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During this "absorption" phase, rates of drug entry into blood due to absorption exceed rates of elimination due to clearance. The maximum concentration (Cmax = 7 units) is reached at time Tmax (1 hour after dosage); at this point, instantaneous absorption and elimination rates are equal. Concentrations then fall, indicating that elimination rates exceed absorption rates. Mean plasma concentrations of midazolam after single intravenous and oral doses administered to healthy volunteers29 (*concentrations were normalized to a 2-mg dose). Based on the relationship in section 9B1, in Table 2, the absolute bioavailability of oral midazolam (F) was calculated as 0. A drug is administered as discrete oral doses at intervals equal to the half-life. The dashed line is the hypothetical curve if the same dosing rate were administered by continuous zero-order intravenous infusion. The elimination half-life is assumed to be 24 hours, and the dosage interval is also 24 hours (as in Figure 13). The plasma concentration starts at Cmin, increases to Cmax, then falls again to Cmin. The mean steady-state concentration (Css, dashed line) is the area under the curve for 1 dose interval divided by the length of the interval. Serum concentrations of a drug at steady state if the drug is given using 3 different dosing schedules: either 500 mg every 24 hours, 250 mg every 12 hours, or 125 mg every 6 hours. In each case the mean steady-state concentration (Css) is the same, since the [(dose)/(dose interval)] ratio does not change. However, the interdose fluctuation becomes smaller as the dose interval becomes smaller. With the oncedaily dosing schedule, the interdose fluctuation is large, and the plasma concentration falls outside the therapeutic range just after and just before each dose (in part from reference 16, with permission). Plasma concentrations (1-compartment model) of one drug with first-order elimination (solid line), and another drug with zeroorder elimination (dashed line). Schematic relation of daily phenytoin dosage (X axis) to phenytoin steady-state plasma concentrations (Y axis). In the lower dosage range, the relation is linear, and Css increases in proportion to dosage. As the daily dosage increases to higher ranges, the kinetic pattern transitions toward zero-order, and Css increases disproportionately with dosage (dashed line). At doses above 350 mg per day, Css falls above the therapeutic range of 10­20 g/mL) (horizontal dotted lines). Pharmacokinetic consequences of a drug­drug interaction that either decreases clearance or increases clearance of the substrate drug (inhibition or induction, respectively). Right: the substrate drug is given as a continuous regimen such that steady state is reached (interdose fluctuation not shown). At the arrow, an inhibiting or inducing drug is coadministered, causing a new steady state to be reached. Note that the onset of action of the inducer is slower than that of the inhibitor. A single 80-mg oral dose of propranolol was administered to a series of healthy volunteers. After the serum Cmax is reached, the contractility measure returns close to zero in advance of the serum concentration. Right: A kinetic-dynamic plot, in which pharmacodynamic effect is shown in relation to serum concentration at corresponding times. The pattern is termed "clockwise hysteresis," and can be observed as a consequence of acute tolerance. The authors thank the American College of Clinical Pharmacology for the opportunity to participate in this project.

Meta-Analysis Summary Heterogeneity Evidence Linkages Preoperative fasting for clear liquids: Adults; 2­4 h vs. Mantel-Haenszel fixed-effect analysis (estimate of common effect size); random effect size analyses were not required. Statistical significance values for homogeneity/heterogeneity of statistical tests; P < 0. Anesthesiology 2017; 126:376-93 386 Practice Guidelines Downloaded From: anesthesiology. Consultant Survey Responses* Percent Responding to Each Item N Preoperative Assessment 1. A review of pertinent records, a physical examination, and patient survey or interview should be performed as part of the preoperative evaluation 2. Verification of patient compliance with the fasting requirements should be assessed immediately prior to the time of the procedure Preoperative Fasting Status Clear Liquids: 4a. For otherwise healthy children (2 to 16 yr of age), fasting from the intake of clear liquids for 2 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained 4c. For otherwise healthy neonates (< 44 gestational weeks), fasting from the intake of breast milk for 4 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained 5b. For neonates, fasting from the intake of infant formula for 6 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained 6b. For children, fasting from the intake of infant formula for 6 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained Nonhuman Milk: 7a. For adults, fasting from the intake of nonhuman milk for 6 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained 37 37 36 Strongly Agree 86. Fasting from the intake of a meal that includes fried or fatty 36 foods for 8 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained Preoperative Gastrointestinal Stimulants 10. Gastrointestinal stimulants should be routinely administered 36 before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia in patients with no apparent increased risk for pulmonary aspiration Preoperative Pharmacologic Blockade of Gastric Acid Secretion 11. Histamine-2 receptor antagonists should be routinely adminis36 tered before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia in patients with no apparent increased risk for pulmonary aspiration 12. Proton pump inhibitors should be routinely administered before 37 elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia in patients with no apparent increased risk for pulmonary aspiration Preoperative Antacids 13a. Preoperative antacids should be routinely administered 36 before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia in patients with no apparent increased risk for pulmonary aspiration 13b. When antacids are indicated for selected patients, only 36 nonparticulate antacids should be used Preoperative Antiemetics 14. Preoperative antiemetics should be routinely administered 37 before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia in patients with no apparent increased risk for pulmonary aspiration Preoperative Anticholinergics 15. Preoperative anticholinergics should be routinely adminis37 tered before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia to decrease the risk of pulmonary aspiration Preoperative Multiple Agents 16. Preoperative multiple agents should be routinely adminis37 tered before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia in patients with no apparent increased risk for pulmonary aspiration *An asterisk beside an agreement value represents the median. Patients should be informed of fasting requirements and the reasons for them sufficiently in advance of their procedures 3. For otherwise healthy infants (< 2 yr of age), fasting from the intake of clear liquids for 2 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained 4b. For otherwise healthy adults, fasting from the intake of clear liquids for 2 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained Breast Milk: 5a. For otherwise healthy infants, fasting from the intake of breast milk for 4 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained Infant Formula: 6a. For infants, fasting from the intake of infant formula for 6 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained 6c. For infants, fasting from the intake of nonhuman milk for 6 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained 7b. For children, fasting from the intake of nonhuman milk for 6 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained 7c. For adults, fasting from the intake of nonhuman milk for 6 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained 470 470 468 Strongly Agree 93. Fasting from the intake of a meal that includes fried or fatty 470 foods for 8 or more hours before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia should be maintained Preoperative Gastrointestinal Stimulants 10. Gastrointestinal stimulants should be routinely administered 468 before elective procedures requiring general anesthesia, regional anesthesia, or procedural sedation and analgesia in patients with no apparent increased risk for pulmonary aspiration Preoperative Pharmacologic Blockade of Gastric Acid Secretion 11.

For now, the treatment threshold should be unaffected by age, at least up to 80 years. Thereafter, decisions should be made on an individual basis; in any case, therapy should not be withdrawn from patients over 80 years of age (275, 276). Clinic and population-based survey data continue to suggest that the lower the blood pressure achieved, the lower the rate of cardiovascular events (278­280). In people over 55 years of age, the systolic blood pressure is more important (281), so the primary goal of therapy is to lower systolic blood pressure to 140 mmHg or less. Several trials (277, 282­285) have shown that, in patients with diabetes, reduction of diastolic blood pressure to about 80 mmHg and of systolic blood pressure to about 130 mmHg is accompanied by a further reduction in cardiovascular events or diabetes-related microvascular complications, in comparison with patients with less stringent blood pressure control (277, 284, 285). In patients with high or very high cardiovascular risk, including diabetes or established vascular or renal disease, therefore, blood pressure should be reduced to 130/80 mmHg or less. These trials have demonstrated reductions in both cardiovascular mortality and morbidity with all three drug classes. For the endpoint of total cardiovascular mortality, these meta-analyses showed no strong evidence of differences between drug classes. Data are also emerging on an increased incidence of diabetes in patients treated with thiazides or beta-blockers compared with other classes of antihypertensive drugs, which may influence the choice of first-line drug therapy (288­292). At the beginning of the study, there was a fourth group treated with an alpha-blocker; this treatment was stopped prematurely because of an increased risk of combined cardiovascular disease, to which heart failure was a major contributor. The benefits were largely attributable to protection against stroke, and were particularly striking in the diabetic group (290). The incidence of diabetes was also lower in the group on the amlodipine-based regimen. However, this difference could be largely explained by the difference in systolic blood pressure in the two groups (292). One such study included clinical trials in which a beta-blocker was used as the first-line antihypertensive drug in at least half of all patients in one treatment group, with outcome data for cardiovascular morbidity and mortality, and all-cause mortality. This analysis found no difference in all-cause mortality or myocardial infarction, but the risk of stroke was lower with other antihypertensive drug regimens. However, when beta-blockers were compared with placebo or no treatment, they were found to significantly reduce the risk of stroke. Beta-blockers are as efficacious as other classes of anti- 42 Prevention of cardiovascular disease hypertensive drugs in reducing all-cause mortality and myocardial infarction, but appear to be less effective in reducing the risk of stroke (293). Another meta-analysis (295) investigated the efficacy of beta-blockers in different age groups. The efficacy was found to be similar to that of other antihypertensive agents in younger patients, but lower in older patients, with the excess risk being particularly marked for stroke. A recent Cocharane review assessed the effect of beta-blockers on mortality and morbidity endpoints, compared with placebo or no therapy for hypertension (296). Results showed a relatively weak effect of beta-blockers in reducing stroke and no effect on coronary heart disease. In choosing an antihypertensive drug therapy, there are a number of specific compelling indications (Table 7). Beta-blockers should be considered for first-line antihypertensive therapy only if there is a compelling indication (294­296) (Table 7). For the majority of patients in resource-constrained settings, if there is no compelling indication for another class of drug, a low dose of a thiazide-like diuretic should be considered as the first choice of therapy, on the basis of comparative trial data, availability and cost-effectiveness (286) (Table 7). As previously noted, for many patients, blood pressure should be reduced to lower levels than previously recommended, and more than one drug will often be required (75, 271, 272, 277, 284). It is important to increase gradually the dose of each drug to achieve optimum effect before adding another drug. Adherence to treatment is important to achieve the optimal reduction in blood pressure, and may be facilitated by a once-a-day dosage. If a second antihypertensive drug is added, it should be from a different drug class. In addition to the compelling indications listed in Table 7, other factors may favour the choice of certain drugs. Central alpha-agonists, such as clonidine, or peripheral adrenergic blockers may be used as inexpensive therapies, despite the absence of outcome data.