Viagra Super Active
By I. Ballock. Franklin Pierce University.
To encourage the use of the affected hand quality 50 mg viagra super active erectile dysfunction treatment dallas, patients are fitted with a sling or a mitten that restricts the nonparetic hand controlled by the intact hemisphere viagra super active 50mg cheap erectile dysfunction vitamin d. Training consists of applying a behavioral training regimen in which the patients gradually relearn motor skills relevant to daily living through repetitive practice. In the first study to document neurophysiological plasticity associated with constraint-induced, repetitive, training of the impaired limb, squirrel monkeys were trained to retrieve food pellets from a Klüver board as described in the spontaneous recovery experiments presented in the previous section. However, unlike the spontaneous recovery monkeys, these monkeys were fitted with a soft mesh jacket that restricted the less affected hand (ipsilateral to the infarct) and were subsequently trained for 1 month on the Klüver board. Each monkey was required to retrieve at least 600 food pellets © 2005 by Taylor & Francis Group. By the end of 1 month of training, the monkeys returned to baseline levels on the most difficult food-well. The ICMS motor maps of M1 reflected improvements in behavior that contrasted with motor maps derived from monkeys after a month of spontaneous recovery. Instead of a further loss of distal hand representations and an expansion of proximal arm representations adja- cent to the damaged hand area in M1, as seen after spontaneous recovery, motor skill training maintained the pre-infarct distal hand area in M1 initially spared by the infarct (see Figure 8. The implication of these results is that physical rehabil- itation after stroke can drive physiological changes in the cortex associated with recovering skilled hand use. That is, the physiological changes observed after training more closely reflected the use of the distal hand in motor skill acquisition than those changes observed during spontaneous recovery. Cortical reorganization following clinical rehabilitation has subsequently been studied in stroke patients. Three techniques for tracking cortical reorganization have been commonly used: positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and transcortical magnetic stimulation (TMS). PET and fMRI can be used to produce functional maps of motor areas while subjects engage in relatively simple motor tasks. Typically the tasks consist of finger tapping (either simple or complex sequences of movements) or forced grip in which subjects may be required to apply varying amounts of force. The forced grip task allows examina- tion of the moderately disabled subjects who cannot move their fingers independently. Movement related cortical activation is associated with increased metabolic activity as cellular demands for oxygen increase. TMS is a noninvasive way of stimulating cortical motor neurons through the scalp and skull. An electric current is passed through a stimulating coil that is positioned over the scalp, this generates a magnetic field that causes an electric current to flow through the cortex and depolarize neurons within a small area of the cortex. In several studies the TMS coil is moved in 1 cm increments across the scalp 121,122 however, it has been reported that mapping accuracy of 0. The consistent findings of these studies using fMRI and PET is that after vascular damage to either cortical or sub-cortical motor structures, (e. Several studies that evaluated the effects of CI therapy upon cortical reorganization in chronic stroke patients also found that after CI therapy the spread of activation was reduced compared to pretraining, baseline levels of activation. This reduction was towards typical activation patterns that have been observed in normal subjects. Studies using TMS have also shown reorganization in stroke patients with damage to the sensorimotor cortex after CI therapy. These studies have demonstrated CI therapy was successful in increasing dexterity and that this improvement was associated with an enlargement of distal hand muscle representation adjacent to the damaged cortex. An enlarged area of excitability reflects areas of the cortex that can be potentially involved in a motor task. Several studies using fMRI or PET have demonstrated that the more difficult a task is, the more motor area is recruited within a localized functional area such as M1 or premotor cortex. There is also a nonlocalized spread of activation as multiple hand representations are being recruited. Presumably, this reorganization of cortical activation occurs by strengthening motor areas that are directly affected by an ischemic infarct. That is, motor areas typically involved in the control of the paretic hand, located within the injured cortical hemisphere, regain functional significance in motor control. However, not all fMRI studies have reported reduced spread of bilateral activation associated with CI therapy. Some groups have reported the characteristic bilateral spread of activation seen with fMRI, but not the reduced activation others have reported after CI ther- apy. About half of the corticospinal projection neurons are within M1, the remaining projection neurons are distributed among the nonprimary motor areas.
Steroid Biosynthesis Although the adrenal cortex is primarily involved in the STEROID PHYSIOLOGY synthesis and secretion of corticosteroids 50mg viagra super active with mastercard erectile dysfunction drugs sublingual, it is also ca- pable of producing and secreting such steroid interme- diates as progesterone viagra super active 25 mg for sale female erectile dysfunction treatment, androgens, and estrogens. The Anatomy of the Adrenal Cortex adrenal gland synthesizes steroids from cholesterol, The mammalian adrenal cortex is divided into three which is derived from plasma lipoproteins via the low- concentric zones: the zona glomerulosa, zona fascicu- and high-density lipoprotein pathways. The zona glomerulosa pro- cholesterol is enzymatically released extramitochondri- duces hormones, such as aldosterone, that are responsi- ally from cholesterol esters catalyzed by a cholesterol 686 60 Adrenocortical Hormones and Drugs Affecting the Adrenal Cortex 687 ester hydrolase. The tion of cholesterol ester hydrolase activity provides an rate-limiting step in steroid biosynthesis is the conversion additional source of cholesterol for steroidogenesis. Cholesterol is transported into the mitochondria of Pregnenolone leaves the mitochondria to become steroidogenic tissue, where side chain cleavage is car- the obligatory precursor of corticosteroids and adrenal ried out. The biosynthetic pathway next branches into systems, the cholesterol side chain cleavage requires re- two separate routes. One route passes through proges- duced nicotinamide-adenine dinucleotide phosphate terone and corticosterone to aldosterone, and the other CH3 CH3 CH3 CH C O 3 C O CH3 CH3 CH 3 CH3 CH3 CH3 CH 3 Desmolase 3-3 - 21-Hydroxylase Hydroxysteroid HO HO dehydrogenase O Cholesterol Pregnenolone Progesterone CH3 CH3 C O C O CH3 CH3 OH OH CH3 CH3 21-Hydroxylase HO O 17 -Hydroxypregnenolone 17 -Hydroxyprogesterone O O CH3 CH3 CH3 CH3 HO O Dehydroepiandrosterone Androstenedione CH2OH CH2OH CH2OH C O C O O C O CH HO CH3 CH HO CH3 CH3 CH3 11 -Hydroxylase 18-Hydroxylase O O O 11-Deoxycorticosterone Corticosterone Aldosterone CH2OH CH2OH C O C O CH3 CH3 OH HO OH CH3 CH3 11 -Hydroxylase O O 11-Deoxycortisol Cortisol FIGURE 60. Thus, steroid intermediates are bolic processes are altered, as occurs in liver disease, the converted to steroid end products by sequential 17-, 21-, half-life of cortisol may increase from 100 minutes to 7 and 11-hydroxylation reactions. The first is reduction of double bonds and in- characteristics of a mixed-function oxidase, since two troduction of a hydroxyl group in the A ring to form substrates, steroid and NADPH, are oxidized. All hy- tetrahydric derivatives; this pathway accounts for 20 droxylases seem to be associated with a specific cy- to 30% of the cortisol excreted. Since the last-named enzyme is acts as a reductase, regenerating active glucocorticoids, not detectable in other steroid-producing tissues, the whereas 11 -HSD-2 acts as a dehydrogenase, convert- term 11-oxygenated steroids is considered synonymous ing cortisol to its inactive 11-keto derivative (cortisone). Aldosterone synthesis involves an By inactivating glucocorticoids, 11 -HSD-2 protects the essential 18-hydroxylation step catalyzed by P450c18 mineralocorticoid receptor from occupation by gluco- with corticosterone as the precursor; this reaction also corticoids, thereby endowing specificity to the aldo- takes place within the mitochondria. By contrast, congeni- tal deficiency of 11 -HSD-2 results in inappropriate ac- Steroid Transport in Blood tivation of the mineralocorticoid receptor by cortisol, Glucocorticoids secreted into the systemic circulation leading to hypertension and hypokalemia. The second are reversibly bound to a specific -globulin known as step in the metabolism of cortisol is a glucuronic acid or transcortin or corticosteroid-binding globulin. This bind- sulfate conjugation to form more soluble derivatives ing system has a high affinity and low capacity for corti- that are poorly bound to plasma proteins and readily costeroids, which contrasts with the low-affinity binding pass into the urine. Approximately creted, primarily as sulfates; they constitute about two- 80% of the normal cortisol content in human plasma thirds of the total urinary 17-ketosteroids excreted. In (12 g/dL) is bound to corticosteroid-binding globulin, the male, the other third is contributed by gonadal se- while 10% is bound to serum albumin; the remaining cretions. In addition, when serum albumin levels are low, dioimmunoassay of urinary free cortisol (and plasma less circulating cortisol becomes bound, which yields a cortisol) is supplanting measurements of urinary greater physiological effect. Also, since steroids such as glucocorticoid prednisone also can bind to this macro- prednisone lack glucocorticoid activity until converted molecule. High estrogen states (pregnancy, estrogen ad- to prednisolone by hepatic enzymes, patients with liver ministration, use of oral contraceptives) greatly in- disease should be treated with prednisolone rather than crease circulating transcortin levels. ACTIONS OF THE CORTICOSTEROIDS The pharmacological actions of steroids are generally Steroid Metabolism an extension of their physiological effects. Adrenal cor- Most of the cortisol circulating in the blood is metabo- ticosteroids exert effects on almost every organ in the lized before its excretion. In normal physiological concentrations, they are 60 Adrenocortical Hormones and Drugs Affecting the Adrenal Cortex 689 essential for homeostasis, for coping with stress, and for this effect is the distal tubule (see Chapter 21). Glucocorticoids also principal mineralocorticoid, aldosterone, when adminis- decrease the intestinal transport of calcium by antago- tered in very high doses, has glucocorticoid activity. Such actions on vascular smooth muscle may be secondary to effects mediated through Carbohydrate, Protein, the central nervous system or on circulating volume. Thus, corticosteroids appear to play an important source of this augmented carbohydrate production is role in the regulation of blood pressure by modulating protein, and the protein catabolic actions of the gluco- vascular smooth muscle tone, by having a direct action corticoids result in a negative nitrogen balance. The in- on the heart, and through stimulating renal mineralocor- hibition of protein synthesis by glucocorticoids brings ticoid and glucocorticoid receptors. The resulting hyper- about a transfer of amino acids from muscle and bone tension may predispose patients to coronary heart dis- to liver, where amino acids are converted to glucose. For instance, glucocorticoids stimulate Immune and Defense Mechanisms the synthesis of enzymes involved in glucose and amino acid metabolism, including glucose 6-phosphatase and The inflammatory response is a highly complex process tyrosine transaminase. The relation of this action of glu- that involves a number of cell types of the reticuloen- cocorticoids to their overall effects on general meta- dothelial system and a number of chemical mediators, bolic processes remains obscure, although the latency of including prostaglandins, leukotrienes, kinins, and bio- their therapeutic actions (several hours) is consistent genic amines (See Chapter 36). The inhibitory effects of with the fact that steroids regulate RNA and protein glucocorticoids on various aspects of the inflammatory synthesis.
Particles > 100µm in diameter are trapped in the oropharyngeal cavity; those having dia- meters between 10 and 60µm will be deposited on the epithelium of the bronchial tract viagra super active 25 mg on-line otc erectile dysfunction drugs walgreens. Particles < 2 µm in dia- meter can reach the alveoli buy viagra super active 25 mg cheap erectile dysfunction hypertension drugs, but they will be largely exhaled because of their low tendency to impact on the alveolar epithelium. Drug deposited on the mucous lin- ing of the bronchial epithelium is partly absorbed and partly transported with bronchial mucus towards the larynx. Bronchial mucus travels upwards due to the orally directed undulatory beat of the epithelial cilia. Physiologically, this Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Drug Administration 15 Depth of penetration of inhaled aerosolized drug solution 10% 90% Drug swept up 100 µm is swallowed Nasopharynx 10 µm Trachea-bronchi 1 µm Bronchioli, alveoli Mucociliary transport As complete As little presystemic enteral elimination absorption as possible as possible Low systemic burden Ciliated epithelium A. Application by inhalation Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. The skin is protected from dry- Protective agents are of several kinds to ing, and its hydration and elasticity in- meet different requirements according crease. Hydrophilic agents wash off easily posure to water, regular use of alcohol- and do not impede transcutaneous out- containing disinfectants [p. Distinctions among protective agents are based upon consistency, phy- Dermatologic Agents as Vehicles (B) sicochemical properties (lipophilic, hy- In order to reach its site of action, a drug drophilic), and the presence of addi- (D) must leave its pharmaceutical pre- tives. Powders to leave the drug vehicle (V) is higher exert a drying (evaporative) effect. Be- petroleum jelly, wool fat [lanolin]) and cause the skin represents a closed lipo- may contain up to 10% powder materi- philic barrier (p. Emulsify- fail even to penetrate the outer skin ing ointments are made of paraffins and when applied in a lipophilic vehicle. Lipophilic (oily) cream is an emul- sion of water in oil, easier to spread than oil paste or oil ointments. Hydrogel and water-soluble oint- ment achieve their consistency by means of different gel-forming agents (gelatin, methylcellulose, polyethylene glycol). Drug Administration 17 Solid Liquid Powder Solution Aqueous Alcoholic Paste Dermatologicals solution tincture Oily paste Semi-solid Hydrogel Ointment Lotion Lipophilic Hydrophilic Cream Suspen- Emulsion ointment ointment sion Lipophilic Hydrophilic cream cream Fat, oil Water in oil Oil in water Gel, water Occlusive Permeable, coolant Perspiration impossible possible Dry, non-oily skin Oily, moist skin A. Dermatologicals as skin protectants Lipophilic drug Lipophilic drug Hydrophilic drug Hydrophilic drug in lipophilic in hydrophilic in lipophilic in hydrophilic base base base base Epithelium Stratum corneum Subcutaneous fat tissue B. Dermatologicals as drug vehicles Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Therefore, they must first Speed of absorption is determined enter the blood, usually the venous limb by the route and method of application. There are several pos- It is fastest with intravenous injection, sible sites of entry. When the drug is applied to the introduced directly into the blood- oral mucosa (buccal, sublingual route), stream. In subcutaneous or intramus- plasma levels rise faster than with con- cular injection, the drug has to diffuse ventional oral administration because from its site of application into the the drug preparation is deposited at its blood. Because these procedures entail actual site of absorption and very high injury to the outer skin, strict require- concentrations in saliva occur upon the ments must be met concerning tech- dissolution of a single dose. The same does not hold true for volving subsequent uptake of drug poorly water-soluble or poorly absorb- across the gastrointestinal mucosa into able drugs. Such agents should be given the blood is chosen much more fre- orally, because both the volume of fluid quently. The disadvantage of this route for dissolution and the absorbing sur- is that the drug must pass through the face are much larger in the small intes- liver on its way into the general circula- tine than in the oral cavity. This fact assumes practical signifi- Bioavailability is defined as the cance with any drug that may be rapidly fraction of a given drug dose that reach- transformed or possibly inactivated in es the circulation in unchanged form the liver (first-pass hepatic elimination; and becomes available for systemic dis- p. The larger the presystemic at least a fraction of the drug enters the elimination, the smaller is the bioavail- general circulation via the portal vein, ability of an orally administered drug. Hepatic passage is circumvented when absorption occurs buccally or sublingually, because venous blood from the oral cavity drains directly into the superior vena cava. However, with this route, a local effect is usually intended; a systemic ac- tion is intended only in exceptional cas- es. Under certain conditions, drug can also be applied percutaneously in the form of a transdermal delivery system (p. In this case, drug is slowly re- leased from the reservoir, and then pen- etrates the epidermis and subepidermal connective tissue where it enters blood capillaries.
