睿学教育Wisdome Education

Jonathan David Powell, M.D., Ph.D.

• Associate Director, Bloomberg~Kimmel Institute for Cancer Immunotherapy
• Professor of Oncology

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0006472/jonathan-powell

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Oral administration of ferrous Sideroblastic Anemia salts (generic ferrous sulfate depression experiments clomipramine 10 mg buy online, Feosol mood disorder vs psychotic disorder purchase clomipramine 10 mg with amex, Slo Fe) is preferred depression just want to sleep order cheapest clomipramine, but parenteral iron (iron dextran, InfeD) can be given if Sideroblastic anemia is characterized by excessive iron in oral therapy fails. Toxic reactions occur more frequently the cells that cannot be incorporated into porphyrin to after parenteral iron administration. A patient with pancreatic disease complains of diffi- (D) No vitamin supplement culty driving at night because of vision problems. An epileptic patient who is taking phenytoin and tant to determine whether megaloblastic anemia is lamotrigine to control her seizures is in the first from a deficiency of folic acid or vitamin B12. Vitamin A defi- tion with vitamins C and E, beta carotene, and zinc ciency symptoms include night blindness that can for age-related macular degeneration and vision lead to corneal ulceration. Pregnancy increases the need for vitamins and Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, iron in general. B Vitamins, homocysteine, and neu- of the patient to determine whether higher levels of rocognitive function. You schedule a series of ber from medical school for beriberi, but you fail to tests, including a cardiac stress test. If the pa- the stress test suggest that the patient is in moder- tient were consuming most of his calories as alco- ate congestive heart failure. The patient suffered a hol, he may have a nutritional deficiency, a beriberi- personal loss last year with the death of a son. Soon like syndrome, as a result of insufficient intake of after his son’s death he began drinking heavily. You prescribe a daily vitamin tablet and suspect that the drinking is responsible for his pres- admonish the patient to cut back on alcohol intake. John’s wort 793 Ginseng 790 Soy and other phytoestrogens 794 Herbal therapies have become an integral part of being extraneous, contribute significantly to the herb’s the American health care scene. This does not include the pharmacognosy, which includes the study of herbal many (up to 25%) pharmaceutical products used in medicine. The resurgence of herbal medicine use has conventional practice that originally were, and in some once again made pharmacognosy extremely relevant to cases still are, derived from plants (Table 69. For much of the world’s popu- The popular western herbalism discussed in this chapter is lation, herbal treatments remain the first and some- one of many philosophical systems of herbal treatment. Proponents of is also sometimes described as eclectic, since it has drawn herbal therapy also state that the multiple compounds on many other traditions, including the native American found in most herbal preparations have the advantage and Chinese. Chinese traditional medicine, Ayurvedic of acting synergistically; that is, they act in concert to (Indian), and Tibetan traditions use complex herbal produce a more enhanced effect than would a single recipes and nutrition to achieve “balance” in the ill pa- isolated component. Although these practices are most commonly found (Hypericum perfoliatum), which contains not only hy- in ethnic populations, they are also becoming popular in pericin, the ingredient it is usually standardized for, but some western complementary and alternative circles. The difference is that homeopathic reme- Capsule Encapsulated herbal material dies are serially diluted and shaken until they may lack Syrup Concentrated sugar solution to preserve any molecule of the original herb ingredient. Therefore, infusion there is no risk of pharmacological toxicity from a Compress Cloth soaked in herbal solution Poultice Application of moist herbal paste homeopathic preparation. Bach’s Flower Remedies are a homeopathic variation in which flower essences are created by floating flowers in sunlit water. Thus, herbal products like digitalis, while quite and spiritual rather than specific physical complaints. Other herbs may not be superior to better- treat mood or physical problems either topically (as an researched pharmaceuticals, or they may delay the use adjunct to massage) or through inhalation. While herbal research has un- these oils are quite potent, and if not used in proper di- derstandably lagged far behind that of patented med- lution, they may cause skin irritation or contact allergy. Tinctures consist of an herb arrays of studies both supporting and questioning the steeped in a mix of alcohol and water, and extracts con- effectiveness of a particular herbal product. The alco- flicting findings may result from flawed study design, the hol content can be a concern, particularly with children. In one assessment, 24% of cerns about dosage variability, possible toxicity and imported herbs were found to contain ingredients not adulteration, herb–drug interactions, and above all, lack on the label. Far from being intrinsically harm- pirin, caffeine, diuretics, and even benzodiazepines), not less, many pharmacologically active plant alkaloids and to mention heavy metals, such as lead.

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Moreover mood disorder 6 game buy line clomipramine, the availability of third-generation cephalosporins for gram-negative meningitis has rendered this therapy obsolete in most cases clinical depression symptoms quiz purchase clomipramine 50 mg on line. Such toxicity requires depression definition mental illness clomipramine 50 mg purchase free shipping, at the very least, adjustment of the dosing regimen and should prompt reconsideration of the need for the drug, particularly if there is a less toxic alternative agent. Although there is some cross-resistance between gentamicin and tobramycin, it is unpredictable in individual strains. The daily dose of tobramycin is 5–6 mg/kg intramuscularly or intravenously, traditionally divided into three equal amounts and given every 8 hours. Gentamicin is slightly more active against S marcescens, whereas tobramycin is slightly more active against P aeruginosa; Enterococcus faecalis is susceptible to both gentamicin and tobramycin, but E faecium is resistant to tobramycin. Tobramycin is also formulated in solution (300 mg in 5 mL) for inhalation for treatment of P aeruginosa lower respiratory tract infections complicating cystic fibrosis. The drug is recommended as a 300 mg dose regardless of the patient’s age or weight for administration twice daily in repeated cycles of 28 days on therapy, followed by 28 days off therapy. Serum concentrations 1 hour after inhalation average 1 mcg/mL; consequently, nephrotoxicity and ototoxicity rarely occur. Caution should be used when administering tobramycin to patients with preexisting renal, vestibular, or hearing disorders. It is resistant to many enzymes that inactivate gentamicin and tobramycin, and therefore can be used against some microorganisms resistant to the latter drugs. Many gram-negative bacteria, including many strains of Proteus, Pseudomonas, Enterobacter, and Serratia, are inhibited by 1–20 mcg/mL amikacin in vitro. After injection of 500 mg of amikacin every 12 hours (15 mg/kg/d) intramuscularly, peak levels in serum are 10–30 mcg/mL. Strains of multidrug-resistant Mycobacterium tuberculosis, including streptomycin-resistant strains, are usually susceptible to amikacin. Like all aminoglycosides, amikacin is nephrotoxic and ototoxic (particularly for the auditory portion of the eighth nerve). Target peak serum concentrations for an every-12-hours dosing regimen are 20–40 mcg/mL, and troughs should be maintained between 4 and 8 mcg/mL. Consequently, netilmicin may be active against some gentamicin-resistant and tobramycin-resistant bacteria. Netilmicin is largely interchangeable with gentamicin or tobramycin but is no longer available in the United States. Antimicrobial Activity & Resistance Drugs of the neomycin group are active against gram-positive and gram-negative bacteria and some mycobacteria. The widespread use of these drugs in bowel preparation for elective surgery has resulted in the selection of resistant organisms and some outbreaks of enterocolitis in hospitals. After oral administration, the intestinal flora is suppressed or modified, and the drug is excreted in the feces. With the advent of more potent and less toxic aminoglycosides, parenteral administration of kanamycin has also been largely abandoned. Paromomycin has recently been shown to be effective against visceral leishmaniasis when given parenterally (see Chapter 52), and this serious infection may represent an important new use for this drug. Paromomycin can be used for intestinal Entamoeba histolytica infection and is sometimes used for intestinal infections with other parasites. Topical Administration Solutions containing 1–5 mg/mL are used on infected surfaces or injected into joints, the pleural cavity, tissue spaces, or abscess cavities where infection is present. The total amount of drug given in this fashion must be limited to 15 mg/kg/d because at higher doses enough drug may be absorbed to produce systemic toxicity. Whether topical application for active infection adds anything to appropriate systemic therapy is questionable. Ointments, often formulated as a neomycin- polymyxin-bacitracin combination, can be applied to infected skin lesions or in the nares for suppression of staphylococci but they are largely ineffective. Oral Administration In preparation for elective bowel surgery, 1 g of neomycin is given orally every 6–8 hours for 1–2 days, often combined with 1 g of erythromycin base. In hepatic encephalopathy, coliform flora can be suppressed by giving 1 g every 6–8 hours together with reduced protein intake, thus reducing ammonia production. Use of neomycin for hepatic encephalopathy has been largely supplanted by lactulose and other medications that are less toxic.

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In ternational medical research depression test calm clinic clomipramine 10 mg buy cheap, especially that done with 1948 mood disorder definition buy discount clomipramine, in response to the atrocities perpetrated by Nazi patients in economically developing nations anxiety issues quality 10 mg clomipramine. For ex- experimentation, the Nuremberg Code was developed ample, one controversy focused on a highly publicized to set forth guidelines for the acceptable conduct of sci- placebo-controlled study in Africa examining the pre- entific research. These docu- ically developed nation would probably not have a ments specify basic moral guidelines ultimately founded placebo arm, critics argue that this reflects a double on concerns for autonomy, beneficence, and justice. They assert that one standard guidelines require the following: for ethical research should prevail, regardless of the social and economic conditions of the subjects. The pharmaceutical industry com- efit over and above the status quo, they assert, and did bines a desire for discovery and development with not deprive subjects of anything they could otherwise profit-motivated marketing and sales goals. Yet such “studies in nature” pose complex ethi- scientists and physicians share the desire for drug dis- cal issues. If the research relies on the continuation of covery and development and are motivated by the de- undesirable social conditions, such as the general lack of sire to contribute to scientific advancement and im- prenatal care, critics assert that there is a fundamental proved patient care, pharmaceutical companies are obligation to improve those background conditions simultaneously under strong commercial pressures. In some cases, this financial so, is that the role of pharmaceutical research or a support may compromise professional judgment in con- broader social role that goes beyond what researchers ducting, analyzing, or reporting research. While it would be foolhardy to For example, often a pharmaceutical company will insist that the only ethically acceptable research is done contract with a private physician to recruit patients into on patients with full access to comprehensive health a drug study. While this arrangement frequently offers care, we do not want to make those who are already de- patients access to treatment that might otherwise be un- prived and in poverty into “lab rats” who participate in available, the potential conflict may ultimately result in research that ultimately benefits primarily those in the lack of objectivity in study design, data interpretation, developed world. For example, a Clinical research can target the needs of those in 1986 study in the Journal of General Internal Medicine economically developing nations and those who are found a statistically significant relationship between medically underserved in the United States. Yet we drug company funding and outcomes favoring a new must be cautious in the design and implementation of therapy. The doctor assumes a position of re- must satisfy the needs of the population in which it is sponsibility to the company while simultaneously main- undertaken, and the products developed during the taining the usual duties to protect and benefit his or her course of the research must subsequently be made rea- patients. The interrelationship between scientists, physi- to do with that particular patient’s care and more to do cians, and researchers and the pharmaceutical industry with the physician’s desire to enroll subjects. The pharmaceutical industry depends on scientists enroll and advised of any potential conflicts between and clinicians for research, development, and marketing. Although disclosure to patients is important, pa- While this interdependence often benefits industry, re- tients are generally ill suited to assess how a potential search, and patient care, conflicts of interest may arise in conflict of interest actually affects their treatment. In two main areas: (1) drug research and development and addition to disclosure to patients, we need rigorous re- (2) clinical education and product marketing. Although such visits may keep clini- cians informed about current products, they may also Clinical Education and Product precipitate conflicts of interest. Gifts of more than to- Marketing ken value, trips to resort areas for “educational” pro- The second area for ethical concern is clinical education grams with little scientific merit, and cash incentives for and product marketing. The line between “education” prescribing a drug or having it added to a hospital for- and marketing is frequently a blurry one, and it is often mulary all are cause for concern. The line between a gift difficult to separate a company’s desire to educate and a bribe is not a sharp one, and clinicians and drug physicians about products that may genuinely enhance company employees should strive to avoid any impro- patient care from the company’s desire to increase prof- priety. As the gatekeepers for all prescription drugs, physi- its Current Opinions that gifts should primarily benefit cians have the power to determine which drugs will patients and should not be of substantial value. While compete successfully in the marketplace, making doc- textbooks, modest meals, and educational or work- tors the logical targets for marketing efforts by pharma- related gifts, 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.

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The globin gene clusters on chromosome 16 and Ireland include two -globin genes and on chromosome 11 a -globin gene anxiety zone thyroid buy clomipramine online. The haemoglobinopathies represent the commonest single-gene disorders in the world population and have had 2 1 profound effects on the provision of health care in some 5 developing countries depression index test clomipramine 25 mg purchase with mastercard. Chromosome 16 Various mutations in the -globin gene cause structural Embryonic Fetal Adult alterations in haemoglobin hdrs depression test clomipramine 25 mg order mastercard, the most important being the point haemoglobin haemoglobin haemoglobin mutation that produces haemoglobin S and causes sickle cell disease. Direct detection of this point mutation permits carrier 2 G A 1 detection and first-trimester prenatal diagnosis. Each normal adult chromosome expresses two copies of the -globin gene and disease severity is proportional to the number of -globin genes lost following a mutational event. In the most severe type, Barts hydrops fetalis, all four copies are lost, leading to a severe phenotype associated with stillbirth or early neonatal death. The -globin gene cluster contains a number of repeat regions that increase the likelihood of unequal crossover during meiosis. As a result, relatively large deletions are the commonest type of mutations that give rise to Normal +trait +thalassaemia -thalassamia. Over hydrops) 200 mutations have so far been reported with point mutations and small deletions comprising the majority. Although a large Normal gene number of mutations have been reported, the prevalence of Gene deletion or mutation specific mutations is dependent on the ethnic origin. Approximately Sample 1: F508 homozygote 700 mutations have been described, many of which are Sample 2: Normal pattern Sample 3: 621 1g t heterozygote “private” mutations restricted to a particular lineage. It should be remembered that since the frequency of mutations varies between populations, the panel of mutations tested in one ethnic group may be of less value in another ethnic group and consequently knowledge of the mutation spectrum in the local population is important. The syndrome control sample from the trace of a test sample, highlighting mutations is characterised by mental retardation and accounts for 15–20% and polymorphisms (see lower panel) (screen shot courtesy of Dr Karen of all X linked mental retardation. Mary’s Hospital, Manchester) moderate to severe mental retardation, whereas affected females have milder retardation and phenotypic features. However, if individuals have between 55 and 200 repeats (although apparently unaffected), there is an increased risk of the repeat region expanding further into the full mutation range ( 200 repeats) that is associated with mental Full mutation retardation. After amplification, the size of the repeat from each chromosomal copy is determined by polyacrylamide gel electrophoresis. In prenatal diagnosis, methylation analysis is problematic owing to the 69 presence of fetal methylation patterns, and the size of the 53 repeat becomes the most reliable predictive indicator. The expansion is translated into a 13 polyglutamine tract in the huntingtin protein gene product that is believed to cause a dominant gain of function leading to neuronal loss. In general, the greater the number of repeats an expansions within the pathological range as indicated by the arrows (courtesy of Alan Dodge, Regional Genetic Service, St. Mary’s Hospital, individual has, the earlier the age of onset will be, although this Manchester) relationship is stronger for higher repeat numbers. Rarer clinical forms exist, including the severe Dejerine–Sottas syndrome and hereditary neuropathy 2 with increased reflexes. Most cases are inherited in an autosomal recessive fashion, although some affected families show dominant inheritance. It is estimated to be the second most frequent disease seen in paediatric neuromuscular clinics after Duchenne muscular dystrophy. In type I (Werdnig–Hoffman disease), onset occurs within the first six months of life and children usually die within two years. Samples with deletions are indicated by the arrows (courtesy of and milder, chronic cause with affected children achieving Dr Andrew Wallace, Regional Genetic Service, St. Weakness of the diaphragm and intercostal muscles leads to respiratory insufficiency, and involvement of the myocardium causing dilated cardiomyopathy is common. Two-thirds of cases are caused by deletion of one or more of the dystrophin exons that cluster in Figure 18. Large duplications account for a This analysis simultaneously amplifies exons 43, 45, 47, 48, 50, 51, 52, 53, & 60 with deletions causing loss of bands (arrowed) further 5–10% of cases. Hybridisation with a probe from the centromeric region of the Familial breast cancer X chromosome identifies both chromosomes. Only one X chromosome shows a flourescent hybridisation signal with a probe corresponding to exon 47, which indicates that the other X chromosome is deleted for Breast cancer is the commonest cancer seen in young women this part of the gene (courtesy of Dr Lorraine Gaunt, Regional Genetic from developed countries, affecting about 20% of all women Service, St.

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The administration of a loading dose in these patients will allow achievement of therapeutic concentrations quicker than if maintenance doses alone are given bipolar depression vs depression purchase 50 mg clomipramine overnight delivery. However performance anxiety buy clomipramine 10 mg amex, since the pharmacokinetic parameters used to compute these initial doses are only estimated values and not actual values transient depression definition clomipramine 10 mg purchase with amex, the patient’s own parameters may be much different from the estimated constants and steady state will not be achieved until 3–5 half-lives have passed. The vancomycin clearance versus creatinine clearance relationship is used to estimate the vancomycin clearance for this patient: Cl = 0. Steady-state vancomycin serum concentrations of Cssmin = 5 μg/mL and Cssmax = 25 μg/mL were chosen to treat this patient. However, since the pharmacokinetic parameters used to compute these initial doses are only estimated values and not actual values, the patient’s own parameters may be much different from the estimated constants and steady state will not be achieved until 3–5 half-lives have passed. The first maintenance dose would be given one dosage interval (48 hours) after the loading dose was administered. Moellering Nomogram Method Because the only two patient-specific factors that change when using the pharmacoki- netic dosing method are patient weight and creatinine clearance, it is possible to make a simple nomogram to handle uncomplicated patients. The Moellering dosage nomogram was the first widely used approach that incorporated pharmacokinetic concepts to com- pute doses of vancomycin for patients with compromised renal function (Table 5-3). In order to use the nomogram, the patient’s cre- atinine clearance is computed and divided by their body weight so that the units for creatinine clearance are mL/min/kg. The relationship between vancomycin clearance and creatinine clearance used in the pharmacokinetic dosing method is the one used to construct the Moellering nomogram. Hence, the dosage recommendations made by both these methods are generally similar although not identical because vancomycin peak and trough concentrations cannot be specified using the nomogram. A modification of the vancomycin clearance/creatinine clearance equation can be made that provides a direct calculation of the vancomycin maintenance dose. The patient’s creatinine clearance is estimated using an appropriate technique (Cockcroft-Gault method55 for normal weight patients, Salazar-Corcoran method56 for obese patients). The vancomycin maintenance dose is directly computed using the dosing equation and multiplied by the patient’s weight to convert the answer into the units of mg/h. Compute patient’s creatinine clearance (CrCl) using Cockcroft–Gault method for normal weight or Salazar- Corcoran method for obese patients. To illustrate how this dosing approach is used, the same patient examples utilized in the previous section will be repeated for this dosage approach. However, in this case, the loading dose is nearly identical to the maintenance dose, so the loading dose would not be given. As noted, this patient has good renal function (CrCl ≥60 mL/min) so a loading dose would probably not be prescribed for this patient. Additionally, the authors suggest that the nomogram should not be used in patients undergoing peritoneal dialysis. The nomogram is constructed to produce steady-state vancomycin peak and trough concentrations of 30 μg/mL and 7. A loading dose of 25 mg/kg is given as the first dose, and subsequent maintenance doses of 19 mg/kg are given according to a dosage interval that varies by the patient’s creatinine clearance. The dosage interval supplied by the nomogram is the time needed for 19 mg/kg of vancomycin to be eliminated from the body. By replacing the amount eliminated over the dosage interval with a mainte- nance dose of the same magnitude, the same peak and trough vancomycin concentration/ time profile is reproduced after each dose. To illustrate how the nomogram is used, the same patient examples utilized in the previous section (omitting the obese patient case) will be repeated for this dosage approach. Since the nomogram uses slightly different estimates for volume of distribution and elimination rate constant as well as fixed steady- state peak and trough drug concentrations, differences in suggested doses are expected. While the Matzke nomogram has been shown to provide precise and unbiased dosage recommendations, it does supply relatively large doses because expected peak and trough concentrations are in the middle of their respective therapeutic ranges. Dosage chart is designed to achieve peak serum concentrations of 30 μg/mL and trough concentrations of 7. This dose would be rounded to 1250 mg and given one dosage interval (12 hours) after the loading dose. This dose would be rounded to 1250 mg and given one dosage interval (2 days × 24 hours/day = 48 hours) after the loading dose. Literature-based Recommended Dosing Because of the large amount of variability in vancomycin pharmacokinetics, even when concurrent disease states and conditions are identified, many clinicians believe that the use of standard vancomycin doses for pediatric patients is warranted. The original computation of these doses was based on the pharmacokinetic dosing methods described in the previous section, and subsequently modified based on clinical experience. In gen- eral, the expected vancomycin steady-state serum concentrations used to compute these doses were similar to those for adults.

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Agonist (Ag) approaches the receptor from the extracellular fluid and binds to a site surrounded by the transmembrane regions of the receptor protein depression zoloft withdrawal order 25 mg clomipramine with amex. Lateral movement of these helices during activation exposes an otherwise buried cytoplasmic surface of the receptor that promotes guanine nucleotide exchange on the G protein and thereby activates the G protein bipolar depression quiz online 75 mg clomipramine mastercard, as discussed in the text anxiety attacks symptoms discount clomipramine. This phosphorylation is associated with diminished receptor-G protein coupling and can promote receptor endocytosis. Agonist binding (eg, a catecholamine or acetylcho-line, schematized in Figure 2–11) stabilizes a conformational state of the receptor in which the cytoplasmic ends of the transmembrane helices spread apart approximately 1 nm relative to the inactive conformation, opening a cavity in the receptor’s cytoplasmic surface that binds a critical regulatory surface of the G protein. Receptor Regulation G protein-mediated responses to drugs and hormonal agonists often attenuate with time (Figure 2–12A). This “desensitization” is often rapidly reversible; a second exposure to agonist, if provided a few minutes after termination of the first exposure, results in a response similar to the initial response. If agonist is removed after a short time (typically several to tens of minutes, indicated by broken line on abscissa), cells recover full responsiveness to a subsequent addition of agonist (second light-colored bar). This “resensitization” fails to occur, or occurs incompletely, if cells are exposed to agonist repeatedly or over a more prolonged time period. B: Agonist binding to receptors initiates signaling by promoting receptor interaction with G proteins (G ) located in the cytoplasm (step 1 ins the diagram). Dissociation of agonist from internalized receptors reduces β-Arr binding affinity, allowing dephosphorylation of receptors by a phosphatase (P’ase, step 4) and return of receptors to the plasma membrane (step 5); together, these events result in the efficient resensitization of cellular responsiveness. Repeated or prolonged exposure of cells to agonist favors the delivery of internalized receptors to lysosomes (step 6), promoting receptor down-regulation rather than resensitization. The presence of phosphoserines increases the receptor’s affinity for binding a third protein, β-arrestin. Binding of β-arrestin to cytoplasmic loops of the receptor diminishes the receptor’s ability to interact with G , thereby reducing the agonist response (ie, stimulation of adenylyls cyclase). Endocytosis of receptors promotes their dephosphorylation by a receptor phosphatase that is present at high concentration on endosome membranes, and receptors then return to the plasma membrane. This helps explain the ability of cells to recover receptor-mediated signaling responsiveness very efficiently after agonist-induced desensitization. This process effectively attenuates (rather than restores) cellular responsiveness, similar to the process of down-regulation described above for the epidermal growth factor receptor. Thus, depending on the particular receptor and duration of activation, endocytosis can flexibly regulate effects of endogenous agonists or drugs (Figure 2–12B). It also regulates the production of adrenal and sex steroids (in response to corticotropin or follicle-stimulating hormone), relaxation of smooth muscle, and many other endocrine and neural processes. Milrinone, a selective inhibitor of type 3 phosphodiesterases that are expressed in cardiac muscle cells, has been used as an adjunctive agent in treating acute heart failure. Phosphoinositides and Calcium Another well-studied second messenger system involves hormonal stimulation of phosphoinositide hydrolysis (Figure 2– 14). Some of the hormones, neurotransmitters, and growth factors that trigger this pathway bind to receptors linked to G proteins, whereas others bind to receptor tyrosine kinases. For example, different cell types may contain one or more specialized calcium- and calmodulin-dependent kinases with limited substrate specificity (eg, myosin light-chain kinase) in addition to a general calcium- and calmodulin-dependent kinase that can phosphorylate a wide variety of protein substrates. These and other nonreceptor elements of the calcium-phosphoinositide signaling pathway are of considerable importance in pharmacotherapy. For example, lithium ion, used in treatment of bipolar (manic-depressive) disorder, affects the cellular metabolism of phosphoinositides (see Chapter 29). Atrial natriuretic peptide, a blood-borne peptide hormone, stimulates a transmembrane receptor by binding to its extracellular domain, thereby activating the guanylyl cyclase activity that resides in the receptor’s intracellular domain. After entering the target cell, nitric oxide binds to and activates a cytoplasmic guanylyl cyclase (see Figure 19–2). A number of useful vasodilating drugs, such as nitroglycerin and sodium nitroprusside used in treating cardiac ischemia and acute hypertension, act by generating or mimicking nitric oxide. One such drug is sildenafil, used in treating erectile dysfunction and pulmonary hypertension (see Chapter 12). Phosphorylation: A Common Theme Almost all second messenger signaling involves reversible phosphorylation, which performs two principal functions in signaling: amplification and flexible regulation. In flexible regulation, differing substrate specificities of the multiple protein kinases regulated by second messengers provide branch points in signaling pathways that may be 2+ independently regulated. Inhibitors of protein kinases have great potential as therapeutic agents, particularly in neoplastic diseases. Trastuzumab, an antibody that antagonizes growth factor receptor signaling (discussed earlier), is a useful therapeutic agent for breast cancer.

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The protective index for phenobarbital is approxi- family of dose–response curves depression self test buy discount clomipramine online, such as those given in mately 3 bipolar depression 08 75 mg clomipramine order mastercard. In guinea pig e depression symptoms while on antidepressants buy clomipramine 25 mg line, the maximum re- a drug with a protective index of 1 is useless as an anti- sponse is an increase in heart rate of 80 beats per convulsant, since the dose that protects against convul- minute. An estimate More common than the quantal dose–response rela- of the variation within the population can be indicated tionship is the situation in which a single animal (or pa- by calculating a statistical parameter, such as a confi- tient) gives graded responses to graded doses; that is, dence interval. With It is also possible to construct quantal dose–response graded responses, one can obtain a complete dose– curves for drugs that produce graded responses. A good example is the so, one chooses a quantum of effect, for example, an in- effect of the drug levarterenol (L-norepinephrine) on crease in heart rate of 20 to 30 beats per minute above heart rate. Doses of the drug are then Results of experiments with levarterenol in guinea plotted against the frequency with which each dose pro- pigs are shown in Figure 2. The resulting graph has the what one might obtain from constructing complete same characteristics as the graph for the anticonvulsant dose–response curves in each of five different guinea activity of phenobarbital. Further increases in dose do not produce greater re- There are many reasons for the common practice of us- sponses. At the other extreme, in guinea pig e, doses be- ing geometric scales, some of which will become appar- low 0. Broken mean dose–response curves of three hypothetical drugs lines indicate 50% of maximum response (horizontal) and that increase heart rate. Thus, affinity and efficacy represent kinetic constants that re- 80 a b late the drug, the receptor, and the response at the mo- lecular level. Affinity is the measure of the net molecu- 60 lar attraction between a drug (or neurotransmitter or 40 c hormone) and its receptor. Efficacy is a measure of the efficiency of the drug–receptor complex in initiating the 20 signal transduction process. In contrast, potency and in- trinsic activity are simple measurements, respectively, of 0 the relative positions of dose–response curves on their 0. Drug c is said to a given concentration of an agonist to the maximum to have a lower intrinsic activity than the other two. Such factors as the Although the details are beyond the scope of this text- severity and frequency of undesirable effects associated book, it should be noted that by the use of combinations with each drug and their cost to the patient are more of agonists and antagonists, dose–response curves, and relevant factors in the choice between two similar mathematical relationships, it is possible to estimate the drugs. The The terms agonist and antagonist have already been in- constants that relate an agonist A and its receptor R to troduced. The several types of antagonism can be classi- the response may be represented as follows: fied as follows: k1 k3 1. Noncompetitive antagonism Chemical Antagonism Chemical antagonism involves a direct chemical interac- tion between the agonist and antagonist in such a way as Dose of Agonist (geometric scale) to render the agonist pharmacologically inactive. Chelation involves a particular type of absence (a) and the presence (b, c, d) of increasing doses two-pronged attachment of the antagonist to a metal of an equilibrium-competitive antagonist. One chemical chelator, dimercaprol, is used in the treatment of toxicity from mercury, arsenic, and gold. After complexing with the dimercaprol, mer- cury is biologically inactive and the complex is excreted creased. The curves are parallel, and the maximum ef- Functional antagonism is a term used to represent the fects are equal. The antagonist has shifted the dose– interaction of two agonists that act independently of response curve of the agonist to the right. Thus, response is still possible, but greater amounts of the ag- indirectly, each tends to cancel out or reduce the effect onist are required. A classic example is acetylcholine and epi- creased, the dose–response curve is shifted farther to nephrine. These agonists have opposite effects on sev- the right (curve c), still with no decrease in the maxi- eral body functions. Acetylcholine stimulates onist required to achieve maximum response is greater intestinal movement, and epinephrine inhibits it.

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The coronary The coronary arteries are functional end-arteries and hence follow- sinus drains the vast majority of the heart’s venous blood depression while pregnant discount clomipramine. Under these conditions the increased demand placed on the myocardium cannot be met by the diminished arterial supply beck depression inventory test questions cheap 50 mg clomipramine with amex. It is situated dilating (angioplasty) bipolar depression worse in the morning buy clomipramine with a visa, or surgically bypassing (coronary artery bypass near the top of the crista terminalis, below the superior vena caval grafting), the arterial stenosis. Ischaemic heart disease is the leading cause of death in the tion pathway can lead to dangerous interruption of heart rhythm. The bundle of His divides into right and left branches which send There is considerable variation in size and distribution zones of the Purkinje fibres to lie within the subendocardium of the ventricles. For example, in some people the posterior interven- position of the Purkinje fibres accounts for the almost synchronous tricular branch of the right coronary artery is large and supplies a large contraction of the ventricles. The nerve supply of the heart Similarly, the sinu-atrial node is usually supplied by a nodal branch The heart receives both a sympathetic and a parasympathetic nerve of the right coronary artery but in 30–40% of the population it receives supply so that heart rate can be controlled to demand. Pulmonary trunk They are all covered with Left auricle Posterior pulmonary plexus the mediastinal pleura Sympathetic trunk Phrenic nerve Descending aorta Left ventricle Greater splanchnic nerve Oesophageal plexus on oesophagus Subclavian artery Oesophagus Subclavian vein Trachea Left brachiocephalic Vagus nerve vein Superior vena cava Pulmonary artery Acending aorta Fig. Here the right phrenic enters the caval opening and immediately penetrates the The thoracic sympathetic trunk (Figs 9. It descends in the thorax behind the pleura immediately lateral to costal vein to descend in front of the left lung root onto the pericardium the vertebral bodies and passes under the medial arcuate ligament of the overlying the left ventricle. Note: the phrenic nerves do not pass The thoracic chain bears a ganglion for each spinal nerve; the first beyond the undersurface of the diaphragm. However, they also transmit fibres which are sensory preganglionic fibres from its corresponding spinal nerve and sends to the fibrous pericardium, mediastinal pleura and peritoneum as well back a grey ramus, bearing postganglionic fibres. Upper limb sympathectomy is used for the treatment of hyperhidro- Irritation of the diaphragmatic peritoneum is usually referred to the sis and Raynaud syndrome. Hence, upper abdominal pathology such as a perfor- of part of the thoracic sympathetic chain (usually for two interspaces) ated duodenal ulcer often results in pain felt at the shoulder tip. It finally reaches the lower oesophagus where it visceraathe heart and great vessels, the lungs and the oesophagus. From this plexus, Mainly preganglionic fibres from T5–12 form the splanchnic nerves, anterior and posterior vagal trunks descend (carrying fibres from both which pierce the crura of the diaphragm and pass to the coeliac and left and right vagi) on the oesophagus to pass into the abdomen through renal ganglia from which they are relayed as postganglionic fibres to the oesophageal opening in the diaphragm at the level of T10. It is itself crossed here by the left superior intercostal (T5–10), lesser splanchnic (T10–11) and lowest splanchnic (T12). Below, it descends behind the lung root to reach the oesophagus They lie medial to the sympathetic trunk on the bodies of the thoracic where it contributes to the oesophageal plexus mentioned above (see vertebrae and are quite easily visible through the parietal pleura. The cardiac plexus Vagal branches This plexus is for descriptive purposes divided into superficial and deep The left recurrent laryngeal nerve arises from the left vagus below parts. The nerves of the thorax 25 10 Surface anatomy of the thorax Cervical plexus 2 2 4 4 Cardiac notch of lung Transverse fissure 6 6 Oblique fissure Costodiaphragmatic recess 8 8 10 10 Apex of lower lung Oblique fissure 6 Beginning of transverse fissure 8 Costodiaphragmatic recess Fig. The areas of auscultation for the aortic, pulmonary, mitral and tricuspid valves are indicated by letters 26 Thorax The anterior thorax pleura passes laterally for a small distance at the 4th costal cartilage and Landmarks of the anterior thorax include: descends vertically lateral to the sternal border to the 6th costal cartil- The angle of Louis (sternal angle): formed by the joint between the age. It is an important landmark as the cross the 8th rib in the mid-clavicular line, the 10th rib in the mid- 2nd costal cartilages articulate on either side and by following this line axillary line and finally reach the level of the 12th rib posteriorly. The apex and mediastinal border of the right lung follow the pleural The suprasternal notch: situated in the midline between the medial outline. In mid-inspiration the right lung lower border crosses the 6th ends of the clavicles and above the upper edge of the manubrium. The oblique fissures separate the lungs into upper The first palpable spinous process is that of C7 (vertebra prominens). The The transverse fissure: is represented by a line drawn horizontally spinous processes of the thoracic vertebrae can be palpated and counted from the 4th costal cartilage to a point where it intersects the oblique in the midline posteriorly. The fissure separates the upper and middle lobes of the right The scapula is located on the upper posterior chest wall. The heart The borders of the heart are illustrated by joining the four points Lines of orientation shown (Fig.

Riordian, 26 years: An example using this method is a patient with a ventricular arrhythmia after a myocardial infarction needing treatment with lidocaine at a Css of 3. Tyramine (see Figure 6–5) is a normal byproduct of tyrosine metabolism in the body and can be produced in high concentrations in protein-rich foods by decarboxylation of tyrosine during fermentation (Table 9–5).

Asaru, 43 years: The sequential oral contraceptive preparations as well as estrogens alone often decrease sebum production. When man is standing and his (1922) on the relations existing in man between the visual axis is horizontal he is in his natural attitude” labyrinth and erect posture, Girard defined, in 1923, (Broca 1862, 1873 p.

Berek, 47 years: Ordinary consumption of methylxanthine-containing beverages usually produces slight tachycardia, an increase in cardiac output, and an increase in peripheral resistance, raising blood pressure slightly. What supportive therapies may be used to manage the patient’s hypotension and resulting metabolic acidosis?

Moff, 25 years: The lat- Generic Name Trade Names ter are called thiazidelike diuretics; they include metola- Bendroflumethiazide Naturetin zone, xipamide, and indapamide. Large quantities of antibiotics have been used in agriculture to stimulate growth and prevent infection in livestock, and this has added to the selection pressure that results in resistant organisms.

Dan, 63 years: Brown will be paid $1000 for viding them with the level of care available to oth- her consulting services. For example many over-the- throughout the brain but a particular cluster in the hypo- counter sleep-promoting agents contain antihistamines, thalamus (ventrolateral preoptic nucleus) can be consid- which block the histamine H -receptor and so decrease ered to be the sleep ‘switch’.

Akascha, 50 years: Therapeutic Levels & Dosage Primidone is most efficacious when plasma levels are in the range of 8–12 mcg/mL. In a moribund person, a certain degree tency 5000 times that of morphine and a of euphoria, possibly associated with dimin- long duration of action.

Yugul, 53 years: A short time later, another physician at the table developed similar signs and symptoms with marked orthostatic hypotension. As it does not possess antimuscarinic activ- ity, it does not exhibit the troublesome effects of that group of drugs.

Kippler, 61 years: In choosing a diuretic for the patient with kidney disease, there are a number of important limitations. When it is feasible, these agents are effects, but they can cause cataracts; this is a primary rea- given orally.

Derek, 33 years: 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. The drug is classified as a partial agonist at α receptors because it also inhibits pressor effects of other α agonists.

Tizgar, 45 years: Foot bones 311 Bones of the left foot attachments A from above 16 A B 16 B from below 10 Joint capsules and minor 8 18 ligaments have been 15 omitted. What information (signs, symptoms, laboratory values) indi- cates the presence or severity of hyperphosphatemia and hyper- 1.

Sven, 28 years: As previously mentioned, an ideal anesthetic should have a rapid onset (induction), and its effect should be rapidly terminated. Bone development and growth in children as the highest level of intake of a nutrient that will not have also been linked to adequate vitamin A intake.

Joey, 36 years: Cortisol is Sequelaeofexaggeratedglucocorticoidaction effective when given orally (30 mg/day, 2/3 are(a)increasedgluconeogenesisandrelease a. A steady-state trough valproic acid serum concentration should be measured after steady state is attained in 3–5 half-lives.

Uruk, 29 years: One of the best examples of imprinting in human disease is shown by deletions in the q11-13 region of chromosome 15, which may cause either Prader–Willi syndrome or Angelman syndrome. Several branches of the brachial plexus cervical nerves C2 and C3, emerges from the posterior may be visible in the posterior triangle (see Fig.

Chenor, 59 years: The ceiling and lateral walls of the nasopharynx pharyngeal wall is between the superior and middle con­ form a domed vault at the top of the pharyngeal cavity that strictor muscles of the pharynx and the posterior border of is always open. The diaphragm is Inferior vena cava Superior epigastric arery Right phrenic nerve Central tendon Left phrenic nerve Esophagus with anterior and posterior vagal trunks Inferior phrenic Greater splanchnic nerve arery Hemi-azygos vein Lesser splanchnic nerve Least splanchnic nerve Sympathetic trunk Right crus Fig.

Barrack, 34 years: As discussed previously, sodium restriction may be effective treatment for many patients with mild hypertension. D Right ventricle 9 from the front 13 1 Anterior cusp of tricuspid valve 2 Anterior papillary muscle 4 3 Ascending aorta 7 3 4 Auricle of right atrium 5 Chordae tendineae 6 Inferior vena cava 7 Infundibulum of right ventricle (conus 12 arteriosus) 8 Posterior papillary muscle 9 Pulmonary trunk 10 Right atrium 11 Septomarginal trabeculation (moderator 10 band) 12 Septal papillary muscle (of conus) 13 Superior vena cava 11 1 5 The septomarginal trabeculum (11), which conducts part of the right limb of the 2 atrioventricular bundle from the interventricular septum (13) to the anterior papillary muscle (2), was formerly known as 6 8 the moderator band.

Irhabar, 35 years: Which of the following would be the best was one of several children sent home from day care treatment for the patient? Midodrine is a prodrug that is enzymatically hydrolyzed to desglymidodrine, a selective α -receptor agonist.

Marius, 54 years: For instance, hy- fied as “slow metabolizers” or poor metabo- pertensive patients carrying an arginine at lizers” in contrast to “normal metabolizers. Basic polypeptides, such nitude depends on the concentration of histamine in- as bradykinin, neurotensin, substance P, somatostatin, jected, the degree of baroreceptor reflex compensation, polymyxin B, and the anaphylatoxins resulting from and the extent of histamine-induced release of adrenal complement activation, also stimulate histamine release.

Tempeck, 38 years: The shoulderjoint is flled with saline, A 35-year-old baseball pitcher cameto the clinic with which distends it, allowing the arthroscope to move a history of a recurrent dislocation of the shoulder around the joint and inspect the joint surfaces, including (Fig. He has a history of hypertension and coronary artery disease with symptoms of stable angina and can walk only half a block before pain in his legs forces him to stop.

Kaelin, 24 years: It is most effective if given in a ratio of at least 10:1 of charcoal to estimated dose of toxin by weight. Enter patient’s demographic, drug dosing, and serum concentration/time data into the computer program.

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