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Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. This indication is approved under accelerated approval based on overall response rate. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [see Clinical Studies (14. These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials [see Clinical Studies (14. Review the Prescribing Information for ipilimumab for additional information prior to initiation. Review the Prescribing Information for ipilimumab for recommended dose modifications. There are no recommended dose modifications for hypothyroidism or hyperthyroidism. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucenttowhite, proteinaceous particles. Administration Administer the infusion over 30 minutes through an intravenous line containing a sterile, nonpyrogenic, low protein binding inline filter (pore size of 0. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2) or more severe (Grade 34) pneumonitis, followed by corticosteroid taper. Complete resolution of symptoms following corticosteroid taper occurred in 67% of patients. Approximately 84% of patients with pneumonitis received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 30 days (range: 5 days to 11. All patients with pneumonitis required systemic corticosteroids, including 92% who received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 19 days (range: 4 days to 3. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life threatening (Grade 4) colitis. Approximately 91% of patients with colitis received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 23 days (range: 1 day to 9. Approximately 96% of patients with colitis received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1. Approximately 23% of patients required addition of infliximab to highdose corticosteroids. All patients with colitis required systemic corticosteroids, including 80% who received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day to 27 months). Approximately 23% of patients with immunemediated colitis required addition of infliximab to highdose corticosteroids. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or lifethreatening (Grade 4) transaminase elevations, with or without concomitant elevation in total bilirubin. All patients with hepatitis received highdose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 23 days (range: 1 day to 2 months). Two patients required the addition of mycophenolic acid to highdose corticosteroids. Approximately 92% of patients with hepatitis received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1. Approximately 19% of patients with immunemediated hepatitis required addition of mycophenolic acid to highdose corticosteroids. Administer hormone replacement as clinically indicated and corticosteroids at a dose of 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) or greater hypophysitis. Approximately 67% of patients with hypophysitis received hormone replacement therapy and 33% received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 14 days (range: 5 to 26 days). Approximately 75% of patients with hypophysitis received hormone replacement therapy and 56% received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 19 days (range: 1 day to 2. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe (Grade 3) or lifethreatening (Grade 4) adrenal insufficiency. Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy and 25% received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 11 days (range: 1 day to 1 month). Approximately 57% of patients with adrenal insufficiency received hormone replacement therapy and 33% received high dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 9 days (range: 1 day to 2. Approximately 94% of patients with adrenal insufficiency received hormone replacement therapy and 27% received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 12 days (range: 2 days to 5. Approximately 79% of patients with hypothyroidism received levothyroxine and 4% also required corticosteroids. Approximately 26% of patients with hyperthyroidism received methimazole, 9% received carbimazole, 4% received propylthiouracil, and 9% received corticosteroids. Approximately 73% of patients with hypothyroidism or thyroiditis received levothyroxine. Approximately 29% of patients with hyperthyroidism received methimazole and 24% received carbimazole. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for lifethreatening (Grade 4) increased serum creatinine. All patients received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day to 15. Approximately 67% of patients received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 13. Approximately 78% of patients with immunemediated nephritis and renal dysfunction received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 17 days (range: 1 day to 6 months). For immunemediated rash, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe (Grade 3) or lifethreatening (Grade 4) rash. Approximately 16% of patients with rash received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 12 days (range: 1 days to 8. Approximately 17% of patients with rash received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 14 days (range: 2 days to 4. All patients with immunemediated rash required systemic corticosteroids, including 19% who received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 22 days (range: 1 day to 23 months). If other etiologies are ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients with immunemediated encephalitis, followed by corticosteroid taper. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions [see Dosage and Administration (2. Follow patients closely for evidence of transplantrelated complications and intervene promptly. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. The most common adverse reactions (reported in at least 20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus. The most common immunemediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). Across both trials, the most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. The population characteristics were: median age 63 years (range: 29 to 83), 92% White, and 60% male. The most frequent (fi2%) serious adverse reactions were pneumonia, dyspnea, pneumonitis, pleural effusion, and dehydration. The most common (fi20%) adverse reactions were fatigue, decreased appetite, musculoskeletal pain, dyspnea, nausea, diarrhea, constipation, and cough. The most frequent serious adverse reactions reported in at least 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. Rate of death on treatment or within 30 days of the last dose of study drug was 4. The most common adverse reactions (reported in at least 20% of patients) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. Treatment could continue until disease progression, maximal clinical benefit, or unacceptable toxicity. The most frequent serious adverse reactions reported in at least 1% of patients were pneumonia, infusionrelated reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. The most common adverse reactions (reported in at least 20%) among all patients were upper respiratory tract infection, fatigue, cough, diarrhea, pyrexia, musculoskeletal pain, rash, nausea, and pruritus. Table 16 summarizes the adverse reactions, excluding laboratory terms, that occurred in at least 10% of patients in the safety population. After an immune mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred up to 30 days after completing the initial nivolumab course. Twenty eight patients (11%) had newonset peripheral neuropathy, and 3 of 40 patients had worsening of neuropathy from baseline. The most common (reported in at least 20%) treatmentemergent laboratory events included cytopenias, liver function abnormalities, and elevated lipase. Other common findings (reported in at least 10%) included elevated creatinine, electrolyte abnormalities, and elevated amylase. After an immunemediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred within 30 days of completing the initial nivolumab course. The most frequent serious adverse reactions reported in at least 2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite. Table 18 summarizes adverse reactions that occurred in greater than 10% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. Immunemediated hepatitis requiring systemic corticosteroids occurred in 8 (5%) patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There was no evidence of altered pharmacokinetic profile or increased incidence of infusion reactions with antinivolumab antibody development. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U. Nivolumab administration resulted in a nondoserelated increase in spontaneous abortion and increased neonatal death. No overall differences in safety or effectiveness were reported between elderly patients and younger patients. No overall difference in safety was reported between elderly patients and younger patients. In elderly patients with intermediate or poor risk, no overall difference in effectiveness was reported. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady state. Steadystate concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 3. The predicted exposure of nivolumab after a 30minute infusion is comparable to that observed with a 60minute infusion.

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Addition of folic acid to staple foods as a selective nutrition intervention strategy arthritis diet list 120mg etoricoxib overnight delivery. Development of neurologic manifestations of perni cious anemia during multivitamin therapy arthritis pain joint effective 60 mg etoricoxib. Effect of increasing dietary folate on red cell folate: Implications for prevention of neural tube defects arthritis medication diclofenac purchase etoricoxib line. Prevention of congenital abnormalties by periconceptional multi vitamin supplementation arthritis in neck natural remedies order online etoricoxib. Prevention of the first occurrence of neuraltube defects by periconceptional vitamin supplementation numbness in fingers due to arthritis generic 120 mg etoricoxib mastercard. Pregnancy outcomes in a randomized con trolled trial of periconceptional multivitamin supplementation psoriatic arthritis medication side effects buy etoricoxib 90mg. Homo cysteine and coronary artery disease in French Canadian subjects: Relation with vitamins B12, B6, pyridoxal phosphate, and folate. Effects of different enzyme treatments on extrac tion of total folate from various foods prior to microbiological assasy and radioassay. Food standards: Amendment of the standards of identity for enriched grain products to require the addition of folic acid. Food standards: Amendment of the standards of identity for enriched grain products to require addition of folic acid. Folate and vitamin B12 concentrations in maternal and fetal blood, and amniotic fluid in second trimester pregnancies complicated by neural tube defects. Plasma and red cell folate values and folate requirements in formulafed term infants. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. A candidate genetic risk factor for vascular disease: A common mutation in methylenetet rahydrofolate reductase. Association between nutritional status and cognitive functioning in a healthy elderly population. Chemical and nutritional aspects of folate research: Analyti cal procedures, methods of folate synthesis, stability and bioavailability of di etary folates. Ad equacy of extraction techniques for determination of folate in foods and other biological materials. Experience with pteroylglutamic (synthetic folic acid) in the treatment of pernicious anemia. Symptomatic and asymptomatic methylenetetrahydro folate reductase deficiency in two adult brothers. Departmental Consolidation of the Food and Drugs Act and the Food and Drug Regulations with Amendments to December 19, 1996. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Correlates of folate deficiency with alco holism and associated macrocytosis, anemia, and liver disease. Recurrence of neural tube defect in a group of at risk women: A 10 year study of Pregnavite Forte F. Can terathanasia explain the protective effect of folic acid supplementation on birth defectsfi Association between dietary fiber intake and the folate status of a group of female adolescents. Homocysteine increases as folate decreases in plasma of healthy men during shortterm dietary folate and methyl group restriction. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentra tions. Postpartum folic acid supplementation of adolescents: Impact on maternal folate and zinc status and milk composi tion. Subnormal serum folate and macrocytosis associated with anti convulsant drug therapy. Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylenetet rahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Feeding human milk to rats increases bifidobacterium in the cecum and colon which correlates with enhanced folate status. Plasma homocysteine in acute myocardial infarction: Homocysteinelow ering effect of folic acid. Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. Doubleblind randomized controlled trial of folate treatment before conception to prevent recurrence of neural tube defects. Aspirin and folate binding: In vivo and in vitro studies of serum binding and urinary excretion of endog enous folate. Measurable folates in human milk are increased by treatment with amylase and protease. Neuropsychiatric disorders caused by cobal amin deficiency in the absence of anemia or macrocytosis. The effect of folates on the reflex activity in the isolated hemisected frog spinal cord. Methylenetetrahydrofolate reductase poly morphism, plasma folate, homocysteine, and risk of myocardial infarction in U. Methylenetetrahydrofolate reduc tase polymorphism, dietary interactions, and risk of colorectal cancer. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Study of dose dependence and urinary folate excretion produced by ethanol in humans and rats. Epithelial cell folate depletion occurs in neoplastic but not adjacent normal colon mucosa. National Insti tute of Child Health and Human Development Neural Tube Defects Study Group. Folate status of adult males living in a metabolic unit: Possible relationships with iron nutriture. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. Genetic effects on variation in redbloodcell folate in adults: Implications for the familial aggre gation of neural tube defects. Hyperhomocyst(e)inaemia: An independent risk factor for intermittent clau dication. Thermolabile variant of 5, 10methylenetetrahydro folate reductase associated with low redcell folates: Implications for folate intake recommendations. Folate status of rheumatoid arthritis patients receiving long term, lowdose methotrexate therapy. Maternal intake of folate, vitamin B12, and zinc and risk of orofacial cleft birth defects. Intrastriatal folic acid mimics the distant but not local brain damaging properties of kainic acid. Influence of smoking on folate intake and blood folate concentrations in a group of elderly Spanish men. Absorption of folate from fortified cerealgrain products and of supplemental folate consumed with or without food determined by using a duallabel stableisotope protocol. Determination of folate in cereal grain food products using trienzyme extraction and combined affinity and reversedphase liquid chromatography. Are common mutations of cystathionine betasynthase involved in the aetiology of neural tube defectsfi Age and genderspecific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation. Urinary folate excretion after ingestion of pteroylmonoglutamic acid and food folate. Relations of vitamin B12, vitamin B6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Folate and vitamin B6 from diet and supplements in rela tion to risk of coronary heart disease among women. Bacterially synthesized folate in rat large intestine is incorporated into host tissue folyl polyglutamates. The development and progression of sub acute combined degeneration of the spinal cord in patients with pernicious anemia treated with synthetic pteroylglutamic (folic) acid. Increased urinary excretion and prolonged turnover time of folic acid during ethanol ingestion. Folate nutrition is optimal in exclusively breastfed infants but inadequate in some of their mothers and in formulafed infants. Sensitivity of serum methyl malonic acid and total homocysteine determinations for diagnosing cobal amin and folate deficiencies. Genetic poly morphism of methylenetetrahydrofolate reductase and myocardial infarction. Use of multivitamin/mineral prenatal supplements: Influence on the outcome of pregnancy. Myo cardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene. Mater nal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Liver extract, folic acid, and thymine in pernicious anemia and subacute combined degeneration. The association between gastric achlorhydria and subacute combined degenera tion of the spinal cord. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatographymass spectrometry. Reduced recurrence of orofacial clefts after peri conceptional supplementation with highdose folic acid and multivitamins. Promotion of vascular smooth muscle cell growth by homocysteine: A link to atherosclerosis. Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study. Commentary: the roles of folate and pteridine derivatives in neurotransmitter metabolism. Results of Bvitamin supple mentation study used in a prediction model to define a reference range for plasma homocysteine. Effective homocysteine metabolism may protect South African blacks against coronary heart disease. Prevention of neural tube defects by and toxicity of Lhomocysteine in cultured postimplantation rat embryos. Altered folate and vitamin B12 metabolism in families with spina bifida offspring. Sequence analy sis of the coding region of human methionine synthase: Relevance to hyper homocysteinaemia in neuraltube defects and vascular disease. Correlation of peripheral white cell and bone marrow changes with folate levels in pregnancy and their clinical significance. Primary prevention of neural tube defects with folic acid supplementation: Cuban experience. Observations on the maintenance of a normal hematologic status and on the occurrence of combined system disease at the end of one year. In vivo folate kinetics during chronic supplementation of human subjects with deuteriumlabeled folic acid. Effects of serum vitamin B12 and folate status on episodic memory performance in very old age: A population based study. Mice deficient in cystathionine betasynthase: Animal models for mild and severe homocyst(e)inemia. Plasma ho mocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. Bioavailability for humans of deuteriumlabeled monoglutamyl and polyglutamyl folates is affected by se lected foods. The reduced unsubstituted pteroate moiety is required for folate toxicity of cultured cerebellar granule neurons. A genetic defect in 5, 10 methylenetetrahydro folate reductase in neural tube defects. Megaloblastic anemia in scurvy with response to 50 micrograms of folic acid daily. Childhood leukaemia and intramuscular vitamin K: Findings from a casecontrol study. Effect of alphatocopherol and alphatocopherolquinone on vitamin Kdependent carboxylation in the rat. Dietary vitamin K1 and stability of oral anticoagulation: Proposal of a diet with constant vitamin K1 content.

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Edrophonium binds to the anionic site on acetylcholinesterase by electrostatic attraction and to the esteratic [578] subsite by hydrogen bonding arthritis in staffy dogs order etoricoxib american express. In addition arthritis in neck after cervical fusion buy cheap etoricoxib 90mg on-line, anticholinesterases may also increase the Page 69 Pharmacology of Muscle Relaxants and Their Antagonists release of acetylcholine from presynaptic nerve terminals arthritis diet ginger discount etoricoxib 90mg on line, block neural potassium channels rheumatoid arthritis in feet and hands purchase etoricoxib 120mg mastercard, [27] and have a direct agonist effect arthritis detox diet generic etoricoxib 90mg without prescription. Details of the mechanisms of action of these [579][580] anticholinesterases have been described in review articles rheumatoid arthritis genetic testing generic 60mg etoricoxib with visa. Major Determinants of Speed and Adequacy of Reversal Antagonism of nondepolarizing blockade is time dependent. Reversal occurs at a rate that depends primarily on five factors: (1) the depth of block at the time of administration of the antagonist, (2) the antagonist administered, (3) the dose of antagonist, (4) the rate of spontaneous recovery from the neuromuscular blocker, and (5) the concentration of the inhaled anesthetic present during reversal. Depth of Block As was shown with the longacting neuromuscular blocker pancuronium, more time is [254][581][582] required to antagonize profound levels of block than lesser levels of block. Lesser degrees of block are associated with more rapid recovery of neuromuscular function. Recovery of singletwitch height from deep levels of neuromuscular blockade requires, as demonstrated in these older studies, 15 to 30 minutes. Neostigmine shortened recovery, whether administered at 1%, 10%, or 25% spontaneous recovery, by approximately 40%. Recommendations regarding the timing of administration of anticholinesterase remain unclear. However, because the time from administration of the anticholinesterase to full recovery is shortened by waiting for a greater degree of spontaneous recovery before administering the anticholinesterase, it would seem prudent to not administer the [584] anticholinesterase at the earliest degrees of recovery. If adequate recovery does not occur within this time, subsequent recovery is slow and requires ongoing elimination of the neuromuscular blocker from plasma. Subsequent recovery is at the same rate as spontaneous recovery and is due to the decrease [571][587] in plasma concentration of vecuronium as the drug is eliminated. Administration of a [571] second dose of neostigmine has no further effect on recovery because acetylcholinesterase is already maximally inhibited. If the block at the time of neostigmine administration is sufficiently deep that adequate recovery does not occur within 10 minutes, the time at which full recovery of neuromuscular function will occur depends on the inherent duration of action of the [582] neuromuscular blocker. With drugs that have a long duration of action, this period of inadequate neuromuscular function can be 30 to 60 minutes or longer, whereas with drugs that have an intermediate duration of action, it will be much shorter. For this reason and because of its lesser atropine requirement, edrophonium regained popularity as an [585] [589] antagonist during the 1980s. The relative potencies of edrophonium and neostigmine differ at various intensities of [591] blockade. Edrophonium becomes less potent with respect to neostigmine as the depth of blockade becomes more intense. In other words, the doseresponse curves are not parallel and become increasingly divergent as the depth of blockade intensifies. This difference indicates that edrophonium may be less effective than neostigmine when antagonizing very deep levels of blockade. ure 1330 First twitch height (logit scale) versus dose (log scale) 10 minutes after administration of neostigmine and edrophonium given at either 1% (99% block) or 10% (90% block) recovery of the first twitch. This relationship is true up to the point of the maximum effective dose, beyond which further amounts of anticholinesterase will not produce any further antagonism. Page 72 Pharmacology of Muscle Relaxants and Their Antagonists [593] Donati and associates studied the reversal of 90% block induced by either dTc or pancuronium to demonstrate the relationship of the dose of neostigmine to the speed of reversal. Neostigmine and edrophonium do not [594][595] potentiate each other; in fact, their effects in combination may not even be additive. Therefore, when inadequate reversal occurs, one should not be tempted to add a different anticholinesterase but should ensure only that the maximum dose of the original drug has been administered. Ventilation should then be supported until adequate neuromuscular function is achieved. Rate of Spontaneous Recovery from the Neuromuscular Blocker After administration of an anticholinesterase, two processes contribute to recovery of neuromuscular function. The first is antagonism induced by the effect of the anticholinesterase at the neuromuscular junction; the second is the natural process of decrease in the plasma concentration of the neuromuscular blocker (and hence the [582][587] concentration of the neuromuscular blocker at the neuromuscular junction). Therefore, the more rapid the elimination of the neuromuscular blocker, the faster the recovery of adequate neuromuscular function after the administration of an antagonist. A clear illustration of this principle is the difference in antagonizing a block induced by neuromuscular blockers with an intermediate versus a long duration of action. Plasma concentrations of drugs with an intermediate duration of action decrease more [245] rapidly than do concentrations of drugs with a long duration of action, and consequently [586][594][595] recovery of neuromuscular function is more rapid. The incidence of inadequate neuromuscular function in the postoperative period is less with intermediateacting than [59][60] with longacting neuromuscular blockers. Nevertheless, the blocks from all [597] intermediateacting muscle relaxants should be reversed with an anticholinesterase drug. Because of the inability to detect subtle neuromuscular blocks clinically and persistence in [598] the recovery room, pharmacologic reversal should be routine. ure 1331 Comparative mean speed of antagonism by neostigmine of neuromuscular blockade induced by longacting Page 73 Pharmacology of Muscle Relaxants and Their Antagonists drugs (doxacurium, pancuronium, pipecuronium), intermediateacting drugs (atracurium and others), and the shortacting drug mivacurium. Review Course Lectures, 67th Congress, Cleveland, Ohio, International Anesthesia Research Society, 1993. The rate of spontaneous recovery from mivacuriuminduced blockade is more rapid than that from any other nondepolarizing neuromuscular blocker because of its rapid hydrolysis by butyrylcholinesterase. Neostigmineinduced reversal of [315][599] mivacurium is similar to or faster than that of atracurium. During profound (<3% twitch recovery) mivacuriuminduced blockade, administration of neostigmine may [600] possibly prolong recovery. First, it inhibits acetylcholinesterase at the neuromuscular junction, thereby effectively increasing the acetylcholine concentration and facilitating recovery. Second, it inhibits butyrylcholinesterase, the enzyme responsible for the metabolism of mivacurium, and slows [601][602] the normally rapid decrease in plasma concentration of mivacurium. In contrast, [601][603] edrophonium is not as potent an inhibitor of butyrylcholinesterase, and it should have little effect on the metabolism of mivacurium. It has been suggested that routine administration of an anticholinesterase may often be [605] omitted because spontaneous recovery from mivacurium is so rapid. However, this strategy may lead to inadequate recovery and postoperative weakness unless at least 20 [599][604] minutes is allowed for spontaneous recovery. As indicated earlier, administration of [598] an anticholinesterase drug should probably be routine. Because mivacurium is metabolized by butyrylcholinesterase, recovery, in theory, may be made more rapid by the administration of exogenous human butyrylcholinesterase. Administration of purified human cholinesterase does produce some antagonism of [606] [601] mivacuriuminduced blockade, but it is ineffective in a profound block and no better [607] than edrophonium alone. It may be justified to administer purified butyrylcholinesterase to patients homozygous for atypical butyrylcholinesterase who have a prolonged [320][608] block, but this therapy has yet to be adequately tested and is expensive. Concentration of Inhaled Anesthetic Several studies have documented that antagonism of residual blockade is actually retarded [609][610][611][612][613] by anesthetizing concentrations of volatile anesthetics. For example, [609] Delisle and Bevan showed that pancuronium reversal by neostigmine under enflurane anesthesia occurred more slowly than under nitrous oxide and intravenous anesthetics. It has even been suggested that the effect is different for different anesthetics and that [610] sevoflurane may impede neostigmineinduced antagonism more than isoflurane does. When compared with isoflurane anesthesia, the recovery variables are prolonged during [614][615] desflurane or sevoflurane anesthesia. Withdrawal of the inhaled anesthetic at the end Page 74 Pharmacology of Muscle Relaxants and Their Antagonists of surgery, with subsequent reduction of its enhancement of neuromuscular blockade, will [572] speed pharmacologic reversal. To antagonize lesser degrees of block, smaller doses of anticholinesterases may be administered, with additional anticholinesterase given if adequate recovery has not occurred in 10 minutes. Giving too much anticholinesterase to antagonize residual neuromuscular blockade may actually render [570][616][617] patients weaker, probably because of the excess of acetylcholine at the neuromuscular junction that remains available to interact with the acetylcholine receptor. Other Factors That May Interfere with Antagonism It is not advisable to administer further anticholinesterase if maximal doses of edrophonium (1. These doses inhibit acetylcholinesterase completely, and if they fail to fully antagonize residual blockade, another likely cause of the inadequate antagonism should be sought. Some of these additional potential causes of inadequate antagonism of neuromuscular blockade are described in the following sections. AcidBase State Both metabolic and respiratory acidosis may augment a nondepolarizing neuromuscular [588][618][619] blockade, but only respiratory acidosis prevents adequate antagonism. Therefore, if a patient hypoventilates, attempts to antagonize a residual block may fail. Administration of narcotics to relieve pain may, by producing hypoventilation, increase the likelihood of this adverse event. Although metabolic acidosis might also be predicted to prevent antagonism by neostigmine, [588][618][619] this theory has not been substantiated. Metabolic alkalosis, but not metabolic [588][618][620] acidosis, prevents neostigmine antagonism of dTc and pancuronium. These results suggest that the extracellular hydrogen ion concentration (pH) may not be as important as changes in electrolytes and intracellular pH. Electrolyte Imbalance [621] Although it has been the subject of review articles, few data are available on the effect of electrolyte imbalance on antagonism of nondepolarizing neuromuscular blockade by Page 75 Pharmacology of Muscle Relaxants and Their Antagonists neostigmine. Low extracellular concentrations of potassium enhance the blockade from nondepolarizing neuromuscular blockers and diminish the ability of neostigmine to antagonize the blockade. This effect is based on the increase in endplate transmembrane potential that results from a higher ratio of intracellular to extracellular potassium. Thus, a decrease in extracellular potassium causes hyperpolarization and produces resistance to depolarization. Patients with an imbalance in potassium may have other diseases or injuries [622] that alter their response to neuromuscular blockers. Cohen and [621] Feldman speculated that in chronic diseases, both intracellular and extracellular potassium is depleted with little net effect on transmembrane potential. Therefore, the response to neuromuscular blockers and their antagonists should be normal. However, muscle transmembrane potentials are changed in patients who are severely ill or bedridden [623] for a few days. In addition, severe dehydration will concentrate the neuromuscular blocker present in plasma, in effect decreasing the volume of distribution and increasing muscle relaxant activity. In an animal model of chronic hypokalemia, cats were given a diuretic without potassium supplementation for 15 days. Less pancuronium was required for [624] neuromuscular blockade and more neostigmine for antagonism. Even though the differences were small, the blockade was always antagonized completely. Assuming that this animal model approximates the clinical situation, changes in potassium appear to be of relatively minor consequence with respect to the clinical question of adequacy of reversal. Other Factors the calcium channel blocker verapamil will potentiate nondepolarizing neuromuscular [625][626] blocking drugs and may make it difficult to achieve adequate reversal of blockade. When attempting reversal of neuromuscular blockade in patients receiving verapamil, [625][626] edrophonium may be more effective than neostigmine. Other factors that may interfere with antagonism are hypothermia and the administration of antibiotics, particularly the aminoglycoside or polypeptide classes (see "Drug [467][468][469][470][471][472][473][474] Interactions"). In the case of antibiotics, administration of an anticholinesterase may in fact deepen the blockade. Monitoring with a nerve stimulator, if [627] aminoglycosides have been administered, may give misleading results. Side Effects of Anticholinesterases Cardiovascular Effects Because only the nicotinic effects of edrophonium, neostigmine, and pyridostigmine are [27] desired, the muscarinic effects must be blocked by atropine or glycopyrrolate. To minimize cardiovascular changes, atropine is better suited for administration with the rapidacting [27] edrophonium, and glycopyrrolate is better suited for administration with the slower [628] acting neostigmine and pyridostigmine. Atropine administration 30 seconds before [629] edrophonium will decrease the ventricular ectopy associated with this anticholinesterase. Dysrhythmias can occur, and Page 76 Pharmacology of Muscle Relaxants and Their Antagonists [632] anticholinesterases should be used with caution in patients with autonomic neuropathy. Nausea and Vomiting Reports on the effect of anticholinesterase administration on postoperative nausea and vomiting are conflicting. Neostigmine administration has been implicated as a cause of [636][637] postoperative nausea and vomiting. It has also been described as having antiemetic [638] [639] properties and as having no impact on postoperative nausea and vomiting. A meta [640] analysis by Tramer and FuchsBader looked at the results of anticholinesterase administration in over 1100 patients. They found a doseresponse relationship for the incidence of nausea and vomiting after the administration of neostigmine. Discrepancies in the other studies may have been at least in part attributable to different dosing regimens.

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