This article provides an update about catecholamine metabolism, with emphasis on correcting common misconceptions relevant to catecholamine systems in health and disease. Importantly, most metabolism of catecholamines takes place within the same cells where the amines are synthesized. This mainly occurs secondary to leakage of catecholamines from vesicular stores into the cytoplasm. These stores exist in a highly dynamic equilibrium, with passive outward leakage counterbalanced by inward active transport controlled by vesicular monoamine transporters. In catecholaminergic neurons, the presence of monoamine oxidase leads to formation of reactive catecholaldehydes. Production of these toxic aldehydes depends on the dynamics of vesicular-axoplasmic monoamine exchange and enzyme-catalyzed conversion to nontoxic acids or alcohols. In sympathetic nerves, the aldehyde produced from norepinephrine is converted to 3,4-dihydroxyphenylglycol, not 3,4-dihydroxymandelic acid. Subsequent extraneuronal O-methylation consequently leads to production of 3-methoxy-4-hydroxyphenylglycol, not vanillylmandelic acid. Vanillylmandelic acid is instead formed in the liver by oxidation of 3-methoxy-4-hydroxyphenylglycol catalyzed by alcohol and aldehyde dehydrogenases. Compared to intraneuronal deamination, extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism. The single largest source of metanephrines is the adrenal medulla. Similarly, pheochromocytoma tumor cells produce large amounts of metanephrines from catecholamines leaking from stores. Thus, these metabolites are particularly useful for detecting pheochromocytomas. The large contribution of intraneuronal deamination to catecholamine turnover, and dependence of this on the vesicular-axoplasmic monoamine exchange process, helps explain how synthesis, release, metabolism, turnover, and stores of catecholamines are regulated in a coordinated fashion during stress and in disease states.

Catecholamine Metabolism: A Contemporary View with Implications for Physiology and Medicine

Four cases of cauda equina syndrome occurring after continuous spinal anesthesia are reported. In all four cases, there was evidence of a focal sensory block and, to achieve adequate analgesia, a dose of local anesthetic was given that was greater than that usually administered with a single-injection technique. We postulate that the combination of maldistribution and a relatively high dose of local anesthetic resulted in neurotoxic injury. Suggestions that may reduce the potential for neurotoxicity are discussed. Use of a lower concentration and a "ceiling" or maximum dose of local anesthetic to establish the block should be considered. If maldistribution of local anesthetic is suspected (as indicated by a focal sensory block), the use of maneuvers to increase the spread of local anesthetic is recommended. If such maneuvers prove unsuccessful, the technique should be abandoned.

Cauda equina syndrome after continuous spinal anesthesia.

Pain, nausea and vomiting are frequently listed by patients as their most important perioperative concerns. With the change in emphasis from an inpatient to outpatient hospital and office-based medical/surgical environment, there has been increased interest in the ‘big little problem’ of postoperative nausea and vomiting (PONV). Currently, the overall incidence of PONV is estimated to be 25 to 30%, with severe, intractable PONV estimated to occur in approximately 0.18% of all patients undergoing surgery. PONV can lead to delayed postanaesthesia care unit (PACU) recovery room discharge and unanticipated hospital admission, thereby increasing medical costs. The aetiology and consequences of PONV are complex and multifactorial, with patient-, medical- and surgery-related factors. A thorough understanding of these factors, as well as the neuropharmacology of multiple emetic receptors [dopaminergic, muscarinic, cholinergic, opioid, histamine, serotonin (5-hydroxy-tryptamine; 5-HT)] and physiology [cranial nerves VIII (acoustic-vestibular), IX (glossopharyngeal) and X (vagus), gastrointestinal reflex] relating to PONV are necessary to most effectively manage PONV. Commonly used older, traditional antiemetics for PONV include the anticholinergics (scopolamine), phenothiazines (promethazine), antihistamines (diphenhydramine), butyrophenones (droperidol) and benzamides (metoclopramide). These antiemetics have adverse effects such as dry mouth, sedation, hypotension, extrapyramidal symptoms, dystonic effects and restlessness. The newest class of antiemetics used for the prevention and treatment of PONV are the serotonin receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron). These antiemetics do not have the adverse effects of the older, traditional antiemetics. Headache and dizziness are the main adverse effects of the serotonin receptor antagonists in the dosages used for PONV. The serotonin receptor antagonists have improved antiemetic effectiveness but are not as completely efficacious for PONV as they are for chemotherapy-induced nausea and vomiting. Older, traditional antiemetics (such as droperidol) compare favourably with the serotonin receptor antagonists regarding efficacy for PONV prevention. Combination antiemetic therapy improves efficacy for PONV prevention and treatment. In the difficult-to-treat PONV patient (as in the chemotherapy patient), suppression of numerous emetogenic peripheral stimuli and central neuroemetic receptors may be necessary. This multimodal PONV management approach includes use of: (i) multiple different antiemetic medications (double or triple combination antiemetic therapy acting at different neuroreceptor sites); (ii) less emetogenic anaesthesia techniques; (iii) adequate intravenous hydration; and (iv) adequate pain control.

Prevention and Treatment of Postoperative Nausea and Vomiting

Initially thought to be virtually free of negative effects, benzodiazepines are now known to carry risks of dependence, withdrawal, and negative side effects. Among the most controversial of these side effects are cognitive effects. Long-term treatment with benzodiazepines has been described as causing impairment in several cognitive domains, such as visuospatial ability, speed of processing, and verbal learning. Conversely, long-term benzodiazepine use has also been described as causing no chronic cognitive impairment, with any cognitive dysfunction in patients ascribed to sedation or inattention or considered temporary and associated with peak plasma levels. Complicating the issue are whether anxiety disorders themselves are associated with cognitive deficits and the extent to which patients are aware of their own cognitive problems. In an attempt to settle this debate, meta-analyses of peer-reviewed studies were conducted and found that cognitive dysfunction did in fact occur in patients treated long term with benzodiazepines, and although cognitive dysfunction improved after benzodiazepines were withdrawn, patients did not return to levels of functioning that matched benzodiazepine-free controls. Neuroimaging studies have found transient changes in the brain after benzodiazepine administration but no brain abnormalities in patients treated long term with benzodiazepines. Such findings suggest that patients should be advised of potential cognitive effects when treated long term with benzodiazepines, although they should also be informed that the impact of such effects may be insignificant in the daily functioning of most patients.

/pdf/the-effects-of-benzodiazepines-on-cognition-1vjy5hj3lf.pdf

The effects of benzodiazepines on cognition.

Aversive experiences have been thought to provoke or exacerbate clinical depression. The present review provides a brief survey of the stress-depression literature and suggests that the effects of stressful experiences on affective state may be related to depletion of several neurotransmitters, including norepinephrine, dopamine, and serotonin. A major element in determining the neurochemical changes is the organism's ability to cope with the aversive stimuli through behavioral means. Aversive experiences give rise to behavioral attempts to cope with the stressor, coupled with increased utilization and synthesis of brain amines to contend with environmental demands. When behavioral coping is possible, neurochemical systems are not overly taxed, and behavioral pathology will not ensue. However, when there can be no behavioral control over the stressful stimuli, or when the aversive experience is perceived as uncontrollable, increased emphasis is placed on coping through endogenous neurochemical mechanisms. Amine utilization increases appreciably and may exceed synthesis, resulting in a net reduction of amine stores, which in turn promotes or exacerbates affective disorder. The processes governing the depletions may be subject to sensitization or conditioning, such that exposure to traumatic experiences may have long-term repercussions when the organism subsequently encounters related stressful stimuli. With continued uncontrollable stimulation, adaptation occurs in the form of increased activity of synthetic enzymes, and levels of amines approach basal values. It is suggested that either the initial amine depletion provoked by aversive experiences or a dysfunction of the adaptive processes, resulting in persistent amine depletion, contributes to behavioral depression. Aside from the contribution of behavioral coping, several organismic, experiential, and environmental variables will influence the effects of aversive experiences on neurochemical activity, and may thus influence vulnerability to depression.

Depression: The predisposing influence of stress

Uptake of local anesthetics injected into the subarachnoid space determines which neuronal functions are affected during spinal anesthesia. Elimination of local anesthetics from the subarachnoid space determines the duration of these effects. Distribution of local anesthetics within cerebrospinal fluid (CSF) determines the extent of altered neuronal function. Uptake and elimination have been reviewed previously (1). The present review deals with distribution, the determinant of the level of spinal anesthesia. Studies of drug distribution usually rest upon measurements of concentrations of the drug as a function of time after administration. Technical and ethical considerations make it impossible to take multiple samples of CSF at different levels of the subarachnoid space in patients. Reliance must, therefore, be placed upon estimates of distribution of local anesthetics in CSF not by measuring drug concentrations in CSF but, instead, by measuring the extent of neurologic responses to local anesthetics in CSF. The neurologic response that will be relied upon in this review, for estimation of local anesthetic distribution in CSF, is the spinal segmental level of anesthesia. Anesthesia is defined (for the present purposes only) as loss of pinprick sensation. This definition of anesthesia is employed because it is the definition most widely used by clinicians in determining the level to which local anesthetic solutions have spread. Differences between the levels of anesthesia as thus defined and levels of analgesia, somatic motor paralysis, sympathetic denervation, and other forms of neuronal impairment are not dwelt upon. These other forms of

Distribution of local anesthetic solutions within the subarachnoid space.

A direct method has been employed to estimate the rate of production by human brain of 3-methoxy-4-hydroxyphenethyleneglycol, the major metabolite of brain norepinephrine, a brain neurotransmitter. Venous specimens were obtained from the internal jugular vein from ten awake human subjects at a puncture site above the common facial vein, the first major source of extracranial inflow. Arterial specimens were simultaneously obtained from the radial artery. Plasma samples were assayed and a highly significant difference was found in the concentration of the metabolite in plasma coming out of the brain (venous blood) as compared to plasma entering the brain (arterial blood). This venous-arterial difference was calculated to be 0.7 +/- 0.1 nanogram per milliliter of blood. Assuming an adult brain weight of 1400 grams and normal cerebral blood flow, it is estimated that the rate of production of 3-methoxy-4-hydroxyphenethyleneglycol by the awake human brain is approximately 597 nanograms per minute or 35.8 micrograms per hour. Urine specimens were also collected from six of these subjects during a period of 1 to 3.5 hours, which bracketed the time the blood samples were obtained. For these six subjects the output of 3-methyoxy-4-hydroxyphenethyleneglycol by whole brain was estimated to be 40.9 micrograms per hour, whereas the rate of its excretion into urine was 64.5 micrograms per hour.

3-Methoxy-4-hydroxyphenethyleneglycol production by human brain in vivo

The central nervous system the cardiovascular system pulmonary ventilation and haemodynamics hepatic function renal function endocrine function metabolism and acid-base balance obstetrical physiology gastrointestinal tract epidural anaesthesia.

Nicholas M. Greene

Papers

Distribution of local anesthetic solutions within the subarachnoid space.

3-Methoxy-4-hydroxyphenethyleneglycol production by human brain in vivo

Physiology of spinal anesthesia

Physiology of spinal anesthesia

Area of differential block in spinal anesthesia with hyperbaric tetracaine.