Klaus Turnheim

Drug therapy in the elderly.

Drug dosage in the elderly requires an understanding of the age-dependent changes in drug disposition and sensitivity. The most important pharmacokinetic alteration is a decline in renal function, the elderly should therefore be treated as renally insufficient patients. Metabolic clearance is primarily reduced with drugs that display high hepatic extraction, whereas the metabolism of drugs with low hepatic extraction usually is not diminished. The reduction of metabolic clearance is especially pronounced in malnourished or frail patients. The water content of the aging body decreases, the fat content rises. Hence the distribution volume of hydrophilic drugs may be reduced in the elderly, resulting in increased plasma concentrations. In contrast, the distribution volume of liphophilic drugs is increased, their plasma concentrations may decrease. Intestinal absorption of most drugs is not altered in the elderly. Aside of these pharmacokinetic changes, one of the characteristics of old age is a progressive decline in counterregulatory (homeostatic) mechanisms. Therefore, drug effects are attenuated less, the responses are usually stronger than in younger subjects, the rate and intensity of adverse effects are higher. Examples of drug actions augmented is this manner are postural hypotension with agents that lower blood pressure, dehydration and electrolyte disturbances in response to diuretics, bleeding complications with oral anticoagulants, hypoglycemia with antidiabetics, and gastrointestinal irritation with non-steroidal anti-inflammatory drugs. The brain is an especially sensitive drug target in old age. Psychotropic drugs, anticonvulsants, and centrally acting antihypertensives may impede intellectual function and motor coordination. Hence drugs should be used restrictively in geriatric patients.

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 β-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, psycho-tropic 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.

Rabbit distal colon epithelium: I. Isolation and characterization of basolateral plasma membrane vesicles from surface and crypt cells.

SummaryA method has been developed for the simultaneous isolation of basolateral plasma membrane vesicles from surface and crypt cells of rabbit distal colon epithelium by sequential use of differential sedimentation, isopycnic centrifugation and Ficoll 400 barrier centrifugation. The protein yield was high (total 0.81 mg/g mucosa) and surface and crypt cell-derived basolateral membrane fractions have been purified 34- and 9-fold with respect to the homogenate. The pattern of marker enzyme enrichments revealed only minor contamination by subcellular organelles. Latency of ouabain-sensitive (Na+, K+)-ATPase activity prior and after trypsin treatment of membranes indicated a vesicle configuration of sealed right side-out: sealed inside-out: leaky of approximately 2∶1∶1. The presence of sealed vesicles was also evident from the osmotic sensitivity of thed-[1-14C] mannitol equilibrium space determined with either fraction. Although considerably different in protein profile, surface and crypt basolateral membranes were similar in cholesterol to phospholipid molar ratio and membrane fluidity as determined by steady-state fluorescence polarization.Stopped-flow light scattering experiments revealed a rather low water permeability of the membranes with a permeability coefficient of 6 μm/sec at 35°C, which is one order of magnitude lower than reported for small intestinal plasma membranes. Both membrane fractions have been shown to effectively generate outward uphill potassium ion gradients, a process that is energized by ATP and inhibited by the membrane-permeant cardiacglycoside digitoxin. These characteristics are consistent with the activity of a (Na+, K+) pump operating in inside-out vesicles.

Simultaneous isocratic HPLC determination of vigabatrin and gabapentin in human plasma by dansyl derivatization

A rapid and low-cost assay for simultaneous vigabatrin (VGA) and gabapentin (GBP) determination is described that can be performed with simple HPLC instrumentation. The method involves derivatization of the primary amine group of VGA and GBP with dansyl chloride followed by isocratic separation (column: &mgr;Bondapak C-18, 10 &mgr;m, 300 × 3.9 mm; mobile phase: 50 mmol/L NaH2PO4 in 40% acetonitrile) at 50°C and fluorometric detection (excitation and emission wavelength: 318 and 510 nm, respectively) of the fluorescent product, which is stable for at least 7 days. Correlation coefficients of the calibration curves are >0.999 with a lower limit of detection of 0.3 &mgr;g/mL. Between- and within-run coefficients of variation are below 4.5%, and assay time is 15 minutes. This method may be used for therapeutic drug monitoring in the case of GBP and to control patient compliance in the case of VGA.

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.

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 &mgr;g/mL ± 8.2 [SD] versus 4.75 ± 3.5 &mgr;g/mL; P < .0001). In all samples (n = 8), serum lidocaine concentrations were below a minimum detectable level of 0.02 &mgr;g/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%.

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.

Absorption and secretion of potassium by rabbit descending colon.

Measurements of K fluxes under a variety of conditions have provided an internally consistent set of data that demonstrate active absorption and active secretion of K by rabbit descending colon in vitro. The properties of K diffusion across the paracellular pathway are those of a free solution shunt. With Na and Cl present on both sides of short-circuited tissues the two opposing active K transport systems balance each other, so that there is no net K transport. Net K absorption results when the transcellular secretory K flux is inhibited by 1. serosal addition of ouabain, 2. serosal addition of furosemide, or 3. omission of either Na or Cl from the serosal solution. Hence basolateral K uptake appears to be mediated by a furosemide-sensitive Na−Cl−K cotransport system in addition to the Na−K exchange pump. Luminal addition of mersalyl or orthovanadate inhibits active K absorption. The adenosine analogue 5′-N-ethylcarboxamide adenosine and the β-adrenergic agent isoproterenol, added to the serosal solution, cause net K secretion which is inhibitable by furosemide. The secretory K fluxes, both under stimulated and non-stimulated conditions, are abolished by an opposing electrical gradient, suggesting conductive K exit across the apical cell membrane, whereas K absorption appears to be an electroneutral process.

Arzneimittelwechselwirkungen mit Antiepileptika

Drug interactions with antiepileptic agents are based in large part on pharmacokinetic mechanisms. Most prominent are induction or inhibition of enzymes of the cytochrome P450 (CYP) system, which is of central importance for metabolic elimination of lipophilic xenobiotics. Potent inductors of CYP isoenzymes are carbamazepine, phenobarbital, phenytoin, and primidone, thereby decreasing not only their own plasma levels and efficacy but also that of other antiepileptics and other drugs. Felbamate, oxcarbazepine, and topiramate are weak inductors of the CYP isoenzyme 3A4, whereas they inhibit CYP2C19. Valproic acid is a potent inhibitor of several CYP isoenzymes and glucuronyltransferases, resulting in an increase in plasma concentrations and toxicity of antiepileptics and other drugs. Antiepileptics that are not involved in drug interactions include gabapentin, levetiracetam, and vigabatrine. The P-glycoprotein may mediate the exit of antiepileptics from the brain. This transport mechanism is inhibited by carbamazepine, which may explain the enhanced clinical efficacy of a combination of carbamazepin with other antiepileptics. Other possible pharmacokinetic interactions are precipitation of antiepileptics in the stomach by antacids or sucralfate and displacement from plasmaprotein binding of one antiepileptic agent by another. Therapeutic drug monitoring (TDM) may be helpful in assessing pharmacokinetic drug interactions. Pharmacodynamic interactions appear to be responsible for the enhanced efficacy of antiepileptic combination therapy. In prescribing drugs, their spectrum of interactions has to be known.SummaryDrug interactions with antiepileptic agents are based in large part on pharmacokinetic mechanisms. Most prominent are induction or inhibition of enzymes of the cytochrome P450 (CYP) system, which is of central importance for metabolic elimination of lipophilic xenobiotics. Potent inductors of CYP isoenzymes are carbamazepine, phenobarbital, phenytoin, and primidone, thereby decreasing not only their own plasma levels and efficacy but also that of other antiepileptics and other drugs. Felbamate, oxcarbazepine, and topiramate are weak inductors of the CYP isoenzyme 3A4, whereas they inhibit CYP2C19. Valproic acid is a potent inhibitor of several CYP isoenzymes and glucuronyltransferases, resulting in an increase in plasma concentrations and toxicity of antiepileptics and other drugs. Antiepileptics that are not involved in drug interactions include gabapentin, levetiracetam, and vigabatrine. The P-glycoprotein may mediate the exit of antiepileptics from the brain. This transport mechanism is inhibited by carbamazepine, which may explain the enhanced clinical efficacy of a combination of carbamazepin with other antiepileptics. Other possible pharmacokinetic interactions are precipitation of antiepileptics in the stomach by antacids or sucralfate and displacement from plasmaprotein binding of one antiepileptic agent by another. Therapeutic drug monitoring (TDM) may be helpful in assessing pharmacokinetic drug interactions. Pharmacodynamic interactions appear to be responsible for the enhanced efficacy of antiepileptic combination therapy. In prescribing drugs, their spectrum of interactions has to be known.ZusammenfassungDer Großteil der Arzneimittelwechselwirkungen, an denen Antiepilepika beteiligt sind, hat pharmakokinetische Gründe. Im Vordergrund stehen die Induktion oder Hemmung von Cytochrom P450 (CYP) Enzymen, die eine zentrale Rolle im Rahmen der metabolischen Elimination von Pharmaka spielen. Starke Induktoren von CYP-Isoenzymen sind Carbamazepin, Phenobarbital, Phenytoin und Primidon. Diese Wirkstoffe können dadurch nicht nur die eigenen Plasmaspiegel sondern auch die anderer Antiepilepika und anderer Pharmaka vermindern. Von den neueren Antiepilepika sind Felbamat, Oxcarbazepin und Topiramat schwache Induktoren des CYP Isoenzyms 3A4 aber schwache Hemmer von CYP2C19. Valproat hemmt verschiedene CYP-Isoenzyme sowie die Glucuronyltransferasen stark, die Plasmakonzentrationen von Antiepilepika oder anderer Arzneistoffe können zunehmen. Interaktionen dieser Art treten bei Gabapentin, Levetiracetam und Vigabatrin nicht auf. Für den Auswärtstransport von Antiepileptika durch die Blut-Hirnschranke scheint das P-Glycoprotein von Bedeutung zu sein, das durch Carbamazepin gehemmt wird, wodurch die gesteigerte klinische Wirksamkeit einer Kombinationstherapie mit Carbamazepin und anderen Antiepileptika erklärt werden kann. Andere pharmakokinetische Wechselwirkungen sind die komplexartige Bindung von Antiepileptika im Magen durch Antacida oder Sucralfat sowie die Verdrängung eines Pharmakons aus der Eiweißbindung durch ein zweites. Bei Verdacht auf pharmakokinetische Wechselwirkungen sind die Möglichkeiten des therapeutischen Drug Monitorings (TDM) zu nutzen. Pharmakodynamische Interaktionen im Sinne eines Synergismus spielen bei der Kombinationstherapie mit Antiepileptika eine Rolle. Bei der Auswahl von Pharmaka hat der Arzt das Spektrum möglicher Wechselwirkungen zu berücksichtigen.

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

SummaryIn anaesthetized 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.