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Each sternotomy to obtain access to the heart generic indocin 75 mg with amex rheumatoid arthritis nursing care plan, including the neurovascular bundle is situated deep to the external coronary arteries and the cardiac valves generic indocin 25 mg amex arthritis diet natural news. The patient is placed in the appropriate position Minimally invasive thoracic surgery (video-assisted to access the rib order indocin 50mg with amex rheumatoid arthritis diet gluten. The diaphragm is a thin musculotendinous structure In the median sagittal plane discount indocin 50mg amex arthritis diet omega 3, the diaphragm slopes that flls the inferior thoracic aperture and separates the inferiorly from its anterior attachment to the xiphoid, thoracic cavity from the abdominal cavity (Fig. Internal thoracic arteries Esophageal hiatus Esophagus Inferior vena cava Phrenic nerves Inferior phrenic arteries Musculophrenic artery Fig. During breathing, the dimensions of the thorax change • The thoracic duct passes behind the diaphragm with the in the vertical, lateral, and anteroposterior directions. Elevation and depression of the diaphragm signifcantly • The azygos and hemiazygos veinsmay also pass through alter the vertical dimensions of the thorax. Depression the aortic hiatus or through the crura of the results when the muscle fbers of the diaphragm contract. Changes in the anteroposterior and lateral dimensions Other structures outside the posterior attachments of result from elevation and depression of the ribs (Fig. The greater, lesser, and least splanch­ column, whereas the anterior ends of most ribs articulate nic nerves penetrate the crura. Because the anterior ends of the ribs are inferior to the posterior ends, when the ribs are elevated, they move the Arterial supply sternum upward and forward. Also, the angle between The arterial supply to the diaphragm is from vessels that the body of the sternum and the manubrium may become arise superiorly and inferiorly to it (see Fig. Whenthe ribs are depressed, the sternum above, pericardiacophrenic and musculophrenic arteries moves downward and backward. These vessels are branches of the movement changes the dimensions of the thorax in the internal thoracic arteries. This "bucket handle" phrenic arteries, which branch directly from the abdomi­ movement increases the lateral dimensions of the thorax nal aorta. Any muscles attaching tothe ribs can potentially move one rib relative to another and therefore act as accessory Venous drainage respiratory muscles. Muscles in the neck and the abdomen Venous drainage of the diaphragm is by veins that gener­ can f or alter the positions of upper and lower ribs. Innervation • Inferiorly, they extend to a level just above the costal The diaphragm is innervated bythephrenic nerves (C3, margin. Pleura Each pleural cavity is lined by a single layer of flat cells, mesothelium, and an associated layer of supporting con­ nective tissue; together, they form the pleura. The pleura is divided into two major types, based on location: • Pleura associated with the walls of a pleural cavity is parietal pleura (Fig. As a result, • Pleura covering the mediastinum is the mediastinal the surface of the lung, which is covered by visceral pleura, part. Parietal pleura The names given to the parietal pleura correspond to Covering the superior surface of the cervical pleura is a the parts of the wall with which they are associated distinct dome-like layer of fascia, the suprapleural mem­ (Fig. The suprapleural mem­ brane provides apical support for the pleural cavity in the The peripheral reflections of parietal pleura mark the root of the neck. This inferior slope of rib I to its articulation with the sleeve-like covering, and the structures it contains, forms manubrium. The root joins the medial surface Anteriorly, the pleural cavities approach each otherpos­ of the lung at an area referred to as the hilum of the terior to the upper part of the sternum. Here, the mediastinal pleura is continuous with the to the lower part of the sternum, the parietal pleura does visceral pleura. Visceral pleura Costomediastinal recesses The visceral pleura is continuous with the parietal pleura Anteriorly, a costomediastinal recess occurs on each at the hilum of each lung, where structures enter and leave side where costal pleura is opposed to mediastinal pleura. The visceral pleura is frmly attached to the The largest is on the left side in the region overlying the surface of the lung, including both opposed surfaces of the heart (Fig. Costodiaphragmatic recesses Although the visceral pleura is innervated by visceral afferent nerves that accompany bronchial vessels, pain is The largest and clinically most important recesses are generally not elicited from this tissue. The costodiaphragmatic recesses are the The lungs do not completely fll the anterior or posterior regions between the inferior margin of the lungs and infe­ inferior regions of the pleural cavities (Fig. They are deepest after results in recesses in which two layers of parietal pleura forced expiration and shallowest after forced inspiration. Oxygen­ from the midclavicular line and around the thoracic wall ated blood returns to the lef atrium via the pulmonary to the vertebral column, the inferior margin of the lung veins. The costodiaphragmatic recess is the region between Each lung has a half-cone shape, with a base, apex, two the two margins. During expiration, the inferior margin of thelung rises and the costodiaphragmatic recess becomes larger. In the clinic • The two surfaces-the costal surface lies immediately Pleural efusion adjacent to the ribs and intercostal spaces of the A pleural efusion occurs when excess fluid accumulates thoracic wall. As the fuid accumulates the mediastinum anteriorly and the vertebral column within the pleural space the underlying lung is posteriorly and contains the comma-shaped hilum compromised and may collapse as the volume of fuid of the lung, through which structures enter and increases. Unlike the ante­ rior and inferior borders, which are sharp, the posterior In the clinic border is smooth and rounded. Pneumothorax A pneumothorax is a collection of gas or air within the The lungs lie directly adjacent to, and are indented by, pleural cavity. The heart and tissue elasticity of the parenchyma causes the lung to major vessels form bulges in the mediastinum that indent collapse within the chest, impairing the lung function. Pathology, such as tumors, or abnormalities in accumulate to such an extent that the mediastinum is one structure can affect the related structure. It is covered by a sleeve of medi­ occur as a result of trauma, inflammation, smoking, and other underlying pulmonary diseases. The region outlined by this pleural reflec­ determined by the degree of air leak and the rate at tion on the medial surface of the lung is the hilum, where which the accumulation of gas occurs and the ensuing structures enter and leave. They include pain, shortness ofbreath, A thin blade-like fold of pleura projects inferiorly from and cardiorespiratory collapse, if severe. It may stabilize the position of the inferior lobe and may Lungs also accommodate the down-and-up translocation of The two lungs are organs of respiration and lie on either structures in the root during breathing. Air enters and leaves the lungs via main posterior to the roots of the lungs, while the phrenic nerves bronchi, which are branches of the trachea. Pulmonary artery (deoxygenated blood) Pulmonary veins (oxygenated blood) Pulmonary artery Pulmonary veins Pulmonary ligament Right lung Lef lung Fig. These include the: • two pulmonary veins, • a main bronchus, • heart, • bronchial vessels, • inferior vena cava, • nerves, and • superior vena cava, • lymphatics. Generally, the pulmonary artery issuperior atthe hilum, the pulmonary veins are inferior, and the bronchi are The right subclavian artery and vein arch over and are somewhat posterior in position. The Right lung oblique fssure of the left lung is slightly more oblique The right lung has three lobes and two fssures (Fig. Normally, the lobes are freely movable against During quiet respiration, the approximate position of each other because they are separated, almost to the hilum, the left oblique fssure can be marked by a curved line by invaginations of visceral pleura. The largest surface of the superior lobe is in contact with the upper part of the anterolateral wall, and the apex The approximate position of the oblique fssure on a of this lobe projects into the root of the neck. The costal patient, in quiet respiration, can be marked by a curved line surface of the inferior lobe is in contact with the posterior on the thoracic wall that begins roughly at the spinous and inferior walls. From the anterior border of the lower part of the supe­ The largest surface of the superior lobe is in contact rior lobe a tongue-like extension (the lingula of the left with the upper part of the anterolateral wall and the apex lung) projects over the heart bulge.

Additionally generic indocin 75 mg on-line can arthritis in neck cause headaches, the time difference between t2 and t1 discount 25 mg indocin fast delivery rheumatoid arthritis jewelry, in minutes order 25mg indocin free shipping arthritis cramps in fingers, was determined and placed directly in the calculation buy indocin 50 mg amex arthritis thumb. Additionally, the time difference between t2 and t1, in minutes, was determined and placed directly in the calculation. 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. The pharmacokinetic parameters that generated the estimated serum concentrations closest to the actual values are remem- bered by the computer program, and the process is repeated until the set of pharmacoki- netic parameters that result in estimated serum concentrations that are statistically closest to the actual serum concentrations are generated. 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 population parameters. Results from studies that compare various methods of dosage adjustment have consistently found that these types of computer dosing programs per- form at least as well as experienced clinical pharmacokineticists and clinicians and better than inexperienced 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. Many Bayesian pharmacokinetic com- puter programs are available to users, and most should provide answers similar to the one used in the following examples. He started taking procainamide sustained-release tablets 500 mg four times daily at 0700, 1200, 1800, and 2200 H. Enter patient’s demographic, drug dosing, and serum concentration/time data into the computer program. In this patient’s case, it is unlikely that the patient is at steady state so the linear phar- macokinetics method cannot be used. The pharmacokinetic parameters computed by the program are a volume of distribu- tion of 152 L, a half-life equal to 3. The oral one-compartment model equation used by the program to compute doses indicates that 2000 mg of procainamide every 6 hours will produce a steady-state trough concentration of 6. On the second day of therapy before the morning dose is administered, the procainamide serum concentra- tion equals 4. Enter patient’s demographic, drug dosing, and serum concentration/time data into the computer program. In this patient case, it is unlikely that the patient is at steady state so the linear pharma- cokinetics method cannot be used. The pharmacokinetic parameters computed by the program are a volume of distribu- tion of 110 L, a half-life equal to 15. The oral one-compartment model equation used by the program to compute doses indicates that 250 mg of procainamide sustained-release tablets every 8 hours will pro- duce a steady-state trough concentration of 5. Yesterday, he was prescribed procainamide 500 mg four times daily, and received the first two doses at 0800 H and 1200 H. Because he felt that his arrhythmia may have returned, the patient phoned his physician who advised him to increase the dose to 1000 mg (1800 H and 2200 H). Compute a procainamide sustained-release tablet dose that will provide a steady-state trough concentration of 6 μg/mL. Enter patient’s demographic, drug dosing, and serum concentration/time data into the computer program. In this patient’s case, it is unlikely that the patient is at steady state so the linear phar- macokinetics method cannot be used. The pharmacokinetic parameters computed by the program are a volume of distribu- tion of 114 L, a half-life equal to 7. The oral one-compartment model equation used by the program to compute doses indi- cates that 500 mg of procainamide immediate-release tablets every 6 hours will produce a steady-state trough concentration of 5. In this setting, it would not be acceptable to simply increase the maintenance dose and wait 3–5 half-lives for therapeutic serum concentrations to be established in the patient. A rational way to increase the serum concentrations rapidly is to administer a booster dose of procainamide, a process also known as “reloading” the patient with procainamide, computed using pharmacokinetic techniques. If the vol- ume of distribution for procainamide is known for the patient, it can be used in the calcu- lation. However, this value is not usually known and is assumed to equal the population average for the disease states and conditions present in the patient (Table 8-1). Concurrent with the administration of the booster dose, the maintenance dose of pro- cainamide is usually increased. However, usually the difference between the post- booster dose procainamide concentration and the ultimate steady-state concentration has been reduced by giving the extra dose of drug. After receiving an initial loading dose of procainamide (300 mg) and a main- tenance infusion of procainamide equal to 4 mg/min for 16 hours, her procainamide concentration is measured at 2. Some dosing schemes link together logically when considered according to their basic approaches or philosophies. In gen- eral, oral procainamide dosage forms, including most sustained-release tablets and cap- sules, have a bioavailability equal to 0. The equivalent oral sustained-release procainamide dose using a 12-hour dosage inter- val would be: Dpo = (k0 ⋅ τ ⋅ 60 min/h) / F = (5 mg/min ⋅ 12 h ⋅ 60 min/h) / 0. Clinicians should always con- sult the patient’s chart to confirm that current antiarrhythmic and other drug therapy is appropriate. Additionally, all other medications that the patient is taking, including pre- scription and nonprescription drugs, should be noted and checked to ascertain if a poten- tial drug interaction with procainamide exists. Suggest an initial oral procainamide dosage regi- men designed to achieve a steady-state procainamide concentration equal to 4 μg/mL. Compute a new oral procainamide dose that will provide a procainamide steady-state concentration of 6 μg/mL. Suggest an initial procainamide dosage regi- men designed to achieve a steady-state procainamide concentration equal to 4 μg/mL.

Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Box: Buspirone) discount 50 mg indocin amex rheumatoid arthritis swelling. Other classes of drugs that exert sedative effects include antipsychotics (see Chapter 29) indocin 75 mg low price rheumatoid arthritis facts, and many antidepressant drugs (see Chapter 30) buy 25mg indocin free shipping arthritis in dogs cost. Certain antihistaminic agents including hydroxyzine and promethazine (see Chapter 16) are also sedating discount indocin 50mg with visa arthritis worse at night. Other antihistaminic drugs with hypnotic effects, eg, diphenhydramine and doxylamine, are available in over-the-counter sleep aids. Absorption and Distribution The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Most of the barbiturates and other older sedative- hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration. This property is responsible for the rapid onset of the effects of triazolam, thiopental (see Chapter 25), and the newer hypnotics. If sedative-hypnotics are given during the predelivery period, they may contribute to the depression of neonatal vital functions. Sedative-hypnotics are also detectable in breast milk and may exert depressant effects in the nursing infant. Biotransformation Metabolic transformation to more water-soluble metabolites is necessary for clearance of sedative-hypnotics from the body. The microsomal drug-metabolizing enzyme systems of the liver are most important in this regard, so elimination half- life of these drugs depends mainly on the rate of their metabolic transformation. Ramelteon and Tasimelteon Melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep-wake cycle (see Chapter 16). In polysomnography studies of patients with chronic insomnia, ramelteon reduced the latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant withdrawal symptoms. The drug is rapidly absorbed after oral administration and undergoes extensive first-pass metabolism, forming an active metabolite with longer half-life (2–5 hours) than the parent drug. Concurrent use with the antidepressant fluvoxamine increases the peak plasma concentration of ramelteon over 50-fold! However, many phase I metabolites of benzodiazepines are pharmacologically active, some with long half-lives (Figure 22–5). For example, desmethyldiazepam, which has an elimination half-life of more than 40 hours, is an active metabolite of chlordiazepoxide, diazepam, prazepam, and clorazepate. Alprazolam and triazolam undergo α-hydroxylation, and the resulting metabolites appear to exert short-lived pharmacologic effects because they are rapidly conjugated to form inactive glucuronides. The short elimination half-life of triazolam (2–3 hours) favors its use as a hypnotic rather than as a sedative drug. The formation of active metabolites has complicated studies on the pharmacokinetics of the benzodiazepines in humans because the elimination half-life of the parent drug may have little relation to the time course of pharmacologic effects. Benzodiazepines for which the parent drug or active metabolites have long half-lives are more likely to cause cumulative effects with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with such drugs as estazolam, oxazepam, and lorazepam, which have relatively short half-lives and are metabolized directly to inactive glucuronides. Some pharmacokinetic properties of selected benzodiazepines and newer hypnotics are listed in Table 22–1. The metabolism of several commonly used benzodiazepines including diazepam, midazolam, and triazolam is affected by inhibitors and inducers of hepatic P450 isozymes (see Chapter 4). Buspirone Buspirone has selective anxiolytic effects, and its pharmacologic characteristics are different from those of other drugs described in this chapter. The drug is not effective in blocking the acute withdrawal syndrome resulting from abrupt cessation of use of benzodiazepines or other sedative-hypnotics. In marked contrast to the benzodiazepines, the anxiolytic effects of buspirone may take 3–4 weeks to become established, making the drug unsuitable for management of acute anxiety states. Buspirone is rapidly absorbed orally but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites. The drug does not potentiate effects of conventional sedative-hypnotic drugs, ethanol, or tricyclic antidepressants; and elderly patients do not appear to be more sensitive to its actions. Nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, headache, tinnitus, gastrointestinal distress, and paresthesias and a dose-dependent pupillary constriction may occur. Barbiturates—With the exception of phenobarbital, only insignificant quantities of the barbiturates are excreted unchanged. The major metabolic pathways involve oxidation by hepatic enzymes to form alcohols, acids, and ketones, which appear in the urine as glucuronide conjugates. The overall rate of hepatic metabolism in humans depends on the individual drug but (with the exception of the thiobarbiturates) is usually slow. The elimination half-lives of secobarbital and pentobarbital range from 18 to 48 hours in different individuals. Newer hypnotics—After oral administration of the standard formulation, zolpidem reaches peak plasma levels in 1–3 hours (Table 22-1). The elimination half-life of the drug is greater in women and is increased significantly in the elderly. In most cases, changes in renal function do not have a marked effect on the elimination of parent drugs. Phenobarbital is excreted unchanged in the urine to a certain extent (20–30% in humans), and its elimination rate can be increased significantly by alkalinization of the urine. This is partly due to increased ionization at alkaline pH, since phenobarbital is a weak acid with a pK of 7. Factors Affecting Biodisposition The biodisposition of sedative-hypnotics can be influenced by several factors, particularly alterations in hepatic function resulting from disease or drug-induced increases or decreases in microsomal enzyme activities (see Chapter 4). In very old patients and in patients with severe liver disease, the elimination half-lives of these drugs are often increased significantly. The activity of hepatic microsomal drug-metabolizing enzymes may be increased in patients exposed to certain older sedative-hypnotics on a long-term basis (enzyme induction; see Chapter 4). Barbiturates (especially phenobarbital) and meprobamate are most likely to cause this effect, which may result in an increase in their hepatic metabolism as well as that of other drugs. Increased biotransformation of other pharmacologic agents as a result of enzyme induction by barbiturates is a potential mechanism underlying drug interactions (see Chapter 66). In contrast, benzodiazepines and the newer hypnotics do not change hepatic drug-metabolizing enzyme activity with continuous use. Multiple subunits of several of these classes have been characterized, eg, six different α, four β, and three γ. Binding of benzodiazepines and the newer hypnotic drugs such as zolpidem occurs at a single site between α and γ subunits, facilitating the process of chloride ion channel opening.

The smaller the diam- ing neutrophil chemotaxis to decrease overall Chemotherapeutic Drugs 245 infammation order 25mg indocin arthritis diet myths. Pegloticase does not impair neutro- 149 The answer is E: None of these antibiotics would be phil chemotaxis buy indocin 75 mg arthritis diet control. Methicillin trusted indocin 25 mg arthritis medication infusion, oxacillin 50mg indocin visa arthritis in back help, dicloxacil- treat gout that increases urate excretion in the kid- lin, and nafcillin are b-lactam antibiotics related to ney tubules. When indicated, dosage adjustments for patients with renal dysfunction further minimize the risk for 146 The answer is C: Letter C. Initially, thiopental is redistributed to blood, history of epilepsy and would not likely develop sei- then brain, and then to muscle with peak levels. This agent has symptoms that last longer but they are less severe than that of heroin with- 151 The answer is D: Potassium. On the 10th day of admin- aqueous penicillin G has a high potassium load, istration of penicillin for meningitis, the meninges are which must be taken into account while monitor- minimally infamed. In the United States, there phenytoin and fosphenytoin have a narrow thera- is a boxed warning for women of childbearing age to peutic index. The present American Heart Association seizure prophylaxis because fosphenytoin is metabo- guidelines indicate amoxicillin (2 g given 1 h before lized into phenytoin. For penicillin-allergic patients, cephalexin, cefadroxil, clindamycin, clarithromycin, or azithromy- 153 The answer is D: Hepatic transaminases. The most cin are alternative medications listed as prophylactic common adverse effects reported in clinical trials regimens for dental procedures. Increased hepatic transaminases and (C) Imipenem is also inappropriate because it is broad also elevations in creatine phosphokinases occurred, spectrum and can only be given intravenously. He says that he has had this problem for as 1 A 6-year-old boy presents to his pediatrician for follow- long as he can remember but does not like going to up of recurrent hay fever and asthma. For symptom control, he today to see what his physician might be able to do uses an albuterol inhaler, but his parents would like to for him. Which (B) Diphenhydramine of the following drugs would decrease the amount of (C) Epinephrine asthma attacks by preventing an arachidonic acid deri- (D) Hydroxyzine vative from binding to its receptor? The rationale behind the use (D) Montelukast of this agent in this situation likely involves which of (E) Zileuton the following benefcial effects? You know there are multiple ways to darkness to interfere with the signaling that is causing her symp- (E) Reduction of urinary tract motility to reduce toms. Which of the following drugs would prevent the voiding during the procedure release of the main chemical mediator in her case? She is placed on several immunosuppressants (C) Ranitidine to prophylactically prevent her body rejecting the donor organ. Which of the following immunosup- (D) Loratadine pressants interferes with T-cell activation by modifying (E) Theophylline the activity of calcineurin? Over the next few 10 A 26-year-old man presents to the emergency depart- days, he has signifcant improvement in his symptoms. Physical Which of the following is the most likely mechanism exam reveals rebound tenderness and decreased of action of this agent? Which of the following drugs is the most appropriate treatment for 11 A 22-year-old woman ingests an entire bottle of acet- this patient? He does not have his medication (E) Paralysis of gall bladder causing bile stasis list at his current offce visit with his primary care physician. The 12 A 60-year-old man with agitation is hospitalized on patient states that he is taking all of his medications as the medicine service for hyponatremia. He 13 A 62-year-old man with Parkinson’s disease on develops a tension headache, and the only medica- levodopa and carbidopa presents to his primary care tion he has at home is aspirin. He is following his pre- regular-sized aspirin tablets, there was an increase scribed course of medications. Infammation, Immune Pharmacology, and Toxicology 249 (A) Drug toxicity 18 A 34-year-old man is a chronic alcoholic and is in and (B) Overactivity of dopamine at basal ganglia receptors out of a rehabilitation center on a monthly basis. His (C) Subtherapeutic dosing with low plasma levels of physician administers a blocker of aldehyde dehydro- medication genase. Which of the following effects is most likely to (D) Underlying undiagnosed subclinical dementia be exhibited by this patient following administration? His physician administers a blocker of aldehyde dehy- (A) Adalimumab drogenase and the patient becomes violently ill with (B) Certolizumab nausea, vomiting, chills, sweats, and hyperventilation. Which of the following should be admin- 16 A 21-year-old male presents to the clinic with 6 weeks istered to chelate the excess iron in his body? Which of (B) Deferoxamine the following drugs used for ulcerative colitis has both (C) Dimercaprol anti-infammatory and antibacterial properties? Which of the following agents is 17 A 5-year-old boy is brought to his primary care physi- most likely to cause this adverse effect? Which of the following (D) Steatorrhea is the most plausible mechanism of action of this (E) Tinnitus product? Over the next few days, however, she develops 28 Thiopental is used as an anesthetic agent during ringing in her ears. Approximately 1 day after his sur- (A) Acetazolamide gery, toxicology studies still reveal some thiopental (B) Furosemide present in the bloodstream. In addition to being suspended from his hospital because of his actions, he would likely 29 A 39-year-old man who suffered a work-related injury exhibit which of the following behaviors? A few days later, she develops small, (E) Weakened transverse colonic musculature red lesions near the wound and a red track ascending her hand toward her trunk. Her doctor prescribes 30 A 71-year-old man who has chronic back pain after itraconazole for the sporotrichosis. What is the mech- falling from a frst-foor apartment 25 years ago is anism of action of this medication? Which of the following effects will still likely (C) Inhibits conversion of lanosterol to ergosterol be maintained by the device at this time? Infammation, Immune Pharmacology, and Toxicology 251 31 A 23-year-old man is a driver who is involved in a 35 A 59-year-old man with a long history of cardiac motor vehicle accident. He is found to have sents to his primary care physician complaining of a blood alcohol level of 850 mg/dL. Physical examination way the body handles ethanol, the conventional “half- reveals a bilateral malar rash with erythema. The mother men- 33 An 18-year-old woman presents to her primary care tions that she is on a medication for schizophrenia but physician after experiencing a one-sided headache for could not remember the name. What 34 A 63-year-old woman with a history of cardiac arrhyth- should also be given to avoid a potentially serious side mia maintained on quinidine presents to her primary effect of cyclophosphamide? She is given a prescription for cipro- (C) N-acetylcysteine foxacin 500 mg to be taken twice daily for 7 days.

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Another method is to collect the waste dialysis fluid used during the dialysis proce- dure order 75mg indocin with visa what triggers arthritis in fingers, and measure several serum drug concentrations during the same time interval (Figure 3-15) buy discount indocin 25mg arthritis pain relief during pregnancy. The final method is to collect all the waste dialysis fluid used during the dialysis period cheap 25mg indocin mastercard arthritis back nerve pain, and measure a single serum drug concentration at the midpoint of the procedure discount indocin 50 mg fast delivery i have arthritis in my fingers. The pore size in hemofilters is large, which allows drug molecules up to 20,000 Da to cross its semipermeable membrane. These processes do not use a dialysis fluid, so plasma water that passes through the hemofilter is collected and discarded. The hemofilter has hemodialysis fluid on the other side of the semipermeable mem- brane containing the patient’s blood. The sieving coefficient is the ratio of the drug concentration in the hemofiltrate to the drug concentration in the serum. When hemofiltration procedures that incorporate dialysis fluid are used, an additional 15–20 mL/min is added to these values. The peritoneal membrane covering the internal organs is highly vascularized, so when dialysis fluid (1–3 L) is introduced into the peritoneal cavity using the catheter, waste products move from the blood vessels of the peritoneal membrane (a semipermeable membrane) into the dialysis fluid along a concentration gra- dient. The dialysis fluid comes into contact with capillaries in the peritoneal mem- brane where waste products and drugs pass from the blood into the fluid. After the dwell time has concluded, the dialysis fluid is removed from the peritoneal cavity via the catheter and discarded. Outpatients undergoing chronic ambulatory peritoneal dialysis have dialysis fluid present in their peritoneal cavities all day or most hours of a day. So, it is less likely that replacement drug doses will need to be given during intermittent peri- toneal dialysis, and that drug dosages will need to be increased while patients receive chronic peritoneal dialysis. For instance, in patients with end-stage renal disease, the half- life of aminoglycoside antibiotics is ~50 hours. During hemodialysis, the half-life reduces to ~4 hours, but, during peritoneal dialysis in patients without peritonitis, the half-life only decreases to ~36 hours. In patients receiving chronic peritoneal dialysis, dialysis removal of drug is simply another clearance mechanism taking place in the patient body, so the usual methods of measuring serum concentrations and dosage adjustment require little or no modification. For patients undergoing peritoneal dialysis, clinicians should consult the manufacturer’s package insert for drugs recently marketed (mid-1980s or later), reviews listing the peritoneal dialysis removal of older drugs and updated informa- tion on newer agents,4,6,7 and the primary literature for the newest guidelines for all compounds. If the agent is absorbed from the dialysis fluid into the body, systemic effects due to the drug may occur. Because the development of peritonitis is a common problem in patients receiving peri- toneal dialysis, antibiotics have been administered intraperitoneally for local treatment of the infection using dialysis fluid as the delivery vehicle. Clini- cians should pay particular attention to whether studies measuring peritoneal dialysis removal or absorption of drugs were conducted in patients with peritonitis. Methods to Measure Peritoneal Dialysis Clearance If necessary, peritoneal dialysis clearance can be measured in patients. One method is to collect the waste dialysis fluid used during a peritoneal dialysis period, and measure several serum drug concentrations during the same time interval (Figure 3-15). Another method is to collect all the waste dialysis fluid used during a dialysis period, and measure a single serum drug concentration at the midpoint of the procedure. Advantages of this technique are that it requires only one serum concentration and the volume of dialysis fluid is relatively small. A disadvantage is if only a small amount of drug is removed via dialysis, the drug assay may not be sensitive enough to measure a low concentration. Also, the magnitude of effect that adipose tissue has on the volume of distribution for a drug is dependent on the binding of drug in the tissue itself. If the drug has a large affinity for adipose tissue and is highly bound there, the free fraction in adipose tissue will be small (↓ffat), and a large amount of drug will accumulate in that tissue. Medications that have high lipid solu- bility tend to partition into adipose tissue, and the volume of distribution in obese patients for these drugs can be dramatically larger than in normal weight patients. However, hydrophilic drugs tend to not distribute into adipose tissue so that the volume of distribution for many water-soluble drugs is not significantly different in obese and normal weight patients. The volumes of distribution for digoxin,37 cimetidine,38 and ranitidine39 are similar in overweight- and normal-weight subjects. Although the presence of excessive adipose tissue is the most obvious change that occurs in obese individuals, other physiologic changes are present. While adipose cells contain >90% fat, there are additional supportive tissues, extracellular fluid, and blood present in adipose tissue. The net result of these changes is that hydrophilic drugs with small volumes of distribution may experience distribution alterations in obese patients. For example, the aminoglycoside antibiotics are water-soluble molecules that have relatively small volumes of distribution similar to the value of extracellular fluid (V = 0. Since the volume of distribution is so small (~18 L in a 70-kg person), the addition of just a few liters of extracellular fluid can alter the pharmacokinetics of these antibiotics. The additional extracellular fluid con- tained in excessive adipose tissue and other organs that hypertrophy in obese individuals causes larger volumes of distribution for the aminoglycoside antibiotics in overweight patients. Examples of medications with larger and intermediate volumes of distribution are digoxin (V = 500 L) and vancomycin (V = 50 L); the addition of a few extra liters of extracellular fluid due to obesity will not substantially change the volume of distribution for these agents. This alteration primarily affects hydrophilic drug compounds that are renally elimi- nated and will increase the renal clearance of the agent. Vancomycin,44 the aminoglyco- sides,40–42 and cimetidine38 all have higher clearance rates in obese patients compared to normal weight individuals. Special methods are used to estimate creatinine clearance for obese patients, as previously noted in the Measurement and Estimation of Creatinine Clearance section of this chapter. For many agents, such as carbamazepine35 and cyclosporine,45 obesity does not significantly effect hepatic clear- ance. While for other drugs, obesity increases hepatic clearance, as with diazepam,34 or decreases metabolic clearance, as with methylprednisolone. Half-life changes vary according to the relative alterations in clearance (Cl) and vol- ume of distribution (V): t1/2 = (0. In the case of the aminoglycoside antibiotics, clearance and volume of distribution increases are about the same magnitude in obese patients, so half-life does not change. If two drugs are eliminated by the same enzyme, they may compete for the metabolic pathway and decrease the clearance of one or both compounds. Two drugs eliminated by the same active renal tubular secretion mechanism can compete for the pathway and decrease the renal clearance of one or both agents. Another type of drug interaction displaces a drug from plasma protein binding sites because the two compounds share the same binding site, and the two compete for the same area on plasma proteins. By virtue of its pharma- cologic effect, a drug may increase or decrease blood flow to an organ that eliminates or metabolizes another medication and thereby decrease the clearance of the medication. If two drugs share the same tissue binding sites, it is possible for tissue-binding displace- ment drug interactions to occur and change the volume of distribution for one of the med- ications.