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By E. Jose. Norwich University.

Analysis and reporting should precisely describe the product’s quality purchase benicar 40 mg with visa arrhythmia examples, packing generic benicar 10mg arrhythmia loading, and registration discount benicar 40mg otc blood pressure normal. Failure to adhere to good manu- facturing practices is the root cause of substandard drugs purchase benicar 10 mg online arteria femoralis communis. Quality-control processes and verifcation add expense to manufacture, as does maintaining sterile water fltration and air handling systems. Proper quality control in- cludes dealing only with quality-assured suppliers, but small- and medium- sized manufacturers often neglect supplier quality because of logistical obstacles and cost. Multinational companies, both innovator and generic, operate on a scale that allows them to recoup the costs of running high-quality factories. Initial capital investments and infrastructure problems stand between qual- ity medicines and many small- and medium-sized medicine manufacturers. Small- and medium-sized frms and companies in Africa have a diffcult time securing business improvement loans. The only capital available to these companies is their profts, and reinvesting profts is not a quick or reliable path to building a modern manufacturing infrastructure. The International Finance Corporation and the Overseas Private Invest- ment Corporation can work to encourage better private sector pharmaceu- tical manufacturing in developing countries. With the initial investments made, governments can take on the more manageable role of encouraging partnerships with foreign manufacturers. Recommendation 4-1: The International Finance Corporation and the Overseas Private Investment Corporation should create separate invest- ment vehicles for pharmaceutical manufacturers who want to upgrade to international standards. Governments can complement this effort by encouraging partnerships between local and foreign manufacturers. In practice, it is diffcult to distinguish the quality failures that are to blame on a manufacturer’s inability to meet international best practices from those that come from a decision to cut corners and produce inferior products for poorly regulated markets. When a producer capable of meet- ing international standards fails to do so consistently and only in product lines sold to the poor, one may conclude that noncompliance is part of a more insidious system. Rich countries enforce high quality standards for medicines, and manu- facturers recognize the need to use quality ingredients and good manufac- Copyright © National Academy of Sciences. United Nations agencies and larger international aid organizations will also refuse to do business with com- panies that cannot meet stringent regulatory authority quality standards. Manufacturers are aware, however, that low- and middle-income countries are less likely to enforce these standards. When a manufacturer produces medicines of inferior quality for less exacting markets it is known as tiered or parallel production. When regulatory checks on production are inconsistent, good procure- ment practices can ensure that quality medicines get the largest market share. The frms that offer the cheapest prices do so by buying impure ingredients and cutting corners in formulation. Good procurement dictates that the cheapest tenders are not accepted if they are of dubious quality, but it is diffcult not to be swayed by price. Proper precaution in medicines procurement can prevent poor-quality products from infltrating the mar- ket. Good procurement puts a strong emphasis on controlling corruption and promoting transparency. Recommendation 4-2: Procurement agencies should develop a plan, within the next 3 to 5 years, to comply with the World Health Orga- nization’s Model Quality Assurance System for procurement agencies and work to remove any barriers to compliance. The regulator can only confrm that the producer is unknown and turn the case over to law enforcement. The police and detectives who inherit these cases have a diffcult job gathering suffcient evidence for a prosecution there is usually little if anything to tie the falsifed drug in the market to the culprit. Criminals run lucrative businesses making and traffcking fake medi- cines, and these crimes are mostly opportunistic, emerging where regulatory systems are weakest. When criminals target the products of multinational, innovator pharmaceutical companies, the companies’ security staff build evidence for a conviction. Police are also investigating more pharmaceuti- cal crimes, but most police action is limited to brief raids. It is diffcult for police to keep up momentum for sustained action on pharmaceutical crime, especially given the immediate pressure to investigate murders and other violent crimes. The high demand and erratic supply of drugs, weak regulatory systems, and un- even awareness contribute to the trade in both falsifed and substandard drugs. Medicines are what economists describe as an inelastic good; changes in the unit price of the medicine have proportionately little effect on the demand. Price inelasticity, combined with a high relative price, make medi- cines a major expense for patients around the world. Drug shortages drive up the price of medicines and push consumers to unregulated markets. Reducing the costs and increasing the availability of medicines would help prevent drug scarcity. For generic manufacturers, companies that generally run on low margins, the costs of proving bio- equivalence and preparing a manufacturer’s dossier for regulatory review can be prohibitive to market entry. Different regulatory authorities have different, often widely divergent, requirements. To complicate the problem, many small regulatory authorities lack the technical depth to evaluate the bioequivalence data that generics manufacturers submit. The high cost of market authorization impedes the development of a strong generics industry in poor countries. A more robust generic drug mar- ket could help prevent the drug shortages and price spikes that encourage the sale of poor-quality products. Regulatory authorities can work to better harmonize their procedures, thereby improving their own effciency and reducing barriers to market entry for good-quality generics manufacturers. The use of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Com- mon Technical Document format for registration would ease the regulatory burden on generics companies. Regulators also reap a spillover beneft of more convergent regulatory systems without negotiating cumbersome mu- tual recognition agreements. Recommendation 4-3: Regulatory authorities in low- and middle- income countries should use the International Conference on Harmoni- sation Common Technical Document format for product registration to better harmonize their procedures and reduce application costs for manufacturers. To the same end, they should also conduct joint inspec- tions and use a common inspection report. A functioning medicines regulatory authority is a necessary condition for a robust generic medicines market. Strengthening the drugs regulatory system, building the inspectorate, enforcing quality standards, and licensing in accordance with international standards are es- sential to improving drug quality. Without a competent regulatory authority to inspect wholesalers, distributors, and manufacturers, opportunities to corrupt the drug supply abound. A strategy for compliance with international standards can help reduce redundant work and fragmentation. Both industry and regulators should agree to work toward the priorities identifed in the strategic plan, an openly shared document. Recommendation 4-4: Governments in low- and middle-income coun- tries should support their regulatory agencies to develop strategic plans for compliance with international manufacturing and quality-control standards. In the least developed countries, international organizations should support their efforts. Large pharmaceutical manufacturing nations such as India and China suffer from fragmented regulatory systems and an unclear division of re- sponsibilities between state and national governments. The United States has similar problems, evidenced by the recent fungal meningitis outbreak brought on by a contaminated injectable steroid drug, compounded under unhygienic conditions at the New England Compounding Center. Similar confusion causes regulatory gaps in other countries where national and local governments share responsibilities for drug regulation. During times of crisis, such as the meningitis outbreak, public inter- est in drug quality peaks, but it can be diffcult to maintain.

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Finally generic benicar 20mg with visa blood pressure chart low to high, we must check to see that our Ctrough concentration with this dose is acceptable (assume a dose of 900 mg was given for a desired peak of 26 cheap 20 mg benicar with mastercard blood pressure during heart attack. Even though once-daily dosing is convenient for this patient 20mg benicar amex arrhythmia on ultrasound, we need to consider whether the trough concentration will be adequate for this patient with endocarditis buy benicar 10 mg on-line heart attack calculator. Examples of such recommendations can be found in Morbidity and Mortality Weekly Report (e. Individualization of theophylline dosage maximizes therapeutic benefit while minimizing adverse effects. Theophylline is used less frequently in the treatment of asthma as beta-2 agonists and anti-inflammatory agents (corticosteroids) have become the first-line therapies. However, theophylline is still occasionally used for treatment of nocturnal or mild persistent asthma, and dosage individualization is 1 2 necessary. Although theophylline was once thought to have primarily a bronchodilator effect, it is now recognized to have anti-inflammatory effects as well. The therapeutic range is now generally accepted to be 5-15 mg/L, a decrease from the previously accepted range of 10-20 mg/L. This newer range is probably more relevant to bronchodilator effects; anti-inflammatory effects may be achieved at lower concentrations. Theophylline is eliminated from circulation through hepatic oxidative metabolism (cytochrome P450) and has a low intrinsic clearance (see Lesson 9). Therefore, total hepatic clearance of theophylline is determined by the intrinsic clearance of the liver and is not dependent on liver blood flow. Theophylline may undergo nonlinear, or Michaelis-Menten, pharmacokinetics (see Lesson 10) even within the therapeutic range, but this is more likely to occur at concentrations above the 4 therapeutic range. Diseases that affect liver blood flow, such as cirrhosis and heart failure, may reduce theophylline clearance. Drugs that alter hepatic oxidative metabolism can also dramatically 5 6 affect theophylline clearance. Some drugs, such as cimetidine and erythromycin, will decrease theophylline clearance and cause increased plasma theophylline concentrations (Table 14-1). Suppository and rectal solution forms of the drug are available but are not commonly used. Intravenous infusion involves administration of theophylline itself or in a salt form (such as aminophylline). When theophylline derivatives are used, the theophylline dose equivalent should be calculated. Therefore, to obtain the theophylline dose equivalent, the aminophylline dose should be multiplied by 0. Others are designed to slowly release drug in the gastrointestinal tract for up to 24 hours after administration. Determine an appropriate loading dose of aminophylline to produce a theophylline concentration of 15 mcg/mL. In this case, the desired plasma theophylline concentration is 15 mcg/mL, the aminophylline salt equivalent (S) is 0. In patients more than 7 50% above ideal body weight, volume of distribution should be calculated using ideal body weight. The basic loading dose equation can be derived from the plasma concentration equation we learned in Lesson 1. This 650-mg aminophylline loading dose will produce a serum concentration slightly less than 15 mcg/mL. Note: Remember, aminophylline is a salt form of theophylline and contains approximately 80% theophylline equivalents. In this situation, we will slightly modify the loading dose Equation 14-2 to the following: (See Equation 14-2. This 450-mg aminophylline loading dose will result in a serum concentration slightly less than 15 mg/L. The loading dose is to be given over 30 minutes, and a maintenance infusion is to be started immediately. Suggest an aminophylline infusion rate to achieve a plasma theophylline concentration of 13 mcg/mL. Figure 14-1 demonstrates the relationship between serum levels achieved with the loading and maintenance doses of theophylline or aminophylline. A theophylline level is ordered immediately and is reported by the laboratory as 22 mcg/mL. Now that we have his actual clearance, we can calculate a new maintenance dose that will give us the desired theophylline serum concentration of 13 mcg/mL: (See Equation 14-4. Next we can determine the time we need to wait by using the following equation: -Kt C = C0e (See Equation 3-2. Clinical Correlate The most significant side effects from theophylline occur at serum concentrations higher than 20 mcg/mL. At concentrations higher than 35 mcg/mL, major adverse effects include hyperglycemia, hypotension, cardiac arrhythmias, seizures, brain damage, and death. Plasma concentrations with a loading dose and continuous infusion of theophylline or aminophylline. She has a history of heavy marijuana and tobacco use but no other medical problems. Suggest an oral dosage regimen that will produce a pss average of approximately 12 mcg/mL, using a sustained released product dosed every 12 hours. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute; 1997. Recent advances in our understanding of the use of theophylline in the treatment of asthma. Theophylline: pooled Michaelis-Menten behavior of theophylline and its parameters (Vmax and Km) among asthmatic children and adults. Cimetidine inhibition of theophylline elimination: influence of adult age and time course. Phenytoin is usually administered either orally or intravenously and exhibits nonlinear or Michaelis-Menten kinetics (see Lesson 10). Unlike drugs undergoing first-order elimination (Figure 15-1), the plot of the natural logarithm of concentration versus time is nonlinear with phenytoin (Figure 15-2). Consequently, as the phenytoin dose increases, a disproportionately greater increase in plasma concentration is achieved. This enzyme saturation process can be characterized with an enzyme-substrate model first developed by the biochemists Michaelis and Menten in 1913. In this metabolic process, drug clearance is constantly changing (in a nonlinear fashion) as dose changes. To describe the relationship between concentration and dose, a differential equation can be written as shown below: (See Equation 10-1. Next, this differential equation can be expressed algebraically by assuming that we are at steady state and dX/dt is held constant. Then dX/dt, the change in the amount of drug (X) over time (t), can be expressed as X0/τ (dose over dosing interval), as shown in the following equation: (See Equation 10-1. The oral bioavailability of phenytoin is considered to be 100%, so an F factor is not needed in these calculations. Other pertinent clinical data include: weight, 75 kg; height, 5 feet, 11 inches; serum creatinine, 1. What intravenous loading dose and oral maintenance dose would you recommend to achieve and maintain a phenytoin concentration of approximately 20 mg/L? Calculation of the loading dose is not affected by the nonlinear pharmacokinetics of multiple-dose phenytoin regimens. Therefore: We could then order a dose of 1000 mg of phenytoin mixed in 100 mL of normal saline given intravenously via controlled infusion.

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Because V has units of volume (milliliters or liters) and clearance has units of volume/time (usually milliliters per -1 -1 -1 minute) purchase benicar 40mg mastercard pulse pressure cardiovascular risk, K has units of reciprocal time (minute discount benicar 20 mg line prehypertension causes and treatment, hour discount benicar 20 mg free shipping blood pressure natural remedies, or day ) cheap 10 mg benicar overnight delivery arteria y vena. It is important to understand that the elimination rate constant and plasma drug concentration versus time curve are determined by drug clearance and volume of distribution. Clearance can be related to drug dose by first evaluating the plasma drug concentration versus time curve after a dose. We usually know the dose of drug being administered and can determine plasma drug concentrations over time. These units make sense graphically as well, because when we multiply length times width to measure area, the product of the axes (concentration, in milligrams per liter, and time, in hours) would be expressed as milligrams per liter times hours. If a line is drawn vertically to the x-axis from each measured concentration, a number of smaller areas is described (Figure 3-9). Because we are using the determined concentrations rather than their natural logs, the plasma drug concentration versus time plot is curved. The tops of the resulting shapes are curved as well, which makes their areas difficult to calculate. The area of each shape can be estimated, however, by drawing a straight line between adjacent concentrations and calculating the area of the resulting trapezoid (Figure 3-10). If the time between measurements (and hence the width of the trapezoid) is small, only a slight error results. By knowing how to calculate clearance by the area method, it is not necessary to decide first which model (i. For orally administered drugs, this would only be true if the fraction of drug absorbed from the gastrointestinal tract remained constant. A plasma drug concentration versus time curve can be divided into a series of trapezoids. If two patients receive the same drug and the plots in Figure 3-14 result, which patient has the larger elimination rate constant (faster elimination)? Plasma concentrations were 22 and 15 mg/L at 24 and 48 hours after infusion, respectively. Plot these two plasma concentrations on semilog paper and determine when the concentration would reach 10 mg/L. Using the equation C = C0e , determine the plasma concentration of a drug 24 hours after a -1 peak level of 10 mg/L is observed if the elimination rate constant is 0. For a drug that has an initial plasma concentration of 120 mg/L and a half-life of 3 hours, what would the plasma concentration be 12 hours after the initial concentration? To calculate drug clearance by the area method, it is necessary to first determine whether the drug best fits a one- or two-compartment model. Using Figure 3-17 and knowing that a 500-mg dose was given intravenously, calculate clearance by the area method. This value should be (ln C1 - ln C0) and should be divided by the change in time (t1 - t0). The slope is the natural log of change in concentration divided by the change in time: (ln C1 - ln C0)/(t1 - t0). The elimination rate constant would not have a negative value; this is merely the slope of the line. You may have used 3 hours in the denominator rather than 4 hours for change in time. Be sure your points are plotted on paper that has a log scale for y (concentration) values. A rate constant is a unit change per time expressed as reciprocal time units -1 (e. We would expect the concentration to decrease from 120 mg/L to 60 mg/L, then to 30 mg/L, 15 mg/L, and finally, to 7. To find the T1/2 of 10 hours, find the interval of time necessary for the concentration to decrease from 100 to 50. When using the area method, it does not matter if the drug best fits any particular model. You may have neglected to divide the sum of 100 plus 50 by 2 before then multiplying by the width of 2. Remember, clearance has units of volume/time, so the units in the equation must result in volume/time. This area is estimated by dividing the drug concentration at 12 hours, -1 1 mg/L, by the elimination rate constant, 0. Two plasma concentrations are then determined, and the slope of the plasma concentration versus time curve is calculated. Drug X is given to two patients, and two plasma drug concentrations are then determined for each patient. Why is the half-life of most drugs the same at high and low plasma concentrations? The plasma concentration versus time curves for two different drugs are exactly parallel; however, one of the drugs has much higher plasma concentrations. Explain why a reduction of drug clearance by 50% would result in the same intensity of effect as doubling the dose. The plasma concentration at 9 hours after the dose estimated from a plot of the points on semilog graph paper is: A. This terminal area is calculated by taking the final concentration (at 8 hours) and dividing by K above. Be sure your x-scale for time is correct and that you extrapolated the concentration for 9 hours. First, estimate C0 by drawing a line back to time = 0 (t0) using the three plotted points. You may not have multiplied by 1/2 when calculating the area from 8 hours to infinity. Describe the principle of superposition and how it applies to multiple drug dosing. Calculate the estimated peak plasma concentration after multiple drug dosing (at steady state). Calculate the estimated trough plasma concentration after multiple drug dosing (at steady state). Using these models, we can obtain an elimination rate constant (K) and then calculate volume of distribution (V) and dosing interval (τ) based on this K value. Most clinical situations, however, require a therapeutic effect for time periods extending beyond the effect of one dose. The goal is to maintain a therapeutic effect by keeping the amount of drug in the body, as well as the concentration of drug in the plasma, within a fairly constant range (the therapeutic range). Although intermediate equations are used, only the final equation is important to remember. The first dose produces a plasma drug concentration versus time curve like the one in Figure 4-1. C0 is now referred to as Cmax, meaning maximum concentration, to group it with the other peak concentrations that occur with multiple dosing. If a second bolus dose is administered before the first dose is completely eliminated, the maximum concentration after the second dose (Cmax2) will be higher than that after the first dose (Cmax1) (Figure 4-2). The second part of the curve will be very similar to the first curve but will be higher (have a greater concentration) because some drug remains from the first dose when the second dose is administered. The only difference is that the actual concentrations may be higher at later doses, because drug has accumulated.

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