Peter De Paepe

Pharmacokinetic and Pharmacodynamic Considerations When Treating Patients with Sepsis and Septic Shock

Sepsis and septic shock are accompanied by profound changes in the organism that may alter both the pharmacokinetics and the pharmacodynamics of drugs. This review elaborates on the mechanisms by which sepsis-induced pathophysiological changes may influence pharmacological processes.Drug absorption following intramuscular, subcutaneous, transdermal and oral administration may be reduced due to a decreased perfusion of muscles, skin and splanchnic organs. Compromised tissue perfusion may also affect drug distribution, resulting in a decrease of distribution volume. On the other hand, the increase in capillary permeability and interstitial oedema during sepsis and septic shock may enhance drug distribution. Changes in plasma protein binding, body water, tissue mass and pH may also affect drug distribution. For basic drugs that are bound to the acute phase reactant α1-acid glycoprotein, the increase in plasma concentration of this protein will result in a decreased distribution volume. The opposite may be observed for drugs that are extensively bound to albumin, as the latter protein decreases during septic conditions.For many drugs, the liver is the main organ for metabolism. The determinants of hepatic clearance of drugs are liver blood flow, drug binding in plasma and the activity of the metabolic enzymes; each of these may be influenced by sepsis and septic shock. For high extraction drugs, clearance is mainly flow-dependent, and sepsis-induced liver hypoperfusion may result in a decreased clearance. For low extraction drugs, clearance is determined by the degree of plasma binding and the activity of the metabolic enzymes. Oxidative metabolism via the cytochrome P450 enzyme system is an important clearance mechanism for many drugs, and has been shown to be markedly affected in septic conditions, resulting in decreased drug clearance.The kidneys are an important excretion pathway for many drugs. Renal failure, which often accompanies sepsis and septic shock, will result in accumulation of both parent drug and its metabolites.Changes in drug effect during septic conditions may theoretically result from changes in pharmacodynamics due to changes in the affinity of the receptor for the drug or alterations in the intrinsic activity at the receptor.The lack of valid pharmacological studies in patients with sepsis and septic shock makes drug administration in these patients a difficult challenge. The patients underlying pathophysiological condition may guide individual dosage selection, which may be guided by measuring plasma concentration or drug effect.

Influence of hypovolemia on the pharmacokinetics and the electroencephalographic effect of propofol in the rat.

BackgroundHypovolemia decreases the dose requirement for anesthetics, but no data are available for propofol. As it is impossible to study this in patients, a rat model was used in which the influence of hypovolemia on the pharmacokinetics and pharmacodynamics of propofol was investigated. MethodsAnimals were randomly allocated to either a control (n = 9) or a hypovolemia (n = 9) group, and propofol was infused (150 mg · kg−1 · h−1) until isoelectric periods of 5 s or longer were observed in the electroencephalogram. The changes observed in the electroencephalogram were quantified using aperiodic analysis and used as a surrogate measure of hypnosis. The righting reflex served as a clinical measure of hypnosis. ResultsThe propofol dose needed to reach the electroencephalographic end point in the hypovolemic rats was reduced by 60% (P < 0.01). This could be attributed to a decrease in propofol clearance and in distribution volume. Protein binding was similar in both groups. To investigate changes in end organ sensitivity during hypovolemia, the electroencephalographic effect versus effect–site concentration relation was studied. The effect–blood concentration relation was biphasic, exhibiting profound hysteresis in both hypovolemic and control animals. Semiparametric minimization of this hysteresis revealed similar equilibration half-lives in both groups. The biphasic effect–concentration relation was characterized by descriptors showing an increased potency of propofol during hemorrhage. The effect–site concentration at the return of righting reflex was 23% (P < 0.01) lower in the hypovolemic animals, also suggesting an increased end organ sensitivity. ConclusionsAn increased hypnotic effect of propofol occurs during hypovolemia in the rat and can be attributed to changes in both pharmacokinetics and end organ sensitivity.

Pharmacokinetics of fluoroquinolones in critical care patients: A bio-analytical HPLC method for the simultaneous quantification of ofloxacin, ciprofloxacin and moxifloxacin in human plasma.

A high-performance liquid chromatographic (HPLC) method with fluorescence detection was developed and validated for the simultaneous quantification of ofloxacin, ciprofloxacin and moxifloxacin in human plasma. Sarafloxacin was used as internal standard. Chromatography was carried out using a Waters XBridge C(18) HPLC column and a gradient mobile phase consisting of CH(3)CN/MeOH/0.025M TBA.Cl/TFA (eluent A at 75/25/899/1 (v/v); eluent B at 150/50/799/1 (v/v); both at pH 3.5). Excitation/emission wavelengths were 279/442nm for ciprofloxacin and 290/500nm for ofloxacin, moxifloxacin and internal standard. Prior to chromatography, plasma samples were treated with acetonitrile for protein precipitation, followed by evaporation of the liquid layer and reconstitution in eluent A. The method was validated for the three fluoroquinolones over the clinically relevant concentration range from 0.02 to 7.50mug/ml. The method showed acceptable linearity with correlation coefficients, r(2)>0.995, as well as high precision (RSD% <7% in each case), accuracy (90.4-105.4%) and selectivity. The limit of quantification for the three fluoroquinolones was established at 0.02mug/ml. Ofloxacin, ciprofloxacin and moxifloxacin were extracted from plasma with a mean recovery of 95%, 86.4% and 94.2%, respectively. During validation, the concentration of the three fluoroquinolones was found to be stable after 3 freeze-thaw cycles and for at least 15h after extraction. This bio-analytical method was finally applied to the analysis of samples which have been obtained from patients, participating in a pharmacokinetic study on moxifloxacin.

Abrupt awakening phenomenon associated with gamma-hydroxybutyrate use : A case series

Case reports mention a sudden awakening from GHB-associated coma but do not specify its time course. The aim of the present case series was to investigate the time course of the awakening from GHB intoxication and the relationship to plasma concentrations of GHB and the presence of other drugs. Unconscious (GCS ≤8) participants at six large rave parties who were treated at medical stations were included. Serial blood samples were taken every 10 to 30 minutes for toxicological analysis. At the same time-points, the depth of coma was scored with the Glasgow Coma Score (GCS). Fifteen out of 21 unconscious patients proved to be positive for GHB. Fourteen of these had ingested one or more other drugs. The median GHB plasma concentration upon arrival in the medical station was 212 μg/ml (range 112 to 430 μg/ml). In 10 patients the GCS was scored more than twice, allowing study of the time course. The GCS of these patients remained ≤8 for a median time of 90 minutes (range 30 to 105 minutes). The duration of the transition between GCS of ≤8 and ≥12 was 30 minutes (range 10 to 50 minutes). A subgroup of five patients had a GCS of 3 upon arrival and remained at 3 for a median time of 60 minutes (range 30 to 110 minutes), while the median time for the transition between the last point with GCS 3 and the first with GCS 15 was 30 minutes (range 20 to 60 minutes). This case series illustrates that patients with GHB intoxications remain in a deep coma for a relatively long period of time, after which they awaken over about 30 minutes. This awakening is accompanied by a small change in GHB concentrations. A confounding factor in these observations is co-ingested illicit drugs.

Acute Chlorophenylpiperazine Overdose : A Case Report and Review of the Literature

This case report describes an acute overdose in a female patient with the serotonin mixed agonist-antagonist m-chlorophenylpiperazine (mCPP), a new synthetic drug that is also a metabolite of the antidepressant trazodone. Following ingestion of three multi-coloured tablets, she developed anxiety, agitation, drowsiness, flushing, visual disturbances and tachycardia. The mCPP concentration was 320 ng/mL in plasma and 2300 ng/mL in urine. Amphetamine (40 ng/mL), benzoylecgonine (47 ng/mL) and alcohol (0.7 g/L) were also detected in plasma. The concentration of mCPP in plasma was approximately six times higher than the usual concentration measured in patients under trazodone treatment (26-108 ng/mL, average 56 ng/mL). However, one should be careful to link the observed symptoms to the use of mCPP only as the other drugs that have also been taken or an interaction between the drugs could also have played a role.

The influence of hemorrhagic shock on the pharmacokinetics and the analgesic effect of morphine in the rat

Summary— The influence of hemorrhagic shock (removal of 30% of the blood volume) on the pharmacokinetics and the analgesic effect of morphine was investigated in conscious rats. Plasma concentrations of morphine after a bolus injection (5 mg/kg) are higher in the shock animals, which is attributed to a small decrease in clearance (‐22%; P > 0.05) and a significant decrease in distribution volume (‐33%; P < 0.05) of the drug. The areas under the plasma concentration‐time curve of the metabolite morphine‐3‐glucuronide (M3G) are significantly higher (+237%; P < 0.01) in the shock rats, which is probably explained by a decreased distribution and renal excretion. The analgesic effect of morphine was evaluated using the tail‐flick test during a continuous infusion (10 mg/kg/h) with measurement of the plasma concentrations of morphine and M3G. Data from these experiments show higher plasma concentrations of morphine (+33%; P < 0.05) and M3G (+66%; P > 0.05) during shock, and a significantly increased analgesic effect (+43%; P < 0.05). Our data suggest that the increased analgesic effect of morphine during hemorrhagic shock can most likely be explained by pharmacokinetic changes resulting in higher morphine concentrations.

Possible pathogenic mechanism of propofol infusion syndrome involves coenzyme Q

Background:Propofol is a short-acting intravenous anesthetic agent. In rare conditions, a life-threatening complication known as propofol infusion syndrome can occur. The pathophysiologic mechanism is still unknown. Some studies suggested that propofol acts as uncoupling agent, others suggested that it inhibits complex I or complex IV, or causes increased oxidation of cytochrome c and cytochrome aa3, or inhibits mitochondrial fatty acid metabolism. Although the exact site of interaction is not known, most hypotheses point to the direction of the mitochondria. Methods:Eight rats were ventilated and sedated with propofol up to 20 h. Sequential biopsy specimens were taken from liver and skeletal muscle and used for determination of respiratory chain activities and propofol concentration. Activities were also measured in skeletal muscle from a patient who died of propofol infusion syndrome. Results:In rats, authors detected a decrease in complex II+III activity starting at low tissue concentration of propofol (20 to 25 µM), further declining at higher concentrations. Before starting anesthesia, the complex II+III/citrate synthase activity ratio in liver was 0.46 (0.25) and in skeletal muscle 0.23 (0.05) (mean [SD]). After 20 h of anesthesia, the ratios declined to 0.17 (0.03) and 0.12 (0.02), respectively. When measured individually, the activities of complexes II and III remained normal. Skeletal muscle from one patient taken in the acute phase of propofol infusion syndrome also shows a selective decrease in complex II+III activity (z-score: −2.96). Conclusion:Propofol impedes the electron flow through the respiratory chain and coenzyme Q is the main site of interaction with propofol.

Evaluation of clinical pharmacist recommendations in the geriatric ward of a Belgian university hospital

Objective To evaluate the type, acceptance rate, and clinical relevance of clinical pharmacist recommendations at the geriatric ward of the Ghent university hospital. Methods The clinical pharmacist evaluated drug use during a weekly 2-hour visit for a period of 4 months and, if needed, made recommendations to the prescribing physician. The recommendations were classified according to type, acceptance by the physician, prescribed medication, and underlying drug-related problem. Appropriateness of prescribing was assessed using the Medication Appropriateness Index (MAI) before and after the recommendations were made. Two clinical pharmacologists and two clinical pharmacists independently and retrospectively evaluated the clinical relevance of the recommendations and rated their own acceptance of them. Results The clinical pharmacist recommended 304 drug therapy changes for 100 patients taking a total of 1137 drugs. The most common underlying drug-related problems concerned incorrect dose, drug–drug interaction, and adverse drug reaction, which appeared most frequently for cardiovascular drugs, drugs for the central nervous system, and drugs for the gastrointestinal tract. The most common type of recommendation concerned adapting the dose, and stopping or changing a drug. In total, 59.7% of the recommendations were accepted by the treating physician. The acceptance rate by the evaluators ranged between 92.4% and 97.0%. The mean clinical relevance of the recommendations was assessed as possibly important (53.4%), possibly low relevance (38.1%), and possibly very important (4.2%). A low interrater agreement concerning clinical relevance between the evaluators was found: kappa values ranged between 0.15 and 0.25. Summated MAI scores significantly improved after the pharmacist recommendations, with mean values decreasing from 9.3 to 6.2 (P < 0.001). Conclusion In this study, the clinical pharmacist identified a high number of potential drug-related problems in older patients; however, the acceptance of the pharmacotherapy recommendations by the treating physician was lower than by a panel of evaluators. This panel, however, rated most recommendations as possibly important and as possibly having low relevance, with low interrater reliability. As the appropriateness of prescribing seemed to improve with decreased MAI scores, clinical pharmacy services may contribute to the optimization of drug therapy in older inpatients.

Oral bioavailability of moxifloxacin after Roux-en-Y gastric bypass surgery

OBJECTIVES Roux-en-Y gastric bypass surgery is the most commonly performed procedure for the treatment of morbid obesity. This anatomical alteration may affect the absorption and consequently the bioavailability of oral drugs. This study aims to investigate the oral bioavailability of moxifloxacin in 12 healthy volunteers who underwent gastric bypass surgery. PATIENTS AND METHODS In this randomized crossover study, each subject received two single standard doses of 400 mg of moxifloxacin orally or intravenously administered on two occasions separated by a washout period of 1 week. Serial venous blood samples were drawn up to 72 h after dosing and moxifloxacin plasma levels were measured by a validated HPLC method with fluorescence detection. [clinicaltrials.gov database (identifier: NCT01130922).] RESULTS After oral dosing, moxifloxacin plasma concentrations reached a maximum (C(max)) of 3.38 ± 1.41 mg/L after 1.75 h (0.75-4.00). After intravenous dosing, C(max) and T(max) were 4.53 ± 1.43 mg/L and 1.03 h (0.75-2.50), respectively. The mean areas under the plasma concentration time curve extrapolated to infinity (AUC(∞)) were 46.2 ± 1.4 mg · h/L after oral dosing and 52.3 ± 1.3 mg · h/L after intravenous dosing, resulting in a mean oral bioavailability of 88.32% [90% confidence interval (CI) 85.64%-91.08%]. CONCLUSIONS This study confirms that exposure to moxifloxacin is equivalent for oral and intravenous administration of 400 mg dosages in healthy volunteers who underwent gastric bypass surgery. But these exposures were more than 50% higher than those described for subjects without gastric bypass. This may suggest a higher enterohepatic recirculation of moxifloxacin after gastric bypass.

Augmented renal clearance implies a need for increased amoxicillin/clavulanic acid dosing in critically ill children

ABSTRACT There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [NCT02456974].)