By E. Hauke. University of Pittsburgh at Greenburg.

How is the volume of distribution (V) of digoxin likely to change if a patient has been taking both digoxin and quinidine and the quinidine is discontinued? Assume that plasma volume (Vp) 20 mg atorlip-20 mastercard, tissue volume (Vt) order 20mg atorlip-20 otc, and unbound fraction of drug in plasma (Fp) are unchanged. Solve the equation using Vp = 5 L, then re-solve using 4 L and compare: If Vp is decreased to 4 L, 8-11. Remember, when quinidine is administered concomitantly with digoxin, quinidine competes with digoxin for tissue binding sites and increases the unbound fraction of digoxin in the tissues (Ft). Therefore, assuming Vp and Vt remain unchanged, the effect of quinidine is shown below: When quinidine is discontinued, the unbound fraction of digoxin in the tissues (Ft) decreases as the tissue binding sites formerly occupied by quinidine become available. Draw representative concentration versus time curves for: (a) a drug that diffuses into highly vascularized tissue before equilibrating in all body compartments, and (b) a drug that distributes equally well into all body compartments. Clinically, what type of loading dose adjustments can be made to account for these factors? A patient has a total plasma phenytoin concentration of 19 mcg/mL with a serum albumin concentration of only 2. In the same patient as described in discussion point D-4, calculate a new total phenytoin concentration that would yield a therapeutic unbound phenytoin concentration. Describe the impact of disease and altered physiologic states on the clearance and dosing of drugs. Define the methods of hepatic drug metabolism and the approaches used to quantitate and characterize this metabolism. Define both the physiologic and mathematical relationship of drug clearance to glomerular filtration. Although both organs share metabolic and excretory functions, the liver is principally responsible for metabolism and the kidneys for elimination. The importance of these organs cannot be overestimated in determining the magnitude and frequency of drug dosing. Additionally, an appreciation of the anatomy and physiology of these organs will provide insight into the impact of disease and altered physiologic states, as well as concomitant drug administration, on the clearance and dosing of drugs. The physical and chemical properties of a drug are important in determining drug disposition. For example, lipophilic drugs (compared with hydrophilic drugs) tend to be: • bound to a greater extent to plasma proteins, • distributed to a greater extent throughout the body, and • metabolized to a greater extent in the liver. Hydrophilic drugs, particularly ionized species, tend to have more limited distribution and more rapid elimination (often by renal excretion). Metabolism (also known as biotransformation) involves conversion of the administered drug into another substance. Metabolism can result in the formation of either an active or inactive metabolite, which is then eliminated from the body faster than the parent drug. Two examples of drugs with active metabolites are the antiarrhythmic drugs procainamide and encainide. Consequently, the plasma concentration of an active metabolite must be considered in addition to that of the parent compound when predicting overall pharmacologic response. In this case, the active metabolites formed have a longer half-life than that of the parent compound. In addition, many drugs are actually "pro-drugs," which require activation to their active forms. Examples of pro-drugs include many 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors and angiotensin-converting enzyme inhibitors. Consider the following situation: where drug X represents the intravenous bolus administration of the compound and Km and Kr represent the elimination rate constants for hepatic metabolism of drug X and renal excretion of metabolite Y, respectively. Figure 9-1 shows the decline in plasma concentration of parent drug X (assuming a one- compartment model after intravenous administration). Now consider the profile of metabolite Y after the same dose of drug X (Figure 9-2). If the excretion rate constant of metabolite Y (Kr) is much greater than the elimination rate constant of drug X (Km), the terminal slope of the natural log of concentration of metabolite Y versus time plot will be Km and not Kr. This result occurs because the plasma concentration of metabolite Y is determined by the rate of formation from drug X (the slower rate constant). On the other hand, if Kr is much less than Km, the terminal slope of the plasma metabolite Y concentration versus time plot will be Kr (Figure 9-3). In this case, the relatively slow renal elimination of metabolite Y determines the resulting plasma concentrations. Although the liver is the major organ of drug biotransformation, the intestines, kidneys, and lungs may also metabolize some drugs. Before we can develop the concepts of drug metabolism, we must first examine the anatomy, physiology, and fundamental functions of the liver. The liver lobule is constructed around a central vein, which empties into the hepatic veins and the vena cava. Therefore, the hepatic cells (hepatocytes), which are principally responsible for metabolic functions (including drug metabolism), are exposed to portal blood. The liver (ultimately the liver lobule) receives its blood supply from two separate sources: the portal vein and the hepatic artery. The liver receives approximately 1100 mL/minute of blood from the portal vein and 350 mL/minute of blood from the hepatic artery. After entering the liver, blood flows in the veins and arteries of the portal triads, enters the sinusoidal spaces of the liver, and exits via the central hepatic vein. In the sinusoids, the drug is transferred from the blood to the hepatocytes, where it is metabolized or excreted unchanged into the biliary system (Figure 9-6). The liver is involved in numerous functions, including storage and filtration of blood, secretion and excretion processes, and metabolism. In clinical pharmacokinetics, we are primarily interested in the last role, drug metabolism, and the factors that influence it. It is generally recognized that wide interpatient and intrapatient variability exists in the biotransformation of most drugs. It is also accepted that changes in liver function may greatly alter the extent of drug elimination from the body. To appreciate the importance of these functions and patient factors in the metabolism of a specific drug, it is necessary to understand the mechanisms involved in hepatic drug metabolism and the relative ability of the liver to extract the particular drug from the blood into the hepatocyte. The major hepatic enzyme system responsible for phase I metabolism is called the cytochrome P450 enzyme or mixed function oxidase system, which contains many isoenzyme subclasses with varying activity and specificity in phase I drug metabolism processes. Cytochrome P450 isoenzymes are grouped into families according to their genetic similarities.

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The drug quickly reduces fever purchase 20mg atorlip-20 with mastercard, eliminates pains of various origin and simultaneously it is standard of simplicity in use order 20 mg atorlip-20 overnight delivery. Not a treatment but true delicacy as the syrup is manufactured with taste of orange and strawberry. One more advantage – convenient measuring syringe is attached to the package that allows to calculate necessary quantity of the drug precisely. As though it would be desirable, that all manufacturers of drugs for children in such manner will care of comfort for both child and adult. Dosing devices should have attractive, not frightening appearance, and an instruction for application (leaflet) of a given medical product should contain all necessary information about calibration and usage of a dispenser that young patients will necessarily appreciate. One of the most important requirements shown to closure means for pharmaceuticals of pediatric group is control of their dosing and protection against casual opening. Namely this should be a priority direction in development and creation of closure means and new kinds of packages. It has been developed the device with passive resistance to flow of liquid pediatric dosage forms and also the package of such dosage forms containing single dose. Proceeding from the aforementioned, it is possible to make a conclusion that, speaking about new tendencies in development of package- producing industry, it is impossible to skip a problem of drugs applied in pediatrics. The given medical products require more serious and attentive approach for proper dispensing, high-quality package and rationally designed marking, because children are the most trustful but also the most exacting patients. The structure the lip skin differs from the rest of the skin: due to the large amount of nerve endings they are more sensitive, lips have lack of oil glands and melanin and thin epidermis. That is why the lips are sensitive to external climatic factors (cold, dry air, wind, etc. The aim of the study was to streamline the classification and study the pharmacy range of lip care products that are on the market of Ukraine. During our study analysis of the current literature concerning existing classification and characteristics of lip care products was conducted. Also, during the study methods of semantic analysis and hierarchical classification were used. The range of modern lip care products that are sold through drugstores are hygienic lipsticks, lip balms and creams. Тайсс Натурварен Гмбх» (Germany), «Nature House» (Italy), «Laino», «La Roche», «Vichy», «Uriage Bariederm» , «Сaudalie» (France), Apivita (Greece), etc. Lip creams are presented by «Сaudalie», «Bioderma», «Vichy» (France), Apivita (Greece). Into a separate group can be identified child lip care products («Біокон», «Красота и здоровье», «Моя Прелесть» (Ukraine), Apivita (Greece)), and also lip care for men («Биокон», «Фармаком», «Красота и здоровье» (Ukraine)). The main active ingredient in the composition of lipcare products are mineral and vegetable oils (castor, coconut, almond, sea buckthorn, avocado, jojoba, shea), natural and synthetic waxes. As the bioactive components added vitamins A, E, F and B group, that have regenerating effect, prevent cracking, inflammation. Due to information above, we can conclude that Ukraine market has a wide range lipcare products of hygienic and preventive action. At present, the range of cosmetic products is actively expanding and adding new manufacturers and products. Studying of consumer properties of certain skincare products in the form of sponges from the Asian plant roots. The object of the study was konjac sponge for washing, made of the root of the Asian plant Amorphophallus konjac. Amorphophallus konjac is considered a dietary product and is a vegetarian substitute for gelatin, from it in Asia cook desserts and jellies. Konjac is 97% of water, filled with minerals, thus having an ideal environment pH, which has a positive effect on the skin. That is why in Japan, China and Korea for many years, it is used in the beauty industry and medicine. In the analysis of the range it has been found that this type of sponges is available in different shapes and colors. The color depends on the sponge‘s components that manufacturers add to provide certain cosmetic effect. This plant contains a lot of minerals, vitamins and amino acids, which have a positive effect on the condition of the skin, smoothing out its defects and nourishing with necessary substances. But the main advantage of this sponge is that it has healing and regenerative properties. Purple sponge with lavender oil soothes and moisturizes irritated skin, relieves fatigue. Red sponge with clay contains French red clay, thanks to the properties of which it further helps to even out skin tone, moisturize it and even prevent wrinkles due to soft massage action. In dry form by its hardness the sponge resembles a piece of stone, but being wet, it becomes soft, jelly-like, and very pleasant to the touch. Unlike other sponges for the face, it is not just cleaning, but also has excellent exfoliating action, as well as helping to strengthen the properties of a cleaning agent and cleans the pores. Konjac sponge contributes to liquid penetration to the upper layers of the epidermis, thus moisturizing and making the skin more elastic. Therefore, we can conclude that the konjac sponge due to its consumer properties, exhibits good effect and is suitable for various skin types, at its use there is also no need to the additional use of other cosmetic products. No one denies about the benefits breast milk for feeding a small child, but and there are times when a baby at birth or later have to bring up with artificial milk mixes. However, even the most advanced milk mixes cannot be compared with breast milk, which composition provides optimum flow for the individual child, not only nutritious, but also many other substances and cells: white blood cells, antibodies, enzymes, hormones, etc. According to medical statistics, only 1-3% of women have serious health problems that make it impossible to breastfeeding, while 60% of children from birth to 2 months transferred to artificial feeding. The reason for this is the failure or ignorance of basic rules of breastfeeding baby. To date, this type of baby food (infant mix) presented a wide range of assortment of products of different companies, types, storage, price ranges etc. Aim of our research was to streamline the classification and study of the range of dry milk mixes that are present on the market of Ukraine. During our research were analyzed modern national and foreign literature on the existing of classification and characteristics of dry milk mixes for children. Also, there were used methods of semantic analysis and hierarchical classification.

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The first reported that the provision of counselling and support improved outcomes – several counselling sessions were more effective than few purchase 20 mg atorlip-20 with mastercard, and few were more effective than none generic 20mg atorlip-20 free shipping. Treatment is more likely to be effective when staff believe in the treatment they are delivering. In a trial to demonstrate the potential value of interim methadone (without counselling), it is probable that staff believed this approach would be effective – and it was. The most plausible interpretation is that when staff believe in the treatment they are providing, it works better. While there is little evidence for formal counselling, there is substantial evidence that the quality of interaction between a patient and staff is an important ingredient of treatment (see Section 8. The majority of patients aspire to an opioid-free life without methadone,44 and an orientation to maintenance does not mean that people should be discouraged from seeking to withdraw from treatment if they are doing well, and have sufficient ‘recovery capital’ (social supports such as a relationship, job, family support, affiliation with mutual support groups – see Glossary) to sustain long-term abstinence. People who achieve good social reintegration, particularly employment, are more likely to be able to leave treatment without relapse. An unstructured environment without enforced expectations is unlikely to be a therapeutic environment. Patients should be given detailed information about detoxification and the associated risks, including the loss of opioid tolerance following detoxification; the ensuing increased risk of overdose and death from illicit drug use; and the importance of continued support to maintain abstinence and reduce the risk of adverse outcomes. Peer influence, mediated through a variety of group processes, is used to help individuals learn and assimilate social norms and develop more effective social skills. An essential safety precaution for the medical professional to be aware of and educate patients about is the risk of a fatal overdose if they return to heroin use after naltrexone treatment, because of loss of tolerance to heroin. The results of studies have not been favourable, except in cases where there are added significant external motivating factors, such as might be the case for an opioid-dependent health professional. In a series of small trials, and one large study from Russia, implants were demonstrated to be superior to oral naltrexone and to placebo in reducing the risk of relapse. The assumption underlying most clinical trials in medicine, that people will accept allocation if there is a reasonable expectation that the alternative treatments will be safe and effective, does not apply to people seeking treatment for addiction. Individuals who are addicted to heroin only enter treatment if it is perceived to offer some advantage over their drug-using state. The rewards of everyday life – for most people, a stable, intimate relationship, employment, and family life – are less accessible for people who are marginalised by drug dependence, and lacking in interpersonal and vocational skills. Employment is a key step in social reintegration, and in settings in which unemployment is high, and social cohesion low, prospects for sustained recovery are compromised. There is some evidence that participation in training and employment can be fostered by treatment. In the Swedish trial described earlier,41 two-thirds of patients receiving methadone were in employment or training two years after programme entry (compared to none in the group randomised to no treatment). This occurred in a programme providing ‘intensive’ psychosocial input, including vocational retraining. The programme also involved limit setting – subjects persisting in heroin use were discharged. It is not possible without further research to ascertain whether it was psychosocial support, limit setting, or both, that contributed to better outcomes. The evaluation of ‘low-threshhold’ methadone in Amsterdam showed that failure to suppress heroin use did not protect against blood-borne virus transmission. Patients and practitioners reflect community assumptions that drug use is a matter of personal responsibility, rather than a disease, and many heroin users are reluctant to see themselves as ill. Adopting the role of ‘patient’ involves relinquishing their ‘addict identity’, and they may prefer to see participation in treatment as taking advantage of the supports available to them rather than seeking to recover. It is uncommon for doctors to think of it as management of a chronic medical condition. The first is the risk of death of individuals not in treatment, as a result of diversion (see Glossary) of methadone. Experiencing or witnessing an overdose is a common occurrence among users of illicit opioid drugs,84 but prescribed opioid drugs also carry these risks. It is essential that the medical professional understands the process of careful and safe assessment and prescribing, as well as recognising the times when a patient is most at risk. One important strategy is training users of opioid drugs themselves,84 and also healthcare staff and carers,90 in the recognition of opioid (and other drug) overdose in the community and prison setting, and how to respond, including administration of the opioid antagonist naloxone. Alternative methods of treatment for people not responding to methadone, such as slow-release oral morphine, could enhance consumer choice. Little is known about the efficacy of such approaches and research is needed in this area. In order to deliver such care, doctors report that they need not just initial training, but ongoing supervision, support and reflection. Treatment requires structure, support and monitoring, and has been operationalised into clinical guidelines. In a climate of fiscal austerity, re-tendering of drug treatment programmes has become common, with a view to reducing costs in an already squeezed system. Quite apart from the financial pressure to provide minimalist services, re-tendering in itself risks compromising the quality and continuity of treatment. As reported by Ball and Ross,7 more effective programmes are characterised by stable management, and frequent restructuring of services may compromise effectiveness. Clinical leadership, with well- understood, protocol-driven treatment and support and supervision for staff, are important ingredients of treatment. Summary • Medical management of drug dependence is more difficult and challenging than for other chronic disorders. Many users who present for treatment are socially marginalised, lead chaotic lifestyles and have little to motivate them towards recovery. This attenuates the symptoms of withdrawal from heroin and allows the user to gain control over other aspects of their life, thereby creating the necessary preconditions to cease drug seeking and use. There is substantial evidence that good-quality staff interactions are of benefit for recovery. Some people who use drugs report experiencing disapproval and frustration in their interaction with healthcare services,1 and this can be a significant barrier to accessing healthcare. As discussed in Chapter 8, health professionals who adopt a non- judgemental, non-stigmatising empathic stance are most likely to be effective in delivering healthcare for these patients. There is consistent evidence that in primary care settings, in hospitals, and in mental health settings, doctors frequently do not address alcohol and drug use. The medical frame of reference is a useful one in which to approach drug use – non-judgemental, factual, professional, accurate diagnosis and provision of information and referral, monitoring the response.