Pharmacology in the elderly and newer anaesthesia drugs

In developed countries, a growing proportion of patients presenting for anesthesia and surgery are elderly. Despite this, and the fact that aging is known to be associated with alterations in drug pharmacokinetics and dynamics, there is little detailed information about the impact of aging on the pharmacology of commonly used anesthetic agents. In this review, we discuss existing current knowledge on the physiological changes that occur with age and the way these changes affect the pharmacokinetics and dynamics of anesthetic agents. Also, an overview of up-to-date PK-PD modeling concepts and their usefulness and limitations in modern anesthesiologic practice with respect to the elderly population is given. Finally, newer agents such as sugammadex, remifentanyl, ropivacaine and desflurane are discussed in detail with emphasis on current evidence concerning dosing, safety and efficacy of their use in the elderly.     

Drugs and the liver

The liver is a major organ with multiple functions. A number of drugs are metabolized by the liver during phase 1 and 2 reactions which include complex processes involving cytochrome P450 enzymes. Genetic and acquired variability in cytochrome P450 activity may have profound effects on pharmacokinetics. Additionally, drugs can also modify how the liver functions and cause dysfunction or even failure of the organ both by a direct effect on the liver or by alteration in liver blood flow. It is important to recognize the signs and symptoms of liver failure in patients and identify possible causes including drug interactions. Furthermore, once a patient has been recognized to be suffering with liver dysfunction or failure, drug choice and dosing regime will need to be rationalized. Paracetamol overdose can have severe and life-threatening consequences for patients due to its effect on liver function. It is the leading cause of acute liver failure in the UK. Correct and early management is crucial and will be discussed within this article.     

Influence of age on the pharmacokinetics and pharmacodynamics of oral transmucosal fentanyl citrate

BACKGROUND: Cancer pain is primarily a problem of older persons. Oral transmucosal fentanyl citrate (OTF) was developed to provide rapid analgesia and is the first drug specifically approved for treating breakthrough cancer pain. Fentanyl in OTF is absorbed across the oral mucosa but a considerable portion is swallowed and absorbed enterally. The effects of age on OTF pharmacokinetics and pharmacodynamics are unknown. This investigation evaluated OTF disposition and clinical effects in older (60-75 yr) compared with younger (18-40 yr) volunteers. METHODS: Healthy young (26 +/- 6 yr) and older (67 +/- 6 yr) volunteers (n = 12 each) were studied in an Institutional Review Board approved protocol. They received OTF (10 microg/kg). Plasma fentanyl and norfentanyl concentrations were determined by mass spectrometry. Fentanyl effects were measured by dark-adapted pupil diameter and by subjective self-assessments using visual analog scales. RESULTS: Plasma fentanyl and norfentanyl concentrations and pharmacokinetic parameters did not differ between younger and older subjects. Maximum pupil diameter change from baseline was significantly less in older (3.1 +/- 0.7 mm) compared with younger (4.5 +/- 1.1 mm) subjects (P < 0.05). OTF-dependent subjective assessments of alertness/sedation, energy level, confusion, clumsiness, anxiety, and nausea did not differ in the older subjects. DISCUSSION: The pharmacokinetics of OTF were not altered in older volunteers. In contrast, there was a somewhat diminished response to the miotic effects of fentanyl in older subjects. No change in OTF dosing in the elderly would appear necessary because of altered pharmacokinetics. If the response to OTF in older patients is similar to that in older volunteers and miosis is representative of analgesia and respiratory depression, then changes in OTF dosing with age alone do not appear indicated.     

Drugs and the liver

The liver is a major organ with multiple functions. A number of drugs are metabolized by the liver during phase 1 and 2 reactions which include complex processes involving cytochrome P450 enzymes. Genetic and acquired variability in cytochrome P450 activity may have profound effects on pharmacokinetics. Additionally, drugs can also modify how the liver functions and cause dysfunction or even failure of the organ both by a direct effect on the liver or by alteration in liver blood flow. It is important to recognize the signs and symptoms of liver failure in patients and identify possible causes including drug interactions. Furthermore, once a patient has been recognized to be suffering with liver dysfunction or failure drug choice and dosing regime will need to be rationalized.Paracetamol overdose can have severe and life-threatening consequences for patients due to its effect on liver function. It is the leading cause of acute liver failure in the UK,¹ Correct and early management is crucial and will be discussed within this article.     

Drugs and the liver

The liver is a major organ with multiple functions. A number of drugs are metabolized by the liver during phase 1 and 2 reactions which include complex processes involving cytochrome P450 enzymes. Genetic and acquired variability in cytochrome P450 activity may have profound effects on pharmacokinetics. Additionally, drugs can also modify how the liver functions and cause dysfunction or even failure of the organ both by a direct effect on the liver or by alteration in liver blood flow. It is important to recognize the signs and symptoms of liver failure in patients and identify possible causes including drug interactions. Furthermore, once a patient has been recognized to be suffering with liver dysfunction or failure drug choice and dosing regime will need to be rationalized.Paracetamol overdose can have severe and life threatening consequences for patients due to its effect on liver function. It is the leading cause of acute liver failure in the UK,¹ Correct and early management is crucial and will be discussed within this article.     

Pharmacological models and their use in clinical anaesthesia

Intravenous agents used in anaesthesia belong to a variety of chemical classes and cover a number of different pharmacodynamic responses. Compared to inhalational anaesthesia the combined administration of intravenous agents offers a greater degree of freedom because different pharmacodynamic effects can be controlled separately. This greater degree of freedom, however, requires a more detailed insight into the pharmacology of the drugs to allow control of drug administration and to meet the therapeutic optimum. This review considers the combination of pharmacokinetics and pharmacodynamics as a pharmacological model. The general principles of these two subunits relevant for dosing of intravenous agents are reviewed. In establishing a model of the non-linear system relating dosing to effect, pharmacokinetics introduces an intermediate step which describes the time course of drug concentrations as a function of dosing. It is thought that incorporating the entire dependence of the effect upon time is, in most cases, linear. Pharmacodynamics relate concentration to effect in a non-linear but time-independent manner. It embodies the entire non-linearity of the system, but is assumed to be a static relation. Special attention is given to those principles which apply to any intravenous agent irrespective of its particularities. The impact of distribution and elimination, hysteresis, and ceiling on the induction, maintenance and recovery of anaesthesia, and on improving anaesthesia techniques and drug delivery are considered.     

Chronic cyclosporin A therapy in rats.

We investigated the pharmacokinetics of cyclosporin A (CsA) blood levels and drug toxicity in a chronic rat study in which long-term (30 weeks) CsA was administered. Ninety Lewis rats received subcutaneous CsA at 5 mg/kg/day for 12 weeks, at which time CsA injections were stopped in 50 animals. The remaining 40 rats were maintained on 5 mg/kg CsA daily until week 18 and then switched to an alternate day dosing until week 30. All rats were observed daily and weighed weekly. Whole blood CsA levels were determined by a commercially available radioimmunoassay kit. The daily dosing regimen resulted in greatly elevated trough CsA levels (greater than 1,600 micrograms/liter) and substantial chronic systemic toxicity, with weight loss and death in eight animals. Alternate day dosing reduced trough levels (mean 1,311 micrograms/liter) and decreased toxicity. Chronic administration by the subcutaneous route resulted in a considerable depot effect, with constancy of drug levels over a 48 hr dosing interval and a slow decline of drug levels (15 days) upon cessation of treatment. These results underscore the importance of monitoring both body weight and blood CsA levels in rodent studies when CsA is employed. Investigators should be aware of drug accumulation with chronic therapy and the consequent need to modify dosing to prevent toxicity.     

Influence of Bariatric Surgery on the Use and Pharmacokinetics of Some Major Drug Classes

The purpose of this review is to evaluate the influence of bariatric surgery on the use and pharmacokinetics of some frequently used drugs. A PubMed literature search was conducted. Literature was included on influence of bariatric surgery on pharmacoepidemiology and pharmacokinetics. Drug classes to be searched for were antidepressants, antidiabetics, statins, antihypertensive agents, corticosteroids, oral contraceptives, and thyroid drugs. A reduction in the use of medication by patients after bariatric surgery has been reported for various drug classes. Very few studies have been published on the influence of bariatric surgery on the pharmacokinetics of drugs. After bariatric surgery, theoretically, reduced drug absorption may occur. Correct dosing and choosing the right dosage form for drugs used by patients after bariatric surgery are necessary for optimal pharmacotherapy. Therefore, more clinical studies are needed on the influence of bariatric surgery on the pharmacokinetics of major drugs.     

Anesthesia and concomitant pathologies: anesthesia in the elderly patient

With the increase in the average age of the population, more and more older persons undergo surgery. Major surgery, cardiovascular, orthopaedic and abdominal interventions expose the elderly patient to a significant risk for postoperative morbidity and mortality. This is not only related to the advanced age of these subjects, which is a recognized independent risk factor, but also to the aging process itself and to the greater prevalence of heart and lung diseases affecting this population segment. An important role is also played by the so-called physiologic modification found in subjects without recognized illnesses. Reduced organ function reserve requires accurate preoperative assessment that takes into account cardiovascular reserve and physiologic and pathologic alterations in the respiratory system that may predispose the patient to hypoxemia and favour the development of postoperative infection. Moreover, alterations in pharmacokinetics and pharmacodynamics require individualized drug dosing. Particular attention should also be directed at the prevention of postoperative cognitive disorders that favour the development of complications and negatively affect postoperative recovery of body function.     

Anesthesia for geriatric patients : Part 2: anesthetics, patient age and anesthesia management

Part?2 of this review on geriatric anesthesia primarily describes the multiple influences of age on the pharmacokinetics and pharmacodynamics of different anesthetic agents and their impact on clinical practice. In the elderly the demand for opioids is reduced by almost 50% and with total intravenous anesthesia the dosages of propofol and remifentanil as well as recovery times are more determined by patient age than by body weight. As a result depth of anesthesia monitoring is recommended for geriatric patients to individually adjust the dosing to patients needs. With muscle relaxants both delayed onset of action and prolonged duration of drug effects must be considered with increasing age and as this may lead to respiratory complications, neuromuscular monitoring is highly recommended. The following measures appear to be beneficial for geriatric patients: thorough preoperative assessment, extended hemodynamic monitoring, use of short-acting anesthetics in individually adjusted doses best tailored by depth of anesthesia monitoring, intraoperative normotension, normothermia and normocapnia, complete neuromuscular recovery at the end of the procedure and well-planned postoperative pain management in order to reduce or avoid the use of opioids.     

Chronopharmacology for deoxyspergualin: toxicity and efficacy in the rat.

BACKGROUND: Deoxyspergualin (DSG), a potent immunosuppressive drug, has been clinically used as a rescue therapy for acute graft rejection. However, DSG has severe adverse effects that limits its use. Here, we examined the optimized therapeutic protocol for DSG using chronopharmacological profiles of it. METHODS: First, a dosing time-dependent difference in the toxicity and efficacy of DSG was determined using a heterotopic heart transplantation model. Second, chronokinetics of DSG were examined to reveal the mechanism for dosing time-dependent differences in the effect. RESULTS: In rats treated with DSG at the active period, bone marrow suppression and damage of small intestine were significantly severe. However, no significant difference was found in cardiac allograft survival and pharmacokinetics according to the timing of drug administration. CONCLUSIONS: The toxicity of DSG varied with the dosing time, whereas its efficacy did not. The chronopharmacological approach may provide merits for immunosuppressive therapy with DSG in clinical organ transplantation.     

Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients: Twice Daily Versus Once Daily Dosing

Tacrolimus a macrolide immunosuppressant that is routinely given in two equally divided doses every 12 h. However, the time-dependent pharmacokinetics of tacrolimus suggest that once daily morning administration of tacrolimus may produce appropriate drug exposure. The purpose of this pilot study was to compare the pharmacokinetics and safety of twice vs. once daily administration of tacrolimus in stable kidney transplant recipients. Steady-state tacrolimus pharmacokinetic parameters were estimated on two occasions in an open-label, three-arm, two-period sequential study: twice daily dosing (Phase I) and once daily dosing (Phase II). In phase II, 18 patients were assigned to one of three arms: those taking 67%, 85% and 100% of their total twice daily dose once in the morning. In phase I, the mean area under the blood concentration-time curve (AUC) was higher after the morning dose, AUC(0-12) 117 +/- 40 vs. AUC(12-24) 97 +/- 30 ng/h/mL, p=0.012. In the 85% Group, the mean AUC ratio between twice and once daily was 1.0 (95% CI, 0.9-1.1) which predicted the best conversion ratio. Tacrolimus given once daily in the morning, at 85% of the twice daily dose, provides safe and equivalent drug exposure to twice daily dosing. This convenient dosing schedule may help to increase compliance and lower costs.     

Drug use and nephrotoxicity in the intensive care unit

Patients cared for in the intensive care unit (ICU) undergo multiple interventions to treat serious medical conditions. In addition to the acute illness being treated, underlying chronic conditions require ongoing drug therapy. As a result, these patients are exposed to numerous pharmaceutical agents, many of which have narrow therapeutic windows and toxic potential. Comorbid conditions, altered drug pharmacokinetics, and drug-drug interactions further enhance the risk for both drug overdosing and underdosing and adverse medication effects. Underdosing is complicated by reduced efficacy, whereas overdosing results in various end-organ toxicities. One such complication is acute kidney injury (AKI), a relatively common problem in the ICU, which results from multiple insults. Importantly, potentially nephrotoxic medications contribute significantly to the development of AKI. In view of these issues, it is crucial that clinicians caring for these patients use appropriate drug dosing based on the knowledge of altered pharmacokinetics, vigilant monitoring of drug efficacy and toxicity, recognition of drugs with nephrotoxic potential, and early identification of drug-induced AKI when it develops.     

Piperacillin-tazobactam dosing in anuric acute kidney injury patients receiving continuous renal replacement therapy

Introduction: To determine appropriate dosing of piperacillin-tazobactam in critically ill patients receiving continuous renal replacement therapy (CRRT). Methods: The databases of PubMed, Embase, and ScienceDirect were searched. We used the Medical Subject Headings of “piperacillin-tazobactam,” “CRRT,” and “pharmacokinetics” or related terms or synonym to identify the studies for reviews. A one-compartment pharmacokinetic model was conducted to predict piperacillin levels for the initial 48 h of therapy. The pharmacodynamic target was 50% of free drug level above the minimum inhibitory concentration (MIC) and 4 times of the MIC. The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. Results: Our simulation study reveals that the dosing regimen of piperacillin-tazobactam 12 g/day is appropriate for treating Pseudomonal infection with KDIGO recommended effluent rate of 25–35 mL/kg/h. The MIC values of each setting were an important factor to design piperacillin-tazobactam dosing regimens. Conclusion: The Monte Carlo simulation can be a useful tool to evaluate drug dosing in critically ill acute kidney injury patients receiving CRRT when limited pharmacokinetic data are a concern. Clinical validation of these results is needed.     

Cerebrospinal fluid and plasma pharmacokinetics of the cyclooxygenase 2 inhibitor rofecoxib in humans: single and multiple oral drug administration

Cerebrospinal fluid (CSF) pharmacokinetics of orally administered cyclooxygenase 2 inhibitors, with single or multiple dosing, is of clinical relevance because it may relate to the analgesic efficacy of these drugs. We enrolled 9 subjects with implanted intrathecal catheters in the study. After 50-mg oral rofecoxib administration, the CSF drug concentration lagged slightly behind the plasma drug concentration. The ratio of the 24-h area under the drug-concentration curve (AUC) in CSF to plasma was 0.142. After daily dosing of rofecoxib 50 mg/d for 9 days, rofecoxib concentrations in plasma and CSF were larger on Day 9 than on Day 1, with the 24-h AUC on Day 9 more than twice the Day 1 AUC for both plasma and CSF. After nine consecutive daily doses of rofecoxib, the AUC(CSF)/AUC(plasma) ratio was 0.159. The important findings of this study are that CSF rofecoxib levels are approximately 15% of plasma levels and that repeated daily dosing more than doubles the AUC in CSF.     

The Pharmacokinetics of Methohexital in Young and Elderly Subjects

The pharmacokinetics of methohexital were investigated in ten young adult volunteers and in seven young and seven elderly patients. The latter two groups underwent enflurane and nitrous oxide anesthesia and surgery. Each subject received a bolus dose of 2 mg/kg of methohexital intravenously. Plasma levels of the drug were measured for 8 h after injection by gas chromatography using a nitrogen detector. Anesthesia (combined with surgery) and increase in age did not separately affect the kinetics of the drug; however, the elimination half-life was longer in the elderly patients group than in the young non-anesthetized volunteers.     

Tacrolimus pharmacokinetics in Hispanic children after kidney transplantation

Ethnic differences in drug pharmacokinetics are well recognized including that for tacrolimus (TAC) in adult subjects. However, similar knowledge among pediatric populations is missing. Our limited retrospective study compares steady-state pharmacokinetics of TAC in Hispanic versus non-Hispanic children. Serial blood samples were collected and whole blood concentrations of TAC were measured using radioimmunoassay. Compared with non-Hispanic children, Hispanic children had lower measures of drug exposure (maximum drug concentration [C_max] and area under the drug concentration-time curve [AUC_0-∞]), higher volume of distribution, and faster clearance. Interestingly, only in Hispanic children, significant correlations were found between body weight and clearance, age and volume of distribution, and Schwartz estimated glomerular filtration rate and half-life. In conclusion, our study suggests that ethnic differences exist between Hispanic and non-Hispanic children in TAC PK, and based on our preliminary findings, either a higher or more frequent TAC dosing may be required for effective immunosuppression therapy in Hispanic children.