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By: Nicholas H. G. Holford, MB, ChB, FRACP Professor, Department of Pharmacology and Clinical Pharmacology, University of Auckland Medical School, Auckland

These formulation additives may alter drug dissolution rates by such mechanisms as increasing the wetting of the dosage form buy generic malegra fxt plus 160 mg online erectile dysfunction pills from canada, aiding rapid disintegration of the dosage form purchase 160 mg malegra fxt plus free shipping erectile dysfunction treatment ring, forming poorly absorbable drug-excipient complexes and altering the pH cheap 160 mg malegra fxt plus overnight delivery erectile dysfunction treatment options injections. The effect of formulation factors on the dissolution rate for absorption routes other than the oral route is discussed in the relevant chapters buy antabuse 500 mg without prescription. Drug degradation is generally a first order process and can be described by the following equation: (Equation 1 cheap viagra vigour 800mg fast delivery. Solvolysis involves drug decomposition through a reaction with the solvent present, for example water, ethyl alcohol or polyethylene glycol. These solvents act as nucleophilic agents and attack electropositive centers of the drug molecule. Other degradation reactions include photolysis, racemization, and decarboxylation. The stability of the drug to degradative enzymes is of particular importance in vivo, as discussed above. Pharmacokinetics is the study of how drugs enter the body, reach the site of action and are removed from the body, i. Elimination is defined as the process of removal of the drug from the body, which may involve metabolism and/or excretion. The pharmacokinetic aspects of a drug are obviously just as important as its pharmacodynamics, when considering therapeutic efficacy. For many drugs this occurs by simple diffusion of the unionized form across cell membranes (see Section 1. When drugs are given by iv administration, there is an extremely high initial plasma concentration and the drug may rapidly enter and equilibrate with well-perfused tissues such as the lung, adrenals, kidneys, liver and heart. Subsequently, the drug enters poorly perfused tissues such as skeletal muscle, connective tissue and adipose tissue. As the concentration of drug in the poorly perfused tissues increases, there is a corresponding decrease in the concentration in the plasma and well-perfused tissues. Many drugs show an affinity for specific binding sites on plasma proteins such as albumin and α1-acid glycoprotein, which results in a reversible association, with some important consequences in therapeutics: • Drug binding lowers the concentration of free drug in solution, and thus the concentration of drug available to act at the receptor. This can result in the need to use high doses to compensate for drug wasteage, which is expensive. Unwanted deposition may also result in toxicity problems, arising from drug action at non-target sites. Classic examples of toxic side-effects resulting from unwanted drug distribution are found in cancer chemotherapy.

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Generally order 160mg malegra fxt plus visa erectile dysfunction age factor, keratinized epithelium appears to be more impermeable than non-keratinized epithelium discount 160 mg malegra fxt plus mastercard erectile dysfunction diabetes pathophysiology. The permeability of the oral mucosal epithelium is intermediate between that of the skin epithelium buy malegra fxt plus 160mg on line erectile dysfunction pump demonstration, which is highly specialized for a barrier function (see Section 8 cheap generic propecia uk. Within the oral cavity super viagra 160 mg otc, the buccal mucosa is less permeable than the sublingual mucosa. The thin epithelium of the sublingual mucosa means that extremely rapid absorption is possible via this route. Thus oral mucosal delivery may be particularly attractive for the delivery of enzymatically labile drugs such as therapeutic peptides and proteins. Depending on the animal species and substrates used, buccal homogenates have shown enzyme activites between a few and several hundred percent of the activities of intestinal homogenates. In general, it can be said that enzyme levels are generally lower in the mouth than, for example, levels present in the gastrointestinal tract. Again, this lower metabolic activity makes the oral mucosa an attractive route for the delivery of enzymatically labile biopharmaceuticals. The sublingual area, in particular, is exposed to a lot of saliva which can enhance drug dissolution and therefore increase bioavailability. However, there are also negative aspects for drug delivery associated with salivary flow, including: • a drug moiety may be diluted by the saliva; • excessive salivary flow may cause too rapid dissolution and absorption; • a drug delivery system (e. The mucous secretions may also limit drug delivery via the oral cavity, via a number of mechanisms: • clearance of the drug prior to drug absorption; • forming a physical barrier through which the drug must diffuse, prior to reaching the absorbing surface; • binding drugs specifically, or non-specifically (via electrostatic, hydrophobic- and hydrogen-bonding interactions). In contrast, the sublingual mucosa is unsuitable for adhesive dosage forms for a number of reasons, including: • the mucosa is exposed to a lot of saliva; • the mucosa is highly flexible and moving constantly; • an adhesive dosage form in this region would be uncomfortable and rather disturbing for the patient. Suitable animal models for studying oral mucosal drug delivery include pigs and 174 dogs, as their oral mucosa is quite similar to the human counterpart, both in morphology and permeability characteristics. The major junctional attachment between the epithelial cells is the desmosome, which displays minimal impedence to intercellular diffusion. Thus in the majority of cases, drug absorption for small hydrophilic moieties is thought to occur via paracellular penetration, moving between the cells, as claimed for drug transport through the epidermis of the skin. However, it should also be remembered that the intercellular space of the epithelial cells of the oral cavity contains lipidic material, deposited from the membrane coating granules. Lipidic moieties (depending, as always, on their physicochemical properties) may be able to permeate through this lipidic environment between the cells, thereby being absorbed via the paracellular route. Again, movement occurs down a concentration gradient, according to Fick’s Law (see Section 1. The stratified nature of the epithelium means that lipophilic moieties must permeate across several layers of cells to reach the underlying blood capillaries (Figure 7. Carrier-mediated processes It has also been suggested that the oral mucosa contains active or carrier-mediated systems for small molecules such as mono-saccharides and amino acids.

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B cells react promptly to antigens order malegra fxt plus 160mg without a prescription impotence medication, even self-antigens buy 160 mg malegra fxt plus free shipping erectile dysfunction relationship, which are ar- ranged repetitively order malegra fxt plus now erectile dysfunction doctors san antonio. However discount 100 mg eriacta, they only react to soluble monomeric antigens if they additionally receive T cell help order 5 mg proscar mastercard. Thus, B-cell non-reactivity largely results from a lack of patterned antigen presentation structures or as a result of T-cell tolerance. Tolerance is acquired, and can be measured as the selective absence of immunological reactivity against specified antigens. T-Cell Tolerance A distinction can be made between central tolerance, which develops in the thymus and is based on the negative selection (deletion) of Tcells recognizing self antigens present in the thymus, and peripheral tolerance. Peripheral tolerance results in the same outcome as central tolerance, however, this Kayser, Medical Microbiology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license Immunological Tolerance 91 formoftoleranceinvolvesantigenrecognitionbyantigen-reactiveperipheralT cells, followed by a process of clonal cell proliferation, end differentiation and death. The following mechanisms have been postulated, and in some cases confirmed, to account for a lack of peripheral T-cell responsiveness (Table 2. Most self-antigens, not present in the serum or in lymphohema- topoietic cells, belong to this category and are ignored despite the fact that they are potentially immunogenic. Certain viruses, and their antigens, actu- ally take advantage of this system of ignorance. For instance, the immune system ignores the rabies virus when it is restricted to axons, and papilloma viruses as long as the antigens are restricted to keratinocytes (warts). The main reason why many self antigens, and some foreign antigens, are ignored by T cells is that immune responses can only be induced within the spleen or in lymph nodes, and non-activated (or naive) T cells do not migrate into the periphery. It has also been postulated that those naive T and B cells which do encounter antigens in the periphery will become anergized, or inactivated, due to a lack of the so-called costimulatory or secondary signals at these sites. Experiments seeking to understand the “indifference” of T cells are summarized in the box on p. In all probability, a great many self-antigens (as well as periph- eral tumors) are ignored by the immune system in this way. During such a scenario the responding T cells differentiate into short- lived effector cells which only survive for two to four days. This induction phase may actually correspond to the postulated phenomenon of anergy (see Table 2. Should this be the case, anergy—defined as the inability of T cells to react to antigen stimulation in vitro—may in fact be explained by the responding cells having already entered a pathway of cell death (apoptosis) (see Fig.

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