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The processes may also occur in that an increase in motility may re- involved in rectal absorption are similar to those de- duce contact time in the upper portion of the intestine scribed for other sites generic viagra extra dosage 130mg mastercard impotence in a sentence. Conversely trusted 130 mg viagra extra dosage erectile dysfunction causes medscape, a Although the surface area available for absorption decrease in gastrointestinal motility may promote ab- is not large, absorption can still occur, owing to the ex- sorption by increasing contact time. Serious in- sorbed from the rectum largely escape the biotransfor- testinal diseases, particularly those associated with mation to which orally administered drugs are subject, intestinal sloughing, can be expected to alter drug ab- because a portion of the blood that perfuses the rectum sorption dramatically. Absorption of most drugs from the gastrointestinal tract is reduced or delayed by the presence of food in the gut. Drugs such as the tetracyclines, which are FACTORS AFFECTING RATE OF highly ionized, can complex with Ca ions in mem- GASTROINTESTINAL ABSORPTION branes, food, or milk, leading to a reduction in their In addition to the lipid–water partition coefficient of rate of absorption. For drugs that are ionized in the drugs, local blood flow, and intestinal surface area, other stomach and un-ionized in the intestine, overall ab- factors may affect absorption from the gastrointestinal sorption will be delayed by any factor that delays gas- tract. Finally, increased splanchnic blood flow, as occurs during eating, will increase the rate of drug Gastric Emptying Time absorption. The rate of gastric emptying markedly influences Formulation Factors the rate at which drugs are absorbed, whether they are acids, bases, or neutral substances. In general, fac- The ability of solid drug forms to dissolve and the sol- tors that accelerate gastric emptying time, thus permit- ubility of the individual drug in the highly acidic gas- ting drugs to reach the large absorptive surface of the tric juice must be considered. For example, although small intestine sooner, will increase drug absorption the anticoagulant dicumarol has a very high lipid– unless the drug is slow to dissolve. A list of physiolog- water partition coefficient, it precipitates at the low ical, pathological, and pharmacological factors that in- pH of gastric juice, and the rate of its absorption is TABLE 3. Taken together, the absorbed faster and more completely than tablet or Pgp transporter and the cytochrome P450 enzymes suspension forms. Suspensions of fine particles (mi- form a mechanism to reduce the amount of drug reach- crocrystalline) are better absorbed than are those of ing the systemic circulation. Metabolism and Efflux Transporters ABSORPTION OF DRUGS FROM THE LUNG Drugs may be inactivated in the gastrointestinal tract before they are absorbed. Until recently, only gut mi- The lungs serve as a major site of administration for a croflora were implicated in the metabolism of drugs in number of agents given for both local and systemic ef- the gastrointestinal system, affecting drug absorption. Absorption of agents from the lung is zymes, play a major role in determining the extent of facilitated by the large surface area of the pulmonary drug absorption of some drugs. Significant expression of alveolar membranes (50–100 m2), the limited thickness cytochrome P450 3A4 and 3A5 occurs in the entero- of these membranes (approximately 0. For example, less than 20% of a dose of the im- for diffusion is a combination of the blood–air partition munosuppressant cyclosporine reaches the systemic cir- coefficient (which is a measure of the capacity of blood culation intact. In fact, most of the metabolism of cy- to dissolve drug) and the difference in partial pressure closporine prior to reaching the systemic circulation between the alveoli and the arterial and venous blood. Thus, gut me- quire more drug to be dissolved in the blood for equi- tabolism is the major factor responsible for the low per- librium to be reached. Cytochrome P450 2C9 and 2C19 are also expressed in measurable quantities in the human ABSORPTION OF DRUGS THROUGH intestine. With any of these four cytochrome P450 en- THE SKIN zymes, the variation in expression between individuals is substantial, and so their relative contribution to Most drugs that have been incorporated into creams or presystemic metabolism of drugs will vary from person ointments are applied to the skin for their local effect. However, the stratum corneum, or outer out of a cell) are also present in human intestinal ente- layer of the epidermis, forms a barrier against the rapid rocytes on the apical side nearest the lumen of the in- penetration of most drugs. The predominant transporter protein identified the relatively close-packed cellular arrangement and to date is P glycoprotein (Pgp), which is a product of the decreased amount of lipid in these cells. This transporter was originally identified highly lipid-soluble compounds will be absorbed much as being overexpressed in tumor cells and responsible in more slowly through the skin than from other sites. The part for multidrug resistance because of its role in the dermis, on the other hand, is well supplied with blood efflux of drugs out of tumor cells; thus the name mul- and lymph capillaries and therefore is permeable to tidrug resistance (MDR) gene. If that many of the drugs that are substrates for cy- penetration of the skin by lipid-insoluble compounds tochrome P450 3A4 are also substrates for Pgp. As a does occur, it is probably accomplished by diffusion substrate for Pgp, a drug will enter the cell, usually via through the hair follicles, sweat glands, or sebaceous passive diffusion, but then be picked up by the Pgp glands. Once a drug has entered the blood Administration compartment, the rate at which it penetrates tissues and Intramuscular and subcutaneous injections are by far other body fluids depends on several factors. These in- the most common means of parenteral drug administra- clude (1) capillary permeability, (2) blood flow–tissue tion.

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Since KCl solutions have a rather bit- Kay Ciel elixir Berlex Liquid ter and unpleasant taste purchase 120 mg viagra extra dosage otc erectile dysfunction with normal testosterone levels, this salt was form erly given as Potassium Triplex Lilly Liquid an enteric-coated tablet cheap viagra extra dosage 130 mg with visa erectile dysfunction 18-25. H owever, the rapid release of KCL 10% Purepac Liquid KCl from the tablet after it entered the sm all intestine KCL 20% Stanlabs Liquid K-Lor A bbott Powdera was responsible for a severe local ulceration, hem or- a K-Lyte M ead Johnson Tablets rhage, and stenosis, especially when there was a delay in gut transit tim e; therefore, the enteric-coated tablets aThis product, although supplied as a solid dose, is dissolved in water before ingestion. Sugar-coated products have been m arketed that contain KCl in a wax m atrix (Slow-K and Kaon-Cl) and helpful. Finally, the addition of a K -sparing diuretic to are purportedly slow- and controlled-release prepara- the therapeutic regim en m ay prove useful. A vailable evidence indicates that these slow- The three principal potassium -sparing diuretic release form s of KCl are occasionally capable of causing agents produce sim ilar effects on urinary electrolyte local tissue dam age and therefore probably should be com position. Solutions of tubule and collecting duct, they cause m ild natriuresis potassium gluconate, like the tablets, also have been as- and a decrease in K and H excretion. M icroencapsulated sim ilarities, these agents actually constitute two groups KCl preparations (M icro-K, K-D ur) that are neither en- with respect to their m echanism s of action. Aldosterone Antagonists: Spironolactone Consum ption of potassium -rich foods is the easiest and m ost generally advised m eans of counteracting a The m echanism by which Na is reabsorbed in coupled K deficit. If K -rich A ldosterone and other com pounds with m ineralocorti- foods prove inadequate in replacing large quantities of coid activity bind to a specific m ineralocorticoid recep- the electrolyte or if the increased caloric intake that is tor in the cytoplasm of late distal tubule cells and of part of the dietary supplem entation is not desirable, principal cells of the collecting ducts. A listing receptor com plex is transported to the cell nucleus, of these solutions is given in Table 21. A lthough pa- where it induces synthesis of m ultiple proteins that are tients m ay find m any of these products unpalatable, collectively called aldosterone-induced proteins. The their further dilution with water or fruit juice can be precise m echanism s by which these proteins enhance Na transport are incom pletely understood. H owever, the net effect is to increase Na entry across apical cell m em branes and to increase basolateral m em brane Na –K –A TPase activity and synthesis. Spironolactone thus blocks the hormone-induced Prunes (7) stimulation of protein synthesis necessary for Na reab- Banana (1) D ates (7) sorption and K secretion. Spironolactone, in the presence Figs (4) of circulating aldosterone, promotes a modest increase in Raisins (0. A pricots (6) The observations that spironolactone is ineffective in Sweet potato (1) adrenalectomized patients and that the actions of W hite potato (1) spironolactone can be reversed by raising circulating al- 248 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM dosterone blood levels (surmountable antagonism) sup- especially in patients with im paired renal function or ex- port the conclusion that spironolactone acts by competi- cessive K intake (including the K salts of coadm inis- tive inhibition of the binding of aldosterone with receptor tered drugs, e. Spironolactone acts only when can induce hyponatrem ia and in cirrhotic patients, m eta- mineralocorticoids are present. These Pharmacokinetic Properties include diarrhea, gastritis, gastric bleeding, and peptic ul- Spironolactone is poorly absorbed after oral adminis- cers. Spironolactone is contraindicated in patients with tration and has a delayed onset of action; it may take sev- peptic ulcers. It has a some- blood urea nitrogen, drowsiness, lethargy, ataxia, confu- what slower onset of action than triamterene and sion, and headache. G ynecom astia and m enstrual irreg- amiloride (discussed later), but its natriuretic effect is ularity in m ales and fem ales, respectively, can occur. Spironolactone is rapidly and extensively metab- and duration of therapy), which is generally reversible, olized, largely to the active metabolite canrenone. A nim al studies Canrenone and potassium canrenoate, its K salt, are dem onstrating tum origenic potential support the clinical available for clinical use in some countries outside the judgm ent that spironolactone alone or in com bination United States. Canrenone has a half-life of approximately should not be used for m ost patients who require di- 10 to 35 hours. The metabolites of spironolactone are ex- uretic therapy and its unnecessary use should be creted in both the urine and feces. Eplerenone and canrenone exhibit Triamterene and Amiloride fewer steroidlike side effects (gynecomastia, hirsutism). Triam terene (D yrenium ) or am iloride (M idam or) ad- Clinical Uses m inistration results in changes in urinary electrolyte Spironolactone has been used clinically in the fol- patterns that are qualitatively sim ilar to those produced lowing conditions: by spironolactone. The m echanism by which these agents bring about the alterations in electrolyte loss, however, is quite different.

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This is important discount viagra extra dosage 120mg on-line erectile dysfunction hernia, as many naturopaths continue to produce their own formulations of herbal tinctures buy viagra extra dosage 200 mg on-line erectile dysfunction drugs in bangladesh. They may use a single herb or a combination of herbs to treat a particular disease condition. Combinations of two to five herbs are often used in a formula for either acute or chronic conditions. Siberian ginseng (Eleuthrococcus sinensis) and gotu kola (Centella asiastica) might be considered stimulant nervines. The adaptogens, mostly from Asian traditions (the ginsengs, Withania somnifera), are also considered tonic nervines. This tonic function of herbs is common across herbal traditions and is a class of mechanisms perhaps inadequately attended to among pharmaceutical approaches to neurological disorders. Diet (clinical nutrition) Naturopaths attend to dietary assessment including macro- and micro-nutrient content in foods, individual responses to diets and specific foods and in the application of a variety of therapeutic diets. The use of diet to improve health is a therapeutic foundation in naturopathic medicine as it encompasses aspects of all six of the naturopathic principles. The types of diet that NDs use are highly variable and may include, on a case-by-case basis, low fat, elimination and challenge (hypoallergenic), glutenfree, dairy-free, blood type diet, vegetarian and fasting (juice, water). Clinical evidence evaluating the influence of diet in neurological disease includes the following examples. Epilepsy: the ketogenic diet The ketogenic diet is a high-fat, low-carbohydrate diet that was developed decades ago but which has recently come under consideration in intractable cases. There have been many studies reporting a sig- nificant decrease in seizures of children with severe epilepsy that were 10–12 treated with the ketogenic diet. Although the diet is highly successful in decreasing seizures in difficult-to-treat epileptic children, compliance with the diet is often an 13 issue. There is evidence that it may increase the frequency of kidney stone formation in 14 those on the diet. Migraine headaches: hypoallergenic diets (elimination/challenge diet) The rationale for use of this type of diet for migraine headaches is that food allergies cause platelet degranulation and histamine release that can precipitate vasomotor 15 instability and subsequent migraine. There are a number of studies that have reported a benefit in subjects who suffer from migraines and have eliminated foods that might elicit 16–20 a migraine. The elimination diet requires that a person go on various versions of an oligoallergenic restricted diet (a typical diet may be primarily lamb and rice for a period of 7–10 days) after which they systematically re-introduce food groups to identify foods that will elicit a migraine. Once a food that triggers a migraine is identified, the food is taken out of the diet for a period of time and is re-introduced in smaller quantities. The strategy is not to stay on a highly restricted diet but to identify allergenic foods and to decrease the amounts and frequency of these foods consumed. Naturopathic medicine in neurological disorders 159 Multiple sclerosis: the Swank diet There have been a number of epidemiological studies assessing associations between dietary factors and the risk of developing multiple sclerosis (MS). A number of epidemiological studies have reported a significant positive association between risk of 21,22 MS and consumption of animal fat. Dr Roy Swank has provided evidence that a diet low in saturated fats (less than 15 g/day) combined with cod liver oil supplementation, maintained over a long period of time, tends to retard the disease process, reduce the 23,24 number of attacks and decrease mortality. Oneopen-label pilot clinical trial evaluated the effects of a diet low in saturated fats supplemented with fish oil, vitamin B-complex 25 and vitamin C in subjects with newly diagnosed relapsing-remitting MS. After 2 years of this regimen the study reported a significant decrease from baseline values of relapse rates and disability scores. Preliminary reports from a recent randomized placebo- controlled pilot study evaluating a diet very low in saturated fat (less than 15%) supplemented with fish oil capsules found that, when compared with subjects following the American Heart Diet (less than 30% saturated fat) supplemented with placebo oil capsules, the treatment group had a significant decrease in relapse rate, disability and a 26 decrease in two inflammatory cytokines. These studies suggest that a diet very low in fat combined with fish oil supplementation may help to decrease relapse rates and increase time to disability in people with MS. Nutritional/dietary supplementation Many naturopaths use a variety of nutritional supplements usually as an adjunct to fundamental lifestyle therapies, such as diet, exercise and stress reduction (counseling) to address a specific symptom or condition. Under the DSHEA, dietary supplements are considered foods and not drugs and therefore regulated by the FDA as foods. Examples of substances that are considered dietary supplements include: fish, flax, evening primrose and borage oils, glandulars (usually made from animal sources), enzymes, melatonin and dehydroepiandrosterone (DHEA) (although these are hormones they are regulated and sold as dietary supplements in the USA), garlic capsules, soluble fiber, coenzyme Q10 (CoQ-10), L-carnitine, 5-hydroxytryptophan (5-HTP), etc.

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