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Thus the larger the pA2 value buy cheap cialis jelly 20 mg line impotence signs, the smaller the concentration of antagonist needed and the greater its affinity and effectiveness proven cialis jelly 20mg erectile dysfunction meme. In practice full DRCs are rarely obtainable especially in studies on the CNS, or even necessary, provided that responses to two doses of agonist can be obtained at each concentration of antagonist. This will establish the position of the DRC and allow r to be calculated. If the antagonist does not readily dissociate from the receptor, because it is bound firmly, then the agonist will not be able to displace it and restore a maximal response. An agonist can often achieve a maximal response by activating only a small percentage of its receptors, so in the presence of low concentrations of a non-dissociating antagonist there may be sufficient spare receptors available for increased concentrations of the agonist still to achieve a maximal response. As the concentration of antagonist is increased, however, fewer unoccupied receptors are left and since the agonist cannot displace the antagonist a maximal response cannot be achieved (Fig. It is still competitive because the drugs are competing for the same receptor. This is non- competitive antagonism which may, or may not, be reversible, depending on the action of the antagonist. There are a number of drugs with this action on the glutamate NMDA receptors (Chapter 10). PHARMACOKINETICS This is generally accepted as the term to describe the absorption distribution and metabolism of a drug in vivo and it is these factors which determine how quickly and how much of the administered drug can actually reach its site of action (in the CNS) and be maintained there for the required time (see Fig. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood±brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details 112 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION usually given intravenously or intraperitonealy, but therapeutically most of them are taken orally. The speed of onset of action of a drug depends primarily on how quickly it reaches the circulation. For this reason alone it is not surprising that intravenous admin- istration produces the quickest response. Thereafter the rate and degree of absorption depends on the blood flow to the injected site and the surface area of vessels exposed to the drug. The response to an intramuscular injection in humans is quite rapid since our muscles are large and have a good blood supply. In laboratory animals muscle mass is small and so an intraperitoneal administration may be more effective because the drug solution can be given in relatively large volumes which disperse over a large surface area (the abdominal wall and intestinal surfaces). Most are absorbed in the small intestine where the villi, which penetrate into the lumen, present a large surface area. For an acidic drug this is represented by the Henderson±Hasselbalch equation as conc-unionised drug Cu† Ci pK À pH ˆ log pK À pH ˆ log for basic drug† conc-ionised drug Ci† Cu Thus an acidic drug with a relatively low pK of 3 will be largely unionised (hundredfold) in the acidic environment (pH ˆ 1) of the stomach since Cu 3 À 1 ˆ log 2 ˆ 100 ˆ Ci but in the more basic intestine it will be ionised, i. Drugs absorbed along the length of the gut do not enter straight into the general circulation but pass initially into the portal circulation to the liver where they may be subject to metabolism. In fact a high proportion of some orally administered drugs can be lost in this way without even reaching the main bloodstream but those given sub- lingually (under the tongue) or by suppository into the rectum bypass the portal system. Some drugs can also stimulate the production of microsonal-metabolising enzymes (e. Once in the blood most drugs will leave the circulation by being filtered through pores in the capillaries, provided they have a molecular weight below 6000, which is almost always the case, and are not bound to plasma protein (albumin) which is too large to be filtered. Although such binding, which commonly accounts for over 90% of plasma drug, does restrict movement, it also acts as a drug store. Unfortunately one drug can displace another from such binding and so elevate its free plasma con- centration and create the potential for toxicity. PHARMACOLOGY AND DRUG EFFECTS 113 There are two sites in the body where a drug is not able to pass freely into the tissue. One is the placenta and the other the brain where the blood±brain barrier (see Chapter 1) is a formidable hindrance.

While blood flow may improve cheap 20 mg cialis jelly amex impotence after 40, microvascular pres- sures are elevated discount cialis jelly 20mg on-line erectile dysfunction vascular disease, which worsens cerebral edema. The intestinal vasculature is unusual because three very different tissues—the muscle layers, submucosa, and mucosal layer—are served by branches from a common vasculature lo- SMALL INTESTINE CIRCULATION cated in the submucosa. Most of the intestinal vascular resistance is regulated by small arteries and arterioles preceding the separate The small intestine completes the digestion of food and then muscle and submucosal and mucosal vasculatures. MA, muscular absorbs the nutrients to sustain the remainder of the body. At arteriole; 1A to 5A, successive branches of the arterioles; 1V to rest, the intestine receives about 20% of the cardiac output 4V, successive branches of the venules; MV, muscular venule. Quantification of the architectural of these numbers nearly double after a large meal. Unless the changes observed in intestinal arterioles from diabetic rats. Blood flows of 70 to 100 mL/min high blood flow both at rest and during food absorption, per 100 g in this specialized tissue are probable and much the capillary blood pressure is usually 13 to 18 mm Hg higher than the average blood flow for the total intestinal and seldom higher than 20 mm Hg during food absorp- wall (see Table 17. Therefore, plasma colloid osmotic pressure is ing blood flow in the heart and brain. The interstitial space of the villi is mildly hy- sorption, the plasma protein reflection coefficient for the perosmotic ( 400 mOsm/kg H2O) at rest as a result of NaCl. It is assumed that to 600 to 800 mOsm/kg H2O near the villus tip, compared most of the decrease in reflection coefficient occurs in with 400 mOsm/kg H2O near the villus base. This lowers the ability of plasma cause of high osmolalities in the villi appears to be greater ab- proteins to counteract capillary filtration, with the net re- sorption than removal of NaCl and nutrient molecules. Eventu- is also a possible countercurrent exchange process in which ally, this fluid must be removed. Not surprisingly, the materials absorbed into the capillary blood diffuse from the highest rates of intestinal lymph formation normally oc- venules into the incoming blood in the arterioles. Food Absorption Requires a High Blood Flow Sympathetic Nerve Activity Can Greatly Decrease to Support the Metabolism of the Mucosal Intestinal Blood Flow and Venous Volume Epithelium The intestinal vasculature is richly innervated by sympa- Lipid absorption causes a greater increase in intestinal thetic nerve fibers. Major reductions in gastrointestinal blood flow, a condition known as absorptive hyperemia, blood flow and venous volume occur whenever sympa- and oxygen consumption than either carbohydrate or thetic nerve activity is increased, such as during strenuous amino acid absorption. During absorption of all three exercise or periods of pathologically low arterial blood classes of nutrients, the mucosa releases adenosine and pressure. Venoconstriction in the intestine during hemor- CO and oxygen is depleted. The hyperosmotic lymph and rhage helps to mobilize blood and compensates for the 2 venous blood that leave the villus to enter the submucosal blood loss. Gastrointestinal blood flow is about 25% of the tissues around the major resistance vessels are also major cardiac output at rest; a reduction in this blood flow, by contributors to absorptive hyperemia. By an unknown heightened sympathetic activity, allows more vital func- mechanism, hyperosmolality resulting from NaCl induces tions to be supported with the available cardiac output. Hyperosmolality result- decreased by a combination of low arterial blood pressure ing from large organic molecules that do not enter en- (hypotension) and sympathetically mediated vasoconstric- dothelial cells does not cause appreciable increases in NO tion that mucosal tissue damage can result. These observations suggest that NaCl entering the en- HEPATIC CIRCULATION dothelial cells is essential to induce NO formation. The hepatic circulation perfuses one of the largest organs in The active absorption of amino acids and carbohydrates the body, the liver. The liver is primarily an organ that and the metabolic processing of lipids into chylomicrons maintains the organic chemical composition of the blood by mucosal epithelial cells place a major burden on the mi- plasma. For example, all plasma proteins are produced by crovasculature of the small intestine. There is an extensive the liver, and the liver adds glucose from stored glycogen network of capillaries just below the villus epithelial cells to the blood. The villus capillaries are unusual in and bacteria and detoxifies many man-made or natural or- that portions of the cytoplasm are missing, so that the two ganic chemicals that have entered the body.

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