Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Propofol, a widely-used intravenous anesthetic, causes bradycardia, depression in contractility and hypotension. The cellular mechanisms responsible for these cardiac toxicity remain unclear. In this study, we examined the cellular electropharmacological actions of propofol on calcium current in guinea-pig heart. Single ventricular myocytes were freshly isolated from guinea-pig using modified enzymatic method. Whole-cell voltage-clamp technique was applied with one suction pipette. Transmembrane L-type calcium current (ICa(L)) was separated from other ionic currents by voltage-control, ionic channel blockers and ion substitution methods. Our results show that propofol decreased ICa(L) in a concentration-dependent manner (KD = 54.2 microM). Slope conductance of current-voltage relation was decreased by 56 microM propofol. Propofol did not affect the steady-state activation curve, but shifted the inactivation curve to hyperpolarizing direction. Recovery from inactivation was slowed down by propofol. Marked resting block and use-dependent block were noted. In conclusion, our results indicate that propofol inhibits cardiac L-type calcium current mainly by shifting inactivation curve and retarding the recovery from inactivation.
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PMID:Electropharmacological actions of propofol on calcium current in guinea-pig ventricular myocytes. 855 Nov 77

The goal of therapy in patients with severe head injury is to avoid secondary brain damage. Analgesia and sedation are an essential part of the therapy, and several drugs are in current use. However, few controlled clinical trials have been performed so far, and none of these drugs has proved to be superior. Although in the past the therapy has been focused on controlling elevated intracranial pressure (ICP), many authors emphasize the role of cerebral ischaemia in the prognosis of patients. Therefore, cerebral perfusion pressure (CPP) i.e. the difference between ICP and mean arterial pressure (CPP = MAP-ICP), seems to be more important than ICP alone. Analgesics and sedatives reduce the cerebral metabolic rate (CMR), and the consequent decrease in cerebral oxygen uptake might prevent ischaemic damage in regions with low perfusion. Moreover, a decrease in CMR is often associated with a decrease of cerebral blood flow (CBF) in regions with normal perfusion and, as a result, ICP is also reduced. Basically, the cerebral effects (on ICP, CMR, and CBF) and the haemodynamic effects with respect to maintenance of a sufficient CPP are most important in the selection of drugs for analgosedation. In addition, the effects on general intensive care management must be considered (pulmonary function, immunreactivity bowel motility). The purpose of this paper is to describe drugs commonly used for analgosedation in severe head injury. Barbiturates bring about the most pronounced decrease of CMR and ICP. In the past these drugs were used routinely in high doses ("barbiturate coma"). However, no improvement in outcome was demonstrable, and vitally dangerous side effects, such as infection, pulmonary dysfunction, arterial hypotension, and renal failure often occurred. High-dose barbiturate therapy is therefore only indicated in exceptional cases, such as refractory increase in ICP with preserved CO2 response of cerebral vessels. The effect is dependent on CMR at the start of this therapy. Benzodiazepines are frequently used in patients with head injury. They cause only a moderate decrease of CMR and ICP. In general, side effects are negligible. However, a possible decrease of MAP by reduced central sympathetic drive has to be taken into account. Opioids are also frequently used in patients with head trauma. The observed cerebral effects are inconsistent. Some authors have described increases in ICP, CBF, and CMR, but in most studies no influence on these values, or a decrease, has been observed. In any case, cautious titration of these drugs and cerebral monitoring are therefore desirable. As with benzodiazepines, a decrease in MAP due to central effects is possible. In addition, opioids inhibit bowel motility. Ketamine is generally used because of its favourable circulatory effects, bronchodilatation and absence of inhibition of bowel motility. In patients with increased ICP, however, it is often considered contraindicated, since it can be associated with cerebral vasodilation and ICP increase. Other studies did not confirm an increase of ICP when controlled ventilation and additional sedation were applied. More recent studies have demonstrated the role of neuroexcitatory NMDA-receptors in ischaemic and traumatic brain damage. Since ketamine exerts an antagonistic effect on N-methyl-D-aspartate receptors (NMDA) and studies in animals have demonstrated a protective effect of ketamine against ischaemic and traumatic brain damage, controlled clinical studies in patients with head injury are desirable. Propofol results in a profound decrease of CMR and a significant decrease of ICP, but often also in haemodynamic depression. Few results obtained during long-term administration are available, but it seems to be beneficial. More clinical studies are warranted. Gamma-hydroxybutyrate (GHB) is a physiological substance, which has only sporadically been investigated for sedation in patients with head trauma. The few available studies show beneficial res
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PMID:[Analgesia and sedation in patients with head-brain trauma]. 859 67

Pharmacological praemedication. In patients receiving regional anaesthetics induction of deep sedation prior to the performance of the block should be avoided because during the installation of the nerve block it is an advantage to have a cooperative patient. Adequate anxiolytic effects are achieved by oral administration of chloracepate (0.3-0.5 mg/kg body weight). Intraoperative sedation. Once regional anaesthesia is established deep sedation or even a light sleep might be appropriate to improve the patient's comfort. Short acting i.v. substances are the agents of choice. Propofol (1.5-5 mg/kg per h) and midazolam (0.03-0.09 mg/kg per h) are recommended. Both substances should be titrated as needed. Since respiratory depression or loss of airway patency may occur, close observation and pulse oxymetric monitoring are mandatory. Intraoperative analgesia. Restlessness due to pain is not an indication for sedatives and/or hypnotics. Pain can be caused not only by incomplete regional anaesthesia, but also by a tourniquet or uncomfortable body positions, for example, and it should be treated in different ways according to its cause. In the case of an incomplete block, a catheter technique makes a top-up dose for augmentation possible; additional peripheral nerve blocks can also be used to complete the analgesia. If these attempts are unsuccessful, systemic analgesics (preferable narcotics) or even anaesthetics must be given. Opioids are recommended only in mild to moderate pain or discomfort. The risk of respiratory depression should be considered. The administration of oxygen by mask and pulse oxymetric monitoring are useful. Ketamine is a common drug with a potent analgesic effect, which possesses the advantages of good support for the cardiovascular system, because of its sympathomimetic action, and minimal depression of the ventilatory drive. However, with the exception of a few specific indications, Ketamine is not a drug that is initially an integral part of planned regional anaesthetic procedures. In case of incomplete regional blocks administration of ketamine is more frequently the "ultima ratio" following a number of previous, unsuccessful attempts-primarily with sedatives and/or opioids-to achieve a condition that will permit surgical procedures; as a result, the hypnotic and respiratory depressant effects of subsequently administered drugs are enhanced and potentiated. An important consequence of this complex pharmacodynamic interaction scenario is a potential loss of the advantages that would otherwise be gained by using "subanaesthetic" ketamine doses (< 0.5 mg/kg), namely: a cooperative patient who is breathing spontaneously and has an intact laryngopharyngeal reflex response and, therefore, an uncompromised airway competence. Pulse oxymetric monitoring of the potentially endangered respiratory function is obligatory. The individual transition to general anaesthesia is not easy to determine. Therefore, it is essential that, whenever the need arises, intubation and mechanical ventilation intervention procedures be carried out immediately.
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PMID:[Analgesia and sedation to supplement incomplete regional anesthesia]. 859 70

Sepsis is characterized by myocardial depression and systemic vasodilation, both of which are most likely mediated by nitric oxide. Propofol inhibits nitric oxide synthase and may therefore be beneficial in sepsis. On the other hand, renal blood flow, known to be only minimally affected by propofol in healthy subjects, may be drastically reduced in septic individuals, because the renal microvasculature is known to be very sensitive to nitric oxide. In this study, the effects of propofol in healthy and in septic sheep, and in combination with fentanyl, were analyzed and compared with nonanesthetized septic sheep. In healthy sheep, propofol caused only minor hemodynamic changes. In septic sheep, however, hemodynamics deteriorated. Renal blood flow was reduced to 60% +/- 10% of the preseptic baseline and to 39% +/- 4% of the septic value. This reduction was selective, since the cardiac output decreased significantly less. These adverse effects of propofol on hemodynamics and renal blood flow were reduced when propofol was combined with fentanyl.
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PMID:The effects of propofol on hemodynamics and renal blood flow in healthy and in septic sheep, and combined with fentanyl in septic sheep. 861 90

The effects of etomidate in an alcoholic vehicle and in a lipid-emulsion as well as those of propofol on N-formyl-methionyl-leucyl-phenylalanine (FMLP-) and zymosan-induced oxygen radical production of neutrophils were examined and compared with the effects of their respective vehicles. Furthermore free-radical scavenging capacities of these medications were investigated. The dose-response effects of etomidate, propofol and their respective vehicles on neutrophil function were tested by FMLP- and zymosan-induced chemiluminescence of neutrophils and, in addition, in a cell-free chemiluminescence system. Effects of commercial preparations of etomidate were generally not drug-specific but due to the vehicles and/or to unphysiologic osmolality values. Propofol impaired chemiluminescence of neutrophils in a drug-specific manner, even in the therapeutic concentration range. Free-radical scavenging contributed to this depression of chemiluminescence of neutrophils by propofol. Different composition of the lipid-emulsions of etomidate and propofol resulted in either a stimulation or suppression of chemiluminescence of neutrophils. Propofol but not etomidate impairs chemiluminescence of neutrophils drug-specifically. Besides a potential interaction with the neutrophils, free-radical scavenging accounts for this suppression.
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PMID:Do etomidate and propofol influence oxygen radical production of neutrophils? 877 72

To determine the electrophysiological effects of propofol and to explain the potential mechanism(s) whereby it causes bradyarrhythmias, 10 closed-chest pigs weighing 20-25 kg were studied. Each animal was premedicated by intramuscular administration of ketamine hydrochloride, intubated, and mechanically ventilated. Femoral arterial and venous catheters were placed, and a comprehensive electrophysiologic evaluation was performed at baseline and after two doses (1 mg/kg i.v. bolus and 0.1 mg/kg/min infusion and an extra 1- mg/kg i.v. bolus and 0.2 mg/kg/min infusion) of propofol. The electrophysiological effects obtained on low-and high-dose propofol were compared to baseline values. Propofol caused a dose-related decrease in sinus cycle length (baseline 565 +/- 36 ms, low-dose propofol 541 +/- 28, high-dose propofol 527 +/- 26 ms; p < 0.05), a prolongation of the corrected sinus node recovery time (baseline 119 +/- 35 ms, low-dose propofol 126 +/- 32, high-dose propofol 130 +/- 30 ms; p < 0.01), and an increase in the His-ventricular interval (baseline 33 +/- 4 ms, low-dose propofol 36 +/- 4, high-dose propofol 40 +/- 3 ms; p < 0.005). All other electrophysiological parameters remained unchanged, and there were no cases of spontaneous atrioventricular block or sinus pauses. We conclude that propofol causes dose-related depression of sinus node and His-Purkinje system functions, but has no effect on the atrioventricular node function and on the conduction properties of atrial and ventricular tissues in normal pig hearts.
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PMID:Electrophysiological effects of propofol on the normal cardiac conduction system. 879 67

Effects of propofol (12.5 mg kg-1, i.v. bolus injection) or 0.9% sodium chloride on arterial blood pressure, arterial blood gases and hepatic circulation (radio-labelled microsphere technique) were studied in 15 conscious and unpremedicated rabbits. No significant changes were observed after sodium chloride. Propofol resulted in anaesthesia, respiratory depression (-49 +/- 14% decrease in PaO2; mean +/- SD) and hypotension (-49 +/- 13% decrease in mean arterial pressure; mean +/- SD) but no changes in hepatic arterial and portal venous blood flows. We conclude that propofol does not affect the liver circulation despite marked depression of mean arterial pressure and respiration.
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PMID:Induction of anaesthesia by propofol and hepatic blood flow in the rabbit. 884 71

1. Whole cell patch-clamp and extracellular field recordings were obtained from granule cells of the dentate gyrus in 400-microns-thick brain slices of the adult rat to determine the actions of the intravenous general anesthetic 2,6-diisopropylphenol (propofol) on acute neuronal survival and preservation of synaptic integrity after amputation of dendrites (dendrotomy), and to determine the role of gamma-aminobutyric acid-A (GABAA)-receptor-mediated inhibition in the neuroprotective effects of propofol. The actions of propofol were compared with those exerted by another widely used intravenous general anesthetic, 5-ethyl-5-[1-methylbutyl]-2-thiobarbituric acid (thiopental). 2. Propofol (10 microM) increased the frequency (control: 5.9 +/- 0.9 Hz, mean +/- SE; propofol: 10.5 +/- 1.3 Hz) and the single-exponential decay time constant (tau D) (control: 4.5 +/- 0.2 ms; propofol: 15.3 +/- 1.5 ms) of miniature inhibitory postsynaptic currents (mIPSCs) recorded in control neurons. Thiopental (25 microM) also increased the tau D (14.3 +/- 0.9 ms) of mISPCs, but had no effect on mIPSC frequency. Both anesthetics potentiated mIPSCs at low concentrations (propofol: 5 microM; thiopental: 1 microM). Propofol and thiopental did not change the peak amplitude and rise times of mIPSCs. 3. Propofol (10 microM) was able to depress the excitability of control granule cells, as determined by the reduction in the amplitude of the orthodromic population spikes. This depression could be prevented by the GABAA receptor antagonist bicuculline (50 microM), indicating that propofol reduces excitability via GABAA receptor functions. 4. Propofol and thiopental were neuroprotectant (assessed by antidromic population responses 2-5 h after injury) if present before and during the amputation of the granule cell dendrites. The protective actions were dose dependent, and at high doses (propofol: 200 microM; thiopental: 400 microM) the anesthetics were as neuroprotective against dendrotomy-induced cell death as 2-amino 5-phosphovaleric acid (APV) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX). The protective effects of the anesthetics were completely blocked with the GABAA receptor antagonists picrotoxin or bicuculline, and were mimicked by the GABAA receptor agonist muscimol (100 microM). 5. Propofol, in contrast to APV and CNQX, could not prevent the dendrotomy-induced Ca(2+)-dependent and long-lasting changes in mIPSC decay kinetics (appearance of a double-exponential, prolonged decay). 6. The protective effects of the anesthetics and those of APV and CNQX on neuronal survival were not significant when the drugs were applied after dendrotomy, indicating that dendrotomy carried out 150-200 microns from the soma without neuroprotective agents rapidly induces irreversible acute degeneration in most injured neurons. The failure to rescue cells from dendrotomy-induced injury did not result from a decreased sensitivity of the GABAA receptors to the anesthetics, because the potentiating effects of the anesthetics on mIPSCs from control and dendrotomized neurons were not different. 7. These data indicate that propofol potentiates synaptic inhibition pre- and postsynaptically, and, when present during dendrotomy, it can protect neurons from acute mechanical-injury induced cell death via potentiation of GABAA receptor functions. However, propofol fails to provide neuroprotection against dendrotomy-induced changes in synaptic physiology.
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PMID:Neuroprotection by propofol in acute mechanical injury: role of GABAergic inhibition. 889 14

The efficacy and safety of remifentanil and alfentanil for patients undergoing major abdominal surgery were compared. Premedicated patients received a loading dose of remifentanil (1.0 microgram.kg-1; n = 116) and a continuous infusion of 0.5 microgram.kg-1.min-1, or a loading dose of alfentanil (25 micrograms.kg-1; n = 118) and a continuous infusion of 1.0 microgram.kg-1.min-1. Propofol was administered (10 mg every 10 s) until loss of consciousness. Patients' lungs were ventilated with 66% nitrous oxide and 0.5% (end-tidal) isoflurane in oxygen. The study drug infusion rate was reduced by 50% 5 min after intubation. Alfentanil was discontinued 15 min before the end of surgery, whereas remifentanil was continued in the immediate postoperative period at a reduced dose. Responses to intubation (28%) and skin incision (17%) occurred approximately twice as often in the alfentanil group (15% and 8%; p = 0.014 and p = 0.037, respectively). More patients receiving alfentanil had one or more responses to surgery (72% vs. 57%; p = 0.016). The time to spontaneous respiration, adequate respiration, response to verbal command and time to recovery room discharge were similar. However, owing to decreased variability, the time to extubation was shorter with remifentanil than with alfentanil (p = 0.048). There was a similar overall incidence of adverse events in both groups, 82% and 75% of patients, respectively. Adverse events associated with remifentanil were rapidly controlled by dose reductions. The incidence of intra-operative hypotension and bradycardia was higher in the remifentanil group (p < or = 0.033). An initial remifentanil infusion rate of 0.1 microgram.kg-1.min-1 titrated to individual need provided postoperative pain relief in the presence of adequate respiration in 71% of patients. When using remifentanil in the immediate postoperative setting, rapid administration of bolus doses and infusion rate increases resulted in a relatively high incidence of muscle rigidity, respiratory depression and apnoea. Changing the postoperative regimen to avoid rapid changes in remifentanil blood concentration resulted in more effective analgesia and dramatically reduced the incidence of adverse events during this period. In patients undergoing major abdominal surgery, remifentanil appears to offer superior intra-operative haemodynamic stability during stressful surgical events compared with alfentanil without compromising recovery from anaesthesia. Remifentanil can be administered as a postoperative analgesic agent at a starting dose of 0.1 microgram-.kg-1.min-1; however, it should only be used in the presence of adequate supervision and monitoring of the patient. Administration of bolus doses is not recommended in this setting.
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PMID:A comparison of remifentanil and alfentanil in patients undergoing major abdominal surgery. 961 18

Patient-controlled sedation (PCS) using propofol has been reported to provide safe and effective sedation during a variety of procedures performed under regional or local anesthesia. In a prospective, randomized fashion, this study evaluated propofol PCS compared to anesthesiologist-administered midazolam-fentanyl sedation during interventional neuroradiologic (INR) procedures. Nineteen patients undergoing 24 INR procedures received propofol PCS (PCS dose, 0.5 mg/kg; lockout interval, 3 min) or anesthesiologist-administered midazolam-fentanyl sedation. Study parameters included discomfort, sedation and anxiety visual analogue scores (VAS), cognitive function, patient satisfaction, and complications. No difference was found between the two sedation techniques with respect to the levels of sedation and anxiolysis. Cognitive function was well preserved in both groups. Patient satisfaction was similarly high in both groups. Complications were similar between groups. These included ventilatory depression (two patients in each group) and excessive sedation (two patients in each group). Three patients in the propofol group became excessively restless, resulting in brief interruptions during the respective procedures. Propofol PCS offers a safe sedation technique during INR procedures with a sedation and anxiolysis profile that was not distinguishable from anesthesiologist-administered midazolam-fentanyl sedation.
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PMID:Patient-controlled sedation using propofol during interventional neuroradiologic procedures. 923 86


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