Pharmacokinetics of the local anesthetic ropivacaine after transversus abdominis plane block in healthy volunteers.

PURPOSE: The transversus abdominis plane (TAP) block is a regional anesthetic technique used for pain control following abdominal surgical procedures. While a minimum of systemic side effects is usually expected after local anesthesia, it is unknown to which extent systemic absorption and redistribution to the abdominal wall contributes to the effects of anesthetics. The aim of this study was to determine concentration-time profiles of ropivacaine after the injection of 150 mg of ropivacaine into the lateral abdominal wall in various compartments. METHODS: The microdialysis technique was used to measure ropivacaine in plasma as well as at abdominal wall sites cranial from the injection site (below the 12th rip) and caudal from the injection site (cranial from the iliac crest) and in the skeletal muscle tissue of the contra lateral thigh of eight healthy volunteers. RESULTS: The mean exposure to ropivacaine measured as the area under the concentration-time curve was significantly higher at the two abdominal sites (240.9 ± 409.1  and 86.18 ± 133.50 µg h/mL, respectively) than in plasma (5.1 ± 1.0 µg h/mL) or in peripheral tissue (1.1 ± 1.2 µg h/mL). While the high mean concentrations of ropivacaine measured at the abdominal wall sites support the topical concept of the TAP block, the observed variability was striking. CONCLUSIONS: While the systemic pharmacokinetics was comparable between subjects, the local distribution of ropivacaine was highly variable after TAP block.

Vanadium-induced Cl(-)-secretion in rabbit descending colon is mediated by prostaglandins.

Vanadium in the 4+ (vanadyl-ion) and 5+ (vanadate-ion) oxidation state stimulates furosemide-sensitive electrogenic Cl- secretion in isolated epithelia of rabbit descending colon. This effect is associated with an increased release of prostaglandin E2 from the tissue. Inhibitors of phospholipase A2 or cyclooxygenase abolish both vanadium-induced release of prostaglandin E2 and Cl- secretion. Neuronal mechanisms are not likely to be involved, as tetrodotoxin does not affect the vanadate induced Cl- secretion. Although vanadate is known to inhibit Na+,K(+)-ATPase activity, no inhibition of active Na+ transport was observed in intact colonic epithelia suggesting a rapid intracellular reduction of vanadate ions to vanadyl ions which have no inhibitory effect on the Na+,K(+)-ATPase. The present findings therefore indicate that vanadate stimulated colonic Cl- secretion involves intracellular conversion of vanadate to vanadyl and release of prostaglandin E2.

Pharmacokinetics and pharmacodynamics of the diuretic bumetanide in the elderly.

In a cross-sectional study of the pharmacokinetics and pharmacodynamics of peroral and intravenous bumetanide (0.5 mg, single dose), total and renal clearance of the diuretic was significantly lower in elderly persons than in young adults, resulting in higher bumetanide plasma levels in the aged. Nonrenal clearance, bioavailability, and the volume of distribution were not significantly changed. Together with the decreased delivery into the urine the diuretic and natriuretic effect of bumetanide was reduced in the elderly. Renal clearance of bumetanide was linearly related with creatinine clearance, hence the decreases in bumetanide clearance and diuretic efficacy in the elderly are attributed to the age-dependent decline in renal function. The bumetanide concentration in urine and the fractional sodium excretion were not different in the two age groups, suggesting that the decrease in diuretic response in the elderly is a result of a reduction in the number of functioning nephrons, whereas the response of the remaining nephrons to bumetanide is unaltered.

Pharmacokinetics of indomethacin in the elderly.

In a cross-sectional study the pharmacokinetics of indomethacin were studied in old and young adults without manifest organ failure. Total clearance of indomethacin after a single oral dose of 50mg was 0.8 ml/min/kg in elderly individuals (mean 79.5 +/- 1.3 years) compared with 1.4 ml/min/kg in younger individuals (mean 36.9 +/- 3.0 years). The apparent elimination rate constant averaged 0.23 h-1 in the aged and 0.32 h-1 in the young people. Oral bioavailability was close to 1 in the young but 0.77 in the elderly. The apparent volume of distribution was similar in each group. Based on these results it is suggested that the maintenance dose of indomethacin be reduced by 25% in the elderly.

pH and temperature dependence of adenosine uptake in human erythrocytes.

Kinetic analysis of the saturable adenosine uptake in human erythrocytes suggests the existence of two saturable components, distinguished by different Km values (1.4 and 260 micron, respectively, at pH 7.4 and 25 degrees C). Both components were abolished by p-nitrobenzylthioguanosine or dipyridamole. Total uptake was significantly higher at pH 8 than at pH 7 at adenosine concentrations above 2 micron. The increase in uptake at the higher pH was brought about mainly by an increase in the maximum rate of transport of the low-affinity uptake system. With rising temperature the Km and the V of both uptake components increased. No transition temperature was observed between 12 and 37 degrees C.

Relaxation of coronary artery strips by adenosine and acidosis.

Cumulative dose-response curves of Ca2+-induced tension increments were studied in K+-depolarized helical strips of dog coronary arteries. Adenosine 10(-4) M reduced the Ca2+ sensitivity of the strips without altering the maximal tension with full Ca2+ activation. In contrast, acidosis of pH 7.05 significantly diminished the maximal tension with full Ca2+ activation. The relaxing effect of acidosis was almost completely abolished by 10(-4) M adenosine. It is concluded that adenosine inhibits Ca2+ influx, whereas acidosis depresses the contractile process of vascular smooth muscle directly.

Secretion of monoquaternary ammonium compounds by guinea pig small intestine in vivo.

In anesthetized guinea pigs N-(3H)methylscopolamine (NMScop), N1-(14C)methylnicotinamide (NMN), and (14C)tetraethylammonium (TEA), administered intravenously, were secreted against a concentration gradient into the lumen of the small intestine. The concentration ratio of unmetabolized ammonium base in the intestinal lumen to that in the plasma was 4.3 and 6.5 for NMScop and NMN, respectively, 75 min after the intravenous injection of 1 nmole/g body weight of the individual compounds. The corresponding value for TEA after 180 min was 2.0. The establishment of the concentration gradient between intestinal lumen and plasma was diminished with increasing doses. An excess of NMN inhibited the uphill transport of NMScop. Since the electrical potential difference across the intestinal epithelium and a 'fluid circuit' mechanism cannot solely account for the observed accumulation of the monoquaternary ammonium compounds in the intestinal lumen, the evidence presented supports previous in vitro findings that the small intestine is capable of actively secreting organic cations.

Weak electrolyte transfer in the guinea pig jejunum: secretion of trimethoxybenzoic acid.

In isolated epithelia of guinea pig jejunum the transcellular permeation of 10(-4) M (carboxyl-14C)-3,4,5-trimethoxybenzoic acid (TMBA) in the direction blood-lumen was more than 10 times greater the transcellular permeation of 10(-4) M (carboxyl-was reduced to less than 2 by anaerobiosis or by increasing TMBA concentrations of up to 10(-2) M. Under aerobic conditions the cellular uptake of TMBA (10(-4) M) from the blood side was twice as high as that from the lumen side. In anaerobiosis the percentage of TMBA taken up into the epithelium was enhanced, when TMBA was administered on the lumen side, while the percentage was unchanged after administration on the blood side; thereby the difference in cellular TMBA concentrations was abolished. Similar results were obtained under aerobic conditions, if the TMBA concentration was increased up to 10(-2) M. The results are consistent with a three-compartment model with an intermediate compartment distinguished by a high pH as compared to that of the outer compartments and by a luminal boundary highly permeable for the ionized form of the substrate in contrast to the contraluminal boundary.

Neurogenic chloride secretion induced by scorpion venom and veratrine in rabbit colon.

In earlier reconstitution experiments the venom of the scorpion Leiurus quinquestriatus, LQV, was shown to block Ca(2+)-activated high-conductance K+ channels from the basolateral cell membrane of rabbit colonocytes (Turnheim K, Costantin J, Chan S, Schultz SG (1989) J Membrane Biol 112:247-254). These LQV-sensitive K+ channels do not seem to be involved in active Na+ transport across rabbit colon, as absorptive Na+ fluxes were not significantly affected by serosal addition of LQV to isolated epithelia of rabbit descending colon. While Na+ absorption was not changed, LQV and veratrine caused electrogenic Cl- secretion in this tissue by a neural (tetrodotoxin sensitive) mechanism. The secretory effect of LQV was partly inhibited by atropine, suggesting the involvement of m-cholinoceptors, and by a VIP-antagonist. In contrast to the neurogenic secretion in the small intestine of guinea pig, rat and cat, 5-hydroxytryptamine (5-HT) does not seem to be involved in neurogenic secretion in rabbit colon, as 1) several 5-HT receptor antagonists did not inhibit the LQV effect with the exception of high concentrations of tropisetron, 2) exogenous 5-HT had no secretory effect, and 3) there was no significant release of 5-HT from the tissue during neurogenic secretion. The inhibitory effect of tropisetron on intestinal Cl- secretion seems to be unrelated to its property as a 5-HT3 receptor antagonist.

Topical anesthesia with pH-adjusted versus standard lidocaine 4% for clear corneal cataract surgery.

PURPOSE: To evaluate and compare the efficacy of a sodium-bicarbonate-adjusted preparation of lidocaine 4% (pH = 7.2) and standard lidocaine (pH = 5.2) for topical anesthesia in clear corneal cataract surgery. SETTING: Department of Ophthalmology, University of Vienna, Austria. METHODS: In a prospective, randomized, double-blind clinical trial, clear corneal cataract surgery was performed under topical anesthesia in 44 eyes of 34 patients. In 22 eyes, pH-adjusted lidocaine 4% was administered; in the other 22, standard lidocaine 4%. Aqueous and serum concentrations of lidocaine were measured by high-performance liquid chromatography and ultraviolet detection. Subjective pain was assessed using a visual analog scale of no pain (0%) to worst imaginable pain (100%). On the first postoperative day, visual acuity, intraocular pressure, and corneal staining with fluorescein were examined. RESULTS: In the pH-adjusted lidocaine group, significantly higher lidocaine concentrations were found in the aqueous humor (15.06 microg/mL +/- 8.2 [SD] versus 4.75 +/- 3.5 microg/mL; P < .0001). In all samples (n = 8), serum lidocaine concentrations were below a minimum detectable level of 0.02 microg/mL. Subjective pain ratings were similar in the pH-adjusted and standard lidocaine groups (mean 9.73 +/- 10.4% and 10.0 +/- 15.4%, respectively). There was no significant between-group difference in intraoperative and postoperative outcomes. CONCLUSIONS: In this study, pH-adjusted lidocaine 4% was a safe, effective topical anesthetic for clear corneal surgery and had minimal local and systemic toxicity. Administration of pH-adjusted lidocaine 4% resulted in significantly higher aqueous humor lidocaine concentrations than administration of standard lidocaine 4%.

Drug dosage in the elderly. Is it rational?

Pharmacotherapy in the elderly requires an understanding of the age-dependent changes in function and composition of the body. Aging is characterised by a progressive loss of functional capacities of most if not all organs, a reduction in response to receptor stimulation and homeostatic mechanisms, and a loss of water content and an increase of fat content in the body. The most important pharmacokinetic change in old age is a decrease in the excretory capacity of the kidney; in this regard, the elderly should be considered as renally insufficient patients. The decline in the rate of drug metabolism with advancing age is less marked. In addition, the volume of distribution and the oral bioavailability of drugs may be changed in the elderly compared with younger individuals. Average dosage adjustments for the aged can be derived from simple equations and mean pharmacokinetic parameters from older and younger adults. However, these average dose adjustment factors neglect the large variation in the decline in organ functions among the elderly. Individual dose adjustment factors can be obtained from the drug clearance in a particular patient, where clearance/fractional bioavailability (CL/f) may be calculated from the area under the plasma concentration-time curve (AUC) of the drug in question. Using pharmacokinetic guidelines for dose adjustments, the same plasma drug concentrations result in elderly as in younger adults. However, we are frequently confronted with pharmacodynamic changes in old age which alter the sensitivity to drugs, irrespective of changes in drug disposition. For instance, the sensitivity of the cardiovascular system to beta-adrenergic agonists and antagonists decreases in old age and the incidence of orthostatic episodes in response to drugs that lower blood pressure is increased. The CNS is especially vulnerable in the elderly; agents that affect brain function (anaesthetics, opioids, anticonvulsants, psychotropic drugs) must be used very cautiously in this age group. The increased responsiveness to drugs in the elderly renders the measurement of drug plasma concentrations an attractive method to monitor pharmacotherapy in this age group. Sensitive technology to quantitatively determine plasma drug concentrations is available. However, optimal therapeutic plasma concentrations have not been established for most drugs in the elderly. Investigations concerning drug pharmacokinetic-pharmacodynamic relationships in the aged are an important area of future work in clinical pharmacology.

Epithelial sodium transport: basic autoregulatory mechanisms.

The epithelial cell is equipped with autoregulatory mechanisms that coordinate the rates of apical Na+ entry and basolateral Na+ extrusion, so that intracellular Na+ activity is maintained relatively constant when the rate of active Na+ transport changes. The increase of basolateral Na+ extrusion via the ouabain-inhibitable Na+,K(+)-ATPase during Na+ transport stimulation appears to be a result of both an increase in the number of operative Na+,K(+)-ATPase units in the basolateral cell membrane and in the Na+ turnover per Na+,K(+)-ATPase unit. Further, it is possible that the number of epithelial cells, which are involved in active Na+ transport, changes when the rate of Na+ transport is altered. Not only apical Na+ entry and basolateral Na+ extrusion are coupled, the basolateral membrane K+ conductance also changes in parallel with the rate of basolateral Na+ extrusion ("pump-leak parallelism"). These regulatory mechanisms serve to prevent inordinate changes in intracellular ion composition, transmembrane electrical potential difference, and cell volume. The cellular events taking place during stimulation of active transport resemble the changes during osmotic cell swelling. Hence, it is possible that cell volume changes are responsible for the coordination of apical and basolateral membrane properties.

[Basics of intestinal electrolyte transport (author's transl)]. / Grundlagen des intestinalen Elektrolyttransports.

In the small and large intestine Na and Cl are absorbed via active transport systems, whereas K appears to distribute passively between the lumen and the blood side of the epithelium. Three types of Na influx mechanisms across the luminal cell membrane of the epithelium may be distinguished: 1. In the gall bladder and the small intestine Na and Cl influx are coupled in an obligatory one for one fashion, hence this influx mechanism is electrically neutral. This coupled NaCl uptake process in the luminal cell membrane is inhibited by a rise in intracellular cAMP levels. 2. In the colon Na influx is not dependent on Cl influx. Due to the partition of cations and anions the Na uptake process is electrogenic, i.e. the electrical potential difference across the luminal cell membrane is decreased. This type of Na influx is blocked by the diuretic amiloride and enhanced by aldosterone. The electrogenic Na influx mechanism is also present in the ileum together with the neutral NaCl influx mechanism. Active Cl absorption in the colon is electrically neutral, most likely Cl is exchanged for HCO3 at the luminal membrane. Stimuli which increase cellular cAMP or Ca cause electrogenic Cl secretion. 3. In the ileum exists an additional Na influx mechanism which is dependent on the presence of certain sugars (glucose) or amino acids (alanine) on the luminal side of the epithelium. This process is inhibited by phlorizin. The finding of glucose-stimulated Na absorption has proven to be therapeutically useful: the rate of intestinal fluid loss can be decreased in certain forms of diarrhea by oral administration of electrolyte solutions containing glucose.

[The placebo as a nonspecific treatment factor]. / Plazebo als unspezifischer Behandlungsfaktor.

Nonspecific drug actions result from the social interaction between physician and patient and the medical environment. Positive (therapeutic) placebo effects are produced in approximately 30-35% of treated patients, especially in cases of vegetative and psychic disturbances. There appears to be no distinct group of individuals with specific personality features that can be classified as "placebo responders". Negative (toxic) placebo effects, which are usually minor, are reported in 4-50% of treated patients. The occurrence of side effects may cause the patient to assume treatment with an active agent, thus increasing the therapeutic efficiency of the treatment (placebo amplification by side effects). On the other hand, the lack of a certain side effect may diminish the therapeutic effect of an active drug. The notion that placebo-induced analgesia is endorphin-mediated is not established. Hence at present psychological mechanisms have to be assumed for the placebo effect. The conscious use of a placebo as a therapeutic agent is problematic for ethical reasons, whereas the placebo component of drugs with specific actions should be exploited to enhance their therapeutic efficiency.

[Pharmacology of nonionic roentgen contrast media]. / Pharmakologie nichtionischer Röntgenkontrastmittel.

The non-ionic X-ray contrast media metrizamide, iopamidol, iohexol, and iopromide do not bind calcium and are less hyperosmolar than the conventional ionic contrast media, for instance amidotrizoate (diatrizoate), iothalamate, or ioglicate. Hence the use of non-ionic contrast media is associated with less undesirable side-effects that are attributable to hypertonicity such as an increase in circulating plasma volume, decreased deformability of red blood cells, damage of vascular endothelium with consequent activation of blood coagulation, the complement system and fibrinolysis, increased release of bradykinin and histamine, cardiac arrhythmias, diuresis, vasodilation and decreased blood pressure, pain and heat sensation. Because of less dilution the quality of imaging is also better. According to the intravenous LD50 in experimental animals the acute toxicity of non-ionic contrast media is lower than that of ionic media. With respect to contrast quality and the rate of side-effects the various non-ionic contrast media appear to be equivalent. Despite their higher price and higher viscosity it is probable that the non-ionic contrast media will replace the classical ionic media, especially in angio- and myelography.

[Adverse effects of psychotropic drugs in the elderly]. / Unerwünschte Wirkung von Psychopharmaka im Alter.

As in other organs, homeostatic mechanisms become insufficient in the aging brain, in part because of reduced activity of various neurotransmitter systems. Counter-regulatory processes are therefore reduced and reactions to drugs may be increased. Aside from these pharmacodynamic mechanisms, the increased toxicity of psychotropic agents in the elderly may be a result of pharmacokinetic changes. The total clearance of a number of drugs is reduced in old age, hence steady-state plasma concentrations of these compounds will be increased when conventional doses are used. Because of these changes, the central nervous system is especially vulnerable in elderly. With tranquilizers and hypnotics, sedation is increased and cognitive function may decrease. The risk of falls and injuries is enhanced with all psychoactive drugs. In addition, response to agents with anticholinergic properties (classical antidepressants and neuroleptics) is increased in old age and is accompanied by peripheral symptoms such as urinary retention, obstipation, tachycardia and visual disturbances. In the central nervous system there may be impairment of intellectual capabilities, agitation, and ultimately delirium. Further, the undesirable cardiac effects of tricyclic antidepressants should be noted. The selective serotonin reuptake inhibitors (SSRI) and moclobemide have an advantageous pharmacological profile compared to older antidepressants. Of the neuroleptics, the benefit-risk relation of the newer atypical agents appears to be more favorable than that of classical neuroleptics.

[Coxibs: cyclooxygenase-2 inhibitors]. / Coxibe: Hemmer der Cyclooxygenase-2.

The oxygenating enzyme cyclooxygenase (COX) catalysis the conversion of arachidonic acid to proinflammatory prostaglandins. For many years it was thought that COX is a single enzyme that is present constitutively in most tissues. But in the late 80ies COX activity was found to be increased in inflammatory states with cytokines and bacterial lipopolysaccharides as inducing agents. The expression of the induced COX is inhibited by glucocorticoids which is not the case with the COX known up to then. According to these findings COX exists in two forms, the aminoacid sequences of which are known. The expression of COX-1 is not or only poorly regulated, the prostaglandins produced by it are responsible for the protection of the gastric mucosa, maintenance of normal kidney function and platelet aggregation. COX-2, in contrast, is highly regulated, the prostaglandins produced by this isoenzyme are involved in inflammation, fever and pain but also in the regulation of kidney function. Conventional non-steroidal antiinflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2. The analgesic, antipyretic and antiinflammatory effects of these agents are accounted for by COX-2 inhibition, whereas the toxic effects on the stomach as well as the inhibition of platelet aggregation are attributed to COX-1 inhibition. In search for selective blockers of COX-2, celecoxib and rofecoxib were developed which have an analgetic and antirheumatic potency similar to that of conventional NSAIDs but are associated with significantly fewer adverse gastroduodenal events. The renal toxicity of the selective COX-2 inhibitors is not better than that of the non-selective NSAIDs.

[Geriatric pharmacology. Pharmacokinetics and pharmacodynamics in the elderly. Problems with geriatric and nootropic drugs]. / Geriatrische Pharmakologie. Pharmakokinetik und Pharmakodynamik im Alter. Problematik der Geriatrika und Nootropika.

The reasons for the increased frequency of adverse drug reactions in the elderly are a decrease in drug elimination, primarily via the kidneys, on the one hand and a decrease in adaptive counterregulatory mechanisms on the other hand that attenuate drug effects in younger subjects. Because of the decreased functional reserve in the aged drugs may adversely affect preexisting chronic diseases. Generally, the possibility that clinical symptoms in the elderly are drug-related has to be considered. Abrupt changes in dosage should be avoided. The indication of drug therapy should be reevaluated periodically. However, advanced age is no reason to withhold necessary medication. The compliance with or adherence to drug therapy may be improved by giving clear, written instructions, simplifying the dosage schedule and reducing the number of drugs, for instance by using combination drugs. Elderly patients are particularly vulnerable to the sedative effects of psychotropic drugs, resulting in cognitive impairment and motor incoordination with an increased risk of falls and hip fracture. There is no rational basis for the use of geriatric drugs that claim to stop or slow the aging process. Also the available evidence does not support the therapeutic value of so-called nootropic or cerebroactive drugs to improve mental function in the elderly.

[Pharmacotherapy in the aged]. / Pharmakotherapie im Alter.

The relatively high incidence of adverse drug reactions in the aged is a consequence of polypharmacy on the one hand and of altered pharmacokinetics on the other, changes of intrinsic or receptor properties (pharmacodynamic factors) are usually not of primary importance. Plasma half-lives increase and total clearance rates of many drugs are reduced due to diminished drug metabolism and renal excretion. With the exception of actively transported substances the amount absorbed from the gastrointestinal tract is not altered. Total body water declines with age, whereas the relative content of adipose tissue increases. Hence, the volume of distribution of hydrophilic drugs may be decreased, that of lipophilic drugs increased. The maintainance dose in old age can be calculated from the changes in plasma half-lives or, preferably, total clearance rates, the initial dose is determined by the changes in the volume of distribution. At present there is no rational basis for the use of geriatric drugs, i.e. agents claimed to retard the process of aging.

[Inhibition of sodium transport in the colon by the diuretic amiloride (author's transl)]. / Hemmung des Natriumtransports im Colon durch das Diuretikum Amilorid.

In isolated epithelia of rabbit descending colon the short-circuit current (Isc) is solely attributable to net transepithelial Na-transport, which in turn is identical with the unidirectional Na-influx across the luminal cell membranes. Amiloride blocks Isc by inhibiting luminal Na-influx into the cells. The type of inhibition exerted by amiloride in this tissue has to be termed mixed-type, since both the affinity of Na to its transport system and the maximal transport capacity are reduced. Na, on the other hand, is a competitive antagonist of the amiloride effect with a Ki of 136 mM; therefore KA, the amiloride-concentration at which the amiloride-effect is half-maximal, is increased from 0.14 microM at 5 mM Na in the incubation medium to 0.29 microM at 140 mM Na. It is conceivable that an "amiloride-like" action of Na may be responsible for the saturability of luminal Na-influx with increasing Na-concentrations.