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Cyclic changes in glomerular ﬁltra- preterm infant will not have this protective barrier until tion are noted during the menstrual cycle order torsemide online from canada blood pressure chart standing. Absorption of hexachlorophene soap used to Absorption bathe newborns has resulted in brain damage and Oral absorption of drugs is inﬂuenced by gastric acidity death proven 10 mg torsemide blood pressure instrument. This increased total body water increases the Decreased albumin concentration and binding volume of drug distribution for water-soluble com- Decreased total plasma protein pounds buy cheapest torsemide blood pressure chart hypertension. Differences in total body Excretion water are basically insigniﬁcant after the ﬁrst year of Renal blood ﬂow buy cheap torsemide online blood pressure chart in pregnancy, glomerular ﬁltration rate, and tubular life. Newborns have decreased body fat and therefore function are reduced in both preterm and term less storage ability for fat-soluble drugs. Therefore, newborns, especially those less than Newborns, especially prematures, have decreased 34 weeks’ gestation, require less frequent dosing inter- plasma albumin and total plasma protein concentrations. Aminoglycosides are administered In addition, albumin from these patients shows a de- every 8 hours in older children, every 12 hours in new- creased drug-binding afﬁnity. This may result in increased borns, and every 24 hours in extremely premature in- plasma levels of free drug and the potential for toxicity. The glomerular ﬁltration rate of the term newborn the past, concerns were raised that certain drugs, such as is approximately 50% less than the adult level but sulfonamides, could displace endogenous substances, like reaches adult values by 1 year of age. Tubular secretory functions mature at a slower rate than Although this belief has been challenged recently, reluc- does glomerular ﬁltration. Renal elimination of drugs appears to play a greater role than As with adults, the primary organ responsible for drug does metabolism in newborns. Phase I oxidation reactions and demethylation enzyme systems are signif- Drug Action icantly reduced at birth. However, the reductive enzyme Most drugs are administered to infants and children for systems approach adult levels and the methylation the same therapeutic indications as for adults. Among to the production of different metabolites in newborns these are theophylline and caffeine, which are used to from those in adults. For example, newborns metabolize treat apnea of prematurity; indomethacin, which closes a approximately 30% of theophylline to caffeine rather patent ductus arteriosus; and prostaglandin E1, which than to uric acid derivatives, as occurs in adults. Para- most phase I enzymes have reached adult levels by 6 doxically, drugs such as phenobarbital, which have a months of age, alcohol dehydrogenase activity appears sedating action on adults, may produce hyperactivity in around 2 months of age and approaches adult levels children, and some adult stimulant drugs, such as methyl- only by age 5 years. The immatu- Adverse Reactions rity of the glucuronidation pathway was responsible for Children may display adverse reactions different from the development of gray baby syndrome (see Chapter those noted in adult patients. The plasma half-life was found to be 26 hours in Several problems unique to pediatric drug therapy de- these patients compared with 4 hours in older children. For example, most medications Infants and children have a greater capacity to carry are commercially available only in adult dose forms. For example, Preparing pediatric doses from adult tablets or capsules acetaminophen is excreted predominantly as a sulfate can be very difﬁcult and may require special skill on the conjugate in children as opposed to a glucuronide con- part of the pharmacist. This ﬁgure is increas- suppression Tetracyclines Discolored teeth ing steadily and is expected to reach 50 million by the Phenobarbital Hyperactivity, impaired intellec- year 2020. This segment of our society is the most highly tual development drug-treated and accounts for about 25% of prescrip- Phenytoin (Dilantin) Thickened skull, coarse features tion drugs dispensed. The average Medicare patient in Chloramphenicol Gray baby syndrome an acute-care hospital receives approximately 10 differ- Phenothiazines Extrapyramidal reaction Valproic acid (Depakene) Hepatotoxicity ( 2 yr) ent drugs daily, and this translates into a higher inci- Aspirin Reye’s syndrome in patients with dence of adverse drug reactions in geriatric patients chickenpox or inﬂuenza than in the general population. A clear relationship between the appearance of untoward it is given using techniques usually reserved for adults. It is apparent that an increase in life Most adult drugs must be diluted to achieve appro- span is accompanied by an increase in chronic illnesses priate pediatric dosages. Age-related alterations in pharmacokinetics (ab- Children with chronic illnesses require special con- sorption, distribution, metabolism, and excretion) have sideration. Thus, physiological have increased hepatic metabolism and therefore in- changes in elderly patients, when taken together, may creased drug clearance. This may necessitate the admin- contribute to impairments in drug clearance in this seg- istration of increased drug dosages. Repeated increases in drug dosage are re- more slowly because of decreased splanchnic blood ﬂow quired to accommodate for growth in children receiving or delayed gastric emptying. In summary, children, especially those in the ﬁrst year of life, present signiﬁcant pharmacological chal- Distribution lenges. Drug administration must be tailored to meet the unique needs of children at their varied stages of de- Drug distribution in elderly patients may be altered by velopment. Special attention must be given to unex- hypoalbuminemia, qualitative changes in drug-binding pected drug actions and adverse reactions in these pa- sites, reductions in relative muscle mass, increases in the tients, who are maturing at variable rates. When proportion of body fat, and decreases in total body planning drug therapy for children, it is important to water. The plasma level of free, active drug is often a di- remember: rect function of the extent of drug binding to plasma proteins. Elderly Patients In a carefully controlled clinical study, the plasma half-life of diazepam (Valium), a widely used antianx- Plasma or serum t1/2 iety agent, exhibited a striking age dependency. In pa- tients aged 20 years, the t1/2was about 20 hours, and this Young Elderly increased linearly with age to about 90 hours at 80 Drug (20–30 yr) (65–80 yr) years. These changes in serum albumin may affect the Adverse Drug Effects free drug concentration for a number of highly bound drugs, such as phenytoin, warfarin, and meperidine. The incidence of iatrogenic complications is three to ﬁve times greater in the elderly than in the general pop- ulation. Inappropriate drug use has been In addition to changes in metabolism that occur as a re- noted in almost half of hospitalized elderly patients. Half of adverse drug reactions occur in pa- Reevaluate the continued use of all medications the tients receiving inappropriate drugs. While almost every class Noncompliance is a signiﬁcant problem, with almost of drugs has the potential to produce delirium in the 50% of elderly patients failing to take their medications elderly, it is most frequent with psychoactive drugs. Some of the reasons for noncompliance are risk increases with the number of drugs the patient is re- inability to pay for the drug, side effects, mental impair- ceiving, reaching a 14-fold increase in risk for patients ment, and inability to understand complex instructions. This is virtually The following should be considered when prescribing axiomatic in premature infants, whose severely restricted drugs for elderly patients. Caution Drugs should be prescribed only if nonpharmaco- also must be exerted in prescribing for the elderly popu- logical techniques are ineffective, such as for problems lation, since these individuals may be taking 10 to 15 dif- like sleeplessness and anxiety. Problems associated with drug interac- scribed for these conditions, they should be given for a tion and declining physiological function are very real. It limited time and the patient closely monitored for ad- is simply inadequate to administer drugs to very young verse effects. Prescribe drugs only if you have upon the changing pharmacokinetic characteristics of the available extensive experience and prescribing informa- drug in question, the nature of the disease, and the physi- tion for that drug in elderly patients. Use the least num- ological status of the major organs and tissues involved in ber of drugs and doses per day. It is well established that most drugs taken by preg- (C) Increase in the levels of plasma proteins nant women are capable of crossing the placenta (D) General increase in hepatic drug metabolizing and reaching the developing fetus. The placenta it- capacity self can aid in the protection of the fetus from exces- (E) Decrease in renal clearance of many drugs sive exposure to drugs in the maternal circulation by 4. A neonate is given drug A, a compound with a high (A) Impairing diffusion of lipid soluble drugs afﬁnity for plasma proteins, in a dose that does not (B) Preventing the passage of drugs having a mo- exceed the binding capacity of albumin.
Although it appeared to be more effective then allopurinol as urate-lowering therapy purchase torsemide no prescription blood pressure chart athlete, the allopurinol dosing was limited to 300 mg/d purchase torsemide 20 mg amex prehypertension webmd, thus not reflecting the actual dosing regimens used in clinical practice proven torsemide 10 mg pulse pressure decrease. The most frequent treatment-related adverse events are liver function abnormalities purchase 20 mg torsemide otc blood pressure zinc, diarrhea, headache, and nausea. No dose adjustment is necessary for patients with renal impairment since it is highly metabolized into an inactive metabolite by the liver. Pharmacokinetics and Dosage: The recommended dose for pegloticase is 8 mg every 2 weeks administered as an intravenous infusion. Pharmacodynamics: Urate oxidase enzyme, absent in humans and some higher primates, converts uric acid to allantoin. The presence of antipegloticase antibodies is associated with shortened circulating half-life, loss of response leading to a rise in plasma urate levels, and a higher rate of infusion reactions and anaphylaxis. Monitoring of plasma uric acid level, with rising level as an indicator of antibody production, allows for safer administration and monitoring of efficacy. In addition, other oral urate-lowering agents should be avoided in order not to mask the loss of pegloticase efficacy. Other less frequent side effects noted include upper respiratory tract infection, peripheral edema, urinary tract infection, and diarrhea. There is some concern for hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency because of the formation of hydrogen peroxide by uricase; therefore, pegloticase should be avoided in these patients. Intra-articular injection of 10 mg (small joints), 30 mg (wrist, ankle, elbow), and 40 mg (knee) of triamcinolone acetonide can be given if the patient is unable to take oral medications. These medications are also being evaluated as therapies for prevention of gout flares while initiating urate-lowering therapy. Lago P et al: Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: A randomized controlled trial. Niccoli L, Bellino S, Cantini F: Renal tolerability of three commonly employed non-steroidal anti-inflammatory drugs in elderly patients with osteoarthritis. Rovensky J et al: Treatment of knee osteoarthritis with a topical nonsteroidal anti-inflammatory drug. Results of a randomized, double-blind, placebo-controlled study on the efficacy and safety of a 5% ibuprofen cream. Disease-Modifying Antirheumatic Drugs & Glucocorticoids Atzeni F et al: Potential target of infliximab in autoimmune and inflammatory diseases. Bannwarth B, Kostine M, Poursac N: A pharmacokinetic and clinical assessment of tofacitinib for the treatment of rheumatoid arthritis. Besada E, Koldingsnes W, Nossent J: Characteristics of late onset neutropenia in rheumatologic patients treated with rituximab: A case review analysis from a single center. Emery P et al: Golimumab, a human anti-tumor necrosis factor α monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naïve patients with active rheumatoid arthritis. Keystone E et al: Improvement in patient-reported outcomes in a rituximab trial in patients with severe rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Landewé R et al: Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study. Maurizio Cutolo: The kinase inhibitor tofacitinib in patients with rheumatoid arthritis: Latest findings and clinical potential. Nadashkevich O et al: A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis. Ruperto N et al: Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Strober B et al: Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment. Weinblatt M et al: Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate. Yokota S, Kishimoto T: Tocilizumab: Molecular intervention therapy in children with systemic juvenile idiopathic arthritis. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. In addition to physical findings and measurement of acute-phase reactants such as sedimentation rate or C-reactive protein, it would be wise to get hand and feet radiographs to document whether he has developed joint damage. Adverse events requiring caution are an increased risk of infection, possible appearance of lymphoma and rare liver function test or hematologic abnormalities. Importantly, close follow-up should ensue, including changing medications every 3–6 months until full disease control is achieved. Review of the past history and growth chart demonstrates normal birth weight and birth length, but a progressive fall off in height velocity relative to age-matched normal ranges starting at 6 months of age. The control of metabolism, growth, and reproduction is mediated by a combination of neural and endocrine systems located in the hypothalamus and pituitary gland. The pituitary consists of an anterior lobe (adenohypophysis) and a posterior lobe (neurohypophysis) (Figure 37–1). It is connected to the overlying hypothalamus by a stalk of neurosecretory fibers and blood vessels, including a portal venous system that drains the hypothalamus and perfuses the anterior pituitary. The portal venous system carries small regulatory hormones (Figure 37–1, Table 37–1) from the hypothalamus to the anterior pituitary. Hormones released from the anterior pituitary stimulate the production of hormones by a peripheral endocrine gland, the liver, or other tissues, or act directly on target tissues. Prolactin and the hormones released from the posterior pituitary (vasopressin and oxytocin) act directly on target tissues. The posterior lobe hormones are synthesized in the hypothalamus and transported via the neurosecretory fibers in the stalk of the pituitary to the posterior lobe; from there they are released into the circulation. Drugs that mimic or block the effects of hypothalamic and pituitary hormones have pharmacologic applications in three primary areas: (1) as replacement therapy for hormone deficiency states; (2) as antagonists for diseases caused by excess production of pituitary hormones; and (3) as diagnostic tools for identifying several endocrine abnormalities. In these systems, the secretion of the pituitary hormone is under the control of one or more hypothalamic hormones. Each hypothalamic-pituitary-endocrine gland system or axis provides multiple opportunities for complex neuroendocrine regulation of growth and development, metabolism, and reproductive function. Their β subunits, though somewhat similar to each other, differ enough to confer receptor specificity. Each is under the control of a distinctive hypothalamic peptide that stimulates their production by acting on G protein-coupled receptors (Table 37–1). An important regulatory feature shared by these four structurally related hormones is that they and their hypothalamic releasing factors are subject to feedback inhibitory regulation by the hormones whose production they control. Feedback regulation is critical to the physiologic control of thyroid, adrenal cortical, and gonadal function and is also important in pharmacologic treatments that affect these systems. Prolactin production is inhibited by the catecholamine dopamine acting through the D subtype of dopamine receptors. Whereas all the pituitary and hypothalamic hormones described previously are available for use in humans, only a few are of major clinical importance. The hormone has complex effects on growth, body composition, and carbohydrate, protein, and lipid metabolism.
In contrast order cheap torsemide on line blood pressure medication potassium, pulmonary and renal vessels seem very sensitive to the vasoconstrictor action of serotonin torsemide 20 mg overnight delivery arrhythmia treatments. Serotonin also constricts veins order cheap torsemide blood pressure medication recall 2015, and venoconstriction with increased capillary filling appears to be responsible for the flush that is observed after serotonin administration or release from a carcinoid tumor buy torsemide 20mg lowest price arrhythmia nos. Serotonin has small direct positive chronotropic and inotropic effects on the heart, which are probably of no clinical significance. However, prolonged elevation of the blood level of serotonin (which occurs in carcinoid syndrome) is associated with pathologic alterations in the endocardium (subendocardial fibroplasia), which may result in valvular or electrical malfunction. Serotonin Syndrome and Similar Syndromes Excess synaptic serotonin causes a serious, potentially fatal syndrome that is diagnosed on the basis of a history of administration of a serotonergic drug within recent weeks and physical findings. As suggested by the drugs that precipitate it, serotonin syndrome occurs when overdose with a single drug, or concurrent use of several drugs, results in excess serotonergic activity in the central nervous system. This response, in contrast to2 aggregation induced during normal clot formation, is not accompanied by the release of serotonin stored in the platelets. Gastrointestinal tract—Serotonin is a powerful stimulant of gastrointestinal smooth muscle, increasing tone and facilitating peristalsis. Overproduction of serotonin (and other substances) in carcinoid tumor is associated with severe diarrhea. Serotonin has little effect on gastrointestinal secretions, and what effects it has are generally inhibitory. Although the hyperthermia of serotonin syndrome results from excessive muscle contraction, serotonin syndrome is probably caused by a central nervous system effect of these drugs (Table 16–4 and Box: Serotonin Syndrome and Similar Syndromes). Since eating behavior is an expression of endocrine, neurophysiologic, and psychological processes, prevention and treatment of obesity are challenging. There is considerable scientific and financial interest in developing pharmacologic therapy for the condition. A second metric, which may be an even better predictor of cardiovascular risk, is the ratio of waist measurement to body height; risk is lower if this ratio is less than 0. Although the cause of obesity can be simply stated as energy intake (dietary calories) that exceeds energy output (resting metabolism plus exercise), the actual physiology of weight control is extremely complex, and the pathophysiology of obesity is still poorly understood. Many hormones and neuronal mechanisms regulate intake (appetite, satiety), processing (absorption, conversion to fat, glycogen, etc), and output (thermogenesis, muscle work). Furthermore, the social and psychological aspects of eating are powerful influences that are independent of or only partially dependent on the physiologic control mechanisms. Furthermore, surgery that bypasses the stomach and upper small intestine (but not simple restrictive banding) rapidly reverses some aspects of the metabolic syndrome even before significant loss of weight. However, even a 5–10% loss of weight is associated with a reduction in blood pressure and improved glycemic control. Gastrointestinal flora also influence metabolic efficiency and research in mice suggests that altering the flora can lead to weight gain or loss. These drugs are all amphetamine mimics and are central nervous system appetite suppressants; they are generally helpful only during the first few weeks of therapy. Their toxicity is significant and includes hypertension (with a risk of cerebral hemorrhage) and addiction liability. Clinical trials and phase 4 reports suggest that all three agents are modestly effective for the duration of therapy (up to 1 year) and are probably safer than the single agent amphetamine mimics. A combination of naltrexone and bupropion (Contrave) has just been approved and seems to be similarly effective. Sibutramine and rimonabant were marketed for several years but were withdrawn because of increasing evidence of cardiovascular toxicity. Migraine in its “classic” form is characterized by an aura of variable duration that may involve nausea, vomiting, visual scotomas or even hemianopsia, and speech abnormalities; the aura is followed by a severe throbbing unilateral headache that lasts for a few hours to 1–2 days. Although the symptom pattern and duration of prodrome and headache vary markedly among patients, the severity of migraine headache justifies vigorous therapy in the great majority of cases. Migraine involves the trigeminal nerve distribution to intracranial (and possibly extracranial) arteries. Extravasation of plasma and plasma proteins into the perivascular space appears to be a common feature of animal migraine models and is found in biopsy specimens from migraine patients. The mechanical stretching caused by this perivascular edema may be the immediate cause of activation of pain nerve endings in the dura. The onset of headache is sometimes associated with a marked increase in amplitude of temporal artery pulsations, and relief of pain by administration of effective therapy is sometimes accompanied by diminution of these pulsations. The mechanisms of action of drugs used in migraine are poorly understood, in part because they include such a wide variety of drug groups and actions. Furthermore, some of these drug groups are effective only for prophylaxis and not for the acute attack. Sumatriptan and its congeners are currently first-line therapy for acute severe migraine attacks in most patients (Figure 16–3). Anti-inflammatory analgesics such as aspirin and ibuprofen are often helpful in controlling the pain of migraine. Most adverse effects are mild and include altered sensations (tingling, warmth, etc), dizziness, muscle weakness, neck pain, and for parenteral sumatriptan, injection site reactions. Chest discomfort occurs in 1–5% of patients, and chest pain has been reported, probably because of the ability of these drugs to cause coronary vasospasm. They are therefore contraindicated in patients with coronary artery disease and in patients with angina. Another disadvantage is the fact that their duration of effect (especially that of almotriptan, sumatriptan, rizatriptan, and zolmitriptan, Table 16–6) is often shorter than the duration of the headache. As a result, several doses may be required during a prolonged migraine attack, but their adverse effects limit the maximum safe daily dosage. Naratriptan and eletriptan are contraindicated in patients with severe hepatic or renal impairment or peripheral vascular syndromes; frovatriptan in patients with peripheral vascular disease; and zolmitriptan in patients with Wolff-Parkinson-White syndrome. The brand name triptans are extremely expensive; thus generic sumatriptan should be used whenever possible. Propranolol, amitriptyline, and some calcium channel blockers have been found to be effective for the prophylaxis of migraine in some patients. The anticonvulsants valproic acid and topiramate (see Chapter 24) have also been found to have some prophylactic efficacy in migraine. Flunarizine, a calcium channel blocker used in Europe, has been reported in clinical trials to effectively reduce the severity of the acute attack and to prevent recurrences. Such antagonism is clearly desirable in those rare patients who have carcinoid tumor and may also be valuable in certain other conditions. Storage of serotonin can be inhibited by the use of reserpine, but the sympatholytic effects of this drug (see Chapter 11) and the high levels of circulating serotonin that result from release prevent its use in carcinoid. In2 addition, the ergot alkaloids discussed in the last portion of this chapter are partial agonists at serotonin receptors. It prevents the smooth muscle effects of both amines but has no effect on the gastric secretion stimulated by histamine. The major clinical applications of cyproheptadine are in the treatment of the smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria. It is of some value in serotonin syndrome, but because it is available only in tablet form, cyproheptadine must be crushed and administered by stomach tube in unconscious patients. Anecdotal evidence suggests some efficacy as an appetite stimulant in cancer, but controlled trials have yielded mixed results.
Estimate half-life and elimination rate constant according to disease states and conditions present in the patient cheap torsemide online master card hypertension va rating. The expected procainamide half-life (t1/2) for an individual with normal hepatic and renal function is 3 discount torsemide 20mg fast delivery heart attack jack johnny b bad. The patient is not obese buy 10 mg torsemide with visa blood pressure chart age wise, so the estimated procainamide volume of distribution will be based on actual body weight: V = 2 purchase discount torsemide on line arrhythmia cause. Estimated procainamide clearance is computed by taking the product of the volume of distribution and the elimi- nation rate constant: Cl = kV = 0. Initially, a maximum dose of 600 mg over 25–30 minutes will be given, and the additional 200 mg given, if needed, at a rate of 20 mg/min. Suggest an initial intravenous procainamide dosage regimen designed to achieve a steady-state procainamide concentration equal to 4 μg/mL. Estimate half-life and elimination rate constant according to disease states and conditions present in the patient. Patients with severe renal disease have highly variable procainamide pharmacokinetics and dosage requirements. Renal failure decreases procainamide renal clearance, and the expected procainamide half-life (t1/2) is 13. The patient is not obese, so the estimated procainamide volume of distribution will be based on actual body weight: V = 1. Estimated procainamide clearance is computed by taking the product of the volume of distribution and the elimi- nation rate constant: Cl = kV = 0. Literature-Based Recommended Dosing Because of the large amount of variability in procainamide pharmacokinetics, even when concurrent disease states and conditions are identiﬁed, many clinicians believe that the use of standard procainamide doses for various situations are warranted. The original computation of these doses was based on the pharmacokinetic dosing method described in the previous section, and subsequently modiﬁed based on clinical experience. In gen- eral, the procainamide steady-state serum concentration expected from the lower end of the dosage range was 4–6 μg/mL and 6–10 μg/mL for the upper end of the dosage range. When more than one disease state or condition is present in a patient, choosing the lowest daily dose will result in the safest, most conservative dosage recommendation. For patients with ventricular tachycardia and poor perfusion, 15 mg/kg infused over 30–60 minutes as a single dose can be considered if cardioversion is ineffective. To illustrate the similarities and differences between this method of dosage calculation and the pharmacokinetic dosing method, the same examples used in the previous section will be used. Suggest an initial oral procainamide dosage regimen designed to achieve a steady-state procainamide concentration equal to 4 μg/mL. A procainamide maintenance dose of 50 mg/kg/d is suggested for a patient without heart failure or liver disease requiring a procainamide steady-state serum concentration in the lower end of the therapeutic range. The suggested initial dose would be 3750 mg/d (50 mg/kg/d ⋅ 75 kg = 3750 mg/d), rounded to 4000 mg/d or 1000 mg every 6 hours. Suggest an initial extended-release procainamide dosage regimen designed to achieve a steady-state procainamide concentration equal to 4 μg/mL. Suggest an intravenous procainamide dosage regimen designed to achieve a steady-state procainamide concentration equal to 4 μg/mL. A procainamide maintenance dose of 2–4 mg/min is suggested for a patient without heart failure or liver disease requiring a procainamide steady-state serum concentration in the lower end of the therapeutic range. Suggest an initial intravenous procainamide dosage reg- imen designed to achieve a steady-state procainamide concentration equal to 4 μg/mL. A procainamide maintenance dose of 1–2 mg/min is suggested for a patient with renal failure requiring a procainamide steady-state serum concentration in the lower end of the therapeutic range. In addition to procainamide serum concentrations, important patient parameters (electrocardiogram, clinical signs and symptoms of the arrhythmia, potential procainamide side effects, etc. In most cases, a simple dosage ratio can be used to change procainamide doses assuming the drug follows linear pharmacokinetics. Sometimes, it is useful to compute procainamide pharmacokinetic constants for a patient and base dosage adjustments on these parameters. In this case, it may be possible to calculate and use pharmacokinetic parameters to alter the procainamide dose. In some situations, it may be necessary to compute procainamide pharmacokinetic parameters as soon as possible for the patient before steady-state conditions occur and utilize these parameters to calculate the best drug dose. Computerized methods that incorporate expected population pharmacokinetic characteristics (Bayesian pharmaco- kinetic computer programs) can be used in difficult cases where serum concentrations are obtained at suboptimal times or the patient was not at steady state when serum con- centrations were measured. An additional benefit of this method is that a complete pharmacokinetic workup (determination of clearance, volume of distribution, and half- life) can be done with one or more measured concentrations that do not have to be at steady state. Because nonlinear pharmacokinetics for pro- cainamide has been observed in some patients, suggested dosage increases greater than 75% using this method should be scrutinized by the prescribing clinician, and the risk versus beneﬁt for the patient assessed before initiating large dosage increases (>75% over current dose). Using linear pharmacokinetics, the new dose to attain the desired concentration should be proportional to the old dose that produced the measured concentration. The patient would be expected to achieve steady-state conditions after the ninth day (5 t1/2 = 5 ⋅ 13. Using linear pharmacokinetics, the new dose to attain the desired concentration should be proportional to the old dose that produced the measured concentration. The patient would be expected to achieve steady-state conditions after the second day (5 t1/2 = 5 ⋅ 5. 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 = (8 μg/mL / 4. Pharmacokinetic Parameter Method The pharmacokinetic parameter method of adjusting drug doses was among the ﬁrst techniques available to change doses using serum concentrations. The pharmacokinetic parameter method requires that steady state has been achieved and uses only a steady-state pro- cainamide concentration (Css). During a continuous intravenous infusion, the following equation is used to compute procainamide clearance (Cl): Cl = k0 / Css, where k0 is the dose of procainamide in mg/min. If the patient is receiving oral procainamide therapy, pro- cainamide clearance (Cl) can be calculated using the following formula: Cl = [F(D/τ)] / Css, where F is the bioavailability fraction for the oral dosage form (F = 0. Because this method also assumes linear pharmacokinetics, procainamide doses computed using the pharmacokinetic parameter method and the linear pharmacokinetic method should be identical. Procainamide clearance can be computed using a steady-state procainamide concentra- tion: Cl = [F(D/τ)] / Css = [0. A steady-state procainamide serum concentration could be measured after steady state is attained in 3–5 half-lives. The patient would be expected to achieve steady-state conditions after the ninth day (5 t1/2 = 5 ⋅ 13. Procainamide clearance can be computed using a steady-state procainamide concentra- tion: Cl = [F(D/τ)] / Css = [0. A steady-state procainamide serum concentration could be measured after steady state is attained in 3–5 half-lives. The patient would be expected to achieve steady-state conditions after the second day (5 t1/2 = 5 ⋅ 5. Procainamide clearance can be computed using a steady-state procainamide concentra- tion: Cl = k0/Css = (1 mg/min)/(4. A steady-state procainamide serum concentration could be measured after steady state is attained in 3–5 half-lives. In this situation, two pro- cainamide serum concentrations obtained at least 4–6 hours apart during a continuous infusion can be used to compute procainamide clearance and dosing rates.
The intermediate paravermal zone is related to basilar artery just before its superior terminal di- the emboliform and globose nuclei and is concerned vision into posterior cerebral arteries discount torsemide on line arrhythmia when i lay down. The around the lateral aspect of the crus cerebri in the lateral zone is related to the dentate nucleus and is lateral wing of the ambient cistern cost of torsemide blood pressure chart kpa. At its origin it concerned with initiation buy torsemide canada heart attack proof, planning order torsemide 10 mg overnight delivery arrhythmia nutrition, and timing as is situated beneath the oculomotor nerve. It is with two branches at the level of the inferior clear that the different parasagittal zones of the cere- colliculi posteriorly. These arteries vascularize bellum differ functionally with regard to their con- the superior aspect of the cerebellar hemispheres nections. Most cerebellar lesions are usually not restrict- ing rise to a labyrinthine branch, and ends at the ed to a discrete anatomic region and the results of flocculus. In its route through the cerebellopontine The Brainstem and Cerebellum 253 cistern, the artery courses along the cochleovesti- climbing fibers of the cerebellum: an experimental study bular and facial nerve roots, frequently visualized in the cat with an autoradiographic tracing method. Springer, New York Berlin Heidelberg Flechsig P (1905) Einige Bemerkungen über die Unter- suchungsmethoden der Grosshirnrinde, insbesondere des Menschen. J Brodal A (1981) Neurological anatomy in relation to clinical Neurophysiol 49:1285–1301 medicine, 3rd edn. J Comp Neurol Jansen J, Brodal A (1940) Experimental studies on the intrin- 140:241–254 sic fibers of the cerebellum. University of Min- Springer, Berlin Heidelberg New York nesota Press, Minneapolis, pp 164–174 Olszeweski J, Baxter C (1954) Cytoarchitecture of the human Kunzle H, Akert K (1977) Efferent connections of cortical brain stem. Lippincott, Philadelphia area 8 (frontal eye field) in Macaca fascicularis: a reinves- Parent A (1986). The cerebellar histology of the cerebellum: the human cerebellum, cer- contribution to higher function. J Physiol (Lond) d’un plan de référence céphalique en imagerie par 202:437–470 résonance magnétique: le plan chiasmato-commissural. J Testut L, Latarjet A (1948) Traité d’anatomie humaine, vol 2: Comp Neurol 330:130–146 Angiologie, système nerveux central, 9th edn. Brain Cogn 14:19–25 Optic Pathway and Striate Cortex 257 9 Optic Pathway and Striate Cortex I Introduction right and left side. However, Galen thought that the canals joined each other at the midline, taking the The visual pathways extend from anterior to posteri- aspect of an “X” before they separated immediately or as the optic nerves, chiasm, optic tracts and optic afterwards. He believed that this kind of exchange at radiations, terminating in the striate or visual cortex the level of the chiasm allowed the pneuma to go to on the medial aspect of the occipital lobes. Along this the opposite eyeball and double its strength if the orbitocranial route, the visual paths maintain a other eye was destroyed. Furthermore, Galen at- roughly axial and horizontal orientation from the tempted to justify the arrangement of the optic eyes to the calcarine fissure. This aim is essential because of the great lation of the scientific and philosophic heritage of an- sensitivity of the visual and the oculomotor systems tiquity. The objective is to achieve max- translations (liber de oculis translatus a Demetrio et imal contrast between the optic pathways and the liber de oculis Constantini africani). Diagnostic algorithms The first representation of the chiasm showing a applicable to specific regional pathology are pro- total crossing over of the optic nerves was in 1266, in posed with the respective clinical correlations. The figure also shows the hollow nerves, experiments on the nervous system of animals in which the visual spirit emanates from the brain. First representation of the chiasm showing a com- plete crossing-over of the optic nerve fibers, attributed to Khalifah (1266), and first realistic representation of the eyes and the anterior optic pathways, annotated in Arabic and in- cluding the chiasma that could be attributed to Ibn Al. A half a century before, Da Vinci, fol- sized that Arabic manuscripts of ophthalmology lowing the concept of total decussation of the optic books contain the oldest representations of the eye, nerves elaborated by the Arabs, was the first to de- the chiasm and the brain. Nonetheless, Arabic anatomy was first book devoted to the optic nerve and demon- not free of the traditional mistakes, such as the un- strated its thalamic origin from the lateral aspect of usually deep posterior chamber of the eye, the loca- the third ventricle (Fig. This had been already tion of the lens lying in the center of the eyeball or reported by Eustache, in 1551, but had not been the canal within the optic nerves. Being very poor, Eustache was unable to In the Renaissance era, the discovery of printing print the plates of his anatomical atlas, which were with moveable type greatly advanced the diffusion edited in 1617 by the physician Lancisi. In 1543, Vesali, (1514–1664) in Bel- a very long search, found this work 50 years after the gium, in the Fabrica, his first textbook of modern author’s death. He also suggested the Descartes (1596–1650), in France, still believed in existence of a cavity inside the optic nerves, except this mechanistic representation of vision, i. However, he persisted in be- optic nerves do not decussate at the level of the chi- lieving that there is no real crossing-over of the asm. Each nerve was thought to originate from a pre- nerves, but rather a simple juxtaposition at the chi- cise region of the lateral ventricle and follow a paral- 1234 Optic Pathway and Striate Cortex 259 Fig. Vesali (1543) shows the first exact reproduction of the inferior surface of the brain and the chiasm (Bibl. Varoli (1573) shows the optic nerves and the chiasm as well as a dissection of the optic radiations (Bibl. Museum National d’Histoire Naturelle, Paris) lel chiasmatic route before terminating in the retina and Vieussens (1641–1715) and showed, in his Traité in a precisely defined manner. Images were thus d’Anatomie et de Physiologie, devoted to the brain, a thought to be transmitted to the pineal gland, sepa- cut of the cerebral hemisphere passing through the rately for each eye, before they were memorized in- optic pathways. These speculations may be obtained presently on magnetic resonance imaging, considered as the preliminary steps in understand- shows the optic nerve junction, the optic tract, the ing regionalization of the retinal projections. He dem- From that time, anatomical knowledge of the vi- onstrated that the optic nerve is composed of fasci- sual pathways progressed quickly and continued cles of nervous fibers, instead of a hollow tube, during the nineteenth century. Willis also discov- later Gratiolet, in 1854, described the continuity of ered the tracts connecting the internal structures to the fibers of the visual tract projecting as terminal the cortex and recognized the existence of higher fibers to the vicinity of the calcarine fissure. The supe- Meynert demonstrated the role of the lateral genicu- rior and inferior colliculi were described as glands. Fi- of the optic tracts and their connections to the thala- nally, Flechsig (1896 1900) was the first to elaborate mi; he also dissected the temporal horns of the later- the time course of myelination in the fetus and al ventricle (Fig. Descartes (1664) established the first diagram con- cerning the brain projection of the retinal images (Bibl. Collins (1685) shows an excellent representation of the optic tracts and their connections to the optic thalami, as well as a dissection of the temporal horns of the lateral ventricles (Bibl. The op- The visual pathways develop from the rostral portion tic stalks contain a circular lumen which is continu- of the neural tube which contribute to form the ous with both cavities, the optic vesicles distally and prosencephalon and the posterior optic pathways in the prosencephalon proximally. A simultaneous in- higher mammals, and the mesencephalon, related to vagination of the lower aspect of the optic vesicles the visual sense in lower vertebrates and to the visuo- and stalks forms the fetal, or choroidal, fissure, motor systems in higher vertebrates including human which will allow penetration of the vascular meso- (Polyak 1957; Hamilton et al. A progressive narrowing, until closure of the Optic Pathway and Striate Cortex 261 choroidal fissure and leaving a small opening to the hyaloid artery, is completed at the 6 weeks stage. Soon after, at the 17 mm stage, the nerve fibers be- gin to grow from the ganglion cells of the retina and reach the optic stalk. Penetrating the stalk, the nerve fibers proceed proximally toward the brain, forming the future optic nerves. By the fifth month, the dura mater is noticeable and formation of the arachnoid sheath takes place 1 or 2 months later. At birth, the optic nerves measure about 24 mm and lengthen progressively to adapt to orbital growth until puberty, averaging at this time 40 mm in length and 3 or 4 mm in diameter. Between the fourth and sixth weeks of develop- ment, an intermixing of the optic nerve fibers takes place, forming the optic chiasm at the seventh week.
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