functions within the body. Leptin, which is predominately secreted from adipocytes assists in the maintenance of energy expenditure by decreasing appetite or increasing metabolism (Friedman, 2000). Leptin acts through the hypothalamus of the central nervous system where its receptors are highly expressed. Leptin levels are vital in regulating body mass, imitating some of the actions of insulin (by altering glucose uptake in muscle and fat cells) and lowering glucose production in the liver (Matsuzawa, 2005). It appears that obese persons have elevated leptin levels that do not suppress appetite. This leptin resistance may contribute to pathological processes’ associated with obesity (Blüher et al. Leptin resistance has been associated clinically with hypertension, atherosclerosis and cardiovascular disease (Reilly et al. Other than appetite, immunological functions of leptin include stimulation of cytokines and increases 39 macrophage phagocytosis (Torpy et al. Leptin has also been shown to protect T lymphocytes from apoptosis and regulate T-cell proliferation and activation (Farooqi et al. Another adipokine, adiponectin is secreted from adipose tissue into the systemic circulation, but interestingly, levels are decreased in obese subjects. The actions of adiponectin within the body include glucose maintenance, insulin sensitivity and fatty acid breakdown. Adipose tissue of obese individuals contains an increased number of macrophages and these macrophages appear to be hyperactive in their amount of cytokine secretion. Increased blood glucose levels from ingestion of excess carbohydrates leads to formation of free fatty acids (via increased liver synthesis of free fatty acids) and the formation of triglycerides within adipocytes. Insulin secretion in response to increased carbohydrate levels also reduces lipolysis further increasing adiposity (Musso et al. Although research has not fully elucidated the exact mechanisms underlying obesity and systemic inflammation and diabetes it is likely that adipokines and cytokines produced by adipose tissue play a central role. The increased production of circulating inflammatory cytokines in obesity is hypothesized to alter the inflammatory response, a potential mechanism linking periodontitis and obesity. This study demonstrated that the obese rats were more likely to have periodontal disease than healthy rats. They concluded that the hypertrophy and hyperplasia of the walls of the blood vessels in the periodontium, could possibly alter the vascular, inflammatory and immune pathways. Since this initial animal study, several human cross sectional studies have elucidated a significant increase in periodontitis risk in obese individuals. These results suggest that the upper body fat accumulation is more closely related to risk for periodontitis. These results were postulated to occur because of the proportion and distribution of fat and muscle among males and females. The results of this study revealed prevalence of periodontitis in 14% of normal weight subjects, whereas 29. N = 13665 waist associated with 2005 18–90 years periodontitis especially in younger adults (18–34 years) Buhlin et al. These results again emphasize the influence of fat distribution in the 45 analysis and also, older age may potentially confound the relationship between obesity and periodontitis. The increase in other medical conditions and poly-pharmacy associated with aging may detract from the relationship (Al-Zahrani et al. Obesity is associated with various health related choices that impact periodontal status (e. The association between obesity and periodontal disease has also been shown to be independent of type 2 diabetic status (Saito et al. Although obesity in itself has been independently associated with periodontitis risk, a model linking obesity, diabetes and periodontal disease has been recognized. Only Tannerella forsythia was found in elevated levels in the biofilm of obese individuals with healthy periodontal tissues or gingivitis. This may reflect an overgrowth of this organism that might increase initiation and progression of periodontitis. This study demonstrates the 47 impact of obesity on systemic inflammation and need for not only periodontal intervention but also obesity counseling to reduce cardiovascular risk. The potential observational evidence for obesity to increase the risk for periodontitis, another chronic inflammatory disease has been discussed above. The proposed mechanisms underlying this association are not fully elucidated at present but some lines of evidence exist relating the pathogenesis of these diseases. From early animal experiments it was shown that obese rats were more likely to develop periodontitis than normal rats (Perlstein et al. Obesity is commonly associated high circulating free fatty acids levels which have been shown to directly cause proliferation of the junctional epithelium and bone loss in rat periodontitis lesions (Tomofuji et al. As mentioned earlier, adipose tissue, especially visceral adipose tissue, is an important organ that produces several systemically active substances known as adipocytokines. One study analyzed 49 gingival crevicular fluid levels of tumor necrosis factor-α in young subjects (Lundin et al. Some studies have hypothesized that the association of obesity with periodontitis is inextricably linked with insulin resistance and diabetes. It is hypothesized that this priming of the inflammatory response that causes the immune system to exhibit an exaggerated immune reaction to periodontal pathogens. As already mentioned there is evidence for the independent association of obesity with periodontitis (Saito et al. Proinflammatory cytokines play essential roles in the inflammatory reaction in periodontal disease. The adiopkine leptin stimulates the immune system by increasing cytokine production and phagocytosis by macrophages and increasing oxidative stress (Fantuzzi et 50 al.
It "resets" after several days at higher pressure and is therefore not a useful defense against chronic hypertension order extra super levitra line impotence urologist. Longer-acting regulation depends upon the kidney order extra super levitra 100 mg erectile dysfunction medications otc, which through the renin-angiotensin system purchase extra super levitra 100 mg free shipping erectile dysfunction effexor xr, can provide significant rise in peripheral resistance in response to hypotension of the renal circulation discount 100mg extra super levitra impotence medication. Conversely, long-term systemic hypertension can ensue if a kidney is ischemic secondary to pathologic stenosis of the renal artery. Autoregulation may be involved if the hypertensive state is brought about by increased cardiac output. A rise in peripheral resistance (afterload) would then return output and perfusion to normal at the price of persistent hypertension. The consequences of sustained hypertension are the development of myocardial hypertrophy and eventual congestive heart failure, the increased rate of a atherosclerosis of large and medium- sized arteries, as well as the tendency for distention and rupture of those vessels, and finally, malignant hypertension with severe arteriolar vasospasm, loss of vision and cerebral edema. Drug treatment of hypertension is addressed to the physiologic determinants when no primary cause can be found and removed. Diuretics, 1-blockers and vasodilators compose the majority of effective agents and respectively lower venous return, myocardial contractility (output) and peripheral arterial resistance. It is important to have covered this area but a great deal of emphasis is not necessary compared with other cardiac diseases such as valvular and coronary artery disease. You should know the physiologic effect of pericardial effusions and also that of chronic, healed pericarditis. It is thought, however, that clinically the incidence is much higher and that in many cases the disease is subclinical and can regress and the patient recover fully. There is some circumstantial evidence only that myocarditis may lead to cardiomyopathy. Myocarditis can be caused by bacterial, rickettsial, viral, protozoal and parasitic, fungal and spirochetal agents. In myocardial lesions associated with infectious diseases, the inflammation may be due to an actual invasion of the myocardium by the organisms or to the action of their toxins, although it is possible that an allergic mechanism is responsible in some cases. Gross: The gross appearance of the heart in acute myocarditis is not distinctive, but usually the myocardium is pale and flabby and the chambers are dilated. Abscesses may appear as small yellow or streaky foci occasionally become confluent. In some cases small abscesses may form in the myocardium such as in staphylococcal bacterial endocarditis while interstitial inflammation is minimal. In other instances, nonsuppurative inflammation of the connective tissue is the predominant change with a cellular infiltrate consisting of Lymphocytes, plasma cells, eosinophils, histiocytes and sometimes neutrophils. Sometimes abscesses may develop in the myocardium as a result of certain fungal infections. Some infections produce granulomatous inflammation of the myocardium such as tuberculosis, which may be nodular or miliary or even diffuse. Sarcoidosis is not proved to be an infectious disease but is mentioned here because it resembles lesions of noncaseating forms of tuberculosis. Myocarditis has been described in protozoal diseases in which Chagas’ disease and toxoplasmosis are examples. In Chagas’ disease the inflammation in the myocardium is usually intense, mixed and myocyte necrosis may be prominent. Toxoplasmosis caused by toxoplasma gondii may present with pseudocysts containing the organisms in the muscle fibers without inflammatory reaction or the free organisms in the myocardium provoking a mixed inflammatory reaction. Some helminthic parasites that affect the heart are Trichinella spiralis, and Echinococcus granulosus. Inflammatory reaction is a response to the larvae although Cardiomyopathy, Myocarditis & Atrial Myxoma - Gerald Berry, M. The primary hydatid cysts of the heart tend to rupture into the lumen of a cardiac chamber or into the pericardial sac. The fungi most commonly seen in the heart are blastomycosis, actinomycosis, cryptococcosis, coccidioidomycosis. Myocarditis has been reported in a variety of viral disease including all of the common infections: polio, chicken pox, flu, infectious hepatitis, mumps, infectious mononucleosis, and infections caused by Coxsackie B virus. The microscopic picture in viral lesions is similar and consists of interstitial infiltration by Lymphocytes and neutrophils with focal myocyte necrosis. Later the Lymphocytes and histiocytes predominate and there is connective tissue proliferation. As the name suggests, there is no known cause for this type of myocarditis although it is strongly suspected that it may be viral in origin. The gross appearance of the heart shows chamber dilatation and sometimes hypertrophy. Two forms are usually described: the diffuse type, without the formation of granulomas and the granulomatous type. The diffuse type consists of an interstitial inflammatory infiltrate which may be mixed at first but is usually predominantly mononuclear. With the advent of the endomyocardial biopsy the diagnosis of idiopathic myocarditis is being made more often. Unfortunately, this diagnosis is often confused with “look-a-likes” which can appear to be myocarditis but are, in fact, inflammatory infiltrates due to other causes. It is generally felt that this condition will lead to idiopathic dilated cardiomyopathy if the patient survives the acute phase; however, we have no good direct proof that this is so at this time. In the granulomatous variety throughout the myocardium there are small or large granulomas without caseation and containing giant cells. Myocarditis may occur in rheumatic fever, rheumatoid arthritis and lupus erythematosus. Microscopic changes in the heart muscle have been reported in dermatomyositis and scleroderma. In these cases there is fibrous tissue replacement of the myocardium without a significant inflammatory component. Myocarditis may be seen in response to cardiac trauma as in car accidents where there might be an infiltrate of neutrophils. Irradiation of the heart causes an acute inflammatory reaction with damage to small vessels. As you can see some of them are quite commonly used drugs, such as tetracyclines, immunosuppressives, and antihypertensives. The list of drugs thought to be responsible for causing myocarditis is added to daily so no account of them can be totally up to date. Hypersensitivity (allergic) myocarditis have lesions which are not dose or time dependent and may occur any time during delivery of the drug. In general, hypersensitivity myocarditis is manifested morphologically with an interstitial inflammatory infiltrate which includes many eosinophils. Heart size is usually not markedly affected in acute hypersensitivity myocarditis. Toxic myocarditis and vasculitis induced by drugs is dose related and the effects are cumulative. The inflammatory infiltrate surrounding the damaged myocytes is predominantly that of neutrophils although a mixed infiltrate may also be seen. The anthracycline drugs, particularly adriamycin, also may cause an acute myocarditis-pericarditis syndrome; however, these drugs usually cause a chronic myocardial damage which will not be described here. Drugs associated with toxic myocarditis Arsenicals Anthracyclines Plasmocid Lithium compounds Paraquat Catecholamines Barbiturates Quinidine Antihypertensives Cyclophosphamide Amphetamine Theophylline Fluorouracil Phenothiazines Histamine-like drugs Table 2. Drugs associated with hypersensitivity myocarditis Sulfonamides Streptomycin Isoniazid Sulphonyurease Penicillin Methyldopa Thiazide diuretics Phenylbutazone Diphtheria toxoid Horse serum Tetanus toxoid E. The clinical features of an acute myocarditis usually include a history of a recent flu-like illness with fever, myalgias, fever and shortness of breath. On examination the patient usually has an enlarged cardiac silhouette and heart failure. Usually, however, it is designated according to its anatomic features, such as (1) serous, (2) serofibrinous, - (3) fibrinopurulent, (4) purulent, and (5) hemorrhagic. Pericarditis also may be idiopathic (non-specific) or due to acute bacterial infection, uremia, or associated with myocardial infarction, rheumatic, neoplastic or traumatic. In some conditions such as heart failure an excessive serous transudate may occur into the pericardium slowly or rapidly. In this case there are usually no adhesions Cardiomyopathy, Myocarditis & Atrial Myxoma - Gerald Berry, M. Hemopericardium in which blood enters the pericardial sac may be caused by trauma, such as a knife wound, myocardial rupture or coronary artery rupture. More recently the use of the cardiac biopsy may result in perforation of the ventricle and hemopericardium. Hemorrhage into the pericardium may cause tamponade which is a clinical emergency. Blood should be removed from the pericardial sac rapidly to allow diastolic expansion of the heart and also to prevent organization of the blood. Serofibrinous and fibrinous pericarditis: This is the most frequent type and commonly occurs in uremia, rheumatic fever or infarction. Clinically, this type of pericarditis may cause pain and result in a loud friction rub. Suppurative or purulent pericarditis: This is due to bacteria, mycotic or parasitic organisms. Sometimes it is also due to direct invasion of tuberculosis or pneumonia from the lung.
It should be noted that because of minor differences in dosage causing necessary muscle relaxation and facilitating the development of paralysis of skeletal muscle buy discount extra super levitra 100mg on-line erectile dysfunction treatment by acupuncture, a slight overdose of muscle relaxant compounds can lead to serious damage of respiratory func- tion and a sharp decline in blood pressure purchase extra super levitra 100 mg overnight delivery erectile dysfunction doctor washington dc. Overdose is reversed by introducing anti- cholinesterase agents extra super levitra 100mg with amex erectile dysfunction doterra, which block acetylcholinesterase and elevate the concentration of acetylcholine in the synaptic chain discount 100mg extra super levitra overnight delivery thyroid erectile dysfunction treatment, using artificial respiration with oxygen, and when nec- essary, using drugs that elevate arterial blood pressure (levarterenol). Drugs of the other group, which is represented by succinylcholine, are referred to as depolarizing drugs. Compounds of this group cause initial activation (depolarization) of the receptor and subsequent prolonged, stable blockage, which leads to a delay in repolariza- tion and the inability to subsequently stimulate receptors, and in short, it disturbs the devel- opment of excitation from the nerve to the muscle. Unlike nondepolarizing agents, these drugs are not competitive antagonists, but on the contrary—they are more stable agonists than acetylcholine itself. Today, synthetic compounds as well as tubocurarine, an alkaloid isolated from curare, are used as antide- polarizing or curare-like drugs, which are called antidepolarizing or competitive blockers. Tubocurarine and the majority of synthetic curare-like compounds contain two or more quaternary nitrogen atoms located approximately 1. These drugs are used in operations in which relaxation of skeletal muscle is required, in traumatology for repositioning broken bones, for resetting dislocations, and for tetanus. Respiratory muscles and the diaphragm are last to relax, which leads to a discontinuation of respiration. Compounds of this group include tubocurarine, metocurine, gallamine, pancuronium, vecuronium, and atracurium. Tubocurarine is used mainly in anesthesiology as a myorelaxant, causing prolonged muscle relaxation during an operation. Small doses are successful at causing temporary relaxation of skeletal muscle without any vital change of primary body functions. It is used particularly in endotracheal intubation or orthopedic surgery for repositioning fractures, resetting compound dislocations, and so on. Metocurine: Metocurine, 6,6 ,7 ,12 -tetramethoxy-2,2,2 ,2 -tetramethyltubocuraranium dichloride (15. Pancuronium: Pancuronium, 1,1 -(3α,17β-diacetoxy-5α-androstan-2β,16β-ylene)-bis- (1-methylpiperidinium) dibromide (15. It is used in anesthesiology as a myorelaxant, causing prolonged muscle relaxation during surgical interventions of the thoracic and abdominal cavities, in proctology, ophthalmology, ortho- pedic practice, and in heart surgeries. Only the piperidine substituent on C16 of the steroid skeleton is transformed into a quaternary salt [15,16]. Atracurium: Atracurium is 2,2 -[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]] bis [1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquino- linium] dibenzene sulfonate (15. Two molecules of a secondary amine, tetrahydropapaverine, are joined to the product in a Michael reaction, forming compound (15. Then both nitrogen atoms are methylated by methylbenzenesulfonate, giving atracurium (15. However, since these drugs are inactivated slower than acetylcholine, they act longer in the synapse, causing a more stable depolarization. In this manner, the process of receptor repolarization is blocked and skeletal muscles relax. Succinylcholine has a lot of very practical value in medicine as a neuromuscular blocker. Muscle Relaxants Succinylcholine: Succinylcholine, 2,2 -[(1,4-dioxo-1,4-butanediyl)bis(oxy)]bis[N,N,N- trimethylethanaminium(diacetylcholine)] dichloride, which can be viewed as a dimeric mol- ecule of acetylcholine (diacetylcholine), is synthesized by reacting succinic acid dichloride with 2-dimethylaminoethanol and subsequent transformation of the resulting bis-(2-dimethy- laminoethyl)succinate (15. Unlike nondepolarizing substances, succinylchloride is not a competitive antagonist; con- versely, it is a more stable agonist than acetylcholine. In this manner, succinylcholine dif- fers from acetylcholine only in duration—it lasts longer, causing a more stable depolarization. During this period, muscles that cause fine movement (ocular, facial, neck) are the most sensitive and are blocked first, after which muscles of the extremities are blocked, and finally the most stable respiratory muscles. Therapeutic use of succinylcholine consists of preventing involuntary patient move- ment. It is used for brief operations, intubation of the trachea, and other endoscopic pro- cedures. Unlike other muscle relaxants, it has a direct effect on the contractile mechanism by interfering in the process of calcium ion release from the sarcoplasmic reticulum. This results in a lack of coordination in the mechanism of excitation––contraction of skeletal muscle, which has a greater effect on fast muscle fibers than on slow muscle fibers. Dantrolene is used for controlling the onset of clinical spasticity resulting from serious clinical cases such as wounds, paralysis, cere- bral palsy, and disseminated sclerosis. Of course, neuromuscular blockage reduces spasms; however, it is accompanied by loss of voluntary movement. In conditions of muscle spasticity, there need to be drugs capable of relieving painful muscle spasms that do not take away the ability of voluntary muscle contraction and that do not hamper brain function. Among these it is noteworthy to mention alcohol and barbiturates, which, however, are not used for this purpose because they cause sig- nificant sedation and other effects. Included is a large het- erogenic group of chemical compounds that have an effect on the spinal cord and suppress monosynaptic and polysynaptic reflexes. Among these are baclofen, cyclobenzaprine, cariso- prodol, methocarbamol, chlorphenesin, chlorzoxazone, orphenadrine, and diazepam. According to the first, 4-chlorobenzaldehyde is condensed with two moles of acetoacetic ester, giving the product (15. Reacting this with an alkaline solu- tion of a halogen (Hofmann rearrangement) gives baclofen (15. Adding nitromethane to this in the presence of base gives ethyl ester of β-(4-chlorophenyl)-γ- nitrobutyric acid (15. Signs of muscle spasticity have been shown in disseminated sclerosis and other spinal disorders. It may be useful to patients with muscle spasms resulting from spinal cord injuries. It is used as an adjuvant agent for relieving muscle spasms associated with severe diseased conditions of the muscle. It is used as an adjuvant drug for loss of flexibility of skeletal muscle as well as for relieving pain caused therein. It is used for reliev- ing spasms and skeletal muscle pain as well as for treating tetanus. The discovery and synthesis of histamine was a great achieve- ment in pharmacology, medicine, and immunology. This natural, powerful, biogenic amine is widely distributed in practically all tissues of mammals and is involved in various physio- logical processes. The body’s reaction to histamine is characterized by contraction of smooth muscle, signs of inflammation, constriction of vessels, and symptoms characteristic of shock. It is certain that histamine plays a central role in allergic reactions, hypersensitivity reactions, and is part of the body’s response mechanism in the inflammatory process. Histamine can enter the organism with food; it also can be generated by bacteria of the gas- trointestinal tract. However, these sources do not create additional reserves of histamine since exogenous histamine is easily catabolized in the organism. Histamine is dispersed and stored in mast cells in the majority of organs, in which it is preserved in secretory cytoplasmic granules in the form of a heparin-proteasic matrix mak- ing up over 10% of their mass. Histamine is also found in interstitial fluid such as digestive juices, blood, and urine. It is primarily metab- olized by two enzymes by deamination with deaminoxidase and methylating histamine with N-methyltransferase. Upon being secreted from the tissue, histamine can cause a large number of physiolog- ical effects. Its role in various pathological processes associated with severe and chronic allergic reactions and hypersensitivity reactions has been uniquely proven. At the same time, functions of endogenous histamine (in development of nerve transmission, secretion of digestive juices, tissue growth and restoration) remain inconclusive. Despite the fact that a number of various factors can cause the release of endogenous histamine, it is believed that the most important reason is an immunological response of the organism. Accepted knowledge states that during anaphylaxis and allergies, a specific 219 220 16. Antihistamine Drugs reaction of immunoglobulin E with an antigen takes place on the surface of the mast cell and basophiles, which results in a cascade of biochemical events that lead to degranulation and a release of histamine. Besides such antigen–antibody reactions, which play a critical role in the pathogenesis of many allergic, anaphylactic, and hypersensitivity reactions, histamine also can be released from tissue stores in response to physical stimuli, effects of the so-called hista- mine liberators, a number of chemical substances, various drugs, and toxins. They can be enzymes, toxins, morphine, d-tubocurarine, and polymers such as dextran. Moreover, tissue damage such as trauma, bites, and stress can also cause a release of histamine, and in all probability as a result, an endogenous polypeptide bradykinin is released. Action of all of these listed substances as well as a number of others can facilitate formation of ana- phylactic reactions in the organism. Release of histamine is blocked by various enzyme inhibitors and other substances (nicotinamide). The main physiological effect of histamine is exhibited in the cardiovascular system, nonvascular smooth musculature, and exocrine and adrenal glands. Its most important pharmacological effects are dilation of veins and capillaries, increased permeability of capillaries, increased heart rate, contraction of nonvascular smooth musculature (constriction of bronchi, gastrointestinal tract peristalsis), stimulation of gastric juice secretion, and release of catecholamines from adrenal glands. Two membrane-receptive binding sites called H1 and H2 receptors mediate the pharma- cological effect of histamine. H1 receptors are located in smooth muscle of vessels, and bronchial and gastrointestinal tract, while H2 receptors are found in the walls of the stom- ach, myocardium, and certain vessels. Therefore, it is very likely that contraction of nonvascular smooth muscle is an effect of activation of H1 receptors, while secretion of digestive juice and increased heart rate are connected to activation of H2 receptors; and dilation of vessels and increased permeability of capillaries is a result of combined activation of both types of receptors. There are also specific differences in the location of receptors in various tissues and in various animals.