By B. Ford. Eastern Nazarene College. 2019.

Patients are isolated in hospital for several days initially Blocking doses of antithyroid drugs with added T4 must never after dosing buy generic antabuse on line symptoms lyme disease, to protect potential contacts generic antabuse 250 mg with mastercard treatment kidney cancer symptoms. Minimal effective doses of propylthiouracil should be used during Eye signs usually occur within 18 months of the onset of pregnancy and breast-feeding. Graves’ disease and commonly resolve over one to two years, irrespective of the state of the thyroid. Iodinated oedema can be reduced by sleeping with the head of the bed radio-contrast dyes can cause transient hyperthyroidism. Radiotherapy is used in moderate inhibitors (imatinib, sorafenib, sunitinib, see Chapter 48) can Graves’ ophthalmopathy, provided that this is not threatening cause hypothyroidism and/or goitre. Severe and distressing exophthalmos warrants a trial assessed for the need for continuing the implicated drug and the of prednisolone. Urgent surgical decompression of the orbit is degree of thyroid dysfunction evaluated. If drug therapy has to required if medical treatment is not successful and visual acu- be continued, antithyroid or replacement thyroxine therapy with ity deteriorates due to optic nerve compression. It can arise post-operatively, following radioiodine heat intolerance and sweating. On examination, she appears eously in a previously undiagnosed or untreated patient. Urgent treatment comprises: tremor of the outstretched fingers and lid lag is present. Management • Lugol’s iodine; is complicated by the fact that she is probably pregnant, • glucocorticoids; and specialist input will be essential. Radioactive iodine is absolutely contraindicated in pregnancy and a high dose Aspirin must be avoided, because salicylate displaces of antithyroid drug should be avoided because of the risk bound T4 and T3 and also because of its uncoupling effect on of causing congenital hypothyroidism, and consequent oxidative phosphorylation, which renders the metabolic state mental retardation, in the baby. Radioiodine for hyperthyroidism: perhaps and Metabolism Clinics of North America 2006; 35: 663–86. These include ergo- from progenitor cells and transient depression of osteoblast calciferol (vitamin D2), cholecalciferol (vitamin D3), α-calcidol activity. The metabolism, indirectly increasing gut absorption of calcium metabolic pathway of vitamin D is summarized in Figure 39. It is fat soluble, so bile Several important metabolic diseases affect the bones, is necessary for its absorption. Storage of vitamin D occurs in the body, so a single large Post-menopausal osteoporosis is the most common of these dose may be effective for several weeks. Enzyme induction disorders; iatrogenic glucocorticoid or thyroid hormone excess (Chapter 5), e. Pregnant and lactating and teriparatide (see below) are effective in treating post- women have increased requirements. The small dose of calcium is unnecessary, but a preparation of vitamin D Calcium salts (lactate or gluconate) are used in conjunction alone is not available. Adverse effects • Patients who are receiving vitamin D plus calcium should have periodic checks of their serum Ca2 and Hypercalcaemia, which can accelerate renal dysfunction, is the creatinine concentrations, as the major adverse effect is main problem. Effervescent or chewable Bisphosphonates resemble pyrophosphate structurally, except preparations are available and easy to take. The P-C-P backbone structure renders such com- pounds very stable – no enzyme is known that degrades them. Causes bisphosphonates for the prevention and treatment of osteo- include hyperparathyroidism, malignancy with bone metas- porosis; etidronate is an alternative if these are not tolerated. They are effective for glucocorticoid- associated and post-menopausal osteoporosis. Etidronate is started at low dosage up to six months when many patients The following general measures apply: achieve remission; a further course may be given following 1. High doses should be used only if lower doses Chapter 36); fail or if rapid control of disease is needed. Other adverse effects include the gamut of gastrointest- hypercalcaemia associated with sarcoidosis. Key points Key points Bisphosphonates and bone disease Management of acute hypercalcaemia • Used to treat malignant hypercalcaemia, bone pain from • Avoid thiazides, vitamin D (milk), any calcium metastatic cancer (breast, prostate) and Paget’s disease, preparations and, if possible, immobilization. It is contraindicated in absorbed dose is excreted unchanged in the urine, but the patients with other metabolic bone diseases, including hyper- remainder is excreted over many weeks. This is a 32-amino-acid polypeptide hormone secreted by thy- roid parafollicular C-cells. This is accom- used to lower the plasma calcium concentration in hypercal- panied by a modest reduction in plasma calcium and phos- caemia, especially from malignancy, and in the treatment of phate. It is given by mouth for secondary hyperparathyroidism and for post-menopausal osteoporosis (together with calcium in patients on dialysis for end-stage renal disease and for and vitamin D supplements, if diet is inadequate). Plasma calcium, phosphate, alkaline phos- phatase and if possible urine hydroxyproline excretion are Case history monitored. A 52-year-old woman has had epilepsy since childhood, treated with phenytoin 300mg/day and her fits have been Mechanism of action well controlled. Since the loss of her job and the death of her husband she has become an alcoholic. In the kidney, it decreases the reabsorp- has no sensory symptoms in her limbs and no sphincter prob- 2 lems. Neurological examination of her legs is normal apart tion of both Ca and phosphate in the proximal tubules. Clinical investigations reveal that haemoglobin, white Adverse effects blood and platelets are normal, but her erythrocyte sedi- mentation rate is 30mm per hour, her blood glucose level is Adverse effects include the following: 5. Answer Strontium is a bone-seeking element; it was widely used for This patient has hypocalcaemia with hypophosphataemia and a raised alkaline phosphatase, but no evidence of renal osteoporosis in the 1950s, but there were concerns that it dysfunction. This is the clinical picture of a patient with osteo- inhibited calcitriol synthesis and might cause defective bone malacia. The mechanism of these effects is complex and calcium-deficient diet and incorrect dosing. Phenytoin is a potent indicates that strontium ranelate reduces bone reabsorption inducer of hepatic drug metabolizing enzyme systems, including the enzymes involved in vitamin D metabolism, and increases bone formation, and reduces vertebral and hip specifically metabolism of calciferol to 25 -hydroxycholecal- fractures in women with post-menopausal osteoporosis. It is ciferol by the liver, and its further metabolism to inactive given by mouth at night to older women with osteoporosis products. It also impairs the absorption of vitamin D from the and a history of bone fracture when bisphosphonates are gut. Treatment of this form of drug-induced osteomalacia consists of giving the patient oral Ca2 supplements together contraindicated or not tolerated. Recombinant human parathyroid hormone: osteoporosis is proving amenable to treatment. The adrenal cortex secretes: Adverse effects Adverse effects of glucocorticosteroids are common to all 1.

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Forensic dentists may assist medical examiners and coroners by compar- ing the dentition of decedents with antemortem photographs showing the teeth buy antabuse 250mg line medicine cabinets surface mount. Souviron order discount antabuse on-line medications i can take while pregnant, who has long used what he calls smiley-face photographs to compare to unidentifed bodies. Te grin line method (a smile may not show teeth) using Adobe® Photoshop® has been developed, evaluated, and utilized. Te method and its uses have been presented in the Odontology Section of the American Academy of Forensic Sciences. Tis is true of all anatomic features, including fngerprints and the teeth (see Chapters 6 and 14). Forensic examiners have considered the mathematical probability of an individual dentition having a unique combination of missing or present teeth, restored and unrestored teeth, or restored or unrestored surfaces of those teeth. Te number of diferent combinations possible in this type of mathematical sampling is very large. In the abstract for this paper Keiser-Nielsen cautioned that a dental expert “cannot base his identifcation of an unknown body on the relative frequency of occur- rence of any singular dental feature, its particular discrimination potential. Forensic dental identifcation 173 Instead, he must make a quantitative and qualitative evaluation of the combi- nation of features involved. Keiser-Nielsen’s interest was initiated by the acceptance of fngerprint analysis in courts all over the world based on their accuracy and reliability. Although standards varied in diferent jurisdictions at that time, in most, when twelve concordant fngerprint characteristics could be demonstrated in an antemortem and postmortem comparison, it was maintained that the material must have originated from the same person. Keiser-Nielsen sought to develop a parallel application for the feld of forensic dental identifcation. Specifcally, he sought to quantify the probability that any two individuals would have the same combination of teeth missing and present and teeth restored and unrestored. Te same calculation could be done for other features, for instance, the number of teeth with restorations. Applied to the human dentition, Keiser-Nielsen proposed that even greater discrimination could be established using combinations of features. If only teeth missing/present and teeth restored/unrestored were considered with no regard to which surfaces were restored, the formula involved cal- culating the possible combinations for missing teeth, then multiplying that number by the number determined by calculating the number of possible combinations of restored teeth in the remaining teeth. Using Keiser-Nielsen’s exampleof an individual missing four teeth and having four of the twenty-eight remaining teeth restored, the formulae are: 32 × 31× 30 × 29 For the four missing teeth, K32,4 = = 35,960 , representing 1 × × × the number of diferent possible combinations for four missing teeth. For the four restored teeth in the remaining twenty-eight, K28,4 = 28 × 27 × 26 × 25 = 20,475, representing the number of diferent com- 1 × × × binations of four restored teeth among twenty-eight teeth. Ten by multiplying the two, 35 960 × 20 475 = 736 281 000, Keiser- Neilsen calculated that the number of possible combinations of a person with four missing teeth and four restored teeth is 736,281,000. In other words, the likelihood of any two people having the same four teeth missing and the same four teeth flled (surfaces not considered) is 1 in over 736 million, more than twice the number of people alive in the United States (July 2008). In other words, if there are thirty-two teeth present, and x represents the number of teeth that have been extracted or flled, then the table gives the Table 9. Tis calculation assumes that each tooth has the same likelihood to be missing or flled. If an examined body showed that seven teeth were missing (antemortem, not peri- or postmortem) and sixteen teeth were flled, the odds of two people having the exact same confguration of those features would be 32 32 32 − − K32,7 = × ×→ = 3 365 856 1 2 7 multiplied by 32 32 32 − 16 −1 K32,16 = × ×→ = 601 080 390 1 2 16 3,365,856 × 601,080,390 = 2,023,150,037,163,840 Te likelihood then is 1 in 2 × 105, a fgure that is more than the all-time world population estimated by Haub to be approximately 106 billion. If other features such as endodontic treatment and the types of restorative material used were also considered, the numbers of possible combi- nations of features become enormous. Keiser-Nielsen also suggested that forensic odontological identifcation data should be quantifable, like in fngerprint analysis, and that forensic dentists should follow comparable standards. He suggested that twelve points of com- parison be recorded before establishing certainty in identifcation. Soren Keiser-Nielsen and Riedar Sognnaes were dedicated and visionary practitioners. Teir contributions to forensic odontology were con- siderable and perhaps unsurpassed by other forensic dentists. Tey assumed that these characteristics occurred independently and that their resulting values could be multiplied to produce expected frequencies. In a 2003 paper discussing Keiser-Neilsen’s and Sognnaes’ statistical con- clusions, Adams stated, “Tis type of statistical assessment suggests that all of the various combinations of missing and flled teeth occur randomly and that they are equally probable in the population, an assumption that is not valid. If this were the case, all conceivable dental patterns would be equiprobable in the population, a trend that is certainly not valid. If that assumption were true, the maxil- lary central incisors would be missing with the same frequency as frst molars or third molars and dental restorations would be seen in the facial surfaces of incisors as frequently as in the occlusal surfaces of molars. Also, inter- proximal restorations would occur with frequencies independent of occlusal restorations in the same tooth. While it is undoubtedly possible to develop a statistical analysis that considers all of the variables involved in predicting the frequency of occur- rence of dental features, the method would be very complex. Te program, called OdontoSearch, is described in a paper published by Adams in 2003. Unlike the pure mathematical approach ofered by earlier methods, the data in OdontoSearch analyze the frequency of occurrence for dental and dental treatment patterns in populations. When searching this database for a particular combination of dental characteristics, the user can select one or both of the databases for comparison. Te OdontoSearch online program uses the universal numbering system and does not consider the third molars. Tese databases and search protocols consider twenty-eight adult teeth only and do not consider any teeth distal to the second molars. Searches can be performed by selection of one or both of the databases and entering a combi- nation of desired dental information for the twenty-eight teeth. If a generic search is desired, R is selected for a tooth that has any type of restoration instead of using the specifc surfaces. Te trial entry of data in these felds produces for the user a probability of the specifc combination of coding existing in the given database. To apply the technique, the strength of a match is considered a function of the frequency in which the given dental pattern is observed in X +1 the reference database(s): ⋅100, where X is the total number of pattern N +1 matches and N is the sample size of the data set(s). If no matches are found, X = 0, and the observed pattern is unique within the database. Since the pattern in question is known to exist in at least one person (the case indi- vidual), the number of matches (X) and the sample size (N) are increased by one. By utilizing this empirically derived probability value, matches can be quanti- fed in a manner that is easily defensible in a court of law. Tese include computer hardware and sofware, intraoral photography and videography, digital radi- ography, intraoral laser technology, dental implants, high-strength porcelains, advances in bonding agents, and continued changes in dental esthetic resins, to name a few. Tese same advances in dental technology can also be useful in dental identifcation.

Although the approach is indirect antabuse 500mg medicine zyrtec, it is useful to employ sera obtained from animals administered orally with the test samples for in vitro investigations purchase antabuse 250mg on line treatment vertigo. As the serum samples contained active principles of orally administered kampo medicines, which are absorbed from the gastrointestinal tract, Tashiro advocates a similar approach for the in vitro evaluation of kampo medicines. As a kampo medicine contains many active ingredients, several combina- tion effects are involved in their action. Pharmacological effects These effects may include synergistic, additive and antagonistic actions, new pharmacological activity and reduction of adverse reaction. Pharmaceutical effects These effects affect modulations of taste and pH, absorption, enhancement of extraction and interaction among constituents. Sometimes the decocted extract of the original prescription shows much higher effect than that of the mixture of extracts prepared individually from the respective component herbs at the designated similar ratio. Combina- tions of the component herbs in kampo medicines may also influence the content of active principles when decocted. Combination effect of kampo medicines If only one component herb is replaced in a formulation, the clinical applica- tion may be greatly changed. Maoto, Makyokansekito and Makoyokkanto are similar kampo formulations consisting of four component herbs. Three of the herbs (Ephedrae herba, Ameniacae semen and Glycyrrhizae radix) are common to both formulations but their indications for use are quite different (Table 8. Maoto, Makyokansekito and Makyoyokkanto have all been used for the treatment of influenza, asthma and rheumatoid conditions, respectively. However Maoto is indicated where the patient has no sweating, high fever, muscle and joint pains, whereas Makyokansekito is indicated where there is natural sweating, cough and asthma. It consists of 10 component herbs, but when just one of component herbs was omitted from the original formulation, its activity became negligible. Examples of studies on specific formulae Three kampo formulae are introduced as examples of current pharmaco- logical studies of kampo medicines. Japanese kampo medicine | 239 240 | Traditional medicine Effects of Juzentaihoto on immunological and haematopoietic systems Clinical effects of Juzentaihoto expect that it may improve constitution of the diseases related to immunological system. In vivo animal study suggests that Juzentaihoto has potent immunomodulating activity, such as stimulation of antibody production,16 and the active ingredients were clarified to be 22 different pectic polysaccharides. As kampo medicines have generally been taken orally, active ingredients may not only act by absorption from the intestine but also affect the mucosal immune system. The effect of the active ingredients of Juzentaihoto on intestinal immune system-modulating activities was linked to a lignin–carbohydrate complex and a polysaccharide-containing arabinogalactan. Juzentaihoto also enhances peripheral blood counts in cancer patients who have been administered phase-specific drugs and/or have received radi- ation therapy. Oral administration of Juzentaihoto prolongs the survival of tumour-bearing mice injected with mitomycin C, and enhances proliferation of bone marrow stem cells, which may induce recovery from anaemia and reduce side effects of anti-cancer agents caused by bone marrow injury. As the result, production of antigen-specific secretory IgA antibody is enhanced in local mucus if the antigen such as for influenza virus, is recognised. There- fore a mucosal immune system-enhancing activity may help respiratory infection and endogenous infection. When the influenza vaccine was immu- nised intranasally, antigen-specific secretory IgA antibody is produced in the nasal cavity. Oral administration of Hochuekkito may partly contribute to enhancement of the IgA immune response against intestinal antigen through an increased population of L- selectin-positive B lymphocytes. Improving effect of Kamiuntanto on brain cognitive function The population of older people has been increased by improving health conditions. As a ‘compensation’ for longevity, chronic diseases, senile dementia, osteoporosis, general malaise and complex diseases (diabetes, hypertension, hyperlipidaemia, etc. For the diagnosis and treatment of these diseases imbalance of the whole body must be seen. Therefore kampo medicines would be suitable drugs for the treat- ment of older patients. Alzheimer’s disease and cerebrovascular disorders are popular forms of dementia among older people, with the former char- acterised by memory loss and a progressive global impairment of intellect. Despite the great scientific advances in recent years, effective treatments for Alzheimer’s disease are still limited. Some kampo medicines and herbal extracts were reported to improve the lesion of cognitive function in animal models for dementia, and memory-related behaviour and intellectual function of Alzheimer’s disease patients. When Kamiuntanto and donepezil, which is an anti-Alzheimer’s disease drug, were taken together, after 12 weeks’ treatment, a significant improvement in cognition was noted only in the combination therapy group, not in the monotherapy group. A significant increase in cerebral blood flow was also seen in the frontal region and lenticular nucleus only in patients who received the combination therapy. Therefore the combination of donepezil plus Kamiuntanto is safe and more effective in maintaining cognitive function than monotherapy. The pharmacological activities of widely used kampo medicines are listed in Table 8. Clinical studies The Japanese Ministry of Health and Welfare requested clinical re-evaluation of eight kampo formulations by double-blind, placebo-controlled study in 1991. For the double-blind, placebo-controlled study, it is necessary to prepare placebo granules with similar taste and colour as the active preparation. Three formulae have been re-evaluated: • Shosaikoto (Xiao-Chai-Hu-Tang) was evaluated for efficacy in chronic active hepatitis. Rikkunshito (Liu-Jun-Zi-Tang) and Shakuyakukanzoto (Shao-Yao-Gan- Cao-Tang) were also reported as being effective for the treatment of dysmotility-like dyspepsia and the muscle cramps accompanying cirrhosis, respectively. In the case of Rikkunshito, a low-dose preparation was used as a placebo control because of difficulty in developing control granules. In a separate double-blind, controlled study for re-evaluation, Chotosan (Siao-Tang-San) was also shown to have a beneficial clinical effect in the treatment of vascular dementia. However, kampo medicines have traditionally been used according to the disturbed pathophysiological conditions of the patient (so-called sho clinically), so clin- ical study of kampo medicines needs to consider the concept of sho. Most reliable scientific proofs are obtained by re-evaluation of kampo extract preparations, objective clinical study and the importance of universality. Safety Side effects of kampo medicines If the sho diagnosis was correct, and the correct formulation was given to the patient, kampo medicines show relatively lower adverse reactions compared with western medicines. However, kampo medicines are also drugs, so they must be considered to have certain side effects depending on how they are used. Ephedrae herba Ephedrae herba contains the adrenergic ephedrine, which activates both the sympathetic and central nervous systems, and may produce unwanted symptoms such as insomnia, palpitations, rapid pulse, excitement, elevation of blood pressure, hyperhidrosis, and dysuria. Glycyrrhizin metabolises to the aglycone, glycyrrhetic acid, after oral administration, and glycyrrhetic acid facilitates potassium excretion and lowers total serum potassium. Japanese kampo medicine | 247 Rhei rhizoma Rhei rhizoma contains sennosides that are prodrugs of rhein-anthrone, having cathartic activity. Drug–drug interactions Some western medicines are known to have potent adverse reactions, e.

Frank haemolysis occurs in cause functional and usually reversible renal failure in suscep- only a small proportion of cases generic antabuse 250 mg otc medications information. Nephrotic syndrome place with levodopa discount 500 mg antabuse overnight delivery treatment 0 rapid linear progression, mefenamic acid and beta-lactam results from several drugs (e. This is believed to occur with eral drugs, including non-steroidal anti-inflammatory drugs cephalosporins. Cisplatin, aminoglyco- Aplastic anaemia as an isolated entity is not common, but sides, amphotericin, radiocontrast media and vancomycin may occur either in isolation or as part of a general depression cause direct tubular toxicity. Examples include acid-base disturbances via their predictable direct or indirect chloramphenicol and (commonly and predictably) cytotoxic effects on renal electrolyte excretion (e. The drugs most frequently impli- tubular acidosis from carbonic anhydrase inhibitors), and cated include the following: some cause unpredictable toxic effects on acid-base balance (e. Several drugs (including procainamide, isoniazid, hydralazine, Liver damage (hepatitis with or without obstructive fea- chlorpromazine and anticonvulsants) produce a syndrome tures) as a side effect of drugs is important. It may be insidi- that resembles systemic lupus together with a positive anti- ous, leading slowly to end-stage cirrhosis (e. The development of this is closely related treatment with methotrexate) or acute and fulminant (as in to dose, and in the case of hydralazine it also depends on the some cases of isoniazid, halothane or phenytoin hepatitis). Gallstones (and mechanical disappear when the drug is stopped, but recovery may obstruction) can be caused by fibrates and other lipid-lowering be slow. Immune mechanisms are Both acute and chronic vasculitis can result from taking implicated in some forms of hepatic injury by drugs, but are drugs, and may have an allergic basis. Textbook of adverse drug reac- diagnosed as having a frozen shoulder, for which he is pre- tions, 5th edn. The practitioner knows Amsterdam: Elsevier (see also companion volumes Side-effects of him well and checks that he has normal renal function for drugs annuals, 2003, published annually since 1977). British Journal of full blood count; an absolute eosinophil count raised at Clinical Pharmacology 2006; 63: 136–47. His serum creatinine was 110μmol/L at baseline and is now 350μmol/L with a urea of 22. London: shows 2 protein, urine microscopy contains 100 leuko- Committee on Safety of Medicines and the Medicine Control cytes/hpf with 24% eosinophils. What is the best management plan and should this patient Pirmohamed M, James S, Meakin S et al. Answer 2 Discontinuation of the offending agent is vital and this is sometimes sufficient to produce a return to baseline values of renal function and the disappearance of systemic symptoms of fever and the rash. Recovery may possibly be accelerated and further renal toxicity minimized by a short course (five to seven days) of high-dose oral corticosteroids, while monitoring renal function. The offending agent should not be used again in this patient unless the benefits of using it vastly outweigh the risks associated with its use in a serious illness. Hospital admission provides Drug interaction is the modification of the action of one drug an opportunity to review all medications that any patient by another. There are three kinds of mechanism: is receiving, to ensure that the overall regimen is rational. Pharmaceutical interactions occur by chemical reaction or 60 physical interaction when drugs are mixed. Pharmacodynamic interactions occur when different drugs each infuence the same 50 physiological function (e. Conversely, for drugs with opposing actions, the result may be to reduce the effect of the first (e. These mecha- 0 4 8 12 16 20 nisms are discussed more fully below in the section on adverse (a) Number of drugs administered interactions grouped by mechanism. Multiple drug use (b) Number of drugs administered (‘polypharmacy’) is extremely common, so the potential for drug interaction is enormous. One study showed that on average 14 drugs were prescribed to medical in-patients 30 per admission (one patient received 36 different drugs). Many drugs are not curative, but rather ameliorate chronic 1–10 11–15 16 conditions (e. The populations of western (c) Number of drugs administered countries are ageing, and elderly individuals not Figure 13. Annals of Internal Medicine drug results in an adverse effect that is countered by the 1966; 65: 631. Isoniazid neuropathy is caused Drugs can be used in combination to enhance their effective- by pyridoxine deficiency, and is prevented by the prophylac- ness. The combination of a peripheral dopa that influence different components of the disease mechanism decarboxylase inhibitor (e. Other lower dose of levodopa than is needed when it is used as a sin- examples include the use of a β2 agonist with a glucocorticoid in gle agent, while reducing dose-related peripheral side effects the treatment of asthma (to cause bronchodilation and suppress of nausea and vomiting (Chapter 21). Combinations of antimicrobial drugs are used to prevent the selection of drug-resistant organisms. Drug resistance via synthesis of a Drugs can be used to block an undesired or toxic effect, as for microbial enzyme that degrades antibiotic (e. Another example is the use of the com- bination of ritonavir and saquinavir in antiretroviral therapy Many interactions are based on in vitro experiments, the (Chapter 46). Saquinavir increases the systemic bioavailabil- results of which cannot be extrapolated uncritically to the clin- ity of ritonavir by inhibiting its degradation by gastro- ical situation. This is especially true of drugs with ing the P-glycoprotein that pumps it back into the intestinal shallow dose–response curves and of interactions that depend lumen. Interactions are only likely to be clinically important when Therapeutic effects of drugs are often limited by the acti- there is a steep dose–response curve and a narrow therapeutic vation of a physiological control loop, particularly in the case of window between minimum effective dose and minimum cardiovascular drugs. The use of a low dose of a second drug toxic dose of one or both interacting drugs (Figure 13. This that interrupts this negative feedback may therefore enhance is often not the case. Examples include the combination most clinical situations, is so non-toxic that the usual dose is of an angiotensin converting enzyme inhibitor (to block the more than adequate for therapeutic efficacy, yet far below that renin-angiotensin system) with a diuretic (the effect of which which would cause dose-related toxicity. Consequently, a second is limited by activation of the renin-angiotensin system) in drug that interacts with penicillin is unlikely to cause either treating hypertension (Chapter 28). Instances where clinically important consequences do One large group of potential drug interactions that are seldom occur on introducing a drug that displaces another from clinically important consists of drugs that displace one tissue binding sites are in fact often due to additional actions another from binding sites on plasma albumin or α-1 acid glyco- of the second drug on elimination of the first. However, the simple expectation that reduces the renal clearance of digoxin by a separate mech- the displacing drug will increase the effects of the displaced anism. This is because drug clearance 26) displaces warfarin from binding sites on albumin, and (renal or metabolic) also depends directly on the concentra- causes excessive anticoagulation, but only because it also tion of free drug. Consider a patient receiving a regular main- inhibits the metabolism of the active isomer of warfarin tenance dose of a drug. When a second displacing drug is (S-warfarin), causing this to accumulate at the expense of the commenced, the free concentration of the first drug rises only inactive isomer. Consequently, any increased effect of the displaced bleeding by causing peptic ulceration and interfering with drug is transient, and is seldom important in practice. These include: • Drug interactions may be clinically useful, trivial or • warfarin and other anticoagulants; adverse.

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