睿学教育Wisdome Education

Ronald A. Kahn, MD

• Professor
• Department of Anesthesiology
• Mount Sinai Medical Center
• New York, New York

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The slope for a simple linear equation is the quotient of the change in the y-axis values (Δy) and the change in the x-axis values (Δx): slope = Δy/Δx muscle relaxant non sedating generic zanaflex 4 mg with mastercard. The Michaels-Menten equation can be used to compute steady-state concentrations for a given dose or vica versa muscle relaxant for headache 4 mg zanaflex visa. The patient was prescribed 400 mg/d of extended phenytoin sodium capsules for 1 month spasms 1st trimester 2 mg zanaflex order amex, and the steady-state phenytoin total concentration equals 6. The dosage was increased to 500 mg/d of extended phenytoin sodium capsules for another month, the steady state phenytoin total concentration equals 22. Suggest a new phenytoin dosage regimen designed to achieve a steady-state phenytoin concentration within the therapeutic range. According to the Michaelis-Menten equation, a dose equal to 450 mg of phenytoin sodium is required to achieve a steady-state concentration equal to 10. A steady-state trough total phenytoin serum concentration should be measured after steady state is attained in 7–14 days. Phenytoin serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of phenytoin toxicity. The patient was prescribed 300 mg/d of extended phenytoin sodium capsules for 1 month, and the steady-state phenytoin total concentration equals 10. At that time, the dose was increased to 350 mg/d of extended phenytoin sodium capsules for an additional month, and the resulting steady state concentration was 15. Suggest a new phenytoin dosage regimen increase designed to achieve a steady-state phenytoin concentration within the upper end of the therapeutic range. According to the Michaelis-Menten equation, a dose equal to 400 mg of phenytoin sodium is required to achieve a steady-state concentration equal to 24. Phenytoin serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of phenytoin toxicity. The most reliable computer programs use a nonlinear regression algorithm that incorporates components of Bayes’ theorem. Nonlinear regression is a sta- tistical technique that uses an iterative process to compute the best pharmacokinetic parameters for a concentration/time data set. The computer program has a phar- macokinetic equation preprogrammed for the drug and administration method (oral, intra- venous bolus, intravenous infusion, etc. Typically, a one-compartment model is used, although some programs allow the user to choose among several different equations. Using population estimates based on demographic information for the patient (age, weight, gender, liver function, cardiac status, etc. Kinetic parameters are then changed by the computer program, and a new set of estimated serum concentrations are computed. Bayes’ theorem is used in the computer algorithm to balance the results of the computations between values based solely on the patient’s serum drug concentrations and those based only on patient popula- tion parameters. Results from studies that compare various methods of dosage adjustment have consistently found that these types of computer dosing programs perform at least as well as experienced clinical pharmacokineticists and clinicians and better than inexperi- enced clinicians. Some clinicians use Bayesian pharmacokinetic computer programs exclusively to alter drug doses based on serum concentrations. An advantage of this approach is that consis- tent dosage recommendations are made when several different practitioners are involved in therapeutic drug monitoring programs. However, since simpler dosing methods work just as well for patients with stable pharmacokinetic parameters and steady-state drug concentrations, many clinicians reserve the use of computer programs for more difficult situations. Those situations include serum concentrations that are not at steady state, serum concentrations not obtained at the specific times needed to employ simpler meth- ods, and unstable pharmacokinetic parameters. When only a limited number of phenytoin concentrations are available, Bayesian pharmacokinetic computer programs can be used to compute a complete patient pharmacokinetic profile that includes Vmax, Km, and vol- ume of distribution. These are distinct advantages compared to the other methods used to adjust phenytoin dose based on one steady-state serum concentration. Many Bayesian pharmacokinetic computer programs are available to users, and most should provide answers similar to the one used in the following examples.

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At extensive first-pass extraction in the liver muscle relaxant headache zanaflex 2 mg order line, the start of therapy muscle relaxant starting with z purchase 4 mg zanaflex otc, a prostaglandin-medi- and there hydrolyzed to active metabolites muscle relaxant headache discount 4 mg zanaflex with amex. They may cause damage to liv- tion, ef cient hepatic extraction serves to er and skeletal muscle (myalgia, myopathy, confine the action of statins to the liver. The mechanism of action of hepatic cholesterol content does not fall be- fibrates is not completely understood. By means of diuretics, an Diuretics (saluretics) elicit increased produc- attempt is made to maintain urinary flow. In the strict sense, Use of either osmotic or loop diuretics is the term is applied to drugs with a direct indicated. The predominant action of such Massive use of diuretics entails a hazard of agents is to augment urine excretion by in- adverse effects (A): hibiting the reabsorption of NaCl and water. Inedem a in erythrocyte and thrombocyte concen- there is swelling of tissues owing to accumu- trations, bringing an increased risk of in- lation of fluid, chiefly in the extracellular travascular coagulation or thrombosis. As a result, plasma pro- latory responses (B), namely, activation of tein concentration rises along with oncotic the renin–angiotensin–aldosterone system pressure. Because of the diminished blood water, fluid will shift from interstitium into volume, renal blood flow is jeopardized. Thefluidcontentoftissues leads to release from the kidneys of the hor- thus falls and the edemas recede. The de- mone renin, which enzymatically catalyzes crease in plasma volume and interstitial vol- the formation of angiotensin I. Even augment the effectiveness of diuretics by at low dosage, they decrease peripheral re- preventing this counterregulatory response. By lowering peripheral resistance, diuretics aid the heart in ejecting blood (reduction in afterload, p. The drugs principally used are thiazides (possibly combined with K+-sparing diu- retics) and loop diuretics. Mechanism of edema fluid mobilization by diuretics Protein molecules Edema Hemoconcentration Colloid- osmotic pressure Collapse, Mobilization of danger of edema fluid thrombosis Diuretic B. Therefore, special loops, ultrafiltration of plasma fluid into pores are built into the membrane to allow Bowman’s capsule yields primary urine. These consist of pro- the proximal tubules (pT), ~70% of the ultra- teins called aquaporins that, of necessity, filtrate is retrieved by iso-osmotic reabsorp- occur widely and with many variations in tion of NaCl and water. NaCl is again reabsorbed in the distal eral membrane region to allow passage of convoluted tubules, the connecting segment, water into the interstitium. These polyhydric of aquaporin molecules into the luminal alcohols cannot be absorbed and therefore plasmalemma. Since sage of water comes from the hyperosmolar body cells lack transport mechanisms for milieu of the renal medulla. The ef - tinal epithelium and thus need to be given cient mechanisms of reabsorption permit by intravenous infusion. The result of os- the production of ~1 l/day of final urine m oticdiuresisisalargevolum eofdilute from 150–180 l/day of primary urine. Osmotic diuretics are indicated in the basically occurs in similar fashion in all seg- prophylaxis of renal hypovolemic failure, ments of the nephron. The intracellular con- the mobilization of brain edema, and the centration of Na+ is significantly below that treatmentof acute glaucoma attacks(p. A long te resulting lum inal–intracellular concentrationgradient,movementofsodium ions across the membrane proceeds by a car- rier mechanism. This effectis basedontwomech- anisms: either the inward movement is di- minished or the outward transport impaired. NaCl reabsorption in proximal tubule and effect of mannitol Mannitol [Na+] = [Na+] [Na+] < [Na+] inside outside inside outside Luellmann, Color Atlas of Pharmacology © 2005 Thieme 166 Diuretics Loop diuretics include furosemide (fruse- ‡ Diuretics of the Sulfonamide Type mide), piretanide, and others. The site of action of these glomerulus, they are subject to tubular se- agents is the thick ascending limb of Henle’s cretion.

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Capreomycin (15 mg/kg/d) is an important injectable agent for treatment of drug-resistant tuberculosis spasms under left breastbone zanaflex 2 mg order on line. Strains of M tuberculosis that are resistant to streptomycin or amikacin usually are susceptible to capreomycin spasms down left leg zanaflex 4 mg order. Toxicity is reduced if 1 g is given two or three times weekly after an initial response has been achieved with a daily dosing schedule spasms between shoulder blades cheap zanaflex 4 mg without a prescription. This drug is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychotic reactions. Adverse effects, which are most common during the first 2 weeks of therapy, occur in 25% or more of patients, especially at higher doses. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria. Gastrointestinal symptoms are common and may be diminished by giving the drug with meals and with antacids. Kanamycin had been used for treatment of tuberculosis caused by streptomycin-resistant strains, but the availability of less toxic alternatives (eg, capreomycin and amikacin) has rendered it obsolete. Amikacin is playing a greater role in the treatment of tuberculosis due to the prevalence of multidrug-resistant strains. Prevalence of amikacin-resistant strains is low (< 5%), and most multidrug-resistant strains remain amikacin-susceptible. There is no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well. Serum concentrations of 30–50 mcg/mL are achieved 30–60 minutes after a 15 mg/kg intravenous infusion. Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains. This drug must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases. Fluoroquinolones In addition to their activity against many gram-positive and gram-negative bacteria (discussed in Chapter 46), ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M tuberculosis at concentrations less than 2 mcg/mL. Levofloxacin tends to be slightly more active than ciprofloxacin against M tuberculosis, whereas ciprofloxacin is slightly more active against atypical mycobacteria. Fluoroquinolones are an important addition to the drugs available for tuberculosis, especially for strains that are resistant to first-line agents. Resistance, which may result from one of several single point mutations in the gyrase A subunit, develops rapidly if a fluoroquinolone is used as a single agent; thus, the drug must be used in combination with two or more other active agents. Linezolid Linezolid (discussed in Chapter 44) inhibits strains of M tuberculosis in vitro at concentrations of 4–8 mcg/mL. Linezolid has been used in combination with other second- and third-line drugs to treat patients with tuberculosis caused by multidrug-resistant strains. Significant adverse effects, including bone marrow suppression and irreversible peripheral and optic neuropathy, have been reported with the prolonged courses of therapy that are necessary for treatment of tuberculosis. A 600 mg (adult) dose administered once a day (half of that used for treatment of other bacterial infections) seems to be sufficient and may limit the occurrence of these adverse effects. Although linezolid may prove to be an important new agent for treatment of tuberculosis, at this point it should only be used for multidrug-resistant strains that also are resistant to several other first- and second-line agents. Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. The typical dosage of rifabutin is 300 mg/d unless the patient is receiving a protease inhibitor, in which case the dosage should be reduced. If efavirenz (also a cytochrome P450 inducer) is used, the recommended dosage of rifabutin is 450 mg/d.

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This fatty double-layered vascular omentum spasms from overdosing proven zanaflex 4 mg, which then adheres to the diseased area membrane hangs like an apron from the greater curvature of bowel muscle relaxant starting with b purchase cheapest zanaflex. Direct omental spread by a referred to as the "policeman of the abdomen" because of transcoelomic route is common for carcinoma of the its apparent ability to migrate to any infamed area and ovary muscle relaxant lactation zanaflex 4 mg purchase on line. When a part of bowel becomes infamed, it ceases In computed tomography imaging and during peristalsis. This a peristaltic area is referred to as a local laparotomy, the thickened omentum is referred to paralytic ileus. They allow some movement and provide a conduit for vessels, nerves, and lymphatics to reach the viscera and include: • the mesentery-associated with parts of the small intestine, • the transverse mesocolon-associated with the trans­ verse colon, and • the sigmoid mesocolon-associated with the sigmoid colon. Mesentery The mesentery is a large, fan-shaped, double-layered fold of peritoneum that connects the jejunum and ileum to the posterior abdominal wall (Fig. Its superior attach­ ment is at the duodenojejunal junction, just to the lef of the upper lumbar part of the vertebral column. It passes obliquely downward and to the right, ending at the ileoce­ cal junction near the upper border of the right sacro-iliac joint. In the fat between the two peritoneal layers of the mesentery are the arteries, veins, nerves, and lymphatics that supply the jejunum and ileum. Transverse mesocolon The transverse mesocolon is a fold of peritoneum that Root of the sigmoid mesocolon connects the transverse colon to the posterior abdominal wall (Fig. Between its layers are the arteries, veins, nerves, and lymphatics related to the trans­ vertebra SilL The sigmoid and superiorrectalvessels, along verse colon. The anterior layer of the transverse mesocolon withthe nerves and lymphatics associatedwiththe sigmoid is adherent to the posterior layer of the greater omentum. Sigmoid mesocolon Ligaments The sigmoid mesocolon is an inverted, V-shaped perito­ Peritoneal ligaments consist of two layers of peritoneum neal fold that attaches the sigmoid colon to the abdominal that connect two organs to each other or attach an organ wall (Fig. They the left common iliac artery into its internal and external are usually named after the structures being connected. Stomach Associated with the esophagus, asitenters the abdomi­ Thestomach is themostdilated partof thegastrointestinal nal cavity, are the anterior and posterior vagal trunks: tract and has a J-like shape (Figs. Posi­ tioned between the abdominal esophagus and the small • The anterior vagal trnnk consists of several smaller intestine, the stomach is in the epigastric, umbilical, and trunks whose fbers mostly come from the left vagus left hypochondrium regions of the abdomen. Short gastric arteries Splenic artery Esophageal branch Right gastric artery Left gastro­ omental artery Right gastro-omental artery Posterior superior pancreaticoduodenal artery Anterior superior pancreaticoduodenal artery Gastroduodenal artery Fig. It is marked on the surface of the organ by the pyloric constriction and contains a thick­ ened ring of gastric circular muscle, the pyloric sphinc­ ter. Other features of the stomach include: Lesser curvature Angular • the greater curvature, which is a point of attachment forthe gastrosplenic ligament and the greater omentum; • the lesser curvature, which is a point of attachment for the lesser omentum; • the cardial notch, which is the superior angle created when the esophagus enters the stomach; and curvature • the angular incisure, which is a bend on the lesser Body curvature. This hollow tube, which is this part of the duodenum is referred to as the ampulla approximately 6 to 7 m long with a narrowing diameter or duodenal cap, and most duodenal ulcers occur in this from beginning to end, consists of the duodenum, the part of the duodenum. This Its anterior surface is crossed by the transverse colon, C-shaped structure, adjacent to the head of the pancreas, posterior to it is the right kidney, and medial to it is is 20 to 2 5 em long and is above the level of the umbilicus; the head of the pancreas. It contains the major duodenal papilla, which is the Inferior vena cava Poral vein Right suprarenal Bile duct Duodenum -superior par Position of minor duodenal papilla Left kidney Position of major Superior mesenteric duodenal papilla vein and artery Descending colon Duodenum -ascending part Fig. It is mostly in the left upper quadrant Posterior superior pancreaticoduodenal artery Left gastric artery Hepatic artery proper Gastroduodenal Right gastro­ artery omental artery Anterior superior pancreaticoduodenal Superior mesenteric artery artery Posterior inferior pancreaticoduodenal Abdominal aorta artery Anterior inferior pancreaticoduodenal artery Fig. Additionally, the inner mucosal lining of the jejunum is characterized by numerous prominent folds that circle the lumen (plicae circulares). The less prominent arterial arcades and longer vasa recta (straight arteries) compared to those of the ileum are a unique char­ acteristic of the jejunum (Fig. Ileum The ileum makes up the distal three-ffths of the small intestine and is mostly in the right lower quadrant. Com­ pared to the jejunum, the ileum has thinner walls, fewer and less prominent mucosal folds (plicae circulares), shorter vasa recta, more mesenteric fat, and more arterial arcades (Fig. Two flaps pro­ jecting into the lumen of the large intestine (the ileocecal fold) surround the opening (Fig. Possible functions of the ileocecal fold include preventing reflux from the cecum to the ileum, and regulating the passage of contents from the ileum to the cecum. In the clinic Epithelial transition between the abdominal esophagus and stomach The gastroesophageal junction is demarcated by a transition from one epithelial type to another epithelial type. In some people, the histological junction does not lie at the physiological gastroesophageal junction but is in the lower one-third of the esophagus. This may predispose these people to esophageal ulceration and is also associated with an increased risk of Jejunal and ileal arteries adenocarcinoma.

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The natural monobactams have little imipenem is combined with cilastatin muscle relaxant pakistan generic zanaflex 4 mg overnight delivery, an inhibitor of antimicrobial activity spasms during pregnancy order line zanaflex. Additional pharmacokinetic infor- (Azactam) spasms icd 9 code buy zanaflex 4 mg low cost, has excellent activity against gram-negative mation appears in Table 45. Aztreonam has low Imipenem–cilastatin is one of the drugs of first affinity for penicillin-binding proteins in streptococci, choice for the empirical therapy of many polymicrobial staphylococci, and anaerobes and therefore has no sig- pulmonary, intraabdominal, and soft tissue infections. Risk factors for relates to the aminothiazolyl oxime moiety on the acyl seizures are old age, head trauma, previous seizure dis- side chain. The pharmacokinetic properties of aztreonam are similar to those of the parenteral cephalosporins (Table Meropenem 45. Aztreonam is not bioavailable after oral adminis- Meropenem (Merrem) is another carbapenem antibi- tration. During its distribution phase, the drug can otic with a broad spectrum of activity comparable to achieve therapeutic concentrations in cerebrospinal that of imipenem. Conse- position on the five-member ring confers stability to de- quently, aztreonam is an alternative antibiotic to the hydropeptidase I. Consequently, meropenem does not cephalosporins for the therapy of meningitis caused by require administration with cilastatin. Most of the ad- imipenem–cilastatin and meropenem are used to treat verse effects of aztreonam are local reactions at the site infections caused by highly resistant Klebsiella pneumo- of injection. The major clinically relevant dis- lergic reactions in patients with a history of type I hy- tinction between imipenem–cilastatin and meropenem persensitivity to other -lactam antibiotics. A 32-year-old man with quadriplegia and neuro- (A) Amikacin genic bladder was admitted to the hospital from a (B) Lomefloxacin long-term care facility. A year ago, the patient de- (D) Netilmicin veloped urticaria, wheezing, and hypotension within (E) Penicillin V an hour after his first dose of nafcillin. He had had unpro- rent admission, the physician examiner noted fever, tected intercourse with multiple partners. Physical quadriplegia, and chronic indwelling bladder examination revealed a purulent urethral discharge catheter. She linking of peptides in cell wall murein (peptidogly- could not recall signs or symptoms of primary or can) secondary syphilis in the past year. Parents brought their 3-year-old boy to the outpa- vious syphilis serology tests for purposes of compar- tient clinic because of a facial rash. Which of the following would be the best was one of several children sent home from day care treatment for the patient? Physical examination re- (A) Benzathine penicillin G vealed a normal, healthy boy with discrete erythe- (B) Doxycycline matous papular eruptions on his cheeks. A 26-year-old woman, a kindergarten teacher, had (A) Dapsone pharyngitis last year treated with ampicillin for 3 (B) Dicloxacillin days. The carbapenems (imipenem streptococcal test of a pharyngeal specimen is posi- and meropenem) and the monobactam (aztreonam) tive. Amphotericin should avoid drugs in the penicillin class, including B inhibits fungal cell membrane integrity by bind- penicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, ing to ergosterols to create pores. Isoniazid inhibits ampicillin, amoxicillin, ticarcillin, piperacillin, and KasA, a -ketoacyl carrier protein synthetase, and mezlocillin. The causative organism with a history of type I allergic response to penicillin is either Streptococcus pyogenes (group A) or S. Aztreonam may be used safely in patients with his- Doxycycline is used to treat skin infections with tory of type I allergic response to penicillin. The patient is pregnant and has latent syphilis of (bacillary angiomatosis), Borrelia burgdorferi (Lyme indeterminate duration. Benzathine penicillin G is the drug of (acne vulgaris), Vibrio vulnificus and Vibrio damsela first choice for treating latent syphilis. The question does and tetracycline are alternatives treatments for non- not provide historical or epidemiological informa- pregnant patients with latent syphilis. Ketoconazole is Spectinomycin is not effective against syphilis; it is a used to treat fungal infections of the skin (tinea treatment for disseminated gonorrhea in patients capitis, tinea cruris, tinea corporis, tinea pedis, tinea who are allergic to cephalosporins. The patient has exudative pharyngitis, presum- Penciclovir is a treatment for herpes simplex virus ably secondary to group A streptococcus. Ureidopenicillins and beta- Other reasonable alternatives are benzathine peni- lactam/beta-lactamase inhibitor combinations.

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However muscle relaxant baclofen 4 mg zanaflex buy with mastercard, the presence of the antagonist at the receptor site will block access of agonists to the receptor and prevent the usual agonist effect spasms hand purchase 4 mg zanaflex visa. What will happen if a drug has a much stronger affinity for the R than for the R state and stabilizes a large fraction ini a the R –D pool? In this scenario the drug will reduce any constitutive activity muscle relaxant pregnancy safe order 2 mg zanaflex with mastercard, thus resulting in effects that are the opposite ofi the effects produced by conventional agonists at that receptor. Inverse agonists of this receptor system cause anxiety and agitation, the inverse of sedation (see Chapter 22). Similar inverse agonists have been found for β adrenoceptors, histamine H and H receptors, and1 2 several other receptor systems. In some cases, the effect lasts only as long as the drug occupies the receptor, and dissociation of drug from the receptor automatically terminates the effect. In many cases, however, the action may persist after the drug has dissociated because, for example, some coupling molecule is still present in activated form. In the case of drugs that bind covalently to the receptor site, the effect may persist until the drug-receptor complex is destroyed and new receptors or enzymes are synthesized, as described previously for aspirin. In addition, many receptor-effector systems incorporate desensitization mechanisms for preventing excessive activation when agonist molecules continue to be present for long periods. Receptors and Inert Binding Sites To function as a receptor, an endogenous molecule must first be selective in choosing ligands (drug molecules) to bind; and second, it must change its function upon binding in such a way that the function of the biologic system (cell, tissue, etc) is altered. The selectivity characteristic is required to avoid constant activation of the receptor by promiscuous binding of many different ligands. The body contains a vast array of molecules that are capable of binding drugs, however, and not all of these endogenous molecules are regulatory molecules. Binding of a drug to a nonregulatory molecule such as plasma albumin will result in no detectable change in the function of the biologic system, so this endogenous molecule can be called an inert binding site. Such binding is not completely without significance, however, because it affects the distribution of drug within the body and determines the amount of free drug in the circulation. Pharmacokinetic Principles In practical therapeutics, a drug should be able to reach its intended site of action after administration by some convenient route. In some cases, however, an inactive precursor chemical that is readily absorbed and distributed must be administered and then converted to the active drug by biologic processes—inside the body. In only a few situations is it possible to apply a drug directly to its target tissue, eg, by topical application of an anti- inflammatory agent to inflamed skin or mucous membrane. Most often, a drug is administered into one body compartment, eg, the gut, and must move to its site of action in another compartment, eg, the brain in the case of an antiseizure medication. This requires that the drug be absorbed into the blood from its site of administration and distributed to its site of action, permeating through the various barriers that separate these compartments. For a drug given orally to produce an effect in the central nervous system, these barriers include the tissues that make up the wall of the intestine, the walls of the capillaries that perfuse the gut, and the blood-brain barrier, the walls of the capillaries that perfuse the brain. Finally, after bringing about its effect, a drug should be eliminated at a reasonable rate by metabolic inactivation, by excretion from the body, or by a combination of these processes. Passive diffusion in an aqueous or lipid medium is common, but active processes play a role in the movement of many drugs, especially those whose molecules are too large to diffuse readily (Figure 1–4). Drug vehicles can be very important in facilitating transport and permeation, eg, by encapsulating the active agent in liposomes and in regulating release, as in slow release preparations. Newer methods of facilitating transport of drugs by coupling them to nanoparticles are under investigation. Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg, tight junctions, A), or through lipid cell membranes (B). Very impermeant drugs may also bind to cell surface receptors (dark binding sites), be engulfed by the cell membrane (endocytosis), and then released inside the cell or expelled via the membrane-limited vesicles out of the cell into the extracellular space (exocytosis, D). Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the permeating drug, a downhill movement described by Fick’s law (see below). Drug molecules that are bound to large plasma proteins (eg, albumin) do not permeate most vascular aqueous pores. If the drug is charged, its flux is also influenced by electrical fields (eg, the membrane potential and—in parts of the nephron—the transtubular potential).

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The radial nerve travels into the forearm deep to the The base of the cubital fossa is an imaginary margin of the brachioradialis muscle anterior to the elbow line between the readily palpable medial and lateral joint quinine spasms generic 4 mg zanaflex with mastercard. The radial artery is immediately readily visible in the distal forearm and can be used as lateral to this tendon and this site is used for taking a landmarks to locate major vessels and nerves muscle spasms zinc cheap 2 mg zanaflex free shipping. In the anterior aspect of the distal forearm kidney spasms causes zanaflex 4 mg buy, the tendons • The tendon of the flexor carpi ulnaris iseasily palpated of the flexor carpi radialis, flexor carpi ulnaris, and pal­ along the medial margin of the forearm and inserts maris longus muscles can be easily located either by palpat­ on the pisiform, which can also be palpated by following ing or by asking a patient to flex the wrist against the tendon to the base of the hypothenar eminence resistance. The ulnar artery and ulnar nerve travel Thenar eminence Flexor carpi radialis tendon Radial artery A Flexor carpi ulnaris Hypothenar eminence Pisiform Extensor carpi radialis brevis tendon carpi ulnaris tendon Extensor digitorum c tendon Abductor pollicis longus tendon Extensor pollicis brevis tendon Anatomical snuffbox Extensor pollicis longus tendon B D Fig. The median nerve is also medial to the flexor carpi radialis tendon and lies under the pal­ maris longus tendon. Their position can be visualized by rapidly and repeatedly flexing and extending the fngers frommedial to lateral. The medial margin of this triangular area is the tendon of the extensor pol- licis longus, which swings around the dorsal tubercle of the radius and then travels into the thumb. The pulse of the radial artery can be felt in the floor of the anatomical snuffox in the relaxed wrist. The cephalic vein crosses the roof of the anatomical A thenar eminence occurs at the base of the thumb and snuffox, and cutaneous branches of the radial nerve is formed by the underlying thenar muscles. A similar can be felt by moving a fnger back and forth along the hypothenar eminence occurs along the medial margin of tendon of the extensor pollicis longus muscle. The appearance of the thenar and hypothenar eminences, and the positions of the fngers change when the ulnar and median nerves Normal appearance of the hand are compromised. In the resting position, the palm and digits of the hand Major superfcial veins of the upper limb begin in the have a characteristic appearance. The pad of the thumb the medial side of the network and the cephalic vein origi­ is positioned at a 90° angle to the pads of the fngers. Motor function of the median and ulnar nerves in the hand • The pisiform bone is readily palpable at the distal end of The ability toflex the metacarpophalangeal joints while at the flexor carpi ulnaris tendon. Animaginary line between these two points marks the Adducting the fngers tograsp anobject placed between proximal margin of the flexor retinaculum. Flexing the metacarpophalangeal joints and extending the interphalangeal joints: the "ta-ta" position. Visualizing the positions ofthe superfcial • Axillary pulse: axillary artery inthe axilla lateral tothe and deep palmar arches apex of the dome of skin covering the floor of the axilla. The positions of the superfcial and deep palmar arches in • Brachial pulse in midarm: brachial artery on the medial the hand can be visualized using bony landmarks, muscle side of the arm in the cleft between the biceps brachii eminences, and skin creases (Fig. The arch curves laterally across the palm is the position where a stethoscope is placed to hear the anterior to the longflexor tendons in the hand. The deep palmar arch of the extensor pollicis brevis and abductor pollicis is more proximal in the hand than the superfcial palmar longus muscles. Proximal transverse Distal wrist crease Proximal Supericial palmar arch Deep palmar arch Hook of hamate Fig. The proximal transverse skin crease of the palm and distal wrist crease are labeled and the superfcial and deep palmar arches shown in overlay. A 45-year-old mancame tohisphysician complaining The supraspinatus and infraspinatus muscles are supplied of pain and weakness in his right shoulder. The patient only these muscles were involved, it is highly likely that recalled having some minor shoulder tenderness the muscle atrophy is caused by denervation. On examination ofthe shoulder, there was marked wasting of the muscles in the supraspinous and The typical site for compression of the suprascapular infraspinous fossae. The patient found initiation nerve isthe suprascapular notch (foramen) on the of abduction diffcult and there was a weakness superior margin of the scapula. The surgeon was intrigued and asked patient will improve, but she was happy that she had an the patient to reveal this spike. Once the axillary artery has been identifed, a small needle can be placed beside the vessel The anesthetic was injected into the axillary sheath. It would be almost impossible to anesthetize the wrist in The local anesthetic tracks along the axillary sheath in the forearm because local anesthetic would have to be this region.

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The pontine tegmentum is reduced as 3 The Pons at the Level compared to the large ventral portion infantile spasms 2012 zanaflex 2 mg purchase with visa, which appears of the Advent of the Cerebellum even larger than at the upper or lower levels spasms pancreas purchase zanaflex 4 mg with amex. The medial longitudinal fasciculi are still visible beneath This axial cut spasms 1983 cheap 2 mg zanaflex visa, situated at the advent of the cerebel- the floor of the fourth ventricle in their paramedian lum, passes through the caudal pons, showing later- 238 Chapter 8 complex in the medulla and ascending fibers origi- nating from the lower brainstem reticular formation projecting to the thalamus. Most anteriorly and later- ally in the cerebellopontine cisterns emerge the root fibers of the cochleovestibular and facial nerves. C The Medulla Oblongata This section passes through the inferior part of the floor of the fourth ventricle. Anterior to the midal tract; 11, transverse pontine bundles; 12, brachium restiform body on the midlateral aspect of the me- pontis (middle cerebellar peduncle); 13, brachium dulla, the most characteristic structure of the cut is conjunctivum (superior cerebellar peduncle); 14, dentate represented by the large inferior olivary nuclear nucleus; 15, vestibular nerve; 16, facial nerve; 17, flocculus; 18, complex, which is a convoluted band of gray matter nodulus; 19, basilar artery; 20, cerebellar hemisphere; 21, cerebellopontine angle; 22, transverse sinus; 23, tonsil of cer- appearing as a folded bag with a hilus opening medi- ebellum; 24, cochlea; 25, semicircular canals; 26, internal au- ally. Anterior to this olivary nucleus and its sur- ditory canal; 27, cochlear nerve; 28, inferior vestibular nerve; rounding myelinated fibers forming the amiculum 29, middle cerebellar peduncle; 30, pons. Dorsal to the pyramids are the medial lemnisci, oc- cupying the paramedian areas on each side of the ally the massive middle cerebellar peduncles (Fig. The cavity of the fourth ventricle is enlarged at Immediately dorsolateral to the inferior olive on the this level as compared to the upper level, the nodule lateral aspect of the medulla are situated the anterior of the inferior vermis occupying its roof, bordered and lateral spinothalamic tracts, which are separated laterally in the cerebellar white matter by the dentate from the medial lemnisci (Figs. The ventral portion shows anteriorly the The central gray matter spreads out over the floor massive bundles of the corticofugal, corticospinal, of the fourth ventricle cutting and containing vent- and corticobulbar fibers and, in the anterior portion, rolaterally the hypoglossal nucleus, the dorsal nucle- the transverse pontine fibers which contribute to us of the vagus and the nucleus of the tractus solitar- form the middle cerebellar peduncles. At the mid-olivary level, the medullary reticular the longitudinal corticospinal tracts are the crossing formation occupies the area ventral to the periven- fibers bundles of the trapezoid body, traversing hor- tricular gray matter and dorsal to the inferior olivary izontally the ventral portion of the medial lemnisci complex. Laterally mainly represented by the gigantocellular reticular are found the lateral and ventral spinothalamic nucleus, in the area medial and dorsal to the inferior tracts and dorsolaterally the central tegmental tracts. The medulla is surrounded anteriorly and lat- Dorsolateral to the latter is a nuclear mass corre- erally by the perimedullary cistern, containing ante- sponding at least partly to the facial motor nucleus. This tract con- sists mainly of descending fibers from the mesen- cephalic nuclei which project to the inferior olivary The Brainstem and Cerebellum 239 formation of the brainstem is continuous rostrally with the intralaminar nuclear group of the thalamus and some of the subthalamic region, and caudally with the intermediate gray matter of the spinal cord. In the brainstem, the reticular formation is bound by the long ascending and descending tracts as well as the nuclei of the origin of the cranial nerves, occupy- ing a large area of the brainstem tegmentum. The reticular formation plays an important role in the regulation of autonomic functions, muscle reflexes, pain sensation, and behavioral arousal. These bral artery; 19, sigmoid sinus; 20, lateral or transverse sinus longitudinal zones show distinctive cytoarchitectur- al organization as well as fiber connections (Brodal 1957, 1981; Martin et al 1990; Olszewsky and Baxter 1954). In addition, the longitudinal subdivisions are not independent entities, but are largely intercon- nected. In fact, almost all neurons of the reticular formation project axonal fibers in both rostral and caudal directions with collaterals oriented in all di- rections. It is often impossible, in fact, to define ana- tomically definite conduction paths in the reticular formation due to the diffused patterns of connec- tions. The reticular nuclei are often very poorly delineated, consisting mainly of groups of aggregated neurons Fig. Thus, nus; 13, cerebellar falx; 14, clivus currently, only topographical data may help in local- izing some of the major nuclear formations de- D The Brainstem Reticular Formation scribed below. The reticular formation is a phylogenetically old 2 Functional and Clinical Considerations portion of the brain, occupying the central region of the brainstem throughout most of its extent and con- a The Raphe Nuclei or Median Zone sisting of intermingled gray and white matter. The The median zone contains the raphe nuclei, which term reticular formation refers to the fact that the include the dorsal raphe nucleus in the midbrain, the cytoarchitecture of this region is composed of loose- superior central nucleus, the pontine raphe nucleus, ly arranged cells and diffusely organized related fi- and the nucleus raphes magnus in the pons, and the bers arranged in a complex network. Topographically, the large dorsal c The Lateral Reticular Zone raphe nucleus is located in and ventral to the periaq- The lateral reticular formation is limited to the pons ueductal gray matter. The pontine raphe nucle- cludes the pedunculopontine nucleus, the medial us is located between the nucleus raphe magnus and and the lateral parabrachial nuclei in the pons, and the central superior nucleus, which is situated in the the lateral reticular nucleus in the medulla. The nucle- dunculopontine nucleus is found in the lateral teg- us raphes pallidus is found in the ventral medulla mentum, ventral to the inferior colliculus. At the oblongata, and the nucleus raphes obscurus is found pontine level, surrounding the medial and lateral more dorsally to the latter at the same level. Histoflu- regions of the superior cerebellar peduncle, are orescence and immunohistochemical techniques found the medial and lateral parabrachial nuclei. The have shown that many cell groups lying in this medi- medial nucleus receives inputs from the gustatory an zone are serotoninergic neurons expressing in- nucleus of the nucleus solitarius, and the lateral nu- dolamine serotonin. Other neurons display immu- cleus receives general visceral afferents from the cau- noreactivity through neuropeptides and amino dal portion of the nucleus solitarius. The fibers originating from serotoninergic project efferents to the hypothalamus and the neurons in the brainstem are extensively distributed amygdaloid body.

Will, 51 years: Assume that this concentration of free drug produces the desired effect in the patient without producing toxicity. He is certainly also alcohol dependent, and abrupt termination will likely lead to a withdrawal syndrome (eg, agitation, hallucinations, tremor, seizures, etc). Posterior to the neck of the pan­ denum just above the major duodenal papilla at the minor creas, the superior mesenteric and splenic veins join to duodenal papilla (Fig.

Urkrass, 24 years: The ability the basal plasma membrane into the pertechnetate and of the thyroid gland to concentrate radioactive pertech- eventually into the circulation. The manifestation of this phenomenon in the subject is the placebo response (Latin, “I shall please”) and may involve objective physiologic and biochemical changes as well as changes in subjective complaints associated with the disease. White cell and differential counts and a throat culture are indicated in such cases, followed by appropriate antibiotic therapy.

Hamid, 62 years: It is Cimetidine inhibits cytochromes P450 and there is poten- probably advisable not to co-administer antacids with tial for increased effect from any drug with a low thera- drugs that are intended for systemic effect by the oral route. The same graphical scheme introduced in the hepatic disease section of this chapter can be used to understand the clinical impact of drug interactions (Figures 3-6–3-10). This dose is identical to that derived for the patient using the linear pharmacokinetics method and the Pharmacokinetic Concepts method (65 mg every 12 hours).

Thorus, 49 years: Other single base substitutions may alter the splicing of exons and introns, or affect sequences involved in regulating gene Mis-sense mutation expression such as gene promoters or polyadenylation sites. Pharmacists put the name of the medication on the label unless directed otherwise by the prescriber, and some medications have the name of the drug stamped or imprinted on the tablet or capsule. Duetotheirchelatingpropertieswithcalciumphosphate, Tetracyclines have a broad range of antimicrobial activity tetracyclines are selectively taken up in the teeth and grow- and differences between the individual members have tra- ing bones of the fetus and of children.

Deckard, 34 years: Once confrmed, the clinician must attempt to subcutaneous spread can induce a rare manifestation of stage the tumor. Inability to swallow leads to drooling, while bradyki- specific entities, such as viral inflammation (e. Accumulation of tau appears to be associated with dissociation from microtubules in neurons, which has stimulated interest in drugs that inhibit microtubule disassembly, such as epothilone-D.

Baldar, 65 years: You decide on a nicotine requires attention to both the positive and negative patch and combine this strategy with counseling (withdrawal) reinforcement properties of nicotine and motivational therapy from a professional and tobacco use. Mechanism of Action The mechanism of action of carbamazepine appears to be similar to that of phenytoin. The lithium elimination rate constant is computed using the two serum concentrations: k = (ln C − ln C )/Δt = [ln (0.

Yussuf, 55 years: The cuneocerebellar tract, which is ing from the spinal cord and the cerebral cortex to uncrossed, may be considered as the upper limb the cerebellar cortex. For the purposes of this example, the desired steady-state peak and trough concentrations will be 30 μg/mL and 10 μg/mL, respectively. The suggested initial dosage rate for immediate-release carbamazepine tablets in an adult patient is 200 mg twice daily (400 mg/d).

Amul, 50 years: In Bradykinin exerts its physiological effects via two the brain, natriuretic peptides are involved in the regu- receptors, the B1 and B2 receptors, with most of its lation of central control of cardiovascular functions. Dissemination of infection results in end-organ disease, including retinitis, colitis, esophagitis, central nervous system disease, and pneumonitis. As previously discussed, the identification and subclassification of families of neuronal sodium channels has spurred research aimed at development of more selective sodium channel blockers.

Daryl, 27 years: Yohimbine can greatly elevate blood pressure if administered to patients receiving norepinephrine transport- blocking drugs. Dosage inevitably include cholinergic symptoms, with nausea, tends to be slightly higher and combinations of different diarrhoea and abdominal cramps appearing commonly. The intravenous preparation is transient visual disturbance in 30% of patients (blurring, not available in many countries.

Vatras, 35 years: Environmental modification The effects of some genetic disorders may be minimised by avoiding or reducing exposure to adverse environmental factors. Arteries and veins In the clinic Brachial artery Blood pressure measurement The major artery of the arm, the brachial artery, is found Blood pressure measurement is an extremely important in the anterior compartment (Fig. Pubic tubercle lata Deep fascia and the saphenous opening Fascia lata The outer layer of deep fascia in the lower limb forms a thick "stocking-like" membrane, which covers the limb and lies beneath the superfcial fascia (Fig.

Kerth, 46 years: Third, selectivity of the drug’s actions may be increased by manipulating the concentrations of drug available to receptors in different parts of the body, for example, by aerosol administration of a glucocorticoid to the bronchi in asthma. Why might this patient have changes in urine output, heart rate, and other parameters that are consistent with volume depletion even though he has edema on physical examination and his admission weight was indicative of volume overload? It exits the pelvis briefly through the greater sciatic foramen but between the lateral aspect of the uterus and the pelvic side walls.

Kalan, 39 years: Main is absorbed from the gastrointestinal tract, partly metabo- adverse effects are related to the central nervous system lised and partly excreted in the urine (t½ 13 h). This treatment modality has recently re- 1-2–5-6-Tetrahydropyridine), a neurotoxin, which ceived much attention and consists of lesional sur- produces a chronic form of parkinsonism in mon- gery directed to specific targets or neuro-augmenta- keys, the signs of which are identical to human Par- tive procedures using high frequency stimulation. These arteries originate from the aorta and posterior aspect of the xiphoid process, the inferior part of internal thoracic arteries, which in turn arise from the the body of the sternum, and the adjacent costal cartilages subclavian arteries in the root of the neck.

Sanuyem, 44 years: Impulses The latter phenomenon is known as a reentrant, or cir- may fail to conduct longer in the anterograde direction cus, rhythm. Untreated condition The medical problem is caused by drug abuse, alcohol use, Preventive/prophylactic or smoking. When physostigmine is deemed necessary, small doses are given slowly intravenously (1–4 mg in adults, 0.

Akrabor, 57 years: Drug Combinations Used in the Treatment of Visceral Leishmaniasis The use of drug combinations to improve treatment efficacy, shorten treatment courses, and reduce the selection of resistant parasites has been an active area of research. Treatment is typically indicated in a child whose final height would be otherwise significantly compromised (as evidenced by a significantly advanced bone age) or in whom the early development of pubertal secondary sexual characteristics or menses causes significant emotional distress. It smooth muscle relaxation occurs with b2-receptor decreases acid by mimicking the inhibitory effect of stimulation.

Yokian, 43 years: In addition to flexing and extending the forearm, the The clavicle articulates medially with the manubrium elbow joint allows the radius to spin on the humerus while of the sternum and laterally with the acromion of the sliding against the head of the ulna during pronation and scapula, which arches over the joint between the glenoid supination of the hand. Other nondepolarizing muscle relaxants This compound contains a quaternary nitro- include the pancuroniumcongeners vecuro- gen atom (N) and, at the opposite end of the nium and rocuronium,inadditiontoal- molecule, a tertiary N that is protonated at curonium derived from the alkaloid toxifer- physiological pH. Typically these fractures are associated The skull vault is a remarkably strong structure because it with scalp lacerations and can usually be treated with protects our most vital organ, the brain.

Rakus, 47 years: Thromboembolic prevention is strongly advocated in all Long-term treatment with warfarin is almost mandatory to patients, the level of risk determining the degree to which reduce embolic complications. Loperamide is a nonprescription opioid agonist that does not cross the blood-brain barrier and has no analgesic properties or potential for addiction. Planned procedures at intervals of 2–3 weeks re- forms in cirrhosis is not understood fully but involves ac- store a degree of quality of life.

Mortis, 58 years: It occupies the posterior extent of the in the representation of specific body areas (Penfield paracentral lobule. Using linear pharmacokinetics, the new dose to attain the desired concentration should be proportional to the old dose that produced the measured concentration: Dnew = (Css,new / Css,old)Dold = (9 μg/mL / 12 μg/mL) 170 mg = 128 mg, round to 130 mg The new suggested dose would be 130 mg every 8 hours to be started at next sched- uled dosing time. Amiodarone is effective given orally; agent, whose sole use is in the treatment of its enormous apparent distribution volume (70 L/kg) indi- arrhythmias.

Dennis, 48 years: Patients with severe chronic graft-versus-host disease may have involvement of the skin, liver, eyes, mouth, esophagus, or other organs similar to what might be seen with systemic autoimmune diseases. Within the next (B) H 2 12 h, the baby boy begins to have temperature fuc- (C) H 3 tuations, diffculty breathing, and reduced move- (D) H 4 ments. Polymyxin B (Aerosporin) and co- listin (polymyxin E, Coly-Mycin) are used in the treat- Adverse Effects ment of bacterial diseases.

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