It is comprised of two atria discount methocarbamol 500mg on-line, which receive venous blood; two ventricles buy 500mg methocarbamol free shipping, which pump blood; valves order methocarbamol 500mg line, which prevent the backflow of blood; and a conduction system, which transmits the electrical impulses that drive cardiac activity. The electrical signal is propagated and converted to mechanical activity through a series of biochemical interactions, which involve stereotyped ion fluxes (mainly Na+, Ca++, and K+) through voltage- gated ion “pores” and downstream protein interactions. Although inherited or acquired defects in these components may result in cardiac disease, these same mechanisms form the basis of pharmacological therapies. Electrophysiology Rhythmic and coordinated contraction of the heart is accomplished by the propagation of an electrical impulse (action potential) in a precise manner (Fig- ure 1-1). These cells exhibit automaticity, meaning they spontaneously become electrically active (depolarize). The impulse then spreads to adjacent atrial myocytes via cell-to- cell connections termed gap junctions. This rapidly conducting network acts as “wiring” to convey the impulse to the apex of the heart, allow- ing for a coordinated, mechanically efficient contraction of the ventricles. Action and Resting Potentials At rest, cardiac myocytes maintain a net negative electrical gradient with respect to the extracellular environment (resting potential). The gradient results from the activities of ion channels and transporters within the cell membrane and is essen- tial to the ability of the myocyte (and heart) to propagate electrical impulses. With sufficient stimulus, alterations in the myocyte’s permeability to Na+ result in a net positive electrical gradient with respect to the extracellular environment (depo- larization). Further, changes in the myocyte’s ion permeability to K+, Cl−, and Ca++ result in the eventual restoration of the negative intracellular environment. When plotted against time, the changes in electrical potential are conventionally described as having five distinct phases (Figure 1-2), which correspond to the stereotyped alterations in membrane permeability of the cardiac myocyte. Antiarrhythmic medications exert their influence by altering membrane permeability, affecting the characteristics of the action potential. For example, Class Ia agents (procainamide, disopyramide, and quinidine) affect Na+ influx, resulting in a decreased rate of Phase 0 depolarization and mild prolongation of repolarization. Phase 1 is 0 3 the initial stage of repolarization caused by closure of Na+chan- nels and efflux of Cl−. Phase 3 4 is the rapid repolarization and is Time facilitated primarily by K+efflux. Phase 4 is characterized by the positive slope, indicating gradual depolarization toward threshold, at which point the Phase 0 upstroke is observed. Automaticity Automaticity refers to the intrinsic ability of a cardiomyocyte or cluster of cardiomyocytes to spontaneously depolarize and, thus, initiate propagation of an action potential. Cells of the His-Purkinje system and the ventricular myocardium may also spontaneously depolarize under circumstances of par- ticularly slow cardiac rhythms (e. Because of the more rapid depolarization of the heart’s usual pacemakers, the automaticity of these cells is often not manifested. Furthermore, after cardiac injury, cells that typically do not possess automaticity may acquire altered membrane conductance with resultant current leakage and spontaneous 4 B. Notice the positively sloped Phase 4, progressing toward the threshold potential, at which point, Phase 0 occurs. The slope of the Phase 4 depolariza- tion is a key determinant in the rate of initiation of an action potential and, thus, overall heart rate. Modulation of automaticity occurs via the autonomic nervous system and may, thus, be affected by pharmacological agents acting centrally (dexmedetomidine, clonidine) or those affecting action potential initiation and propagation at the level of the myocytes (digoxin, β-blockers). In clinical practice, there is often an overlap of direct and autonomic effects with many pharmacological agents. On a cellular level, this is accomplished by coupling the changes in electrical environment to changes in mechanical activity (myocardial contraction and relaxation) via fluctuations of cytosolic Ca++ concentration. As a consequence of depolarization, cytosolic Ca++ concentration markedly increases via influx across the cell membrane as well as release of intracellular calcium stores within the sarcoplasmic reticulum. Ca++ directly enables the interaction of the contractile elements actin and myosin, the result of which is myofiber shortening. Dysrhythmias Although an extensive review of all dysrhythmias is outside the scope of this chapter, a brief overview of the mechanisms of the basic categories of dysrhythmias is provided. On the simplest level, heart rhythm abnormalities can be divided into those that are “too slow” (bradyarrhythmias) and those that are “too fast” (tachyarrhythmias). Bradyarrhythmias may also result from disease of the sinus node (ineffective automaticity), such that no appropriate pacemaker 1. However, the mechanism that underlies each can often be categorized as automatic or reentrant. An automatic tachycardia results from a cell or cluster of cells acquiring abnormal automaticity, such that this region of the heart spontaneously depolarizes more rapidly than the sinus node, establishing the heart rate at greater than physiological rates. Examples of automatic tachycardias include ectopic atrial tachycardia, multifocal atrial tachycardia, and junctional ectopic tachycardia. Automatic tachycardias tend to exhibit “warm-up” and/or “cool-down” phases at onset and termination, and, despite the overall rapid rate, there is subtle variability in heart rate over time. In contrast, reentrant tachycardias result from nonphysiological electrical pathways that allow con- duction of an impulse back to a region of the heart that has repolarized after the earlier conduction of the same impulse. Such “short circuits” essentially allow the same impulse to recycle itself and lead to successive depolarizations. Reentrant tachyarrhythmias characteristically have an abrupt onset and ter- mination and a nonvarying rate during the tachycardia. Cardiovascular Physiology Care of the patient with hemodynamic derangements remains rooted in basic physiological concepts—preload, contractility, and afterload—first described in the late 19th century. These factors directly impact stroke volume, which, along with heart rate, are the key determinants of cardiac output (Figure 1-4). Preload, contractility, and afterload each impact cardiac output via their effects on stroke volume. Munoz Preload Preload refers to the ventricle’s intrinsic ability, within a physiological range, to alter the force of contraction based on the degree of ventricular filling just before contraction (end-diastolic volume/fiber length). The greater the end-diastolic volume, and, thus, ventricular myofiber stretch, the greater the force of contraction. Conceptually, preload is most often equated with the intravascular volume status of a patient. Contractility As already noted, within physiological range, the greater the myofiber stretch (preload), the greater the force of contraction. However, contractility (or inotropic state) specifically refers to the magnitude of response to a given preload and can be thought of as the “multiplication factor” for any given preload (Figure 1-5). Contractility is an intrinsic property of the muscle fiber that is relatively inde- pendent of changes in preload or afterload. In other words, for any given preload, the force of contraction will be greater under conditions of increased inotropy (e. Each of these therapies has multiple effects, aside from enhanced inotropy, which may limit their therapeutic efficacy (e. Afterload Afterload is defined as the ventricular wall stress during contraction and is often conceptualized as the load against which the ventricle contracts. Cardiac Physiology Review 7 increased B contractility A normal decreased contractility Left ventricular end-diastolic volume (preload) Figure 1-5. Frank-Starling curve illustrating the relationship between various preloads inotropic states and cardiac output. However, for a given preload A or B, cardiac output is, in part, determined by the inotropic state (contractility). In other words, afterload determines the size of the ventricular cavity at the end of contraction, independent of the ventricular volume before contraction (preload). Munoz Pressure-Volume Loops Visual representations of these physiological concepts can be helpful to best appreciate their individual characteristics and their impact on one another in vivo. One particularly useful way to appreciate the contributions of and interactions between preload, contractility, and afterload is by examination of pressure-volume loops. As shown in Figure 1-6a, ventricular diastolic perform- ance (compliance) and changes in preload are illustrated by the curve at the bottom of the graph (end-diastolic pressure volume relationship), ventricular volume throughout the cardiac cycle is illustrated by the rectangle, and con- tractility is illustrated by the diagonal line (end-systolic pressure volume rela- tionship). With the onset of systole (Point A), there is an increase in pressure (isovolumic contraction) until ventricular pressure exceeds aortic pressure, at which point, the aortic valve opens and blood is ejected from the ventricle (Point B). As the ventricle continues to empty, there is the onset of relaxation of the ventricle, with an eventual drop in pressure below that of the aorta (Point C). At this point, ventricular pressure falls but the volume remains unchanged (isovolumic relaxation) until the pressure drops below that of the left atrium and the mitral valve opens (Point D). The ventricular volume then increases during diastole, until the cycle repeats itself with the next contraction. The area within the rectangle represents stroke work, and the distance along the x axis between the vertical lines is the stroke volume.

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Reliable buy discount methocarbamol 500mg on line, quality-assured and affordable laboratory monitoring tools methocarbamol 500mg fast delivery, adequate health workforce capacity and uninterrupted drug supplies are also essential generic methocarbamol 500mg mastercard. Consolidation promotes the consistency of approaches and linkage between settings. Chapter 1: Describes the background, context, rationale and objectives of the guidelines and the target audience. The chapter proposes steps to ensure fair, inclusive and transparent decision-making processes at the country level; discusses parameters to consider in assessing and adapting the global recommendations in countries; and suggests tools for costing and planning. Considerations for implementation across the health system and for specifc, key recommendations in the guidelines are also discussed. It proposes a range of indicators that may be used to track the implementation of new recommendations and indicators to monitor the performance of programmes across the continuum of care. Chapter 11 also highlights opportunities provided by new recommendations to review and strengthen monitoring and evaluation systems. In the longer term, the guidelines will contribute to and inform efforts to achieve universal health coverage, a key pillar of the post-2015 development agenda. The public health approach seeks to ensure the widest possible access to high-quality services at the population level, based on simplifed and standardized approaches, and to strike a balance between implementing the best-proven standard of care and what is feasible on a large scale in resource-limited settings. Some countries may face signifcant ethical challenges as they seek to implement these guidelines in the context of constraints on resources and health systems. A strong recommendation for a specifc approach to service delivery should not necessarily be viewed as an endorsement of that model over an effective service delivery model already in place in a country. Systematic reviews were outsourced to researchers who developed search protocols and conducted reviews of the available scientifc evidence. Methods and process for developing the guidelines 49 Two global community and civil society consultations on service delivery across the continuum of care in generalized and concentrated epidemic settings. Consultations with health workers working with adults and with children on the values and preferences related to priority areas in the guidelines were conducted through an e-survey (Web Annex www. A full draft of the guidelines was circulated for comment to members of the Guideline Development Groups and the external peer review group. A total of 21 Guideline Development Group members and 12 peer reviewers declared membership of pharmaceutical industry or other advisory panels or receipt of consulting fees, and 23 Guideline Development Group members and 13 peer reviewers declared pharmaceutical industry fnancial support through grants for research. There was also a further declaration at the Guideline Development Group meeting of the involvement of members as investigators in key trials and studies. The broad range of constituencies represented on the different Guideline Development Group panels was also noted, and that the majority of members had no declared interests. All individuals with declared interests therefore proceeded to participate fully in the Guideline Development Group meetings or to act as peer reviewers. The proposed recommendations were then considered, informed by a standardized decision-making table for each topic (Box 3. The Guideline Development Groups discussed both the proposed wording of the recommendations and the rating of its strength (strong or conditional). All decisions were reached by discussion and consensus on the recommendations, including their strength and, where appropriate, the conditions to be attached to the recommendations. Disagreements were resolved through e-mail discussions, teleconferences and redrafting recommendations and rationale. Early drafts of sections of the guidelines were circulated to Guideline Development Group members, and a full draft of the guidelines was circulated to Guideline Development Group members and peer reviewers for comment. The extensive comments from more than 100 reviewers were addressed where possible and incorporated into the revised guidelines. The quality of evidence is defined as the confidence that the reported estimates of effect are adequate to support a specific recommendation. Randomized controlled trials are initially rated as high-quality evidence but may be downgraded for several reasons, including the risk of bias, inconsistency of results across studies, indirectness of evidence, imprecision and publication bias. Observational studies are initially rated as low-quality evidence but may be upgraded if the magnitude of the treatment effect is very large, if multiple studies show the same effect, if evidence indicates a dose–response relationship or if all plausible biases would underestimate the effect (10). The higher the quality of evidence, the more likely a strong recommendation can be made. The strength of a recommendation reflects the extent to which the Guideline Development Group was confident that the desirable effects of following a recommendation outweigh the potential undesirable effects. The strength is influenced by the following factors: the quality of the evidence, the balance of benefits and harms, values and preferences, resource use and the feasibility of the intervention (Table 3. A strong recommendation is one for which the Guideline Development Group was confident that the desirable effects of adhering to the recommendation outweigh the undesirable effects. A conditional recommendation is one for which the Guideline Development Group concluded that the desirable effects of adhering to the recommendation probably outweigh the undesirable effects but the Guideline Development Group is not confident about these trade-offs. The reasons for making a conditional recommendation include the absence of high- quality evidence; imprecision in outcome estimates; variability in the values and preferences of individuals regarding the outcomes of interventions; small benefits; applicability in all settings versus specific settings; and benefits that may not be worth the costs (including the costs of implementing the recommendation). The more that the benefts outweigh the risks, the more likely that a strong recommendation will be made. Values and If the recommendation is likely to be widely accepted or highly valued, a preferences strong recommendation will probably be made. If there are strong reasons (acceptability) that the recommended course of action is unlikely to be accepted, a conditional recommendation is more likely to be made. Costs and fnancial Lower costs (monetary, infrastructure, equipment or human resources) implications or greater cost–effectiveness will more likely result in a strong (resource use) recommendation. Feasibility If an intervention is achievable in a setting where the greatest impact is expected, a strong recommendation is more probable. Recommendations that require updating are noted, and it is clearly stated where updated guidelines are planned. This applies to specific topics in Chapter 9, including retention across the continuum of care, but this did not lead to formal recommendations. A short version will summarize key new and existing recommendations for easy reference. A library of all supporting documentation and evidence will also be made available on the web site. Assistance will be provided to Member States to adapt the guidelines to their national contexts. An evaluation of how users have implemented the guidelines has been developed to assess the uptake of the recommendations and the barriers to effective implementation. Interim technical and programmatic updates may be developed if important new evidence becomes available. These include existing recommendations that have been updated, where a new evidence review was undertaken as part of this guidelines process. They are presented in the following format to reflect the full evidence review and discussion held within the Guideline Development Group for new recommendations. When the recommendation relates to a specific population, the key issues for that population may be briefly summarized. The new evidence on which the recommendation is based and other key operational and programmatic considerations that informed the development of the recommendation are summarized. In some cases, key clinical implementation issues specific to the recommendation are listed. For several key recommendations, discussion of implementation considerations relevant to programme managers is presented in Chapter 10. In some cases, critical issues requiring further research are briefly described or listed, where these are integral to the recommendations. The references relating to each section are listed at the end of the guidelines by chapter number. In general, these are presented in the following format: Background; Source(s) for recommendation(s); Additional guidance (where appropriate); and Existing recommendation(s). The population relevant to each recommendation is clearly specifed and also marked by an appropriate symbol for quick reference. The tables highlight selected topics that are particularly relevant to the respective populations. However, the topics listed are not exhaustive and many of the recommendations and other guidance are relevant across different populations. Algorithms for the 2013 recommendations for pregnant and breastfeeding women Annex 6. Adolescents may access care in a variety of settings, including paediatric and antenatal care clinics, as well as adult clinics. Since few health systems provide adolescent-specific services it can be challenging for adolescents to access health care and maintain adherence to treatment regimens. In general, in these guidelines, clinical and general care recommendations for adults apply to adolescents.

H2-receptor antagonists suppress acid secreton and they may relieve symptoms and permit reduc- ton in antacid consumpton buy methocarbamol 500 mg on-line. Zollinger-Ellison Syndrome Management of Zollinger-Ellison syndrome requires high dose H2-receptor antagonist treatment cheap methocarbamol 500mg free shipping. The proton pump inhibitors are more efectve partcularly for cases resistant to other treatment but they are more expensive buy 500mg methocarbamol visa. Contraindicatons Hypophosphataemia; undiagnosed gastroin- testnal or rectal bleeding; appendicits; por- phyria; hypersensitvity to aluminium salts. Precautons Impaired renal functon and renal dialysis; hepatc impairment (Appendix 7a); constpaton; dehydraton; fuid restricton; gastrointestnal disorders associated with decreased bowel motlity or obstructon; pregnancy (Appendix 7c); interactons (Appendix 6c); oedema, cirrhosis and low sodium diets. Adverse Efects Constpaton, intestnal obstructon (large doses); hypophosphataemia with increased bone resorpton, hypercalciuria and risk of osteomalacia (patents on low phosphate diet or prolonged therapy); hyperalbuminaemia- resultng in osteomalacia, encephalopathy, dementa, microcytc anaemia (in chronic renal failure treated with aluminium hydroxide as phosphate-binding agent); loss of appette. Gastro-oesophageal refux disease Adult: 20 mg twice daily for 6-12 week or up to 40 mg twice daily if there is oesophageal ulceraton. Zollinger-Ellison syndrome Adult: Initally, 20 mg every 6 hr, up to 640 mg daily if necessary. Intravenous Benign gastric and duodenal ulceraton Adult: 20 mg every 12 hr, as an injecton over at least 2 minutes or as an infusion over 15- 30 minutes. Contraindicatons Hypersensitvity Precautons Possibility of gastric malignancy should be excluded, Impaired renal functon, liver cirrhosis, pregnancy (Appendix 7c), lactaton, children and elderly, interactons (Appendix 6c). Adverse Efects Headache, dizziness, constpaton, diarrhoea, nausea, vomitng, anorexia, rash, fatgue, gynaecomasta and impotence. Storage Store protected from light, Tablets to be stored at room temperature, 15 -30⁰C (59- 86⁰F). Precautons Renal impairment; hepatc impairment (Appendix 7a); interactons (Appendix 6c); abdominal pain. Adverse Efects Diarrhoea; in renal impairment- hypermagnesaemia resultng in loss of deep tendon refexes and respiratory depression with other symptoms including nausea, vomitng, fushing of skin, thirst, hypotension, drowsiness, confusion, muscle weakness, bradycardia, coma and cardiac arrest; allergic reacton. Dose Oral Benign gastric and duodenal ulcers: 20 mg once a day for 4 weeks in duodenal ulcers, for 8 weeks in gastric ulcers, Increase to 40 mg in severe case. Prophylaxis in case of history associated with gastric/duodenal ulcers or dyspepsia: 20 mg daily. Gastric acid reducton during gastric surgery: 40 mg on preceding evening then 40 mg 2 to 6 h before surgery. Precautons Interactons (Appendix 6c, 6d); pregnancy (Appendix 7c); concomitant gastric malignancy. Storage Store protected from light and moisture at a temperature not exceeding 30⁰C. Precautons Hepatc impairment; monitor liver functon; pregnancy (Appendix 7c); cyanocobalamin defciency; tumorogenicity. Refux oesophagits: 150 mg twice daily or 300 mg at night for up to 8 weeks, or if necessary 12 weeks (moderate to severe, 150 mg 4 tmes daily for up to 12 weeks). Zollinger- Ellison syndrome: 150 mg 3 tmes daily (up to 6g daily in divided doses has been used). Gastric acid reducton (prophylaxis of acid aspiraton) in obstetrics: 150 mg at onset of labour, then every 6 h. Surgical procedures: 150 mg 2 h before inducton of anaesthesia and also, when possible on the preceding evening. Intramuscular injecton Adult- Benign gastric and duodenal ulceraton, refux oesophagits, Zollinger- Ellison syndrome: 50 mg every 6 to 8 h. Slow intravenous injecton Benign gastric and duodenal ulceraton, refux oesophagits, Zollinger-Ellison syndrome: 50 mg diluted to 20 ml and given over at least 2 min, may be repeated every 6 to 8 h. Surgical procedures: 50 mg 45 to 60 min before inducton of anaesthesia (intravenous injecton diluted to 20 ml and given over at least 2 min). Intravenous infusion Benign gastric and duodenal ulceraton, refux oesophagits, Zollinger-Ellison syndrome: 25 mg/h for 2 h, may be repeated every 6 to 8 h. Prophylaxis of stress ulceraton: inital slow intravenous injecton of 50 mg diluted to 20 ml and given over at least 2 min then by contnuous intravenous infusion, 125- 250 µg/kg per h (may be followed by 150 mg twice daily by mouth when oral feeding commences). Antallergics and Drugs used in Anaphylaxis Anthistamines are used to treat drug allergies, food aller- gies, insect stngs and some of the symptoms of anaphylaxis and angioedema. Drug treatment and other supportve care should not be delayed in critcally ill patents. Specifc precip- itants should be sought and if identfed, further exposure avoided and desensitzaton considered. Drowsiness and sedaton are partcular disadvantages of the older anthistamines and the patent should be warned against driving or operatng machinery. Other central nervous system depressants, including alcohol, barbiturates, hypnotcs, opioid analgesics, anxiolytcs and neuroleptcs, may enhance the sedatve efects of anthistamines. Since anthistamines inter- fere with skin tests for allergy, they should be stopped at least one week before conductng a skin test. Allergic reactons of limited duraton and with mild symp- toms, such as urtcaria or allergic rhinits, usually require no treatment. If on the other hand, symptoms become persistent, anthistamines consttute the mainstay of treat- ment. However, oral cortcosteroids may be required for a few days in an acute atack of urtcaria or for severe skin reactons. Oral cortcosteroids are also used to relieve severe exacerbatons in chronic urtcaria, but long-term use should be avoided. Cortcosteroids may be used topically to reduce infammaton in allergic rhinits but should only be used systemically for this conditon when symptoms are disabling. Allergic Emergencies Anaphylactc shock and conditons such as angioedema are medical emergencies that can result in cardiovascular collapse and/or death. They require prompt treatment of possible laryngeal oedema, bronchospasm or hypotension. Thera- peutc substances partcularly associated with anaphylaxis include blood products, vaccines, hyposensitzing (allergen) preparatons, antbiotcs (especially penicillins), iron injec- tons, heparin and neuromuscular blocking drugs. In the case of drug allergy, anaphylaxis is more likely to occur afer parenteral administraton. Resus- citaton facilites should always be available while injectng a drug associated with risk of anaphylactc reactons. First-line treatment of a severe allergic reacton includes administering epinephrine, keeping the airway open (with assisted respiraton if necessary) and restoring blood pres- sure (laying the patent fat, raising the feet). Epinephrine should immediately be given by intramuscular injecton to produce vasoconstricton and bronchodilaton and injecton should be repeated if necessary at 5-min intervals untl blood pressure, pulse and respiratory functon have stabilized. If there is cardiovascular shock with inadequate circulaton, epinephrine must be given cautously by slow intravenous injecton of a dilute soluton. An anthistamine such as chlorpheniramine is a useful adjunctve treatment given afer epinephrine injecton and contnued for 24 to 48 h to reduce the severity and duraton of symptoms and to prevent relapse. An intravenous cortcosteroid such as hydrocortsone has an onset of acton that is delayed by several hours but should be given to help prevent later deterioraton in severely afected patents. Furthertreatmentofanaphylaxismayincludeintravenousfuids, an intravenous vasopressor such as dopamine, intravenous aminophylline or injected or nebulized bronchodilator, such as salbutamol. Vital Functons: Maintain an open airway; give oxygen by mask, restore blood pressure (lay patent fat, raise feet) 3. Dose Intramuscular injecton Anaphylaxis: preferable site is the midpoint in anterior thigh [1:1000 soluton]. Slow intravenous injecton When there is doubt regarding adequacy of circulaton and absorpton from the intramuscular site; slow intravenous injecton of 1:10000 (10 mg/ml) soluton be injected in severely ill patents only. Contraindicatons Narrow angle glaucoma, organic brain dam- age, cardiac dilaton, coronary insufciency. Precautons Hyperthyroidism, hypertension, diabetes mellitus, heart disease, arrhythmias, cerebrovascular disease; second stage of labour; elderly; interactons (Appendix 6c); pregnancy (Appendix 7c); lactaton (Appendix 7b). Adverse Efects “Epinephrine fastness”, tachycardia and arrhythmias, hypertension, tremor, anxiety, sweatng, nausea, vomitng, weakness, hyperglycaemia, dizziness, pulmonary oedema have all been reported; headache common. Chlorpheniramine* Pregnancy Category-C Schedule H,G Indicatons Symptomatc relief of allergy, allergic rhinits (hay fever); conjunctvits; urtcaria; insect stngs and pruritus of allergic origin; adjunct in the emergency treatment of anaphylactc shock and severe angioedema. Contraindicatons Prostatc enlargement, urinary retenton; ileus or pyloroduodenal obstructon; asthma; child under 1 year; hypersensitvity, narrow angle glaucoma, pregnancy (Appendix 7c), lactaton (Appendix 7b). Precautons Performing works requiring utmost alertness such as vehicle driving, operatng machines etc within 24 h of taking the drug should be avoided. Lactaton (Appendix 7b); renal and hepatc impairment (Appendix 7a); epilepsy; interactons (Appendix 6a); atropic gastrits, elderly.

Spectroscopy Spectroscopy is a class of analytical techniques that measures the in- teraction of matter and radiation cheap methocarbamol 500mg amex, thereby giving insight into chemical structure and contents cheap methocarbamol 500mg. These techniques all provide qualitative data buy generic methocarbamol 500 mg line, and some provide signifcant quantitative data as well. Often referred to as the chemical fngerprints of drugs, the various spectra produced using these techniques elucidate different aspects of drug composition; characteristic absorption or emission peaks correspond to aspects of chemical composi- tion and molecular structure. A chemist can extract detailed chemical and structural information from a spectrum, and an inspector with minimal training can also identify falsifed and substandard medicines by comparing the drug spectra to reference materials in drug spectra databases (Kaur et al. Molecular vibration and rotation energies occur in the infrared regions of the electromagnetic spectrum, and these movements may be observed with infrared, near-infrared, or Raman spectrometers. These techniques are relatively straightforward to use and moderately expensive, and routine comparative applications do not require extensive training. Chemists ana- lyze the absorption peaks in these spectra primarily to identify molecular functional groups; most active pharmaceutical ingredients and some or- ganic excipients and impurities have characteristic spectral peaks or spectral fngerprints that can be used to help identify them. Infrared spectroscopy The infrared range of the electromagnetic spectrum can be divided into three subregions: the near-infrared, mid-infrared, and far-infrared. The mid-infrared range is the more discerning and commonly used region (Deisingh, 2005). Figure 6-4 shows the different infrared spec- tra of the antimalarial artemisinin and its derivative, artemether. This comparison can identify the common substitution of artemisinin for more effective and expensive antimalarials (Kaur et al. There are several ways to collect infrared spectra, each having ad- Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 266 Copyright © National Academy of Sciences. Some manufacturers label their packaging to take advantage of the fact that only inks that absorb in the infrared range will be visible under infrared radiation. Near-infrared and Raman spectroscopy Recent developments of portable near-infrared and Raman spectrometers have led to an increase in the use of these techniques for drug quality analysis (Fernandez et al. Both techniques are nondestructive, fast, and require no sample preparation; radiation can pass through samples in blister packs (Kaur et al. Near-infrared is better suited than mid-infrared to quantitative analysis of drug contents. Near-infrared can identify active ingredients and is particularly useful for detecting incorrect concentrations of excipients, a common inconsistency in falsifed and substandard drugs (Deisingh, 2005). When used with imaging techniques, near-infrared can yield information about a tablet’s composi- tion. Koehler and colleagues demonstrated this by comparing images of a pain relief tablet, one captured using near-infrared imaging and the other Copyright © National Academy of Sciences. The red spots indicate active ingredient and other colors indicate other ingredients. Near-infrared spectra of two different compounds are often only subtly different, and accurately interpreting results may require signifcant training (Martino et al. Portable, battery-powered near-infrared spectrom- eters are a more accessible alternative to traditional spectrometers (Dowell et al. The model they used weighed 4 pounds and contained a battery that could operate for 10 hours after a full charge, making it a powerful feld tool (Bate et al. Raman spectroscopy can readily identify many active ingredients and give further information about excipients, as well as the relative concen- tration of active ingredients to excipients (Deisingh, 2005). These ratios can be key to detecting falsifed and substandard drugs, because criminal manufacturers often take care to use the correct amount of active ingredi- ent but may not be as exacting about the excipients, which may vary even among genuine manufacturers (Deisingh, 2005; Nyadong et al. For example, artesunate tablets may contain either of the highly similar sugars lactose or sucrose, depending on the manufacturer (Nyadong et al. Raman can distinguish between these, and a Raman spectrum of Cialis identifes both the active ingredient, tadalafl, and the primary excipient, lactose (Lim, 2012). Raman spectroscopy is particularly useful for detecting Copyright © National Academy of Sciences. On the other hand, some blister packs, capsule materials, and tablet coatings can interfere with Raman scattering and make readings diffcult (Martino et al. If the materials used produce fuorescence, they interfere with Raman signals, especially those read with handheld Raman spectrometers. Though far more widely available and useful for feld in- spections, these portable devices have less tolerance for fuorescence than their full-sized counterparts. This is especially problematic in screening antimalarials, as artesunate is somewhat fuorescent (Martino et al. But some investigators maintain that the fuorescence of genuine artesunate can serve as a tool to distinguish between good- and poor-quality samples, as those without suffcient active ingredient will not produce as much fuorescence (Ricci et al. Ricci and colleagues found that fuores- cence interfered more with their readings on the handheld scanner, but it ultimately produced as reliable results as the Fourier-transformed Raman scanner (Ricci et al. Like Raman and near-infrared spectrometry, it is a nondestructive, reliable technique, applicable to nuclei that have a non- zero spin, such as those in hydrogen and carbon-13, that yields quantitative data with little sample preparation. Integrating the area under each absorption peak can provide detailed information about molecular composition and structure; the area under each peak corresponds to the number of nuclei (in protons or carbon-13 atoms) contributing to that particular signal. Many common chemical con- taminants produce characteristic absorption peaks (Gottlieb et al. Using these methods, sci- entists have successfully differentiated between many authentic and falsifed versions of antimalarials, erectile dysfunction drugs, and antidepressants (Martino et al. X-ray diffraction and X-ray fuorescence are other techniques that can give substantial information about drug contents. X-ray diffraction can be used to analyze active ingredients and excipients, while X-ray fuorescence is used for elemental analyses that can often distinguish real from falsifed drugs (Kaur et al. Mass Spectrometry Mass spectrometry, generally called mass spec, is a sophisticated ana- lytical technique that requires extensive training and expertise to use. It provides abundant structural information and the precise molecular weight of the compound under investigation. Mass spec can identify many ac- tive ingredients and excipients, as well as some impurities (Kaur et al. This technique successfully detected falsifed halofantrine syrup, an antimalarial, in West Africa that instead contained a sulphonamide antibiotic (Wolff et al. When mass spectrometers were the size of a dishwasher (Stroh, 2007), their value in the poorest countries was hard to realize, but newer, portable machines can take this sophisticated technology into the feld (Yang et al. However, mass spectrometers require a stable electrical power source, which may be dif- fcult to obtain in some developing countries. An isotope ratio mass spectrometer provides detailed information about the abundance of various elemental isotopes. Many elements have naturally occurring isotopes that are present in minute quantities in any sample. The exact ratio of isotopes varies over time and space and with dif- ferent production techniques. Isotopic ratios have been able to distinguish different sources of drugs and therefore may be useful for combating highly sophisticated copies (Lim, 2012). Regulators and law enforcement can use isotopic ratios to connect seemingly disparate events and build evidence that separate drug seizures have a common source. Documenting the iso- topic ratios of a selection of common elements, such as carbon, hydrogen, oxygen, or nitrogen, can help identify these patterns (Lim, 2012). Direct ionization mass spec, for one, is a relatively new class of mass spectrometric analysis that does not require lengthy sample preparation. For example, an artesunate sample with homogeneous surface distribution of lactose and paracetamol, a fever reducer, is illegitimate; an authentic, good-quality sample should have homogeneous distribution of artesunate and scattered distribution of lactose (Martino et al. The most sophisticated drug copies may resist identifcation with any technology other than mass spectrometry. These analogues can be so chemically and structurally similar that they behave the same under nearly any analy- sis. Mass spectrometry’s ability to precisely measure molecular weight and compare fragmentation patterns can help distinguish between compounds that differ by only one or two atoms. For example, the erectile dysfunction drug Cialis is often copied with varying degrees of sophistication (Putze et al.

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