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Superficial infections caused by candida species may be treated with topical applications of clotrimazole purchase 25 mg nortriptyline fast delivery anxiety disorder symptoms, miconazole buy nortriptyline 25 mg with mastercard anxiety symptoms medication, econazole generic nortriptyline 25mg otc azor 025mg anxiety, ketoconazole buy cheap nortriptyline anxiety disorder, oxiconazole, ciclopirox olamine, nystatin, or amphotericin B. Miconazole (Monistat, Micatin) is available for topical application as a cream or lotion and as vaginal cream or suppositories for use in vulvovaginal candidiasis. Clotrimazole (Lotrimin, Mycelex) is available for topical application to the skin as a cream or lotion and as vaginal cream and tablets for use in vulvovaginal candidiasis. Ketoconazole (Nizoral) is available as a cream for topical treatment of dermatophytosis and candidiasis and as a shampoo or foam for the treatment of seborrheic dermatitis. Topical antifungal-corticosteroid fixed combinations have been introduced on the basis of providing more rapid symptomatic improvement than an antifungal agent alone. Once- or twice-daily application to the affected area will generally result in clearing of superficial dermatophyte infections in 2–3 weeks, although the medication should be continued until eradication of the organism is confirmed. Paronychial and intertriginous candidiasis can be treated effectively by any of these agents when applied three or four times daily. Seborrheic dermatitis should be treated with twice-daily applications of ketoconazole until clinical clearing is obtained. Adverse local reactions to the imidazoles may include stinging, pruritus, erythema, and local irritation. This agent appears to inhibit the uptake of precursors of macromolecular synthesis; the site of action is probably the fungal cell membrane. Pharmacokinetic studies indicate that 1–2% of the dose is absorbed when applied as a solution on the back under an occlusive dressing. Ciclopirox olamine is available as a 1% cream and lotion (Loprox) for the topical treatment of dermatomycosis, candidiasis, and tinea versicolor. Topical 8% ciclopirox olamine (Penlac nail lacquer) has been approved for the treatment of mild to moderate onychomycosis of fingernails and toenails. Although well tolerated with minimal side effects, the overall cure rates in clinical trials are less than 12%. The antifungal activity derives from selective inhibition of squalene epoxidase, a key enzyme for the synthesis of ergosterol (see Figure 48–1). They are available as 1% creams and other forms for the topical treatment of dermatophytosis, to be applied on a twice-daily dosing schedule. As with the allylamines, butenafine inhibits the epoxidation of squalene, thus blocking the synthesis of ergosterol, an essential component of fungal cell membranes. Butenafine is available as a 1% cream to be applied once daily for the treatment of superficial dermatophytosis. Tolnaftate (Aftate, Tinactin) is available as a cream, solution, powder, or powder aerosol for application twice daily to infected areas. Recurrences following cessation of therapy are common, and infections of the palms, soles, and nails are usually unresponsive to tolnaftate alone. The powder or powder aerosol may be used chronically following initial treatment in patients susceptible to tinea infections. Nystatin is limited to topical treatment of cutaneous and mucosal candida infections because of its narrow spectrum and negligible absorption from the gastrointestinal tract following oral administration. Amphotericin B has a broader antifungal spectrum and is used intravenously in the treatment of many systemic mycoses (see Chapter 48) and to a lesser extent in the treatment of cutaneous candida infections. The recommended dosage for topical preparations of nystatin in treating paronychial and intertriginous candidiasis is application two or three times a day. Oral candidiasis (thrush) is treated by holding 5 mL (infants, 2 mL) of nystatin oral suspension in the mouth for several minutes four times daily before swallowing. An alternative therapy for thrush is to retain a vaginal tablet in the mouth until dissolved four times daily. Recurrent or recalcitrant perianal, vaginal, vulvar, and diaper area candidiasis may respond to oral nystatin, 0. Vulvovaginal candidiasis may be treated by insertion of 1 vaginal tablet twice daily for 14 days, then nightly for an additional 14–21 days. The recommended dosage in the treatment of paronychial and intertriginous candidiasis is application two to four times daily to the affected area. Adverse effects associated with oral administration of nystatin include mild nausea, diarrhea, and occasional vomiting. The drug may cause a temporary yellow staining of the skin, especially when the cream vehicle is used. As discussed inChapter 48, imidazole derivatives act by affecting the permeability of the cell membrane of sensitive cells through alterations of the biosynthesis of lipids, especially sterols, in the fungal cell. Fluconazole and itraconazole are effective in the therapy of cutaneous infections caused by epidermophyton, microsporum, and trichophyton species as well as candida. In view of this long half-life, daily doses of 100 mg are sufficient to treat mucocutaneous candidiasis; alternate-day doses are sufficient for dermatophyte infections. The plasma half-life of itraconazole is similar to that of fluconazole, and detectable therapeutic concentrations remain in the stratum corneum for up to 28 days following termination of therapy. Itraconazole is effective for the treatment of onychomycosis in a dosage of 200 mg daily taken with food to ensure maximum absorption for 3 consecutive months. Recent reports of heart failure in patients receiving itraconazole for onychomycosis have resulted in recommendations that it not be given for treatment of onychomycosis in patients with ventricular dysfunction. Additionally, routine evaluation of hepatic function is recommended for patients receiving itraconazole for onychomycosis. Administration of oral azoles with midazolam or triazolam has resulted in elevated plasma concentrations and may potentiate and prolong hypnotic and sedative effects of these agents. Griseofulvin’s mechanism of antifungal action is not fully understood, but it is active only against growing cells. Following the oral administration of 1 g of micronized griseofulvin, drug can be detected in the stratum corneum 4–8 hours later. Micronized griseofulvin is available as 250 mg and 500 mg tablets, and ultramicronized drug is available as 125 mg, 165 mg, 250 mg, and 330 mg tablets and as 250 mg capsules. The usual adult dosage of the micronized (“microsize”) form of the drug is 500 mg daily in single or divided doses with meals; occasionally, 1 g/d is indicated in the treatment of recalcitrant infections. Griseofulvin is most effective in treating tinea infections of the scalp and glabrous (nonhairy) skin. In general, infections of the scalp respond to treatment in 4–6 weeks, and infections of glabrous skin will respond in 3–4 weeks. Fingernails may respond to 6 months of therapy, whereas toenails are quite recalcitrant to treatment and may require 8–18 months of therapy; relapse almost invariably occurs. Adverse effects seen with griseofulvin therapy include headaches, nausea, vomiting, diarrhea, photosensitivity, peripheral neuritis, and occasionally mental confusion. It is contraindicated in patients with porphyria or hepatic failure or those who have had hypersensitivity reactions to it in the past. Therefore, in patients undergoing prolonged therapy, routine evaluation of the hepatic, renal, and hematopoietic systems is advisable. Coumarin anticoagulant activity may be altered by griseofulvin, and anticoagulant dosage may require adjustment. Recommended oral dosage is 250 mg daily for 6 weeks for fingernail infections and 12 weeks for toenail infections.
Inhibitors of the synthesis or antagonists of the action of the adrenocortical steroids are important in the treatment of several conditions order generic nortriptyline online anxiety 2 calm. Some have minimal biologic activity and function primarily as precursors purchase nortriptyline on line amex anxiety verses, and there are some for which no function has been established cheap 25 mg nortriptyline mastercard anxiety symptoms full list. The hormonal steroids may be classified as those having important effects on intermediary metabolism and immune function (glucocorticoids) buy nortriptyline cheap online symptoms 9f anxiety, those having principally salt-retaining activity (mineralocorticoids), and those having androgenic or estrogenic activity (see Chapter 40). In humans, the major glucocorticoid is cortisol and the most important mineralocorticoid is aldosterone. Androstenedione can be converted to testosterone and estradiol in extra-adrenal tissues (Figure 39–1). Adrenal androgens constitute the major endogenous precursors of estrogen in women after menopause and in younger patients in whom ovarian function is deficient or absent. Its synthesis and secretion are tightly regulated by the central nervous system, which is very sensitive to negative feedback by the circulating cortisol and exogenous (synthetic) glucocorticoids. The remainder is free (about 5–10%) or loosely bound to albumin (about 5%) and is available to exert its effect on target cells. Albumin has a large capacity but low affinity for cortisol, and for practical purposes albumin- bound cortisol should be considered free. The sensitivity of tissues to glucocorticoids is also circadian but inverse to that of cortisol, with low sensitivity in the late morning and high sensitivity in the evening and early night (lower panel). Only 1% of cortisol is excreted unchanged in the urine as free cortisol; about 20% of cortisol is converted to cortisone by 11-hydroxysteroid dehydrogenase in the kidney and other tissues with mineralocorticoid receptors (see below) before reaching the liver. About one third of the cortisol produced daily is excreted in the urine as dihydroxy ketone metabolites and is measured as 17-hydroxysteroids (see Figure 39–3 for carbon numbering). Many cortisol metabolites are conjugated with glucuronic acid or sulfate at the C and C3 21 hydroxyls, respectively, in the liver; they are then excreted in the urine. The acetonide-substituted derivatives (eg, triamcinolone acetonide) have increased surface activity and are useful in dermatology. Dexamethasone is identical to betamethasone except for the configuration of the methyl group at C16: in betamethasone it is beta (projecting up from the plane of the rings); in dexamethasone it is alpha. Mechanism of Action Most of the known effects of the glucocorticoids are mediated by widely distributed glucocorticoid receptors. These proteins are members of the superfamily of nuclear receptors, which includes steroid, sterol (vitamin D), thyroid, retinoic acid, and many other receptors with unknown or nonexistent ligands (orphan receptors). All these receptors interact with the promoters of—and regulate the transcription of—target genes (Figure 39–4). In the absence of the hormonal ligand, glucocorticoid receptors are primarily cytoplasmic, in oligomeric complexes with chaperone heat-shock proteins (hsp). Free hormone from the plasma and interstitial fluid enters the cell and binds to the receptor, inducing conformational changes that allow it to dissociate from the heat shock proteins. When the complex binds a molecule of cortisol, an unstable complex is created and the hsp90 and associated molecules are released. A variety of regulatory factors (not shown) may participate in facilitating (coactivators) or inhibiting (corepressors) the steroid response. These transcription factors have broad actions on the regulation of growth factors, proinflammatory cytokines, etc, and to a great extent mediate the anti-growth, anti- inflammatory, and immunosuppressive effects of glucocorticoids. This variability suggests that this important class of steroid receptors has complex stochastic activities. This region folds into a “two-finger” structure stabilized by zinc ions connected to cysteines to form two tetrahedrons. The amino-terminal domain is involved in the transactivation activity of the receptor and increases its specificity. The coregulators do this by serving as bridges between the receptors and other nuclear proteins and by expressing enzymatic activities such as histone acetylase or deacetylase, which alter the conformation of nucleosomes and the transcribability of genes. The number and affinity of receptors for the hormone, the complement of transcription factors and coregulators, and post-transcription events determine the relative specificity of these hormones’ actions in various cells. Some of the effects of glucocorticoids can be attributed to their binding to mineralocorticoid receptors. A mineralocorticoid effect of the higher levels of cortisol is avoided in some tissues (eg, kidney, colon, salivary glands) by expression of 11β-hydroxysteroid dehydrogenase type 2, the enzyme responsible for biotransformation to its 11-keto derivative (cortisone), which has minimal action on aldosterone receptors. As shown in Figure 39– 2, lower panel, the glucocorticoid target tissue sensitivity rhythm generated is in reverse phase to that of circulating cortisol concentrations, explaining the increased sensitivity of the organism to evening administration of glucocorticoids. Among the proposed mechanisms are direct effects on cell membrane receptors for the hormone or nongenomic effects of the classic hormone-bound glucocorticoid receptor. For example, recent studies implicate G protein-coupled membrane receptors in the response of glutamatergic neurons to glucocorticoids in rats. Such receptors are available for direct interactions with and effects on various membrane-associated or cytoplasmic proteins without the need for entry into the nucleus and induction of transcriptional actions. Physiologic Effects The glucocorticoids have widespread effects because they influence the function of most cells in the body. The major metabolic consequences of glucocorticoid secretion or administration are due to direct actions of these hormones in the cell. Although many of the effects of glucocorticoids are dose-related and become magnified when large amounts are administered for therapeutic purposes, there are also other effects—called permissive effects—without which many normal functions become deficient. For example, the response of vascular and bronchial smooth muscle to catecholamines is diminished in the absence of cortisol and restored by physiologic amounts of this glucocorticoid. Metabolic Effects The glucocorticoids have important dose-related effects on carbohydrate, protein, and fat metabolism. The same effects are responsible for some of the serious adverse effects associated with their use in therapeutic doses. Glucocorticoids stimulate and are required for gluconeogenesis and glycogen synthesis in the fasting state. They stimulate phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and glycogen synthase and the release of amino acids in the course of muscle catabolism. Glucocorticoids increase serum glucose levels and thus stimulate insulin release and inhibit the uptake of glucose by muscle cells, while they stimulate hormone-sensitive lipase and thus lipolysis. The increased insulin secretion stimulates lipogenesis and to a lesser degree inhibits lipolysis, leading to a net increase in fat deposition combined with increased release of fatty acids and glycerol into the circulation. The net results of these actions are most apparent in the fasting state, when the supply of glucose from gluconeogenesis, the release of amino acids from muscle catabolism, the inhibition of peripheral glucose uptake, and the stimulation of lipolysis all contribute to maintenance of an adequate glucose supply to the brain. Supraphysiologic amounts of glucocorticoids lead to decreased muscle mass and weakness and thinning of the skin. Catabolic and antianabolic effects on bone are the cause of osteoporosis in Cushing’s syndrome and impose a major limitation in the long-term therapeutic use of glucocorticoids. This effect may be partially prevented by administration of growth hormone in high doses, but this use of growth hormone is not recommended. Anti-Inflammatory and Immunosuppressive Effects Glucocorticoids dramatically reduce the manifestations of inflammation. This is due to their profound effects on the concentration, distribution, and function of peripheral leukocytes and to their suppressive effects on the inflammatory cytokines and chemokines and on other mediators of inflammation. Inflammation, regardless of its cause, is characterized by the extravasation and infiltration of leukocytes into the affected tissue.
While compete successfully in the marketplace order nortriptyline 25 mg on-line anxiety symptoms body zaps, making doc- textbooks safe nortriptyline 25 mg anxiety symptoms valium treats, modest meals discount generic nortriptyline uk anxiety dreams, and educational or work- tors the logical targets for marketing efforts by pharma- related gifts cheapest nortriptyline anxiety symptoms and treatment, such as notepads or textbooks, may be ceutical ﬁrms. Between $8,000 and $13,000 is spent annually on gift might compromise or appear to compromise the each physician. A helpful criterion suggested by arrangements may conﬂict with the physician’s respon- the American College of Physicians when considering sibility to act in the best interest of the patient. A vol- the ethical appropriateness of a particular interaction untary code has recently been adopted by the Pharma- between a physician and drug company is to ask ceutical Research and Manufacturers of America which whether one would be willing to have the arrangement establishes guidelines for relationships between the generally known. Ultimately, prescribing practices are the main source Medical students and residents are not exempt from of concern, as physicians may be induced to prescribe the inﬂuence of drug companies. Many students and some products rather than others based on factors other residents are offered gifts of educational books or than therapeutic effectiveness or cost. Many drug com- equipment or are invited to attend company-sponsored panies have generous programs for providing their events. Young professionals need to be extremely care- products free of charge to those who cannot afford ful to avoid impropriety and should receive speciﬁc in- them. However, free samples provided by drug compa- struction about the ethically appropriate scope and lim- nies directly to physicians’ ofﬁces should be used cau- its of interactions with drug company representatives. While some industry-sponsored educa- get patients started on a particular product which pre- tion provides a good opportunity for unbiased scientiﬁc sumably will have to be continued and paid for by the exchange, such as when a drug company underwrites patient or a third-party payer. The patient, as a health the cost of an educational program but places no re- care consumer, is not in a position to assess the need for strictions on topics discussed or speakers chosen, too of- a certain drug or decide whether it is prescribed appro- ten “education” is a euphemism for marketing. To be priately and sometimes cannot accurately determine considered legitimate, a conference or meeting must be whether it is therapeutically effective. Thus, the patient primarily dedicated to scientiﬁc and educational activi- is entitled to be protected by the physician, whose pri- ties, and the main incentive for bringing attendees to- mary role is that of patient advocate as dictated by the gether must be to further broad knowledge. In addition, physicians may be invited to serve as a Product marketing presents other ethical issues as drug company “consultant. In addition to direct product advertising in med- vited to a company-sponsored symposium, which is ical journals and direct to consumer advertising in the sometimes nothing more than a sales pitch for that com- popular media, pharmaceutical company sales repre- pany’s products with little real interaction or consul- sentatives frequently visit physicians. While consultants who provide genuine services 8 Contemporary Bioethical Issues in Pharmacology and Pharmaceutical Research 77 may receive reasonable compensation and accept reim- professional peer-reviewed journals and not rely solely bursement for travel expenses, token consulting or ad- on material provided by drug companies. First, would it be embarrassing for the clini- their presentation to the same level of scientiﬁc rigor as cian if the public knew about the ﬁnancial arrange- they would apply to a presentation at a professional ment? In particular, they should refrain from allow- or lead others to suspect a conﬂict of interest should be ing the pharmaceutical company to inﬂuence the data avoided. Second, can the physician reveal the ﬁnancial they present, the means of presenting it, or the out- arrangements to patients whom the clinician invites to comes drawn. If the physician feels uncom- ferences or lectures other than their own, the organizers fortable discussing the remuneration with patient re- of the conference should maintain control over the top- cruits because of the appearance of a conﬂict of interest, ics and speakers selected. Third, would the tion a speciﬁc product, he or she should be sure to avoid clinician pursue the same treatment strategy if there any appearance of impropriety by comparing it fairly were no ﬁnancial incentive? Researchers likely choose another treatment were it not for the ﬁ- and clinicians who are invited to conduct studies sup- nancial rewards from the drug company, the physician ported by drug companies and present their data at should reconsider offering enrollment for the patient. In addition, industry sponsorship should be complex relationship between science, industry, and pa- noted in any publication reporting study results. To develop a broad understanding of these is- both attendees and speakers should demand that ﬁnan- sues, that basic framework should be ﬁlled in with an cial sponsorship be revealed before registration and understanding of cultural considerations, profession- that ﬁnancial relationships between speakers and the based duties and obligations, and an analysis of previ- promoter be plainly stated. Continual scrutiny of bioethical is- ity and eliminate any appearance of conﬂict of interest, sues in pharmacology is warranted as we develop better doctors should get their information primarily from insight into the moral dilemmas of the ﬁeld. Modern’s repre- mentally retarded children, has been approached by sentative points out that the incidence of conjunc- the Modern Pharmaceutical Company. Martin to enroll children aged 4 to 7 excellent setting for the study to be completed in one of their clinical trials for a new drug to treat quickly. Martin’s concerns is: formed consent or refusal on behalf of their chil- (A) Autonomy dren, that risks have been minimized, and that over- (B) Beneﬁcence all, the study drug is likely to help the participants. The main ethical problem with medical research in (B) Determine whether she feels favorably toward economically developing nations in which subjects Modern’s product line; if she already prescribes are medically underserved is that: Modern products and prefers them to the competi- (A) Subjects are frequently not compliant, as they tion’s, she cannot be biased by their presentations, do not understand the importance of the study, rais- so there is no ethical issue in attending. A helpful criterion suggested by the American (D) Subjects are included in studies of treatments College of Physicians when considering the ethical that are not available in underserved countries but appropriateness of a particular interaction between are available in the United States, raising issues of eq- a physician and industry is to: uity and fairness toward disadvantaged populations. The principle of justice is a relevant considera- quately tion when subjects are selected for clinical research. Susan Brown, a community-based internist in Little tonomy would be most relevant to the parents’ abil- Town, U. Brown Martin believes risks have been minimized and the to attend a medical consultants’ meeting at the overall study drug is likely to help the participants, Golden Sunset Resort, an elegant resort about an so the study has satisﬁed the principles of nonmalef- hour away from Little Town. The principle of medical Saturday morning presentation by representatives priority is not mentioned in the chapter and per- from Modern, with time over lunch for the medical tains to treating the most medically needy patients consultants to give feedback to the company repre- ﬁrst, which is not at issue here. Brown will be paid $1000 for viding them with the level of care available to oth- her consulting services. Brown should: damaging to a study, do not pose ethical problems (A) Decide whether she thinks she would be bi- in medically underserved populations not encoun- ased toward Modern products by the company’s tered elsewhere. Effective study design can over- generosity; if she believes she can remain objective, come problems with generalizing from one popula- it is acceptable to attend. Subjects everywhere should be 8 Contemporary Bioethical Issues in Pharmacology and Pharmaceutical Research 79 provided with information at a level the subject can tant for company employees but bears little rele- comprehend and asked to give informed consent. Finally, although patient are available in their own country, only those that care may not be directly affected by an action, the are available only elsewhere. A conﬂict of interest occurs when an individ- impression that the physician is under undue inﬂu- ual’s personal interests conﬂict with ofﬁcial respon- ence of the pharmaceutical company and thereby sibilities, such as those required by one’s profession. Drug promotion and scientiﬁc exchanges: products from other companies as carefully because The role of the clinical investigator. Some recent developments in the interna- amount this company will spend on her expenses tional guidelines on the ethics of research involving and honoraria far exceed what is reasonable. Ethical considerations in the conduct of have an arrangement generally known is a quick clinical pharmacokinetic studies. Physicians and the Pharmaceutical Industry: standard for what they would be willing to have Is A Gift Ever Just a Gift? Why do American drug companies spend tion falls within the law does not make it morally more than $12 billion a year pushing drugs? Drew recruits through his small private practice, question at hand while minimizing risks and he will receive $1,000 to help defray the costs of maximizing beneﬁts to subjects. Drew should quarterly blood draws and the additional consider whether subjects will be selected fairly, and paperwork required by the study. Drew’s should consider the quality of the ethical and computer system to enable better patient tracking. Drew could really use the protocol raises ethical issues that have not been ﬁnancial support but wonders what beneﬁts this addressed. Is it simply a me-too or whether the payment offered is commensurate with copycat drug, designed primarily to make money the time, effort, and actual expenditures to enroll for the drug company?
It enabled a reduction should be initiated only by a specialist and form part of in the co-prescription of antipsychotic medication previ- a comprehensive treatment programme of psychological discount 25mg nortriptyline anxiety children, ously used for behavioural symptoms such as agitation educational and social measures purchase nortriptyline us anxiety symptoms losing weight. Methyl- ase inhibitor may be more effective than the acetylcholin- phenidate and dexamfetamine increase synaptic dopamine esterase inhibitor alone safe 25mg nortriptyline anxiety symptoms jelly legs. Dosage inevitably include cholinergic symptoms discount 25mg nortriptyline visa anxiety fatigue, with nausea, tends to be slightly higher and combinations of different diarrhoea and abdominal cramps appearing commonly. Unwanted effects of stimulants include some slowing of growth, loss of appetite and sleep, irritability, increased Children do suffer psychiatric illnesses. Many drugs used in blood pressure and occasionally other cardiovascular prob- childhood psychiatric illness are not properly tested in lems. In children height (in general) to have safety tests in children subsequent to should also be monitored to assess growth. Some drugs are deemed not to instant release formulations can be abused and some have have adequate risk:benefit ratios in children, e. It is thought to act by increasing noradrenaline/norepinephrine Summary and dopamine availability in the frontal cortex (where do- Table 20. Theyalsohave arolein treatmentresistant social anxiety disorder and some evidence supports the use of pregabalin in other anxiety disorders. They delay the onset of severe illness but cannot ultimately halt or change the course of the disease. Second-line treatment options include clonidine and the antipsychotic agents, risperidone, haloperidol and sulpiride. Second-generation versus first- based guidelines for treating statement on posttraumatic stress generation antipsychotic drugs for depressive disorders with disorder from the International schizophrenia: a meta-analysis. Treatment of International Consensus Group on disorder: revised second edition – depression in children and Depression and Anxiety. The days) does not in itself qualify as epilepsy, since these sei- treatments of other common neurological disorders zures may have been due to a febrile illness or drug intox- are covered in other sections: namely: headaches (Pain ication that themselves later resolve. Only one-third of people other neurological disorders, including: movement having seizures develop chronic epilepsy. The other half A seizure is a clinical symptom or sign caused by abnormal of adult epilepsy is due to acquired causes, such as alcohol, electrical discharges within the cerebral cortex. Because of its unusual manifestations epilepsy intercession from Saint Valentine to relieve their condition. Wilson J V K, Reynolds E H 1990 more than one Saint Valentine and it is unclear whether he was also Medical History 34:192. Following a single seizure the chance discharges occur within the brain leading to a partial sei- of a further seizure is approximately 25% over the zure – i. Importantly, partial seizures can majority of first seizures are provoked by a reversible, propagate very quickly to become a ‘secondary generalised and often recognisable, factor, e. For these reasons, following a single ilepsy is maldevelopment of the medial temporal lobes seizure6 anticonvulsants are not generally prescribed, (‘mesial temporal sclerosis’) believed to be due to injury, whereas after two or more distinct seizure episodes. Although the choice of anticonvulsants is • Educate the patient about the disease, duration of large (approximately 20), first-line therapy is generally treatment and need for compliance. As the number of • For most cases with recurrent seizures, an antiepileptic single anticonvulsants tried increases, the incremental drug is prescribed with subsequent monitoring and likelihood that any new one will offer a significant adjustment of dosage or drug type (see below). For example, few minutes, rectal or buccal diazepam or intranasal carbamazepine is an effective first-line therapy for partial seizures but may worsen primary generalised, 4 absence or myoclonic seizures; similarly phenytoin can So-called ‘primary’ or ‘idiopathic’ generalised epilepsies that reflect the fact that the specific cause is usually undetermined, although presumed to be developmental (e. Ethosuximide, Dosage and administration by contrast, is only effective in primary generalised, and The manner in which drug dosing is initiated depends on: not partial, seizures. Phenytoin and phenobarbital seizure types allowing for more confidence of use allow for a rapid loading (within 24 h); valproate, levetir- even when seizure type is uncertain. Thus sodium acetam and oxcarbazepine allow for escalation over days or valproate, lamotrigine and levetiracetam are active a few weeks, whilst lamotrigine and carbamazepine require against both primary and secondary generalised gradual escalations over many weeks. If seizures are infre- epilepsy, and being relatively well tolerated, account quent at the time of presentation, e. In one head-to-head tiepileptics should generally be started at their lowest dose, study comparing popular first-line therapies for with small increments made every 1–2 weeks. In this way, generalised and partial seizures, lamotrigine was the risk of unwanted effects, especially dizziness or ‘feeling generally tolerated better than other drugs, while drunk’ are minimised. A slow introduction of lamotrigine valproate was the most efficacious; carbamazepine is also essential to reduce the risk of rash or more severe hy- and topiramate were more likely to cause unwanted 7 persensitivity reactions, Most drugs have a generally recog- effects. These range that achieves a reasonable degree of seizure control categories of patients prompt selection of particular should be established. Monitoring of blood concentrations drugs and avoidance of others (see below for more is helpful in guiding dosage of carbamazepine, phenytoin detail). Polytherapy offers mended maintenance dose range having been reached, the theoretical advantage of controlling neuronal there are numerous possible explanations: hyperexcitability by more than one mechanism, that Non-compliance, diarrhoea and vomiting, patients • can be synergistic. In reality, increasing polytherapy instructed to be ‘nil by mouth’ (revealed by measuring often adheres to the law of diminishing returns, viz. For years, it is reasonable to consider withdrawal of antiepi- example, in catamenial epilepsy, clobazam can be lepsy drug therapy. The toxicological hazard must be weighed against epilepsy, temporal or frontal lobe epilepsies often the risk of seizures which themselves can be harmful to require lifelong treatment. Discontinuing antiepilepsy medication is associated with Advance planning is preferred because: about 20% relapse during withdrawal and a further 20% • neural tube defects are related to deficiencies in folic relapse over the following 5 years; after this period re- acid stores before pregnancy, so that antiepileptic drugs lapse is unusual. In general, patients having Driving regulations and epilepsy seizures with blackouts should be on an effective dose Multiple driving regulations exist that relate epilepsy of an anticonvulsant, because of the risks of anoxia, (and neurological conditions predisposing to epilepsy, lactic acidosis and trauma. These rules are based upon statistical data relating lamotrigine before conception require a gradually in- specific diagnoses or clinically described events (e. Epileptic patients who wish to Secondly, enzyme-inducing drugs often aggravate a rela- continue driving therefore need to contact their national tive deficiency of vitamin K that occurs in final trimester driving licensing body so that each case can be judged women, predisposing to postpartum haemorrhage; vita- on its merits; while waiting for a decision, patients must min K is therefore given by mouth during the last 2 weeks not drive. Exceptions include: pa- Breast feeding tients who have had exclusively nocturnal seizures for at Antiepilepsy drugs pass into breast milk: phenobarbital, least 3 years, or patients in whom a single seizure has oc- primidone and ethosuximide in significant quantities, phe- curred more than 6 months earlier, providing they have nytoin and sodium valproate less so. Pregnancy and epilepsy Pregnancy worsens epilepsy in about a third of patients, 10Aswellasspinabifida,cleftpalates,cardiacandurogenitalanomaliesin but also improves epilepsy in another third. One of the the fetus, valproate during early pregnancy or pre-conception is main concerns in this patient group is that all anticonvul- associated with a particular dysmorphic appearance of the newborn (‘fetal valpraote syndrome’) characterised by wide, flat nasal bridge, sants increase the chance of teratogenicity slightly, with long philtrum, thin lip, widely spaced eyes (hypertelorism) and valproate, phenytoin and phenobarbital carrying most epicanthic folds. Treatment of seizures is initially with the intravenous benzodiazepine lorazepam Many antiepileptic drugs induce steroid-metabolising en- (0. The speed of action of these drugs and wishing to remain on the combined con- lorazepam and diazepam are both rapid. Subsequently a maintenance dose suboptimal level of contraception, and a non-oestrogenic of approximately 300 mg/day is given and adjusted accord- form of contraception is preferred. At this point, the level of sedation (due both to seizures and drugs) is usually sufficiently great to warrant general anaes- Epilepsy in children thesia, e. In some those used inadults,butcertain seizure types necessitate drugs cases, midazolam (nasally) may be preferred, e.
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Meperidine is an exception to this generalization because its antimuscarinic action can result in tachycardia order generic nortriptyline pills anxiety symptoms in women. Blood pressure is usually well maintained in subjects receiving opioids unless the cardiovascular system is stressed generic nortriptyline 25mg on line anxiety symptoms google, in which case hypotension may occur discount nortriptyline 25mg visa anxiety 6 year old boy. This hypotensive effect is probably due to peripheral arterial and venous dilation order nortriptyline 25mg without prescription anxiety 24 weeks pregnant, which has been attributed to a number of mechanisms including central depression of vasomotor- stabilizing mechanisms and release of histamine. No consistent effect on cardiac output is seen, and the electrocardiogram is not significantly affected. However, caution should be exercised in patients with decreased blood volume, because the above mechanisms make these patients susceptible to hypotension. Gastrointestinal tract—Constipation has long been recognized as an effect of opioids, an effect that does not diminish with continued use. In the stomach, motility (rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase—particularly in the central portion; gastric secretion of hydrochloric acid is decreased. Small intestine resting tone is increased, with periodic spasms, but the amplitude of nonpropulsive contractions is markedly decreased. In the large intestine, propulsive peristaltic waves are diminished and tone is increased; this delays passage of the fecal mass and allows increased absorption of water, which leads to constipation. The large bowel actions are the basis for the use of opioids in the management of diarrhea, and constipation is a major problem in the use of opioids for control of severe cancer pain. The sphincter of Oddi may constrict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase and lipase levels. Occasionally, ureteral colic caused by a renal calculus is made worse by opioid-induced increase in ureteral tone. Although the mechanism for this action is unclear, both μ- and κ- opioid receptors are expressed in human uterine muscle. Fentanyl and meperidine (pethidine) inhibit uterine contractility but only at supraclinical concentrations; morphine had no reported effects. These effects suggest that endogenous opioid peptides, through effects in the hypothalamus, modulate these systems. Patients receiving chronic opioid therapy can have low testosterone resulting in decreased libido, energy, and mood. Pruritus—The opiates, such as morphine and codeine, produce flushing and warming of the skin accompanied sometimes by sweating, urticaria, and itching. Although peripheral histamine release is an important contributor, all opioids can cause pruritus via a central (spinal cord and medullary) action on pruritoceptive neural circuits. When opioids are administered to the neuraxis by the spinal or epidural route, their usefulness may be limited by intense pruritus over the lips and torso. However, studies have demonstrated the efficacy of selective κ agonists (eg, nalfurafine) in the treatment of itch. Immune—The opioids modulate the immune system by effects on lymphocyte proliferation, antibody production, and chemotaxis. In addition, leucocytes migrate to the site of tissue injury and release opioid peptides, which in turn help counter inflammatory pain. However, natural killer cell cytolytic activity and lymphocyte proliferative responses to mitogens are usually inhibited by opioids, which may play a role in tumor progression. Although the mechanisms involved are complex, activation of central opioid receptors could mediate a significant component of the changes observed in peripheral immune function. These effects are mediated by the sympathetic nervous system in the case of acute administration and by the hypothalamic-pituitary-adrenal system in the case of prolonged administration of opioids. In either case, values indicate the magnitude of pain as: mild (1–3), moderate (4–6), or severe (7– 10). There are specialized scales for patients with specific conditions including rheumatoid arthritis and dementia. More comprehensive questionnaires such as the McGill Pain Questionnaire address the multiple facets of pain. For a patient in severe pain, administration of an opioid analgesic is usually considered a primary part of the overall management plan. Determining the route of administration (oral, parenteral, neuraxial), duration of drug action, ceiling effect (maximal intrinsic activity), duration of therapy, potential for adverse effects, and the patient’s past experience with opioids all should be addressed. One of the principal errors made by physicians in this setting is failure to assess adequately a patient’s pain and to match its severity with an appropriate level of therapy. Just as important is the principle that following delivery of the therapeutic plan, its effectiveness must be reevaluated and the plan modified, if necessary, if the response was excessive or inadequate. Use of opioid drugs in acute situations should be contrasted with their use in chronic pain management, in which a multitude of other factors must be considered, including the development of tolerance to and physical dependence on opioid analgesics. Analgesia Severe, constant pain is usually relieved with opioid analgesics having high intrinsic activity (see Table 31–2), whereas sharp, intermittent pain does not appear to be as effectively controlled. The pain associated with cancer and other terminal illnesses must be treated aggressively and often requires a multidisciplinary approach for effective management. Such conditions may require continuous use of potent opioid analgesics and are associated with some degree of tolerance and dependence. However, this should not be used as a barrier to providing patients with the best possible care and quality of life. Research in the hospice setting has also demonstrated that fixed-interval administration of opioid medication (ie, a regular dose at a scheduled time) is more effective in achieving pain relief than dosing on demand. However, there is little evidence to support long-term (greater than 6 months) use of sustained release opioids to manage chronic pain in the non-cancer patient. If disturbances of gastrointestinal function prevent the use of oral sustained-release morphine, then a fentanyl transdermal system (fentanyl patch) can be used over long periods. Furthermore, buccal transmucosal fentanyl can be used for short episodes of breakthrough pain (see Alternative Routes of Administration). Administration of strong opioids by nasal insufflation is also efficacious, and nasal preparations are now available in some countries. In addition, stimulant drugs such as the amphetamines can enhance the analgesic actions of opioids and thus may be very useful adjuncts in the patient with chronic pain. Because opioids cross the placental barrier and reach the fetus, care must be taken to minimize neonatal depression. The phenylpiperidine drugs (eg, meperidine) appear to produce less depression, particularly respiratory depression, in newborn infants than does morphine; this may justify their use in obstetric practice. The acute, severe pain of renal and biliary colic often requires a strong agonist opioid for adequate relief. However, the drug-induced increase in smooth muscle tone may cause a paradoxical increase in pain secondary to increased spasm. Acute Pulmonary Edema The relief produced by intravenous morphine in patients with dyspnea from pulmonary edema associated with left ventricular heart failure is remarkable. Proposed mechanisms include reduced anxiety (perception of shortness of breath) and reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance). However, if respiratory depression is a problem, furosemide may be preferred for the treatment of pulmonary edema. On the other hand, morphine can be particularly useful when treating painful myocardial ischemia with pulmonary edema.