Condet

Gwendolen Toni Buhr, MD

• Associate Professor of Medicine

https://medicine.duke.edu/faculty/gwendolen-toni-buhr-md

This leads to the series of oxidative injuries described above with Immune Hemolytic Anemia Immunologic destruction of erythrocytes is mediated by the interaction of IgG or IgM antibodies with antigens expressed on the surface of the erythrocyte acne quotes purchase accutane 5mg with mastercard. A number of mechanisms have been implicated in xenobioticmediated antibody binding to erythrocytes (Arndt and Garratty acne scar laser treatment order accutane 40 mg without prescription, 2005) skin care zurich purchase 40mg accutane mastercard. Some drugs acne zip back jeans discount accutane 5 mg mastercard, of which penicillin is a prototype, appear to bind to the surface of the cell, with the "foreign" drug acting as a hapten and eliciting an immune response. The antibodies that arise in this type of response only bind to drug-coated erythrocytes. Other drugs, of which quinidine is a prototype, bind to components of the erythrocyte surface and induce a conformational change in one or more components of the membrane. This type of interaction can give rise to a confusing array of antibody specificities. Some of the antibodies recognize only the drug-membrane component complex; others are specific for the membrane component, but only when drug is present; whereas still others may recognize the membrane component in the presence or absence of the drug. A third mechanism, for which -methyldopa is a prototype, results in production of a drug-induced autoantibody that cannot be distinguished from the antibodies arising in idiopathic autoimmune hemolytic anemia. The mechanism for induction of this group of antibodies is not understood, but may be related to development of an autoimmune response. A variant of this type of response is the augmentation of autoimmune hemolytic anemia that may occur during therapy of some lymphoproliferative disorders. Autoimmune phenomena, including autoimmune hemolytic anemia, are known to occur in lymphoproliferative disorders such as chronic lymphocytic leukemia. It has been hypothesized that therapy further disrupts regulation of the autoimmune phenomenon, allowing increased antibody production. Some xenobiotics are associated with nonspecific deposition of proteins on erythrocytes. This was first associated with cephalosporins but has also been seen with other drugs, including cisplatin and the beta-lactamase inhibitors sulbactam and clavulanate (Arndt and Garratty, 2005). Immunoglobulin and complement proteins may be among the proteins deposited on the erythrocyte surface. These proteins may cause a positive direct antiglobulin test, suggesting a drug-induced antibody response. This form of antibody deposition is generally not associated with hemolysis, although the possibility of hemolysis related to this type of reaction has been raised. The clinical picture of extravascular hemolysis depends on the rate of hemolysis but is usually less dramatic. Serologic studies usually show evidence of IgG and/or complement on the surface of erythrocytes, although it may be difficult to document that antibody binding is drug-dependent. The mainstay of therapy in patients with druginduced hemolytic anemia is removal of the offending drug and avoidance of re-exposure. Eosinophils and basophils are far more difficult to study, with changes in these populations most frequently associated with reactions to other target organ or systemic toxicity. Examples include the eosinophilia observed with the toxic oil syndrome in northwestern Spain that resulted from exposure to rapeseed oil denatured with aniline (Kilbourne et al. Peripheral eosinophilia is often but not reliably observed with hypersensitivity reactions to drugs (Roujeau, 2005), while tissue eosinophilia can be diagnostic, in the context of a suggestive clinical course, in conditions such as drug-induced cutaneous vasculitis (Bahrami et al. This variability in systemic response can be genetically predisposed, as demonstrated in studies using transgenic mice on genetic restrictions in people afflicted by the aforementioned toxic oil syndrome (Gallardo et al. The time course of the reaction can also influence whether eosinophilia can be demonstrated in hypersensitivity disease (Roujeau, 2005). Evaluation of Granulocytes the most informative test to assess the neutrophil compartment is the blood neutrophil count. Accurate interpretation requires an understanding of neutrophil kinetics and the response of this tissue to physiologic and pathologic changes. In the blood, neutrophils are distributed between circulating and marginated pools, which are of equal size in humans and in constant equilibrium (Athens et al. A blood neutrophil count assesses only the circulating pool, which remains between 1800 and 7500 L-1 in a healthy adult human (Dale, 2006). This constancy is remarkable, considering that as many as 1011 neutrophils are released from the marrow daily, and this circulating pool represents only 1% of the total body neutrophils (Semerad et al. The latter is down regulated by the phagocytosis of apoptotic neutrophils in the tissues, which provides an important negative feedback loop.

Absorption of gases in the lungs differs from intestinal and percutaneous absorption of compounds in that the dissociation of acids and bases and the lipid solubility of molecules are less important factors in pulmonary absorption because diffusion through cell membranes is not rate-limiting in the pulmonary absorption of gases skin care face cheap accutane 30 mg with amex. First acne skin care purchase 10mg accutane amex, ionized molecules are of very low volatility skin care victoria bc discount accutane 20 mg otc, so that they do not achieve significant concentrations in normal ambient air skin care 5 steps cheap accutane 30 mg amex. Second, the epithelial cells lining the alveoli-that is, type I pneumocytes-are very thin and the capillaries are in close contact with the pneumocytes, so that the distance for a chemical to diffuse is very short. Third, chemicals absorbed by the lungs are removed rapidly by the blood, and blood moves very quickly through the extensive capillary network in the lungs. When a gas is inhaled into the lungs, gas molecules diffuse from the alveolar space into the blood and then dissolve. The end result is that gas molecules partition between the two media: air and blood during the absorptive phase and blood source: Modified from Dreyfus et al. Table 5-4 pH of the Gastrointestinal Contents of Various Species pH species Monkey Dog Rat Rabbit stomach 2. The magnitude of this diversity can translate into differences up to two orders of magnitude in the concentration of the nonionized versus ionized moiety of a weak organic acid or base available for absorption. In general, the intestinal Table 5-5 Number of Microbes and their Distribution along the Gastrointestinal Tract of Various Species species Monkey Dog Rat Rabbit Man stomach 23 19 18 4 2 jejunum 24 20 23 5 4 colon 41 40 37 13 10 feces 38 43 38 13 - Expressed as log10 of viable counts. As the contact of the inspired gas with blood continues in the alveoli, more molecules dissolve in blood until gas molecules in blood are in equilibrium with gas molecules in the alveolar space. At equilibrium, the ratio of the concentration of chemical in the blood and chemical in the gas phase is constant. This solubility ratio is called the blood-to-gas partition coefficient, and it is unique for each gas. When equilibrium is reached, the rate of transfer of gas molecules from the alveolar space to blood equals the rate of removal by blood from the alveolar space. For example, chloroform has a relatively high bloodto-gas partition coefficient (approximately 20), whereas ethylene has a low coefficient (0. By comparison, a smaller percentage of the total ethylene in the lungs is removed into the blood during each circulation because the low blood-to-gas partition coefficient dictates that blood is quickly saturated with this gas. Therefore, an increase in the respiratory rate or minute volume does not change the transfer of such a gas to blood. In contrast, an increase in the rate of blood flow increases the rate of uptake of a compound with a low solubility ratio because of more rapid removal from the site of equilibrium, that is, the alveolar membranes. A gas with a high blood-to-gas partition coefficient, such as chloroform, is readily transferred to blood during each respiratory cycle so that little if any remains in the alveoli just before the next inhalation. The more soluble a toxic agent is in blood, the more of it will be dissolved in blood by the time equilibrium is reached. Consequently, the time required to equilibrate with blood is much longer for a gas with a high blood-to-gas partition coefficient than for a gas with a low ratio. This has been calculated to take a minimum of 1 hour for compounds with a high solubility ratio, although it may take even longer if the gas also has high tissue affinity. With highly soluble gases, the principal factor limiting the rate of absorption is respiration. Because the blood is already removing virtually all gases with a high solubility ratio from the lungs, increasing the blood flow rate does not substantially increase the rate of absorption. However, the rate can be accelerated greatly by increasing the rate of respiration. In each tissue, the gas molecules are transferred from the blood to the tissue until equilibrium is reached at a tissue concentration dictated by the tissue-to-blood partition coefficient. After releasing part of the gas to tissues, blood returns to the lungs to take up more of the gas. The process continues until a gas reaches equilibrium between blood and each tissue according to the tissue-to-blood partition coefficients characteristic of each tissue. This equilibrium is referred to as steady state, and at this time, no net absorption of gas takes place as long as the exposure concentration remains constant. Aerosols and Particles Absorption of aerosol and particles is distinguished from gases and vapors by the factors that determine absorption from the inhalation route of exposure. The absorption of gases and vapors by inhalation is determined by the partitioning of the compound between the blood and the gas phase along with its solubility and tissue reactivity.

Resumption of car driving or other skilled activity after anaesthesia is a special case skin care in your 40s accutane 10mg on-line, and an extremely variable one acne toner purchase 30mg accutane fast delivery, but where a sedative acne pictures cheap 10 mg accutane mastercard. The emphasis on psychomotor and physical aspects (injury) should not distract from the possibility that those who live by their intellect and imagination (politicians and even journalists may be included here) may suffer cognitive disability from thoughtless prescribing skin care 30s order accutane 10 mg overnight delivery. Age the very old and the very young are liable to be intolerant of many drugs, largely because the mechanisms for disposing of them in the body are less efficient. For convenience, we describe here the porphyrias,14 a specific group of disorders for which careful prescribing in a subgroup, the acute porphyrias, is vital. The porphyrias comprise a number of rare, genetically determined, single-enzyme defects in haem biosynthesis and give rise to two main clinical manifestations: acute neurovisceral attacks and/or skin lesions. Non-acute porphyrias (porphyria cutanea tarda, erythropoietic protoporphyria and congenital erythropoietic porphyria) present with cutaneous photosensitivity that results from the overproduction of porphyrins, which are photosensitising. In porphyria cutanea tarda, a mainly acquired disorder of hepatic enzyme function, one of the main provoking agents is alcohol (and prescribed oestrogens in women). The acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria and hereditary co-proporphyria) are characterised by severe attacks of neurovisceral dysfunction precipitated principally by a wide variety of drugs (also by alcohol, fasting and infection). Anticancer agents warrant special care as they are by their nature cytotoxic (see Ch. Use of these and other drugs may raise longer-term issues of mutagenicity, carcinogenicity and teratogenicity. Ingredients of a formulation, rather than the active drug, may also cause adverse reactions. Examples include the high sodium content of some antacids, and colouring and flavouring agents. The latter are designated in the list of contents by E numbers; tartrazine (E102) may cause allergic reactions. The prescriber needs to be aware that adverse reactions may occur after a drug has been used for a long time, at a critical phase in pregnancy, is abruptly discontinued (see p. Induction of the haem-containing hepatic oxidising enzymes of the cytochrome P450 group causes an increased demand for haem. Therefore drugs that induce these enzymes would be expected to precipitate acute attacks of porphyria, and they do so: tobacco smoking and alcohol excess may also act via this mechanism. Apparently unexplained attacks of porphyria should be an indication for close enquiry into all possible chemical intake, including recreational substances such as marijuana, cocaine, amfetamines and ecstasy. Patients must be educated to understand their condition, to possess a list of safe and unsafe drugs, and to protect themselves from themselves and from others, including, especially, prescribing doctors. Great care in prescribing for these patients is required if serious illness is to be avoided and it is therefore essential that patients and their clinicians have access to information concerning the safe use of prescription medication. Drug lists should be reviewed regularly, and a recent initiative in Europe has made a consensus-based list of safe drugs (available at. If no recognised safe option is available, use of a drug about which there is uncertainty may be justified. Badminton15 writes: `Essential treatment should never be withheld, especially for a condition that is serious or life threatening. The clinician should assess the severity of the condition and the activity of the porphyria and make a risk versus benefit assessment. Measure porphyrin and porphobilinogen before Chapter 9 the environment and social habits Drug metabolism may be increased by hepatic enzyme induction from insecticide accumulation. Antimicrobials used in feeds of animals for human consumption have given rise to concern in relation to the spread of resistant bacteria that may affect man. While macromolecules (proteins, peptides, dextran polysaccharides) can act as complete antigens, most drugs are simple chemicals (mol. The chief target organs of drug allergy are the skin, respiratory tract, gastrointestinal tract, blood and blood vessels. Allergic reactions in general may be classified according to four types of hypersensitivity, and drugs can elicit reactions of all types.

Asthma skin care kit cheap accutane 20mg with mastercard, rhinosinusitis (causing postnasal drip) and oesophageal reflux are the commonest causes of persistent cough skin care videos youtube discount 5 mg accutane overnight delivery. Recently acne and diet discount accutane 10mg online, eosinophilic bronchitis has been recognised as a possibly significant cause; it responds well to inhaled or oral corticosteroid skin care olive oil best 40 mg accutane. Clearly the overall approach to persistent cough must involve attention to underlying factors. The British Thoracic Society publishes guidelines on cough and its management that are available online. Cough is also under substantial voluntary control and can be inducible by psychogenic factors (e. Deciding on which agent to use depends largely on whether sedation and analgesia may be useful actions of the linctus. Hence methadone or diamorphine linctus may be preferred in patients with advanced bronchial carcinoma. In contrast, dextromethorphan, being non-sedating and non-addictive, is widely incorporated into over-the-counter linctuses (see Table 4 in footnote 1). Cough originating above the larynx often benefits from syrups and lozenges that glutinously and soothingly coat the pharynx (demulcents2). Small children are prone to swallow lozenges, so a sweet on a stick may be preferred. Linctuses are demulcent preparations that can be used alone and as vehicles for other specific antitussive agents. Their exact constitution is not critical, and medical students in 1896 were taught the following: Many of you know that this (simple) linctus used to be very much thicker than it is now, and very likely the thicker linctus was more efficacious. It was discovered that a large number of children came to the surgery complaining of cough, and they were given the linctus, but instead of their using it as a medicine, they took it to an old woman out in Smithfield, who gave them each a penny, took their linctus, and made jam tarts with it. Compound benzoin tincture4 may be used to give the inhalation a therapeutic smell (aromatic inhalation). This manoeuvre may have more than a placebo effect by promoting secretion of a dilute mucus that gives a protective coating to the inflamed mucous membrane. Local anaesthetics can also be used topically in the airways to block the mucosal cough receptors (modified stretch receptors and C-fibre endings) directly. Nebulised lidocaine, for example, reduces coughing during fibreoptic bronchoscopy and is also effective in the intractable cough that may accompany bronchial carcinoma. Mucolytics and expectorants Normally about 100 mL fluid is produced from the respiratory tract each day and most of it is swallowed. Respiratory mucus consists largely of water and its slimy character is due to glycoproteins cross-linked together by disulphide bonds. In pathological states much more mucus may be produced; an exudate of plasma proteins that bond with glycoproteins and form larger polymers results in the mucus becoming more viscous. Mucolytics Carbocisteine and mecysteine have free sulphydryl groups that open disulphide bonds in mucus and reduce its viscosity. They are given orally or by inhalation (or instillation) and may be useful chiefly where particularly viscous secretion is a problem (cystic fibrosis, care of tracheostomies). Water inhalation via an aerosol (breathing over a hot basin) is a cheap and effective expectorant therapy in bronchiectasis. Simply hydrating a dehydrated patient can also have a beneficial effect in lowering sputum viscosity. It is of modest value only in patients with cystic fibrosis, whose genetic defect in chloride transport causes particularly viscous sputum. Antitussives that act centrally the most consistent means of suppressing cough irrespective of its cause is blockade of the medullary cough centre itself. Opioids, such as methadone and codeine, are very effective, although part of this antitussive effect could reflect their sedatory effect on higher nervous centres; nevertheless antitussive potency of an opiate is generally poorly correlated with its potency at causing respiratory depression.

These mediators would normally contribute to increased vascular permeability and subsequent changes including oedema skin care bandung order 40mg accutane free shipping, leucocyte migration and fibrin deposition acne 2015 heels buy generic accutane 30 mg. However retinol 05 acne discount accutane 30mg on-line, the distinction is not absolute because cortisol is a stress hormone acne 4 months postpartum cheap accutane 5 mg on-line, and some of its physiological actions are triggered by the increased secretion of cortisol during acute or chronic stress. In the list that follows, the main physiological effects are those concerned with elimination of a water load, and mobilisation of glucose. The suppression of inflammatory mediators may also be seen as part of physiological homeostasis. This action is due to maintenance of glomerular filtration, activation of atrial natriuretic factor, and inhibition of vasopressin secretion. Glycogenolysis and gluconeogenesis are increased and peripheral glucose utilisation is decreased (due to insulin antagonism). Anabolism (conversion of amino acids to protein) decreases but catabolism continues, so that there is a negative nitrogen balance with muscle wasting. The skin atrophies and this, with increased capillary fragility, causes bruising and striae. Cortisol inhibits the number and function of osteoblasts, and the synthesis of collagen. Osteoporosis (reduction of bone protein matrix) is the main consequence of chronic glucocorticoid administration. Lipolysis is increased, and the secretion of leptin (the appetite suppressant) is inhibited. This is why, in practice, different (more selective, and potent) glucocorticoids, not higher doses of prednisolone, need to be used when maximal stimulation of glucocorticoid receptors is desired. Red arrows denote activation, the red line inhibition, the blue arrow repression, and the red X lack of product. Neutrophil and macrophage function are depressed, including the release of chemical mediators and the effects of these on capillaries. Reduction of hypercalcaemia, chiefly where this is due to excessive absorption of calcium from the gut (sarcoidosis, vitamin D intoxication). Growth reduces where new cells are being added (growth in children), but not where they are replacing cells as in adult tissues. Individual adrenal steroids the relative potencies1 for glucocorticoid and mineralocorticoid (sodium-retaining) effects (Table 35. The selectivity of hydrocortisone for the glucocorticoid receptor is due not to a different binding affinity of hydrocortisone to the two receptors but to the protection of the mineralocorticoid receptor by locally high concentrations of the enzyme 11 b-hydroxysteroid dehydrogenase, which converts cortisol to the inactive cortisone. This enzyme saturates at concentrations of cortisol (and some synthetic glucocorticoids) just above the physiological range, which explains the onset of mineralocorticoid action with pathological secretion of cortisol, and pharmacological use of glucocorticoids. Hydrocortisone (cortisol) is the principal naturally occurring steroid; it is taken orally; a soluble salt can be given intravenously for rapid effect in emergency whether due to Table 35. Parenteral preparation for systemic effect: the soluble Hydrocortisone Sodium Succinate Inj. Chapter 35 blocking aldosterone and may need to be used together with amiloride.

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References

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