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Clinical Correlate These initial population estimates for K and V only represent a statistical best average estimate to begin with pletal 50mg low price spasms thoracic spine, and individual patient values can vary widely generic pletal 100 mg fast delivery muscle spasms 37 weeks pregnant. Consequently generic pletal 100mg otc spasms pregnant belly, these estimated values should only be used to initiate a dose 50mg pletal overnight delivery stomach spasms 6 weeks pregnant, and serum drug concentrations should be obtained as soon as possible to calculate patient-specific (i. Clinical Correlate Some clinicians would use the above K and V equations as initial population estimates for all aminoglycosides; however, other clinicians may use similar equations with slightly different numbers based on regression equations from other similar studies. Additionally, most clinicians will use the same estimates for all aminoglycosides; however, some will use slightly different equations for each aminoglycoside. We will use the above equation for all aminoglycosides as they are all excreted renally via the exact same mechanism. Clinical Correlate The values for K and V represent population estimates of the elimination rate and volume of distribution, respectively, based on statistical averages with relatively large standard deviations. Aminoglycosides have concentration- dependent bactericidal actionthat is, larger doses can result in lower bacterial counts in the 3,4 residual population and longer intervals before significant regrowth occurs. If consecutive doses of aminoglycosides are given before significant regrowth of bacteria occurs, the bactericidal effect of each dose accumulates, and the tissue is eventually cleared of the organism. If the dosing interval is too long, however, the bacterial count may rise in the latter portion of each dosing interval, and the effectiveness of the agent is diminished. The ability to prolong the dosing interval of antibiotics without loss of efficacy depends on several factors, including: • effectiveness of host defenses; • pharmacokinetics, such as the elimination rate of the drug; and • pharmacodynamic effects of the drug. The pharmacodynamic characteristics of aminoglycosides favor the use of large, single daily doses of aminoglycoside rather than equivalent dosage spread over the day. Clinical studies of extended-interval dosing of aminoglycosides have shown little difference in 12-15 efficacy or toxicity between the single and multiple daily dose regimens. However, several questions about extended-interval dosing of aminoglycosides remain unanswered, and this dosing 16 regimen may not be appropriate for all patients or for treatment of all infections. Clinical Correlate Extended-interval dosing of aminoglycosides has not been adequately studied in the elderly, obese, or pregnant populations. Moreover, this type of dosing has not been evaluated in patients with a creatinine clearance less than 20 mL/minute. Limited data are available for patients with certain diseases, such as endocarditis, osteomyelitis, and meningitis. Traditional monitoring of peak and trough values in this type of dosing may have limited value because the optimal plasma concentrations have not yet been determined. Several alternatives for plasma concentration assessment have been used by investigators. The distribution phase of high- dose aminoglycoside therapy also has not been adequately studied, so the sampling and interpretation of peak concentrations may have limited clinical value. It has been postulated that higher extended-interval dosing may exhibit a longer distribution phase than smaller extended- interval doses. If the peak plasma concentration is drawn during this longer distribution phase, then the level may be inaccurate. Although peak plasma concentrations are not routinely monitored with extended-interval aminoglycoside dosing, trough levels or levels 18-20 hours after a dose may be measured to assure an aminoglycoside-free interval. Desired Aminoglycoside Plasma Concentrations The traditional ranges for desired aminoglycoside plasma concentrations are a peak of 4-10 mg/L for gentamicin and tobramycin and 15-30 mg/L for amikacin, and a trough of less than 2 mg/L for gentamicin and tobramycin and less than 8 mg/L for amikacin. For extended-interval administration, the dose is typically 4-7 mg/kg actual body weight for gentamicin and tobramycin, and peak concentrations will usually be above these ranges. Attainment of adequate peak concentrations is related to efficacy for some infections, and a low trough concentration may minimize the risk of nephrotoxicity and ototoxicity. These desired concentrations are often modified based on patient-specific variables or pathogen susceptibility. Other pertinent patient data include: height, 5 feet, 1 inch; weight, 55 kg; and serum creatinine, 1. Assume a desired Cpeak of 6 mg/L and a Ctrough of 1 mg/L Population values of K and V for the aminoglycosides should be used to estimate maintenance doses. A patient usually will receive a loading dose over 1 hour when therapy is initiated because a loading dose quickly brings aminoglycoside plasma concentration close to the desired therapeutic concentration. Lessons 4 and 5 describe the mathematical models used for various multiple dose, intravenous, drug dosing situations. For aminoglycosides, which are usually given intravenously over 30-60 minutes at regular (i. A quick review of Lessons 4 and 5 may help you understand the derivation of these equations. Briefly, this equation is arrived at by taking the equation from Lesson 4 for a single intravenous bolus dose and adding the appropriate factors for the following: • multiple doses, • simultaneous drug administration and drug elimination, • drug administration over 30-60 minutes instead of an intravenous bolus, and • attainment of steady state (for simplicity, 1 hour is assumed for the drug administration time). Determine K0 (maintenance dose in mg/hour) To calculate an initial maintenance dose and dosing interval, we use the population estimates of K and V calculated from Equations 12-1 and 12-2: -1 K = 0. The equation below is used to determine the most appropriate dosing interval (τ) that will yield the desired Cpeak and Ctrough. This equation can be used to evaluate several different Cpeak and Ctrough combinations to find an appropriate dosing interval. For a concentration versus time curve (following first-order elimination), the terminal slope equals - K and: (See Equation 3-1. Rearrange the above equation and then solve for τ: (-K)(τ - t) = ln Ctrough - ln Cpeak Step 2. Further rearrange Step 4 by considering the rule of logarithms: log a - log b = log (a/b) Therefore: The equation in either Steps 4 or 5 can be used to calculate the dosing interval (τ). Calculating the dosing interval with both equations (Steps 4 and 5) will serve as an added arithmetic check, because both methods should give the same answer. Note that in this example we are calculating the maintenance dose first and will use it to calculate the proper loading dose. Once K and V have been estimated, the desired Cpeak and Ctrough concentrations determined, and τ calculated, these values can be substituted in our general equation and solved for K0 (maintenance dose): (See Equation 5-1. This amount is the initial estimated maintenance dose until Cpeak and Ctrough results are obtained. This actual Cpeak(steady state) can be determined via a simple ratio: For this patient, the actual Cpeak(steady state) is calculated as follows: Problem 1B. In this case, we are saying that Ctrough equals Cpeak multiplied by the fraction of Cpeak remaining (as -Kt′ described by e ) after elimination has occurred for t hours (i. As shown in Figure 12- 2, because the peak concentration occurs at the end of the 1-hour infusion, t′ in this equation is always (dosing interval) minus t (duration of infusion). Remember that we actually picked a desired Ctrough of 1 mg/L, but we also shortened the desired dosing interval from 13. If, based on clinical judgment, a lower Ctrough is desired, the dose can be recalculated with a longer dosing interval, such as 16 hours. Therefore, we would need to reexamine the rounding of our dosing interval and would probably round it up from 13. Calculate an appropriate loading dose to approximate a plasma concentration of 6 mg/L There are several methods to calculate a loading dose, and two are presented. Because one method requires estimation of the maintenance dose first, the loading dose is determined after the maintenance dose and dosing interval are calculated.
Precautons Renal impairment; peptc ulcer; lactaton (Appendix 7b); heart blockage discount 50mg pletal mastercard muscle relaxant pictures, slow heart- beat; bradycardia discount 100mg pletal amex muscle relaxant pictures, hypotension; urinary tract infecton; epilepsy; asthma; interactons (Ap- pendix 6c); pregnancy (Appendix 7c) discount pletal 50mg without prescription muscle spasms 6 letters. Adverse Efects Abdominal cramps cheap 100 mg pletal free shipping spasms 1982, diarrhoea; pupil dilataton; excess saliva; headache; joint pain; severe allergic reactons; faintng; interrupted breathing; irregular heart beat; seizures; vision changes; anxiety. Precautons Monitor weight; blood pressure, blood glucose and electrolytes, antbiotc coverage may be required, doses should be tapered and not withdrawn suddenly; hepatc impairment (Appendix 7a); lactaton (Appendix 7b); pregnancy (Appendix 7c); interactons (Appendix 6c, 6d). Adverse Efects Inital transient exacerbaton; elevaton of intraocular pressure; optc nerve damage; posterior subcapsular cataract formaton; delayed wound heeling; weight gain; moon face; avascular necrosis; osteoporosis; psychosis and mood change, increased chance of opportunistc infectons. Injecton: Store protected from light, in a single dose or in mult dose containers. Contraindicatons Recent intestnal or bladder surgery; gastrointestnal or urinary tract obstructon; afer suxamethonium; pneumonia; peritonits. Precautons Asthma; urinary tract infecton; cardiovascular disease including arrhythmias (especially bradycardia or atrioventricular block); hyperthyroidism; hypotension; peptc ulcer; epilepsy; parkinsonism; avoid intravenous injecton; renal impairment; pregnancy (Appendix 7c); lactaton. Adverse Efects Muscarinic efects generally weaker than with neostgmine: increased salivaton, nausea, salivaton, vomitng, abdominal cramps, diarrhoea; signs of overdosage include bronchoconstricton, increased bronchial secretons; lacrimaton, excessive sweatng, involuntary defecaton and micturiton, miosis, nystagmus; bradycardia, heart block, arrhythmias, hypotension; agitaton, excessive dreaming, weakness eventually leading to fasciculaton and paralysis, thrombophlebits; rash associated with bromide salt; diaphoresis, increased peristalsis. A classifcaton based on severity before the start of treatment and disease progression is of impor- tance when decisions have to be made about management. It can be divided by severity into intermitent, mild persistent, moderate persistent and severe persistent. Antasthmatcs are useful in the management of the disease since therapy has a stepwise approach which must be discussed with the patent before commencing therapy. The level of therapy is increased as the severity of the asthma increases with stepping-down if control is sustained (see tables on treatment below). Inhalaton: Medicatons for asthma can be administered in several diferent ways, including inhalaton, oral and parenteral (subcutaneous, intramuscular or intravenous routes). The main advantage of delivering drugs directly into the airways via inhalaton is that high concentratons can be delivered more efectvely and rapidly to the airways, and systemic adverse efects avoided or minimized. It is important that patents receive careful instructon in the use of pressurized (aerosol) inhalaton (using a metered- dose inhaler) to obtain optmum results. Afer exhaling as completely as possible, the mouthpiece of the inhaler should be placed well into the mouth and the lips fr mly closed around it. Afer holding the breath for 10 seconds or as long as is comfortable, the mouthpiece should be removed and the patent should exhale slowly. It is important to check that patents contnue to use their inhalers correctly as inadequate technique may be mistaken for drug failure. They may be of beneft for patents such as the elderly, small children and the asthmatc who fnd inhalers difcult to use or for those who have difculty synchronizing their breathing with administraton of the aerosol. A large volume spacing device is also recommended for inhalaton of high doses of cortcosteroids to reduce oropharyngeal depositon which can cause candidosis. The use of metered-dose inhalers with spacers is less expensive and may be as efectve as use of nebulizers, although drug delivery may be afected by choice of spacing device. They are administered over a period of 5-10 min from a nebulizer, usually driven by oxygen in hospital. Systemic adverse efects occur more frequently when a drug is given orally rather than by inhalaton. Drugs given by mouth for the treatment of asthma include β2-agonists, cortcosteroids and theophylline. If the patent is being treated in the community, urgent transfer to hospital should be arranged. Pregnancy: Poorly controlled asthma in pregnant women can have an adverse efect on the fetus, resultng in perinatal mortality, increased prematurity and low birth-weight. Administraton of drugs by inhalaton during preg- nancy has the advantage that plasma drug concentratons are not likely to be high enough to have an efect on the fetus. Acute exacerbatons should be treated aggressively in order to avoid fetal hypoxia. Acute Exacerbaton of Asthma: Severe asthma can be fatal and must be treated promptly and energetcally. Acute severe asthma atacks require hospital admission where resuscitaton facilites are imme- diately available. In emergencies where a nebulizer is not available, salbutamol 100 µg by aerosol inhalaton can be repeated 10-20 tmes preferably using a large-volume spacing device. Patents should also be given a cortcosteroid ; for adults, prednisolone 30-60 mg by mouth or hydrocortsone 200 mg intravenously; for children, prednisolone 1-2 mg/kg by mouth (1-4 years, max. Most patents do not beneft from the addi- ton of intravenous aminophylline or a parenteral β2-agonist; both cause more adverse efects than nebulized β2-agonists. Nevertheless, an occasional patent who has not been taking theophylline, may beneft from a slow intravenous infusion of aminophylline. The use of epinephrine (adrenaline) in asthma has generally been superseded by β2-selectve adrenoceptor agonists. Treatment should never be delayed for investgatons, patents should never be sedated and the possibility of pneumoth- orax should be considered. Patents who deteriorate further despite treatment may need intermitent positve pressure ventlaton. Step down Review Step up If control treatment every 3 to is not achieved, 6 months. Chronic Obstructve Pulmonary Disease: Chronic obstructve pulmonary disease (chronic bronchits and emphysema) may be helped by an inhaled short-actng β2-adrenoceptor agonist used as required or when the airways obstructon is more severe, by an inhaled antcholinergic (antmuscarinic) bronchodilator or both if necessary. Although many patents are treated with an inhaled cortcosteroid its role in chronic obstructve pulmonary disease is not clear at present. A limited trial of high-dose inhaled cortcosteroid or an oral cortcosteroid is recommended for patents with moderate airfow obstructon to determine the extent of the airway reversibility and to ensure that asthma has not been overlooked. Long-term oxygen therapy prolongs survival in some patents with chronic obstructve pulmonary disease. When salbutamol is given by inhalaton (100-200 µg) the efect can last as long as 4 h thus making it suitable for both the treatment (see tables) and preventon of asthma. Salbutamol can also be taken orally in a dose of 2-4 mg up to 4 tmes daily but is less efectve and causes more adverse efects. Adverse Efects Cardiovascular adverse efects (arrhythmias, palpitatons and tachycardia) may occur with salbutamol, but are infrequent with inhaled preparatons. Partcular cauton is required in severe asthma because this efect may be potentated by concomitant treatment with xanthines (for example theophyl- line), cortcosteroids, diuretcs and hypoxia. They relax bronchial smooth muscle relieving bronchospasm and also stmulate respiraton. Absorpton of theophylline from the gastrointestnal tract is usually rapid and complete.
These tests can only be done in central laboratories cheap pletal 100mg stomach spasms 6 weeks pregnant, Copyright © National Academy of Sciences cheap 100 mg pletal amex spasms foot. The return on the time investment is mixed 100mg pletal visa infantile spasms 2013, as chro- matography separates a minimum number of components present in a sample purchase 100 mg pletal with mastercard muscle relaxant 771. Spectroscopy Spectroscopy is a class of analytical techniques that measures the in- teraction of matter and radiation, thereby giving insight into chemical structure and contents. These techniques all provide qualitative data, 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.
Toxoplasmosis: Toxoplasmosis is caused by infecton with the protozoan para- site Toxoplasma gondii proven 100mg pletal muscle relaxant drug test. Congenital transmission may occur if there is a primary infecton in early pregnancy or if the mother is immunodefcient order 50 mg pletal with visa back spasms 32 weeks pregnant. Such cases ofen result in spontaneous aborton pletal 100mg low cost muscle relaxant tv 4096, fetal death or severe congenital disease discount pletal 100 mg online muscle relaxant neck. Ocular toxoplasmosis causes chorioretnits and is ofen the result of a childhood infecton that becomes apparent in adulthood. The treatment of choice for toxoplasmosis is pyrimethamine with sulfadiazine; a folate supplement is also given to coun- teract the megaloblastc anaemia associated with these drugs. Patents receiving these drugs require careful monitoring by appropriately trained health professionals in an adequately resourced setng. Rigorous promoton of measures to prevent new infectons remains essental and its need is not diminished by the availability of antretroviral drugs. Efectve therapy requires the simulta- neous use of 3 or 4 drugs; alternatve regimens are necessary to meet specifc requirements at start-up, to substtute for frst-line regimens in cases of intolerance, or to replace failing regimens. The use of fxed-dose preparatons for these combinatons is also recommended if the pharmaceutcal quality is assured and interchangeability with the single products is demonstrated as specifed by the relevant drug regulatory authority. Selecton of 2 or 3 protease inhibitors from the Model List will need to be determined by each country afer considera- ton of local treatment guidelines and experience, as well as comparatve costs of available products. Low-dose ritonavir is used in combinaton with indinavir, lopinavir or saquinavir as a ‘booster’; ritonavir is not recommended as a drug in its own right. Principles of Treatment: Treatment is aimed at reducing the plasma viral load as much as possible and for as long as possible; it should be started before the immune system is irreversibly damaged. The need for early drug treatment should, however, be balanced against the development of toxicity. Commitment to treatment and strict adherence over many years are required; the regimen chosen should take into account convenience and the patent’s tolerance of it. The development of resistance is reduced by using a combinaton of 3 or 4 drugs; such combinatons should have additve or synergistc actvity while ensuring that their toxicity is not additve. Testng for resistance to antviral drugs, partcularly in therapeutc failure, should be considered. Women of childbearing age receiving antretroviral therapy must have available efectve contraceptve methods to prevent unintended pregnancy. Women who are taking non nucleoside reverse transcriptase inhibitors or protease inhibi- tors which can lower blood concentraton of hormonal oral contraceptves, should be advised to use additonal or alterna- tve contraceptves. Other nucleoside reverse transcriptase inhibitors include abacavir, didanosine, lamivudine, stavudine and zalcitabine. The protease inhibitors include amprenavir, indinavir, lopi- navir, nelfnavir, ritonavir and saquinavir. Ritonavir in low doses is used in combinaton with indinavir, lopinavir or saquinavir as a booster. The small amount of ritonavir in such combi- natons has no intrinsic antviral actvity but it increases the antviral actvity of the other protease inhibitors by reducing their metabolism. Indinavir, nelfnavir, ritonavir and possibly saquinavir inhibit the cytochrome P450 enzyme system and therefore have a potental for signifcant drug interactons. Protease inhibitors are associated with lipodystrophy and metabolic efects (see below). The non-nucleoside reverse transcriptase inhibitors include efavirenz and nevirapine. They interact with a number of drugs metabolized in the liver; the doses of protease inhibitors may need to be increased when they are given with efavirenz or nevirapine. Nevirapine is associated with a high incidence of rash (including Stevens-Johnson syndrome) and occasionally fatal hepatts. Efavirenz treatment has also been associated with an increased plasma cholesterol concentraton. Additonal basic testng should include: • white blood cell count; • diferental cell count (to identfy a decline in neutrophils and the possibility of neutropenia); • total lymphocyte count; • serum alanine or aspartate aminotransferase concen- traton to assess the possibility of hepatts co-infec- ton and to monitor for hepatotoxicity; • serum creatnine and/or blood urea nitrogen to assess baseline renal functon; • serum glucose; • pregnancy tests for women. Desirable supplemental tests include measurement of bilirubin, amylase and serum lipids. Viral load testng is currently considered optonal because of constraints on resources. Changing Therapy: Deterioraton of the conditon (including clinical and viro- logical changes) usually calls for replacement of the failing drugs. Intolerance to adverse efects and drug-induced organ dysfuncton usually require change in therapy. The choice of an alternatve regimen depends on factors such as the response to previous treatment, tolerance and the possibility of cross-resistance. If toxicity occurs, either a new second-line regimen is indicated or, if the toxicity is related to an identfable drug in the regimen, the ofending drug can be replaced with another drug that does not have the same adverse efects. In pregnant women, it may be desirable to initate antretro- viral therapy afer the frst trimester, although for pregnant women who are severely ill, the beneft of early therapy outweighs the potental risk to the fetus. The use of zidovudine, lamivudine, nevirapine, nelfnavir and saquinavir are recommended for women of child-bearing potental or who are pregnant. Efavirenz should be avoided because of its potental teratogenic efect on the fetus in the frst trimester. First-line treatment in pregnant women should when possible include zidovudine and lamivudine. Mono- therapy with either zidovudine or with nevirapine reduces transmission of infecton to the neonate (see also below), but combinaton antretroviral therapy maximizes the chance of preventng transmission and represents optmal therapy for the mother. Low-dose ritonavir is required if either indi- navir or saquinavir is used in pregnancy because adequate drug concentraton is achieved only with ritonavir boostng. Lactc acidosis and hepatc steatosis associated with nucleo- side reverse transcriptase inhibitors may be more frequent in pregnant women and therefore the combinaton of stavudine and didanosine should be used in pregnancy only when no alternatves are available. Protease inhibitors have been asso- ciated with glucose intolerance and pregnant women should be instructed to recognize symptoms of hyperglycaemia and to seek health care advice if they occur. Lactaton: Antretroviral drugs may be present in breastmilk and may reduce viral load in breastmilk and reduce the risk of trans- mission through lactaton. Immediate expert advice should be sought in such cases; natonal guidelines on post-exposure prophylaxis for health- care workers have been developed and local ones may also be available. Lipodystrophy and Metabolic Efects: Combinaton antretroviral therapy, including regimens containing a protease inhibitor, is associated with redistribu- ton of body fat in some patents (for example, decreased fat under the skin, increased abdominal fat, ‘bufalo humps’ and breast enlargement). Protease inhibitors are also associated with metabolic abnormalites such as hyperlipidaemia, insulin resistance and hyperglycaemia. Clinical examinaton should include an evaluaton of fat distributon; measurement of serum lipids and blood glucose should be considered.
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