Kosuke Izumi, M.D., Ph.D.

• Research Center for Epigenetic Disease
• Institute for Molecular and Cellular Biosciences
• The University of Tokyo
• Tokyo, Japan

This is done by decreasing " latest news erectile dysfunction treatment 100 mg zenegra sale," which will decrease "G impotence type 1 diabetes zenegra 100 mg low price," which will decrease self-attraction of dispersed phase particles erectile dysfunction statistics canada discount zenegra 100 mg without a prescription. ExamplE Area increase in o/w emulsion Fifty milliliter of an oil in a graduated cylinder has a total A = 80 cm2 erectile dysfunction causes in early 20s buy cheapest zenegra. To be useful in a pharmaceutical preparation erectile dysfunction causes weight buy generic zenegra 100mg on line, the emulsifying agent must be compatible with the other formulative ingredients and must not interfere with the stability or efficacy of the therapeutic agent causes juvenile erectile dysfunction purchase cheap zenegra. The emulsifier should be nontoxic with respect to its intended use and the amount to be consumed by the patient. Of prime importance is the capability of the emulsifying agent to promote emulsification and to maintain the stability of the emulsion for the intended shelf life of the product. Various types of materials have been used in pharmacy as emulsifying agents, with hundreds, if not thousands, of individual agents tested for their emulsification capabilities. Carbohydrate materials, such as the naturally occurring agents acacia, tragacanth, agar, chondrus, and pectin. These materials form hydrophilic colloids, which, when added to water, generally produce o/w emulsions. Microcrystalline cellulose is employed in a number of commercial suspensions and emulsions as a viscosity regulator to retard particle settling and provide dispersion stability. High molecular weight alcohols, such as stearyl alcohol, cetyl alcohol, and glyceryl monostearate. Cholesterol and cholesterol derivatives may also be employed in externally used emulsions to promote w/o emulsions. In anionic agents, this lipophilic portion is negatively charged, but in the cationic agent, it is positively charged. Owing to their opposing ionic charges, anionic and cationic agents tend to neutralize each other and are thus considered incompatible. Depending on their individual nature, certain members of these groups form o/w emulsions and others w/o emulsions. Agents of the nonionic type include the sorbitan esters and the polyoxyethylene derivatives, some of which appear in Table 14. Nonionic surfactants are effective over pH range of 3 to 10, cationic surfactants are effective over Table 14. Generally, these form o/w emulsions when the insoluble material is added to the aqueous phase if there is a greater volume of the aqueous phase than of the oleaginous phase. However, if the powdered solid is added to the oil and the oleaginous phase volume predominates, a substance such as bentonite is capable of forming a w/o emulsion. The relative volume of internal and external phases of an emulsion is important, regardless of the type of emulsifier used. As the internal concentration of an emulsion increases, so does the viscosity of the emulsion to a certain point, after which the viscosity decreases sharply. At this point, the emulsion has undergone inversion, that is, it has changed from an o/w emulsion to a w/o or vice versa. In practice, emulsions may be prepared without inversion with as much as about 75% of the volume of the product being internal phase. Although the numbers have been assigned up to about 40, the usual range is between 1 and 20. Materials that are highly polar or hydrophilic have been assigned higher numbers than materials that are less polar and more lipophilic. On a small scale, as in the laboratory or pharmacy, emulsions may be prepared using a dry Wedgwood or porcelain mortar and pestle; a mechanical blender or mixer, such as a Waring blender or a milkshake mixer; a hand homogenizer. Wetting agents aid in attaining intimate contact between solid particles and liquids. The soil will be emulsified, and foaming generally occurs and a washing away of the dirt. For example, if a micropipette is used to deliver 3 L of a surfactant to the clean, quiet surface of water, the area over which it spreads, determined experimentally using a film balance, is 12,000 cm2. The actual thickness of the film can be calculated by dividing the volume of surfactant applied by the surface area, as follows: 0. The cross-sectional area can now be calculated by dividing the surface area by the number of molecules (12,000 cm2/5. The quantity of surfactant required to emulsify a selected quantity of oil for the preparation of an oil-in-water emulsion can be calculated as follows: ExamplE To emulsify 50 mL of oil to an average globular diameter of 1 g, the volume of each globule is Vi = 4 3 4 r = 0. Industrial homogenizers have the capacity to handle as much as 100,000 L of product per hour. In the small-scale extemporaneous preparation of emulsions, three methods may be used. They are the continental or dry gum method, the English or wet gum method, and the bottle or Forbes bottle method. In the first method, the emulsifying agent (usually acacia) is mixed with the oil before the addition of water, that is, dry gum. The bottle method is reserved for volatile oils or less viscous oils and is a variation of the dry gum method. The equipment is used for homogenization, dispersion, and emulsification of solids or liquids. For instance, if 40 mL of oil is to be emulsified, 20 mL of water and 10 g of gum would be employed in the primary emulsion, with any additional water or other formulation ingredients added afterward. A mortar with a rough rather than smooth inner surface must be used to ensure proper grinding action and reduction of the globule size. A glass mortar is too smooth to produce the proper reduction of the internal phase. Other liquid formulative ingredients that are soluble in or miscible with the external phase may then be mixed into the primary emulsion. Solid substances such as preservatives, stabilizers, colorants, and any flavoring material are usually dissolved in a suitable volume of water (assuming water is the external phase) and added as a solution to the primary emulsion. Any substances that might interfere with the stability of the emulsion or the emulsifying agent are added as near last as is practical. For instance, alcohol has a precipitating action on gums such as acacia; thus, no alcohol or solution containing alcohol should be added directly to the primary emulsion, because the total alcoholic concentration of the mixture would be greater at that point than after other diluents were added. Provided the dispersion of the acacia in the oil is adequate, the dry gum method can almost be guaranteed to produce an acceptable emulsion. Rather than using a mortar and pestle, the pharmacist can generally prepare an excellent emulsion using the dry gum method and an electric mixer or blender. Should the mixture become too thick, additional water may be blended into the mixture before another portion of oil is added. Then, as with the continental or dry gum method, the other formulative materials are added, and the emulsion is transferred to a graduate and brought to volume with water. Bottle or Forbes Bottle method the bottle method is useful for the extemporaneous preparation of emulsions from volatile oils or oleaginous substances of low viscosities. Powdered acacia is placed in a dry bottle, two parts of oil are added, and the mixture is thoroughly shaken in the capped container. A volume of water approximately equal to that of the oil is then added in portions and the mixture thoroughly shaken after each addition. This method is not suited for viscous oils because they cannot be thoroughly agitated in the bottle when mixed with the emulsifying agent. When the intended dispersed phase is a mixture of fixed oil and volatile oil, the dry gum method is generally employed. In this apparatus, the pumping action of the handle forces the emulsion through a very small orifice that reduces the globules of the internal phase to about 5 m and sometimes less. In Situ Soap method the two types of soaps developed by this method are calcium soaps and soft soaps. The emulsifying agent in this instance is the calcium salt of the free fatty acid formed from the combination of the two entities. In the case of olive oil, the free fatty acid is oleic acid, and the resultant emulsifying agent is calcium oleate. A difficulty that sometimes arises when preparing this self-emulsifying product is that the amount of free fatty acids in the oil may be insufficient on a 1:1 basis with calcium hydroxide. Typically, to make up for this deficiency, a little excess of the olive oil, or even a small amount of oleic acid, is needed to ensure a nice, homogeneous emulsion. Because the oil phase is the external phase, this formulation is ideal where occlusion and skin softening are desired, such as for itchy, dry skin or sunburned skin. A typical example of this emulsion is calamine liniment: Calamine Zinc oxide aa Olive oil Calcium hydroxide solution aa qs ad 1,000. The type of emulsion produced depends on the properties of the oil and surfactants. Hydrophilic surfactants may be used to produce transparent o/w emulsions of many oils, including flavor oils and vitamin oils such as A, D, and E. These emulsions are dispersions of oil, not true solutions; however, because of the appearance of the product, the surfactant is commonly said to solubilize the oil. Surfactants commonly used in the preparation of such oral liquid formulations are polysorbate 60 and polysorbate 80. Both o/w and w/o microemulsions may be formed spontaneously by agitating the oil and water phases with carefully selected aggregation and Coalescence Aggregates of globules of the internal phase have a greater tendency than do individual particles to rise to the top of the emulsion or fall to the bottom. The term is taken from the dairy industry and is analogous to creaming or rising to the top of cream in milk that is allowed to stand. The creamed portion of an emulsion may be redistributed rather homogeneously upon shaking, but if the aggregates are difficult to disassemble or if insufficient shaking is employed before each dose, improper dosage of the internal phase substance may result. It is important to recall that the rate of separation is increased by increased particle size of the internal phase, larger density difference between the two phases, and decreased viscosity of the external phase. Upward creaming takes place in unstable emulsions of the o/w or the w/o type in which the internal phase has a lesser density than the external phase. Additional emulsifying agent and reprocessing through appropriate machinery are usually necessary to reproduce an emulsion. Because other environmental conditions, such as the presence of light, air, and contaminating microorganisms, can adversely affect the stability of an emulsion, appropriate formulative and packaging steps are usually taken to minimize such hazards to stability. Many molds, yeasts, and bacteria can decompose the emulsifying agent, disrupting the system. Even if the emulsifier is not affected by the microbes, the product can be rendered unsightly by their presence and growth and will of course not be efficacious from a pharmaceutical or therapeutic standpoint. Because fungi (molds and yeasts) are more likely to contaminate emulsions than are bacteria, fungistatic preservatives, commonly combinations of methylparaben and propylparaben, are generally included in the aqueous phase of an o/w emulsion. Generally, for an emulsion containing about two-thirds oil, the adult dose is 45 mL, about 3 tablespoonsful. Castor oil is best taken on an empty stomach, followed with one full glass of water. It is prepared by the dry gum method (4:2:1), mixing the oil with the acacia and adding 250 mL of purified water all at once to make the primary emulsion. To this is slowly added with trituration the remainder of the ingredients, with the vanillin dissolved in the alcohol. A substitute flavorant for the vanillin, a substitute preservative for the alcohol, a substitute emulsifying agent for the acacia, and an alternative method of emulsification may be used as desired. There are a number of commercial preparations of emulsified oil, with many containing additional cathartic agents such as phenolphthalein, milk of magnesia, agar, and others. Simethicone Emulsion Simethicone emulsion is a water-dispersible form of simethicone used as a defoaming agent for the relief of painful symptoms of excessive gas in the gastrointestinal tract. Simethicone emulsion works in the stomach and intestines by changing the surface tension of gas bubbles, enabling them to coalesce, freeing the gas for easier elimination. A lotion is an emulsion liquid dosage form applied to the outer surface of the body. A number of topical emulsions, or lotions, are used therapeutically to deliver a drug systemically. An example is Estrasorb (estradiol, Graceway), which contains estradiol for use in the treatment of hot flashes and night sweats accompanying menopause. The castor oil in the emulsion works directly on the small intestine to promote bowel movement. Overuse of castor oil may cause excessive loss of water and body electrolytes, which can have a debilitating effect. A shampoo is a solution, emulsion, or suspension dosage form used to clean the hair and scalp. It may contain an active pharmaceutical ingredient intended for topical application to the scalp. Some gel systems are as clear as water, and others are turbid because the ingredients may not be completely molecularly dispersed (soluble or insoluble), or they may form aggregates, which disperse light. Gels in which the macromolecules are distributed so that no apparent boundaries exist between them and the liquids are called single-phase gels. When the gel mass consists of floccules of small, distinct particles, the gel is classified as a two-phase system and frequently called a magma or a milk. Gels and magmas are considered colloidal dispersions because they contain particles of colloidal dimension. To be more descriptive, a prefix such as hydro- for water (hydrosol) or alco- for alcohol (alcosol) may be employed to indicate the dispersion medium. Although there is no precise point at which the size of a particle in a dispersion can be considered to be colloidal, there is a generally accepted size range. Colloidal particles are usually larger than atoms, ions, or molecules and, generally, consist of aggregates of many molecules, although in certain proteins and organic polymers, single large molecules may be of colloidal dimension and form colloidal dispersions. One difference between colloidal dispersions and true solutions is the larger particle size of the disperse phase of the colloidal dispersion. This turbidity is easily seen, even with dilute preparations, when the dispersion is observed at right angles to a beam of light passed through the dispersion (Tyndall effect). Although reference is made here to dilute colloidal dispersions, most pharmaceutical preparations contain high concentrations of colloidal particles, and in these instances, there is no difficulty in observing turbidity.

The high renin levels observed during pregnancy suggest that the increased plasma volume is a response to the relative under-filling that results from the profound systemic vasodilatation erectile dysfunction chicago discount 100 mg zenegra otc. The dilated collecting system can hold 200 to 300 ml of urine erectile dysfunction effects on women purchase 100mg zenegra with visa, which can act as a reservoir for bacteria erectile dysfunction urologist new york order generic zenegra on line. If untreated erectile dysfunction drugs with the least side effects purchase 100mg zenegra overnight delivery, 30% of pregnant women with asymptomatic bacteriuria will develop pyelonephritis with an increased risk of miscarriage or preterm delivery impotence vitamins cheap 100mg zenegra with mastercard. Chapter 3 Physiology contributing factor to the increased cardiac output in late pregnancy doctor for erectile dysfunction in ahmedabad purchase zenegra on line. There is also a change in glomerular filtration characteristics leading to proteinuria. However, where there is pre-existing kidney disease, hyperfiltration during pregnancy can accelerate renal damage. The renal baroreceptors in the afferent arteriole are modified pressure-sensitive endothelial cells. Aldosterone acts on distal convoluted tubules and the cortical collecting ducts in the kidneys, enhancing sodium and water reabsorption in exchange for potassium. Hypovolaemia leads to production of low volumes of urine that are highly concentrated (>350 mOsm/kg with specific gravity >1. The effects of aldosterone (Na+ and H2O retention, and increased K+ excretion) are believed to be antagonized by the high levels of circulating progesterone (see Table 3. Together with hormonal changes, these effects lead to considerable alterations in electrolyte physiology as follows: 1. Acid-base balance and potassium 52 Dietary intake of proteins and homeostatic metabolism lead to generation of metabolic acids that are cleared by the kidneys under physiological conditions. The daily production of metabolic acids is increased in pregnancy due to an increase in basal metabolic rate, fetal metabolic load, and an increase in daily protein intake. Increased progesterone has a natriuretic effect Increased natriuretic hormones In acid-base terms, this could be described as a metabolic acidosis with respiratory alkalaemia. The renal handling of acid (excretion of H+) and base (reabsorption of bicarbonate) are not altered during a normal pregnancy. Acidosis is usually associated with hyperkalaemia and alkalosis with hypokalaemia. To maintain electrical neutrality, K+ ions are forced out of the intracellular compartment into the extracellular space, creating a state of hyperkalaemia. K+ flows into the cells to maintain electrical neutrality, creating a hypokalaemic state. Potassium excretion is reduced during pregnancy despite high aldosterone levels and relatively alkaline urine. The mechanism is not completely understood but it is likely to be related to the elevated levels of progesterone exerting anti-mineralocorticoid effects, probably through the inhibition of active potassium excretion in the distal tubule and collecting ducts. As a result there is net potassium retention, which, like sodium, is distributed throughout fetal and maternal tissues without causing hyperkalaemia. Clinically, changes in potassium homeostasis result in a relative resistance to kaliuretic drugs Diseases that impair excretion of potassium, such as sickle cell disease, could become more dangerous in pregnancy. Glycosuria can be common in pregnancy and is not diagnostic of gestational diabetes. As pregnancy progresses, uric acid levels rise again due to increased tubular reabsorption. Persistent proteinuria is a cardinal feature of pre-eclampsia or pre-existing renal disease, It can be difficult to distinguish between these conditions, as preexisting renal disease is frequently associated with the occurrence of superimposed pre-eclampsia. The diagnosis of proteinuria can be made with a urine dipstick, but will also require a further method of quantification, such as the urine protein to creatinine ratio on a spot sample or a 24-hour collection. Quantification is essential as management of nephrotic-range proteinuria differs from that for sub-nephrotic proteinuria. The proteinuria is often greater than 3 g per day and can be due to a primary glomerular disease There is loss of anticoagulant proteins in the urine and the risk of venous thromboembolic disease is high, especially if the albumin level falls below 20 mg/dl. Lower quantities of haematuria are not usually visible to the naked eye (microscopic haematuria). Accuracy with this method is high, especially if the sample has been collected after the first morning void and before bedtime. Basic Sciences for Obstetrics and Gynaecology Red blood cell physiology and haematology Blood consists of 55% plasma and 45% cellular components (99% of which are red blood cells and 1% white blood cells and platelets). The site of haematopoiesis varies with age: In the early embryo it is first seen in the yolk sac. Haem is a ferrous iron molecule in a porphyrin ring structure and globin is a polypeptide chain containing two chains and two non- chains. Fetal Hb (HbF) is made up of two and two chains; the switch from HbF to HbA starts at birth and is complete by about 6 months. Combines with protoporphyrin ring to form haem (there are four haem groups to each tetramer of Hb). Found in food as ferric hydroxide, ferric protein complexes, and haem protein complexes, with red meat being the best source available. Granulocytes (or polymorphs) these have large, characteristic granules in their cytoplasm that can be seen under a light microscope. Attracted to sites of infection/inflammation by chemotaxis, where they phagocytose and kill bacteria. Neutropenia or a decrease in numbers occurs with bone marrow failure syndromes, drugs, viral infections, and autoimmune disorders. Replace with oral iron (ferrous sulphate; 67 mg elemental iron per 200 mg tablet) for up to 6 months to correct anaemia and replenish stores: Expected Hb rise of about 2 g/dl every 3 weeks. Manage side effects by reducing dose or using preparation with a lower iron content, Involved in immediate hypersensitivity reactions (asthma, anaphylaxis) and in defence against allergens and parasites. Sickle cell disease: single amino acid substitution occurs on chain (valine substituted for glutamic acid at position 6). Thalassaemias: mutations in one or more of the or globin genes cause a reduction in the amount of HbA produced (alpha thalassaemia is due to deletion or mutation in one or more of the four globin gene copies and Table 3. Basic Sciences for Obstetrics and Gynaecology beta thalassaemia is due to mutations in one or both of the globin genes). Prior to replacement with folic acid, B12 deficiency must be excluded and treated to prevent development or exacerbation of neurological complications. The higher daily dose of 5 mg is recommended for women on antiepileptic drugs as these agents have antifolate properties. Presents with macrocytic, megaloblastic anaemia but severe deficiency may cause neurological complications such as subacute combined degeneration of the cord. The platelets undergo a change in their shape from discs to spheres and extrude long pseudopods, facilitating interaction between platelets. May be caused by: inadequate dietary intake malabsorption: coeliac disease, tropical sprue increased requirements: pregnancy, haemolysis drugs, Investigations: Serum folate levels ; serum B12 levels (N/) Antigliadin and endomysial antibodies Tests for malabsorption, The coagulation cascade has two pathways that lead to fibrin formation: the contact activation pathway (formerly known as the intrinsic pathway) the tissue factor pathway (formerly known as the extrinsic pathway). It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the tissue factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyse the next reaction in the cascade, ultimately resulting in cross-linked fibrin. The following physiological changes in coagulation factors occur in pregnancy: this is the result of intravascular deposition of fibrin and degradation of fibrin/fibrinogen leading to: a coagulation defect due to consumption of coagulation factors and platelets and increased fibrinolytic activity widespread bleeding, large and small vessel thrombosis, and haemorrhagic tissue necrosis. In pregnancy it is associated with: massive haemorrhage septic miscarriage and intra-uterine infection pre-eclampsia/eclampsia abruptio placentae retained dead fetus amniotic fluid embolism hydatidiform mole. Characteristically, there is no previous history and no clinical effect on the baby. Basic Sciences for Obstetrics and Gynaecology Autoimmune thrombocytopenia is caused by an antiplatelet autoantibody (IgG), which may cross the placenta and destroy fetal platelets. RhD-negative individuals can produce IgG anti-RhD antibodies following a sensitizing event, possibly a fetoma- Table 3. Treatment includes phototherapy in mild cases and red cell exchange transfusions for severe jaundice. Prophylactic anti-D IgG is given to Rh (D)-negative women within 72 hours of a potentially sensitizing event. The dose is adjusted according to the number of fetal cells detected in maternal circulation using the KleihauerBetke test. They interact with each other and with other cells of the body to generate the immune response. B lymphocytes are characterized by their expression of surface immunoglobulin (antibody), which acts as a receptor for antigen. These cells recognize native antigens in solution or on the surface of other cells. During B-cell differentiation, individual cells may switch to the production of IgG, IgA, or IgE, while retaining the antigen specificity. T-cell activation causes the cells to divide and secrete various cytokines that modulate immune responses. They include blood monocytes, microglia of the brain, and the Kupffer cells of the liver. The latter express receptors for immunoglobulin and complement components, and may be activated by cytokines released from T cells. Their surface molecules facilitate binding to antigens and subsequent phagocytosis. Some return from the periphery to secondary lymphoid tissues, thereby transporting antigen from the periphery into the spleen and lymph nodes. Each of these chains is formed from a number of globular domains connected by less tightly folded regions of polypeptide chains. Each four-polypeptide unit has two antigen-combining sites, formed by the N-terminal domains, which is very variable between antibodies, the greatest variability being clustered at the extreme ends of the domains where antigen binds. The remaining domains are less variable between antibodies and are called constant or C domains, but even here there is some variability. The heavy chain gene locus of humans can generate nine different types of heavy chain that vary in their three domains (in addition to the huge amounts of variation seen in the V domains) and there is a gene for each of these chains. Note the domain structure and the similarities among the molecules belonging to the immunoglobulin supergene family. The functional significance of there being two different types of TcRs is not known. While all antibodies can bind antigen, each antibody class, and indeed subclass, has a different set of functions. Each TcR is associated with a number of other polypeptide chains in the cell membrane. Antibodies are therefore bifunctional molecules in which the V domains are responsible for antigen binding, while the C domains allow interaction with various effector systems. Each chain folds into three extracellular domains, which are linked non-covalently to the molecule 2-microglobulin, the latter making the fourth domain of the class I molecule. Activators in the alternative pathway include certain microbial cell walls, carbohydrates, and viruses. Complement pathways may be activated by antigen-antibody complexes via the classic pathway or via the alternative pathway. The binding of C3b to receptors on phagocytes increases their level of activation, thereby priming them to eliminate the material they have phagocytosed. Although there is only a modest number of genes for immunoglobulin and TcRs, a complex process of genetic recombination generates an enormous diversity of receptors. Cytokine actions are not confined to classical immune responses but are wide ranging, complex, and intertwined with other biological interactions. Thus, to mount an effective immune response, one of the first steps is the expansion of clones of antigenreactive cells. The interactions of B cells and macrophages with T cells are particularly important in the development of the immune response. Many of the effects of antibodies occur via binding to Fc receptors, which bind to sites in the constant domains of the antibody. Antibodies produced by plasma cells may neutralize pathogens by direct binding They can then damage the target cell by the release of perforins, which polymerize to form polyperforin channels, or via other molecules relased by the Tc, including some cytokines. Implantation and placentation: the nature of the maternofetal immunological interface 4. Physical contact between immunocompetent cells and developing spermatozoa is prevented by the tight junctions between Sertoli cells lining the seminiferous tubules. These same tight junctions prevent the passage of circulating antibody into the tubules. Once sperm leave the epididymis, they become coated with seminal plasma components including lactoferrin. This coating reduces their immunogenicity, probably relevant while the sperms are in the seminal vesicles and when they are deposited in the vagina. Sperm and seminal plasma Antigenicity of spermatozoa A multiplicity of antigens are localized to , and are specific for, particular areas of the spermatozoon. Although some infertile men and women possess antibodies against all of these regions, antibodies against surface antigens of the acrosome and main tailpiece seem to be of the greatest pathological relevance because they cause immobilization and/or agglutination of sperm. The immunosuppressive components of seminal plasma include zinc-containing compounds, the polyamines spermine and spermidine, prostaglandins, transglutaminases, and a protein closely related to pregnancy-associated protein-A. Since spermatogenesis does not commence until long after this self-recognition process is As the zygote traverses the Fallopian tubes and enters the uterus, its protection depends on: 1. Significant immunological problems are, therefore, not posed by the conceptus before implantation. The syncytiotrophoblast, the non-mitotic outer layer of the chorionic villi, is bathed in maternal blood, which also lines the intervillous spaces.

Some studies have demonstrated a greater impact on the quality of life with insulin lispro solution erectile dysfunction pump how do they work purchase zenegra 100 mg line, and it has been shown to be more effective than regular insulin in reducing hypoglycemia associated with exercise within 3 hours after a meal erectile dysfunction protocol free buy zenegra with a mastercard. Insulin lispro solution should be stored in a refrigerator but not in the freezer does erectile dysfunction get worse with age order zenegra 100 mg online. Pharmacokinetic studies in some normal subjects and clinical observations in patients indicate that formulations of human insulin have a slightly faster onset of action and a slightly shorter duration of action than the original purified pork insulin counterparts treatment of erectile dysfunction in unani medicine generic zenegra 100 mg without prescription. At the end of 28 days erectile dysfunction keywords order zenegra overnight, any unused portion of the insulin lispro solution should be discarded impotence 24 buy zenegra 100mg without prescription. This insulin was developed to control postprandial glucose concentrations when administered 5 to 10 minutes before mealtime in a manner similar to that for insulin lispro. Insulin aspart demonstrates pharmacokinetics very similar to those of insulin lispro solution in terms of onset of action (0. When given subcutaneously, insulin glulisine demonstrates a more rapid onset of action and shorter duration of action compared to regular insulin. It is a sterile, clear, aqueous, and colorless solution with a pH of approximately 7. It should be administered 15 minutes prior to a meal or within 20 minutes after a meal. The remainder requirement can be provided by employing an intermediate-acting or a long-acting insulin. It is available in a concentration of 100 U/mL in 10-mL vials and 3-mL cartridges for use in the OptiClik insulin delivery device. Open, in-use cartridges inserted into the OptiClik system should not be refrigerated but kept at room temperature. Isophane Insulin suspension (nPh Insulin) Isophane insulin suspension is a sterile suspension in an aqueous vehicle buffered with dibasic sodium phosphate to pH 7. As mentioned in the discussion of the aqueous insulin solutions, suspensions of insulin with a pH on the alkaline side inherently have a longer duration of action than solutions. This is necessary for it to pass freely through the needle and for absorption of the drug to be consistent from one batch to another. Isophane Insulin suspension and Regular Insulin In years past, patients needing a rapid onset of action and intermediate duration of activity, approximately 1 day, would routinely mix isophane insulin suspension, an intermediate-acting insulin, with regular insulin, a rapid-acting insulin. In addition, it was fairly common for the patient to contaminate one of the vials during mixing. The 70/30 combination consists of 70% isophane insulin suspension and 30% regular insulin, and the 50/50 combination consists of 50% isophane insulin suspension and 50% regular insulin. Humulin 50/50 achieves a higher insulin concentration (Cmax) and maximum glucose infusion rates with more rapid elimination than Humulin 70/30. If Humulin N and Humulin R mixtures are prescribed in a different proportion, the individual insulin products should be mixed in the amounts recommended by the physician. These fixed combinations were developed to give better control for diabetes patients who use a combination of short- and longacting insulins. In comparison to Humulin 70/30, Humalog Mix 75/25 demonstrated lower postprandial blood glucose levels and no difference between the afternoon and overnight glucose values. It can also be used by adults with type 2 diabetes who require long-acting insulin. It is created when the amino acids at position 21 of human insulin are replaced by glycine and two arginines are added to the C terminus of the B chain. This peakless insulin begins working in 2 hours and mimics basal insulin secretion more closely than other longacting insulins for 24 hours. Because insulin glargine provides only basal coverage, it is often used in conjunction with other insulins or oral hypoglycemic drugs. The unique release characteristics of insulin glargine may help to decrease the number of required injections of long-acting insulin from twice daily to once daily. For those patients requiring more than 100 U of basal insulin, the pharmacist can suggest to the diabetologist dividing the dose and injecting it at different sites or at different times. If the patient is changing over to insulin glargine from an intermediate- or long-acting regimen, the dosage may or may not have to be adjusted. This insulin should never be frozen and should be stored in a refrigerator or a cool room out of direct light. Insulin Pens Insulin pens use disposable or single-use cartridges filled with either 150 or 300 U of insulin and packaged five per box (21). These pens are available for a number of insulin types, for example, regular insulin, insulin isophane, insulin glulisine, and insulin glargine. An advantage of the pen devices is that they improve the accuracy of insulin administration when compared to the traditional vial and syringe administration. Just as with the handling of a suspension form of insulin, for example, Novolin 70/30 PenFill (Novo Nordisk), the patients should be instructed to roll the cartridge in their hands gently before administering it. Getting patients to adhere to insulin dosages facilitates glycemic control and provides value to the payers of health care. It is similar in structure to human insulin with the exception of a deletion of the amino acid threonine in position B30 and a C14 fatty acid chain attached to the amino acid position B29. The main objective of pump therapy is strict control of the blood glucose level at 70 to 140 mg/dL to reduce blood glucose variations that increase the risk for micro- and macrovascular complications, for example, gangrene and diabetic retinopathy. Today, an insulin pump is of the size and weight of a personal pager, for example, 3. Inside the pump, depending upon the model, a syringe reservoir will hold up to 300 U of U-100 insulin. Unlike conventional insulin therapy, which normally combines rapidacting and intermediate-acting insulins, the infusion pump delivers either short-acting or rapid-acting insulin. Frequently, a rapidacting insulin, such as aspart (NovoLog) or lispro (Humalog), is preferred. The reservoir delivers insulin through a plastic infusion set, available in 24- or 42-inch lengths. Multiple safety alarms can be set to warn of a low battery, to serve as a reminder to test postprandial blood glucose, to change the infusion site, and to refill the insulin reservoir when a specified number is reached. These alarms can also signal when the infusion line is clogged or when a mechanical problem occurs with the pump. Patients should understand not to place the pump where their clothing may rub against it For optimal working efficiency, the patient should change the infusion site every 2 or 3 days or whenever blood glucose is above 240 mg/dL for two tests in a row. It is very important that patients understand the necessity to monitor their blood glucose so they know to adjust their dosage of insulin. Patients should check their blood glucose level before each meal, at bedtime, and whenever they have symptoms of hypoglycemia, such as sweating, shakiness, nausea, headache, and difficulty concentrating, or symptoms of hyperglycemia, such as polyuria, polydipsia, polyphagia, nocturnal enuresis, weakness, fatigue, blurred vision, and alteration in mental status. Patients should be educated what to observe, for example, inflammation, swelling, soreness, redness, and purulent discharge, if the site becomes infected and to know to contact his/her health care provider. In the meantime, the infusion set should be moved to another site, or insulin may be administered manually until the infection is cured. At night, the insulin pump can be placed on the nightstand close to the bed requiring Table 15. Typically, however, the patient will disconnect the pump, but for no more than 1 hour to allow for bathing or other activity. In addition, to provide coverage over this hour, the educated and skilled diabetes patient may administer a bolus dose of insulin prior to the time the pump is disconnected. Common examples of large-volume parenterals in use today are presented in Table 15. As indicated previously, electrolytes, vitamins, and antineoplastics are frequently incorporated into large-volume parenterals for coadministration to the patient. It is the responsibility of the pharmacist to understand the physical and chemical compatibilities of the additive in the solution or liquid in which it is placed. It is also important to be vigilant for incompatibilities associated with multiple infusions coadministered to a patient. A typical nursing question may be, "Can the dopamine drip be run in with the heparin drip Whenever possible, the pharmacist should attempt to answer these important questions and explain the incompatibilities that come to his or her attention as part of the daily routine. While it is impossible to chart every possible admixture incompatibility, principles can be learned and applied. For example, certain drugs are inactivated or precipitate at either high or low pH values, some drugs Large-volume parenteral solutions are employed in maintenance therapy for the patient entering or recovering from surgery and for the patient who is unconscious and unable to take fluids, electrolytes, and nutrition orally. The solutions may also be used in replacement therapy for patients who have suffered a heavy loss of fluid and electrolytes. These admixtures are very useful for chemotherapy, gastrointestinal patients, and anorexic patients. As a result, many pediatric institutions do not compound three-in-one admixtures for their patients but administer the fat emulsion separately. This was in response to two deaths and at least two other cases of respiratory distress associated with the use of three-inone admixtures. Autopsies revealed diffuse microvascular pulmonary emboli linked to a calcium phosphate precipitate in the admixture. Replacement therapy When the patient has undergone a heavy loss of water and electrolytes, as in severe diarrhea or vomiting, greater than usual amounts of these materials may be initially administered and then maintenance therapy provided. To avoid fluid overload, especially in elderly patients and those with renal or cardiovascular disorders, monitoring of blood pressure is desirable. The usual daily intake of potassium is about 100 mEq, and the usual daily loss is about 40 mEq. Thus, any replacement therapy should include a minimum of 40 mEq plus the amount needed to replace additional losses. Hyperkalemia can be caused by kidney failure or excessive consumption of potassium-rich foods. Prescribed potassium supplements, potassium-sparing diuretic therapy, angiotensin-converting enzyme inhibitors Water Requirement In normal individuals, the daily water requirement is the amount needed to replace normal and expected losses. The normal daily requirement of water for adults is about 25 to 40 mL/ kg of body weight or an average of about 2 L/m2 of body surface area (28). Children and small adults need more water per pound of body weight than do larger adults; water requirements correlate more closely with body surface area than with weight, and a guideline to estimate normal daily requirement for water in these patients is as follows: 1. In water replacement therapy for adults, 70 mL/kg/d may be required in addition to maintenance water requirements; a badly dehydrated infant may require an even greater proportion (28). Undiluted potassium chloride administered intravenously has resulted in fatalities. The most commonly used concentration of potassium chloride for continuous-infusion maintenance therapy is 20 to 40 mEq/L. With a peripheral line, that concentration may increase to 60 mEq/L, and with a central line, the maximum concentration can be up to 80 mEq/L. For intermittent potassium replacement therapy in patients with hypokalemia, the usual infusion rate is 10 mEq/h (maximum recommended rate is 20 mEq/h). When there is sodium loss or a deficit, the daily administration of 3 to 5 g of sodium chloride (51 to 85 mEq) should prevent a negative sodium balance. Sodium has been implicated as a causative factor in about 20% of cases of high blood pressure. Chloride, the principal anion of the extracellular fluid, is usually paired with sodium. Among the components used in parenteral nutrition solutions are the following, listed in quantities commonly provided per liter of fluid. Generally, final concentrations of dextrose (not greater than 10%) can be given peripherally. This device can pump four nutritional solutions (dextrose, water, amino acids, fat) simultaneously to compound nutritional admixtures by gravimetric means. The user programs the volume and specific gravity of the fluid to be pumped, and the device calculates the weight of the solution that has to be transferred from the source station to the bag. The fifth load cell serves as a confirmation of the weights programmed versus weights delivered. This automatically dispenses small-volume nutritional additives into flexible containers that already contain a base nutritional admixture. They also deliver ingredients in a specific order to avoid incompatibilities, for example, calcium ion is delivered last, after a rinse to ensure all phosphates have been washed from the tubing. A dilemma with young patients is that they often have a limited fluid capacity caused by disease As a consequence, pharmacists are asked whether a medication can be administered along with a parenteral nutrition solution. However, the practice of administering medication through a central venous line intended for parenteral nutrition solutions is not without risks. However, to conserve time, a 24-hour supply is much more efficient and now the norm.

In most instances erectile dysfunction medication prices discount 100 mg zenegra with visa, the operator records time and date of each key operation erectile dysfunction from stress generic zenegra 100 mg, and the supervisor signs off on it erectile dysfunction at age 27 discount zenegra 100 mg amex. All product ingredients erectile dysfunction doctor boston order cheap zenegra, equipment impotence due to diabetic peripheral neuropathy zenegra 100mg on line, and drums or other containers of bulk finished product must be distinctively identified by labeling as to content and/or status cannabis causes erectile dysfunction buy discount zenegra line. Inprocess samples are taken from production batches periodically for product control. Each label must contain expiration dating and the production batch or lot number to facilitate product identification. Expiration Dating To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it must bear an expiration date determined by appropriate stability testing. In the primary incident, cyanide was surreptitiously placed in acetaminophen capsules in commercial packages. A tamper-evident package is defined as "one having one or more indicators or barriers to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred" (1). The indicators or barriers may involve the immediate drug product container and/or an outer container or carton. For two-piece hard gelatin capsule products, a minimum of two tamper-evident packaging features is required unless the capsules are sealed with tamper-resistant technology. Even with these safeguards in effect, the possibility of drug product tampering requires the pharmacist and consumer to remain constantly vigilant for signs of product entry. Pharmaceutical manufacturers have the option of determining the type of tamperresistant packaging to use. Animals used in testing components, in-process materials, or drug products for compliance with established specifications shall be maintained and controlled in a manner that assures their suitability for their intended use. Individually sealed dose units; removal requires tearing or breaking individual compartment. Product and container sealed in plastic, usually mounted on display card; plastic must be cut or broken open to remove product. Band or wrapper shrunk by heat or drying to conform to cap; must be torn to open package Paper or foil sealed to mouth of container under cap; must be torn or broken to reach product Paper or foil sealed over carton flap or bottle cap; must be torn or broken to reach product Plastic or metal tearaway cap over container; must be broken to remove Seal over mouth of tube; must be punctured to reach product Carton flaps sealed; carton cannot be opened without damage. Tamper-resistant by design be identified, and adequate records shall be maintained showing the history of their use. This includes equipment cleaning and maintenance logs; specifications and lot numbers of product components, including raw materials and product containers and closures; and label records. These master records must document that each step in the production, control, packaging, labeling, and distribution of the product was accomplished and approved by the quality control unit. The networking of computers in the production and quality control areas fully integrates laboratory information and manufacturing operations into sophisticated management systems. Robotic devices increasingly are being employed to replace manual operations in production lines, analytical sampling, and packaging. Laboratory robotics provides automation in areas such as sample preparation and handling, wet chemistry procedures, laboratory process control, and instrumental analysis (3). Pharmaceutical applications of robotics include automated product handling in production lines and in procedures such as sampling and analysis, tablet content uniformity, and dissolution testing. This allows the plant operator to communicate with the main programmable logical controller. Thus, during this period, the regulatory requirements are applied with flexibility. As the clinical trials progress from Phase 1 to Phase 2, the processes are being characterized and refined, and during Phase 3, they are expected to meet all regulatory requirements. In addition to the active drug product, matching placebo and/or comparator products must be prepared. While the basic regulations for finished pharmaceuticals apply to biologic products as well, the nature of blood, bacterial, and viral products requires specific additional mandates, which are detailed in the regulations. Medical devices also are subject to the reporting of adverse events, to recall, and to termination of approval. The regulations for "good manufacturing practice for medical devices" are similar in organizational structure to those for finished pharmaceuticals. Literally, thousands of medical devices are regulated by the provisions of the Code of Federal Regulations (1). Each device has a specific design with individual performance features and utility. Included are hospital pharmacies that repackage drug products for their own use and for the use of other hospitals, chain pharmacy operations that repackage and relabel bulk quantities of products for distribution in the chain, and similar repackaging and relabeling by individual pharmacists or pharmacies for distribution to other pharmacies or retailers. Professional, legislative, and regulatory attention has been directed toward differentiating between pharmaceutical manufacturing and compounding as practiced by community pharmacists (9). Pharmaceutical manufacturing is large-scale production of drugs or drug products for distribution and sale, whereas compounding is professional preparation of prescriptions for specific patients as a part of the traditional practice of pharmacy. This was affirmed by provision in the Food and Drug Administration Modernization Act of 1997. Many patients need dosage forms, such as suppositories, oral liquids, or topicals, that are not commercially available. Many physicians desire to deliver products in innovative ways, and pharmacists can work with them to solve medication problems. Home health care and the treatment of an increasing number of patients at home have resulted in many community pharmacies and home health care pharmacies preparing sterile products for home use. Hospice care has resulted in new approaches to pain management and higher concentrations and combinations of drugs that are now used. As the extent of compounding increased, many standard-setting agencies and regulatory bodies wanted to ensure quality compounded products; consequently, there was a lot of activity during the mid-1990s to establish guidelines for pharmaceutical compounding. Chapters related to pharmacy compounding were developed and published starting in 1996 (10). In addition, the first of the compounding monographs became official in 1998, and they provide a tested, uniform formulation with valid beyond-use dating. As these chapters are numbered less than <1000>, they are enforceable standards and must be followed. Chapter <795> Pharmacy CompoundingNonsterile Preparations contains the following sections: (1) Introduction; (2) Definitions; (3) Categories of Compounding; (4) Responsibilities of the Compounder; (5) Compounding Process; (6) Compounding Facilities; (7) Compounding Equipment; (8) Component Selection, Handling and Storage; (9) Stability Criteria and Beyond-Use Dating; (10) Packaging and Drug Preparation Containers; (11) Compounding Documentation; (12) Quality Control; (13) Patient Counseling; (14) Training; and (15) Compounding for Animal Patients. The subparts include (A) General Provisions and Definitions; (B) Organization and Personnel; (C) Drug Compounding Facilities; (D) Equipment; (E) Control of Components and Drug Product Containers and Closures; (F) Drug Compounding Controls; (G) Continuous Quality Improvement Program; (H) Labeling Control of Excess Products; and (I) Records and Reports. It also stresses that only personnel authorized by the responsible pharmacist shall be in the immediate vicinity of the drug compounding operation. Subpart (D), Equipment, states that equipment used must be of appropriate design, adequate size, and suitably located to facilitate operation for its intended use and for its cleaning and maintenance. All pharmacists and pharmacy students should become familiar with the individual state requirements in the state in which they practice. PaCkaGinG, laBelinG, and StoraGe of PharMaCeutiCalS the proper packaging, labeling, and storage of pharmaceutical products are all essential for product stability and efficacious use. The container, including the closure, should be clean and dry before it is filled with the drug. The container must not interact physically or chemically with the drug so as to alter its strength, quality, or purity beyond the official requirements. An example would be the sorption of lipophilic drugs, such as diazepam, to low-density plastics resulting in a loss of drug that is available for administration. A single-dose container is one that holds a quantity of drug intended as a single dose and, when opened, cannot be resealed with assurance that sterility has been maintained. These containers include fusion-sealed ampuls and prefilled syringes and cartridges. As the clinical trials advance to their final stage, information on the chemical and physical characteristics of the container, closure, and other component parts of the package system for the proposed product must be developed to ensure drug stability for its anticipated shelf life. Different specifications are required for parenteral, nonparenteral, pressurized, and bulk containers and for those made of glass, plastic, and metal. In each instance, the package and closure system must be shown to be effective for the particular product for which it is intended. Dosage forms, such as tablets, capsules, and oral liquids, may be packaged in singleunit or multiple-unit containers. A singleunit container is designed to hold a quantity of drug intended for administration as a single dose promptly after the container is opened. The single-unit packaging of drugs may be performed on a large scale by a manufacturer or distributor or on a smaller scale by the pharmacy dispensing the medication. In either instance, the single-unit package must be appropriately labeled with the product identity, quality and/or strength, name of manufacturer, and lot number to ensure positive identification of the medication. Although single-unit packaging has a particular usefulness in institutional settings, for example, hospitals and extended care facilities, it is not limited to them. Such equipment seals solid dosage forms into four-sided pouches and imprints dose identification on each package at the same time. The packaging materials may be combinations of paper, foil, plastic, or cellophane. The packaging of solid dosage forms in clear plastic or aluminum blister wells is perhaps the most popular method of single-unit packaging. Seals solid dosage units in a variety of wrapping materials and labels each package simultaneously. Some pharmaceutical manufacturers use unit-of-use packaging, that is, the quantity of drug product prescribed is packaged in a container. For example, if certain antibiotic capsules are usually prescribed to be taken two times a day for 10 days, unit-ofuse packaging would contain 20 capsules. In most instances, a container made of a good quality of amber glass or a light-resistant opaque plastic will reduce light transmission sufficiently to protect a light-sensitive pharmaceutical. Agents termed ultraviolet absorbers may be added to plastic to decrease the transmission of short ultraviolet rays. A recent innovation in plastic packaging is the coextruded two-layer high-density polyethylene bottle, which has an inner layer of black polyethylene coextruded with an outer layer of white polyethylene. The degree of attack is determined by the amount of alkali released from the glass in the specified test conditions. Obviously, leaching of alkali from the glass into a pharmaceutical solution or preparation could alter the pH and, thus, the stability of the product. Pharmaceutical manufacturers must use containers that do not adversely affect the composition or stability of their products. The modern compact-type container used for oral contraceptives, which contains sufficient tablets for a monthly cycle of administration and permits the scheduled removal of one tablet at a time, is a prime example of contemporary plastic packaging. For example, the addition of methyl groups to every other carbon atom in the polymer chains of polyethylene will give polypropylene, a material that can be autoclaved, whereas polyethylene cannot. Among the problems encountered in the use of plastics in packaging are (a) permeability of the containers to atmospheric oxygen and to moisture vapor, (b) leaching of the constituents of the container to the internal contents, (c) absorption of drugs from the contents to the container, (d) transmission of light through the container, and (e) alteration of the container upon storage. Permeability should not be confused with porosity, in which minute holes or cracks in the plastic allow gas or moisture vapor to move through directly. The permeability of a plastic is a function of several factors, including the nature of the polymer itself; the amounts and types of plasticizers, fillers, lubricants, pigments, and other additives; pressure; and temperature. Generally, increases in temperature, pressure, and the use of additives tend to increase the permeability of the plastic. The movement of moisture vapor or gas, especially oxygen, through a pharmaceutical container can pose a threat to the stability of the product. In the presence of moisture, solid dosage forms may lose their color or physical integrity. Most of these adjuncts are carbohydrates, starches, and natural or synthetic gums, and because of their hygroscopicity, they hold moisture and may even serve as nutrient media for the growth of microorganisms. Sublingual nitroglycerin tablets must be dispensed in their original glass container. Desiccant protectants, such as silica gel in small packets, are commonly included in solid-form packaging as added protection against the effects of moisture vapor. Drug substances that are subject to oxidative degradation may undergo a greater degree of degradation when packaged in plastic than in glass. Liquid pharmaceuticals packaged in permeable plastic may lose drug molecules or solvent to the container, altering the concentration of the drug in the product and affecting its potency. An example of solvent loss involves large volume parenterals that are packaged in 1-L plastic bags that are packaged with an "overwrap" that is removed to yield the container of fluid that is actually used. The inside bag may feel slightly damp due to the loss of fluid from the primary container that is entrapped between the primary container and the overwrap. Leaching is a term used to describe the movement of components of a container into the contents. Compounds leached from plastic containers are generally the polymer additives, such as the plasticizers, stabilizers, or antioxidants. Leaching may be influenced by temperature, excessive agitation of the filled container, and the solubilizing effect of liquid contents on one or more of the polymer additives.

This is the key feature distinguishing autonomic nerves from the somatic nerves erectile dysfunction injection medication best purchase for zenegra, whose motor fibres innervate Preganglionic neuron the skeletal muscle as the sole end organ erectile dysfunction and diabetes type 1 generic zenegra 100 mg online. Therefore erectile dysfunction pills not working order generic zenegra from india, in a developmental sense the chromaffin cells of the adrenal medulla are postganglionic cells in their own right impotence only with wife generic 100 mg zenegra otc, except that they did not continue their differentiation to become postganglionic neurons erectile dysfunction treatment south florida purchase 100 mg zenegra otc. In the case of the adrenal medulla the catecholamines are released into the bloodstream and exert their effects through adrenergic receptors on the target tissues erectile dysfunction tumblr purchase generic zenegra. During emergencies the sympathetic nervous system is stimulated, whilst the parasympathetic nervous system is activated during rest periods to restore energy, and during digestion of food. They are the sole innervation to the vascular smooth muscle, sweat glands, and erector pilae muscle in the skin. Tyrosine is taken up into the nerve by an active transport system catalysed by nerve enzyme tyrosine hydroxylase. The juxtaglomerular apparatus is innervated by sympathetic neurons via 2 receptors. Alveolar ventilation is regulated mainly by the central chemoreceptors under normal conditions. Molecular biological techniques are increasingly used to insert, alter, or remove genes from cells to treat diseases, giving rise to the new and growing clinical specialty of gene therapy. These paired processes of transcription and translation give rise to a peptide, which is converted to a fully mature protein (with all of its structural and functional properties) through a series of post-translational modifications that might include: 73 the first three of these, replication, transcription, and translation, together constitute the process of protein synthesis. Cell the cell (from cellula-Latin for a small room) is the basic functional unit of all living organisms, and the building block of all complex life. This plays a crucial role in processing, modifying, and packaging proteins and lipids for cell secretion. This divides by binary fission and in humans is inherited through the maternal line. There are three main classes of cell surface receptors: steroid hormone receptors thyroid hormone receptors retinoic acid receptors vitamin D3 receptors. Intracellular secondary messengers (where the ligand first interacts with a cell surface receptor) include: ion channel-linked receptors enzyme-linked receptors G protein-coupled receptors. They include receptors for chemokines, bradykinin, opioids, leukotriene, relaxin, dopamine, histamine, glucagon, calcitonin, vasopressin, and glycoprotein hormones. This intracellular messenger, known Nitric oxide is an intracellular messenger that causes smooth muscle relaxation. Nucleotides consist of a pentose sugar (either ribose or deoxyribose) plus an organic, nitrogenous base (adenine, guanine, cytosine, thymine, or uracil) to form nucleosides (adenosine, guanosine, cytidine, thymidine, or uridine). Within nucleic acids, a purine base (adenine or guanine) always pairs with a pyrimidine (cytosine, thymine, or uracil) to maintain a uniform distance between the two nucleic acid strands. Purine and pyrimidine nucleotides are all synthesized de novo in the body from amphibolic molecular intermediates. Carbohydrates are the preferred respiratory substrates from which cellular energy is derived and so make relatively limited contributions to cellular structure. In most tissues (except the liver), carbohydrates simply modify pre-existing sub-cellular structures by combining with lipids (to form glycolipids) or proteins (to form glycoproteins), altering the structure-function relationships of the modified lipid/ protein molecules. There are, however, non-energetic functions of nucleic acids, lipids, proteins, and carbohydrates within cells. Lipid molecules form membranes that create the specialist cellular and sub-cellular microenvironments required for tissue- and cell-specific biochemistry Proteins serve three major functions within a typical cell: as components of the cytoskeleton, as enzymes, and as receptors. Enzymes (E) are biochemical catalysts, which accelerate reactions by lowering the activation energy. Hence, any factor that changes the shape of an enzyme so as to alter the conformation of the active site will change the rate of reaction. Vmax = the maximal velocity of the enzyme-catalysed reaction, Vmax/2 = 50% of the maximal velocity, and Km = the Michaelis-Menten constant (the concentration of substrate at which Vmax/2 is achieved). Fuel metabolism the principles of processing respiratory substrates are the same irrespective of the class of biochemical fuel being metabolized. In terms of the initial oxidative pathways, carbohydrates are metabolized by glycolysis, fatty acids by the -oxidation cycle, and amino acids by transamination reactions. As the electrons pass through complex I, protons bind to the matrix face of the complex and are transferred across to be liberated into the intermembrane space. Each of the cytochromes contains at least one haem group in which the iron can either accept or donate electrons (transiting between the Fe2+ and Fe3+ states, respectively). Pyruvate is usually derived from glucose as the end product of glycolysis, but can also be derived from amino acids by transamination or deamination reactions. These alternative names merely indicate whether the carboxylic acids are still capable of acting as proton donors or are in their ionized (basic) state. Glycolysis Glycolysis relies on the cellular uptake of glucose from extracellular fluid/plasma. By virtue of its high proportion of polar hydroxyl groups, glucose is hydrophilic and so cannot diffuse freely across cell membranes. At reaction 4, the hexose (6C) monosaccharides are cleaved into interchangeable triose (3C) molecules (glyceraldehyde-3-phosphate and dihydroxyacetone phosphate), such that all downstream reactions (5 to 9 inclusive) occur twice for every hexose molecule entering the pathway. In the Krebs cycle there is no place for 3C triose molecules such as pyruvate, which must therefore be modified (either to a 4C or 2C metabolite) before it can enter the cycle. Under anaerobic conditions (depicted by the asterisk) pyruvate is reduced to lactate, whereas under aerobic conditions pyruvate can either undergo oxidative decarboxylation to acetyl-CoA, or carboxylation to oxaloacetate. The propionyl grouping has the same problem entering the Krebs cycle as pyruvate: the propionyl group has three carbons, and three is not a number favoured by the Krebs cycle. It is important to appreciate that through the -oxidation cycle, the majority of carbon from a fatty acid molecule enters the Krebs cycle as acetyl-CoA. It is as a consequence of this arithmetic that fatty acids cannot be converted into carbohydrates, whereas excess carbon (and calories) from carbohydrates can be converted into fatty acids and triglyerides. Therefore, questions suggesting the conversion of fatty acids to carbohydrates are trick questions and are false no matter what intermediate molecules are proposed to achieve this. Hydroxybutyrate can be oxidized back to acetoacetate, which is converted to acetyl-CoA (via an acetoacetyl-CoA intermediate) to fuel the Krebs cycle. In the presence of tetrahydrobiopterin, phenylalanine hydroxylase can oxidize phenylalanine to form the aromatic amino acid tyrosine. Other essential nutrients that are not vitamins include the essential amino acids, essential fatty acids, and dietary minerals such as calcium, chloride, iron, potassium, phosphorous, and sodium. In developed countries, vitamin deficiencies are rare due to adequate dietary intake and the fortification of common foods However, during pregnancy, women are often advised to take vitamin supplements While vitamins generally exert beneficial actions, overdose of any single vitamin can produce adverse side effects. Of these, the most relevant are the teratogenic actions of vitamin A (retinol) and its pharmaceutical derivatives To avoid running out of funds, a person needs to earn new money, carry some ready cash in their purse or wallet, have easy access to cash stored temporarily in a current account, and have some funds in a savings account where the money performs better but is harder to access. Before considering the management of glycogen and triglyceride stores in more detail, there are four important points to emphasize: 1. Some tissues, most notably the brain, rely on glucose (or, in starvation, on ketone bodies) as their energy source. The interconversion of excess glucose to fatty acids (lipogenesis) and of amino acids into glucose (gluconeogenesis) relies on intermediates in the Krebs cycle, underscoring the pivotal role for this cycle at the heart of metabolism. The upper part shows the macroscopic, branched, polysaccharide structure of glycogen while the lower part illustrates the role of -1,4- and -1,6-glycosidic bonds in the polymerization of the glucose subunits that comprise glycogen. The glucose-1-phosphate is then isomerized to glucose-6-phosphate by phosphoglucomutase. Since the charged glucose-6-phosphate molecule cannot pass across the plasma membrane of the cells, in most tissues (including the vagina, uterus, and skeletal muscle) glucose-6-phosphate generated by glycogenolysis has to be metabolized (by glycolysis) within the very same cell that held the glycogen store. Only hepatocytes express the glucose-6-phosphatase enzyme required to remove the phosphate ion, and so only the liver can export glucose into the bloodstream to support glycolysis (and the Krebs cycle) at distant sites. Triglyceride Triglycerides are stored predominantly within adipose tissue as the lipid droplets of mature adipocytes. It is this high calorific density, combined with their relatively low weight per unit volume and a diffuse distribution around the body in subcutaneous depots, which makes triglycerides the preferred form for storage of excess calories. Managing fuel reserves in the fed state Following a meal, the elevated plasma glucose concentration (and to a lesser extent increased levels of amino acids and gastrointestinal tract hormones) suppresses the secretion of glucagon (from pancreatic cells) while triggering the secretion of insulin (from pancreatic cells). Insulin exerts several distinct cellular actions to maximize glucose uptake and metabolism, which restore the plasma glucose concentration to the normal range: between 4 and 8 mmol/l. Within all metabolically active cells, insulin stimulates the activity of glycolytic enzymes Finally, insulin stimulates the activity of glycogen synthase and simultaneously inhibits the activity of glycogen phosphorylase to ensure that excess glucose is directed primarily to replenish intracellular glycogen stores, particularly in liver and skeletal muscle. It is crucial to note that while mitochondrial acetyl-CoA (synthesized by pyruvate dehydrogenase and the oxidation cycle) is a substrate for the Krebs cycle, cytosolic acetyl-CoA is the substrate for lipogenesis. This malate can then be exchanged for citrate by the tricarboxylate transporter and the imported malate can be oxidized back to oxaloacetate in the Krebs cycle. Initially, acting through a common cell signalling pathway (the cyclic adenosine monophosphate-protein kinase A signalling system), glucagon and adrenaline activate glycogen phosphorylase while simultaneously inhibiting glycogen synthase, so inducing a net mobilization of glycogen to glucose. Because of the tissue-specific expression of glucose-6-phosphatase in the liver, only hepatic glycogen can be used to increase the plasma glucose concentration; in all other tissues, including the vagina and uterus, glycogen is hydrolysed to form glucose-6-phosphate molecules that must be used locally for glycolysis due to the absence of glucose-6-phosphatase. Once the major glycogen stores begin to run low (as would occur following an overnight fast), glucagon and adrenaline use the same second messenger system to activate hormone-sensitive lipase, so mobilizing fatty acids for -oxidation. This takes the form of gluconeogenesis whereby the carbon skeletons of amino acids (derived by the breakdown of body protein) are converted into glucose in the liver. This metabolic pathway is not as simple as the name implies, since three of the nine reactions in glycolysis (the steps catalysed by hexokinase/glucokinase, phosphofructokinase, and pyruvate kinase) are irreversible. Since significant changes in plasma pH affect the structure and functions of cellular proteins with potentially lethal consequences, multiple mechanisms exist to balance the plasma pH. Hence, each amino acid side chain can buffer small changes in plasma pH around the appropriate pKa value for the chemical group in its side chain. When the plasma pH is low, the excess of free protons effectively displaces Ca2+ ions from the albumin, increasing the free plasma calcium concentration (and so suppressing the parathyroid hormone and vitamin D3/ calcitriol endocrine systems). Conversely, with a sustained elevation in the plasma pH, albumin will ionize to liberate protons, increasing its capacity to bind Ca2+ ions, hence decreasing the free plasma calcium concentration and increasing the synthesis and secretion of parathyroid hormone and vitamin D3/calcitriol. When the plasma pH is exactly equal to the pKa value, the probability of any given side chain being in the protonated state will be exactly equal to the probability of that side chain being in the deprotonated state. They have a very low affinity for glucose, thus allowing absorbed glucose to pass through the portal system and the liver to the systemic circulation without most of it being metabolized by the liver. It is critical for cells that cannot operate the oxidative phosphorylation pathway due to lack of mitochondria or hypoxia. In chronic starvation, the glucose supply is maintained by gluconeogenesis in the liver. Glycogen storage and metabolism Glycogen is the storage form of glucose retained mostly in the liver, cardiac and skeletal muscles, and the kidneys. Glycogen breakdown releases glucose-6-phosphate, which remains trapped within the cell unless it is released by glucose-6-phosphatase. Unlike liver cells, muscle and renal cells lack glucose6-phosphatase, so can only use the glucose from their glycogen stores locally and cannot export this glucose into the general circulation. In between meals the liver uses fatty acids rather than glucose for its own energy requirements, emphasizing the role of hepatic glycogen as a glucose store for the whole body. Steroid and thyroid hormones are hydrophobic and readily cross the lipid bilayer of cell membranes. Their receptors are mainly intracellular and their biologic actions are exerted by generating brand new intracellular proteins, which in part explains why they take longer to act. Classification and general characteristics of hormones There are three main chemical classes of hormones. Protein and peptide hormones this is the most diverse and numerous group and includes hormones secreted by the hypothalamus, pituitary gland, pancreas, and parathyroid glands. Protein and peptide hormones, catecholamines, and melatonin (biogenic amine hormones) are hydrophilic (water soluble) and do not cross the lipid bilayer of cell membranes. For example, secondary messengers may phosphorylate or dephosphorylate protein enzymes to regulate their activity. Modification of already existing proteins allows water soluble hormones to act quickly, although they also have longer-term effects on gene transcription. Neurosecretory cells in the hypothalamus synthesize releasing and inhibiting hormones in their cell bodies and package them in vesicles, which are transported down their axons to the nerve terminals located on the hypophyseal portal capillaries. The secretory vesicles containing the hormones are transported down the axons that pass through the neural stalk, and are stored in the nerve terminals in the posterior pituitary gland. Bound steroid hormone Free steroid hormone Membrane-associated steroid receptors hsps hsps Cell membrane Dimerized hormone/ receptor complex Interaction with cell signalling pathways It mobilizes fat and increases circulating free fatty acids by stimulating the action of hormone sensitive lipase, a major mobilizer of fat from adipose tissues. Numerous other functions have been attributed to this hormone including salt and water balance, growth and development, metabolic actions, immunoregulation, and reproductive functions. During pregnancy, the high concentrations of circulating oestrogens increase prolactin secretion, but along with progesterone block the synthesis of milk. The numbers of prolactin receptors in mammary tissues increase and milk synthesis begins. Secretion of thyroid hormones involves pinocytosis of thyroglobulin droplets at the apical surface, release of T4 and T3 by lysosomal enzymes, and secretion into the circulation and the basal surface of the follicle cell. However, there is 50 times more T4 than T3 in the general circulation because T4 has a higher affinity for binding proteins, hangs around for much longer, and has a longer half life of six days (compared to only one day for T3). T4 has little biological activity and about 80% is converted to T3 in the liver and kidneys, the rest being converted to T3 in target tissues, Goitre is simply an enlarged thyroid gland and does not correlate with functional status. Although there are 50 T4 for every T3 molecule in the circulation, T3 and T4 exert equipotent negative feedback effects on the hypothalamic pituitary axis, because when T4 is taken up by nerve cells or thyrotrophins, it is immediately converted to T3, the biologically active form of the hormone. Cortisol + androgens T3/T4 109 Physiologic actions of thyroid hormones Thyroid hormones act on virtually every cell in the body through nuclear receptors. Chronotropic and inotropic effects on the heart, some of which may be mediated by non-genomic events and may involve changes in the number and affinity of adrenergic receptors. Deficiency of thyroid hormones in fetal, neonatal, and early childhood stages of development can result in impaired neuropsychological function and impaired growth. Fetal growth rate may be normal in the absence of thyroid hormones; however, at birth thyroid hormone replacement must be initiated within 2 weeks to avoid irreversible nervous tissue damage. Clinical features of hyperthyroidism include heat intolerance, tachycardia, tremor, anxiety, and a warm, moist skin. Maternal and fetal thyroid function During pregnancy there is an increased size and vascularity of the thyroid gland.

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