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PubMed2002

Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors.

Cholinesterase inhibitors are the 'first-line' agents in the treatment of Alzheimer's disease. This article presents the latest information on their pharmacokinetic properties and pharmacodynamic activity. Tacrine was the first cholinesterase inhibitor approved by regulatory agencies, followed by donepezil, rivastigmine and recently galantamine. With the exception of low doses of tacrine, the cholinesterase inhibitors exhibit a linear relationship between dose and area under the plasma concentration-time curve. Cholinesterase inhibitors are rapidly absorbed through the gastrointestinal tract, with time to peak concentration usually less than 2 hours; donepezil has the longest absorption time of 3 to 5 hours. Donepezil and tacrine are highly protein bound, whereas protein binding of rivastigmine and galantamine is less than 40%. Tacrine is metabolised by hepatic cytochrome P450 (CYP) 1A2, and donepezil and galantamine are metabolised by CYP3A4 and CYP2D6. Rivastigmine is metabolised by sulfate conjugation. Two cholinesterase enzymes are present in the body, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Tacrine and rivastigmine inhibit both enzymes, whereas donepezil and galantamine specifically inhibit AChE. Galantamine also modulates nicotine receptors, thereby enhancing acetylcholinergic activity at the synapse. These different pharmacological profiles provide distinctions between these agents. Cholinesterase inhibitors show a nonlinear relationship between dose and cholinesterase inhibition, where a plateau effect occurs. Cholinesterase inhibitors display a different profile as each agent achieves its plateau at different doses. In clinical trials, cholinesterase inhibitors demonstrate a dose-dependent effect on cognition and functional activities. Improvement in behavioural symptoms also occurs, but without a dose-response relationship. Gastrointestinal adverse events are dose-related. Clinical improvement occurs with between 40 and 70% inhibition of cholinesterase. A conceptual model for cholinesterase inhibitors has been proposed, linking enzyme inhibition, clinical efficacy and adverse effects. Currently, measurement of enzyme inhibition is used as the biomarker for cholinesterase inhibitors. New approaches to determining the efficacy of cholinesterase inhibitors in the brain could involve the use of various imaging techniques. The knowledge base for the pharmacokinetics and pharmacodynamics of cholinesterase inhibitors continues to expand. The increased information available to clinicians can optimise the use of these agents in the management of patients with Alzheimer's disease.

Aging↗
PubMed1997

Automated procedure for estimation of blood cholinesterase activities in rabbits.

An automated procedure for estimation of blood cholinesterase activities was evaluated and used to determine baseline cholinesterase activities in rabbits. In addition, the kinetics of cholinesterase inhibition and recovery from diazinon challenge were determined by use of this procedure. The procedure developed is a modification of the colorimetric Ellman technique, adapted for use with the Instrumentation Laboratory Multistat III Plus Centrifugal Analyzer. The substrate used in this technique was acetylthiocholine. Baseline cholinesterase activities in domestic rabbits were plasma cholinesterase, 360 mU/ml; red blood cell cholinesterase, 2,658 mU/ml; and whole blood cholinesterase, 1,332 mU/ml. Rabbits were challenged with 0.3 LD50 (40 mg/kg) of diazinon, and blood samples were obtained at hourly, then daily intervals. Cholinesterase activity in these samples was determined to monitor the effect of the cholinesterase inhibitor diazinon in vivo, as estimated by the Multistat III Plus Centrifugal Analyzer procedure. Plasma cholinesterase activity decreased to 4% within 6 h, whereas red blood cell cholinesterase activity decreased to 51%. By 10 days, plasma and red blood cell cholinesterase activities had returned to 100 and 91%, respectively, of pre-challenge activities.

Animals↗
PubMed1998

Variation in human plasma cholinesterase activity during low-dose cocaine administration.

BACKGROUND: Cocaine is metabolized by a number of enzymes, the activity of one of which, plasma cholinesterase has been associated with dinical manifestations of toxicity. Patients with life-threatening complications of cocaine intoxication have lower plasma cholinesterase activity than less toxic controls. In addition, relatively healthy cocaine users have lower plasma cholinesterase activity than noncocaine using controls. Thus, low plasma cholinesterase activity could be a contributing factor to cocaine toxicity, a consequence of cocaine use, or a confounding variable. The following study was designed to further assess the relationship between cocaine use and plasma cholinesterase activity. METHODS: We studied fluctuations in plasma cholinesterase activity in nine subjects enrolled in an inpatient study of the behavioral pharmacology of smoked cocaine. Subjects used at least 2 g of cocaine weekly for at least 1 year prior to enrollment. The subjects were admitted to the research unit where they remained drug-free for 2 days. They then received smoked cocaine for 4 days (up to 405 mg over 5 hours daily) and were then drug-free again for 2 days. Plasma cholinesterase activity was measured at 9 AM and 4 PM each day. RESULTS: Baseline plasma cholinesterase ranged from 265 to 930 U/L (normal > 450 U/L). The mean plasma cholinesterase increased 112+/-100 U/L from day 1 to day 8 (p = 0.025). There was no daily change in plasma cholinesterase levels from 9 AM to 4 PM (15+/-165 U/L, p > 0.6), and there was no difference in the daily change between high- and low-dose cocaine days (-3+/-137 U/L vs 28+/-165 U/L, p = 0.52). CONCLUSION: These preliminary data suggest that plasma cholinesterase levels do not change over a 7-hour period as a result of cocaine administration, but may increase during a period of inpatient study. Such an increase could potentially influence the pharmacokinetics or effects of cocaine studied in an inpatient setting and may give insight into the etiology of the observed low-plasma cholinesterase activity in cocaine users.

Adult↗
PubMed2004

Hydroxychloroquine therapy in patients with primary Sjögren's syndrome may improve salivary gland hypofunction by inhibition of glandular cholinesterase.

OBJECTIVE: To determine whether (i) cholinesterase activity is increased in the saliva of patients with primary Sjogren's syndrome (pSS), (ii) increased levels of cholinesterase of lymphocyte origin could interfere with the secretory activity of submandibular acinar cells, and (iii) hydroxychloroquine at therapeutic doses could interfere with cholinesterase activity. METHODS: The Ellman method was used to determine the levels of salivary cholinesterase activity and the K(i) of both chloroquine and hydroxychloroquine for serum cholinesterase. The ability of lymphocyte cholinesterase to inhibit the acetylcholine (ACh)-evoked rise in [Ca(2+)](i) in mouse submandibular acinar cells was determined using fura-2 microfluorimetry. RESULTS: Patients with pSS had significantly higher levels of cholinesterase activity in both their unstimulated (P < 0.05) and stimulated saliva (P < 0.0001) compared with control subjects. Lymphocyte cholinesterase was capable of inhibiting the ACh-evoked rise in [Ca(2+)](i). The in vitro K(i) for hydroxychloroquine inhibition of cholinesterase was 0.38 +/- 1.4 microM. CONCLUSION: These data suggest that increased levels of cholinesterase present in the salivary glands of patients with pSS may contribute to glandular hypofunction and provide evidence that the therapeutic enhancement of salivary secretion in patients with pSS by hydroxychloroquine may be mediated by inhibition of glandular cholinesterase activity, although further in vivo investigation is needed.

Animals↗
PubMed1983

Use of procainamide gels in the purification of human and horse serum cholinesterases.

Two large-scale methods based primarily on the use of procainamide-Sepharose gels were developed for the purification of horse and human serum non-specific cholinesterases. With method I, the procainamide-Sepharose 4B gel was used in the first step to handle large volumes of serum. With method II, the procainamide-Sepharose 4B gel was used in the final step to obtain pure enzyme. Although both methods gave electrophoretically pure cholinesterase preparations in good yields, they were significantly more efficient at purifying the horse enzyme than the human enzyme. To study this problem, the relative binding of human and horse cholinesterases to procainamide-, methylacridinium (MAC)-, m-trimethylammoniophenyl (m-PTA)- and p-trimethylammoniophenyl (p-PTA)-Sepharose 4B gels were measured, by using two approaches. In one, binding was measured by a procedure involving equilibration of pure cholinesterase in a small volume of diluted gel slurry (4%, v/v). A partially purified preparation of Electrophorus acetylcholinesterase was included. Pure human cholinesterase bound consistently more tightly to each of the gels than did horse cholinesterase, and the acetylcholinesterase appeared to bind the gels 10-100 times more tightly than did the non-specific cholinesterases. The order of binding for the cholinesterases, beginning with the tightest, was: procainamide-Sepharose 4B, MAC-Sepharose 4B, p-PTA-Sepharose 4B and m-PTA-Sepharose 4B. For the acetylcholinesterase the order was: MAC-Sepharose 4B, procainamide-Sepharose 4B, p-PTA-Sepharose 4B and m-PTA-Sepharose 4B. The second approach involved passing native sera or partially purified sera fractions through 1 ml test columns of each of the four affinity gels to determine their retention capacity for the cholinesterases. With these impure samples, the MAC-Sepharose 4B gels proved superior to the procainamide-Sepharose 4B gels at retaining human cholinesterase, but the opposite was true for the horse cholinesterase.

Acetylcholinesterase↗
PubMed2006

Alzheimer's disease: beware of interactions with cholinesterase inhibitors.

(1) Cholinesterase inhibitors such as donepezil, galantamine and rivastigmine, are not very effective in slowing the cognitive decline associated with Alzheimer's disease. Memantine, which is no more effective, has dopaminergic and atropinic effects but is not a cholinesterase inhibitor. (2) Cholinesterase inhibitors have mainly cholinergic adverse effects, causing gastrointestinal, neurological, cardiovascular and urinary disorders (incontinence). (3) Increased mortality, mainly due to cardiovascular events, was observed in placebo-controlled trials of galantamine. In one trial there were more deaths in patients on donepezil than on placebo. (4) Atropinic drugs tend to aggravate cognitive disorders that are treated with cholinesterase inhibitors. (5) Cholinesterase inhibitor + neuroleptic combinations are associated with an increased risk of extrapyramidal adverse effects. An increase in mortality was reported during trials of neuroleptics involving patients with dementia, and also during trials of cholinesterase inhibitors. (6) Combining cholinesterase inhibitors with drugs that reduce the heart rate, depress cardiac conduction, or induce torsades de pointes increases the risk of arrhythmias and cardiac conduction disorders. (7) Donepezil and galantamine are metabolised by cytochrome P450 isoenzymes 3A4 and 2D6, creating a strong potential for pharmacokinetic interactions with inhibitors and inducers of these isoenzymes. Rivastigmine is mainly metabolised by cholinesterases, and binds poorly to cytochrome P450 isoenzymes. (8) Cholinesterase inhibitors inhibit the metabolism of suxamethonium and thereby augment and prolong the neuromuscular blockade induced by this curare. (9) In practice, caregivers should be aware of the potential adverse effects of cholinesterase inhibitors, which often resemble symptoms of Alzheimer's disease and may be due to drug-drug interactions or to antagonist effects with other drugs, such as those with atropinic effects. Additionally, the many adverse effects associated with the use of cholinesterase inhibitors highlights the need for regular re-evaluation of the use of these medicines and of the balance of benefit versus risk in individual patients.

Alzheimer Disease↗
PubMed1981

Serum and red cell cholinesterase activity in people exposed to organophosphate insecticides.

Serum and red cell cholinesterase activities were determined in 2 groups of subjects namely:-I) a group of 10 patients who took organophosphate insecticide and were admitted into the hospital for treatment and II) a group of 65 workers from an organophosphate insecticide factory. Serum cholinesterase levels were considerably depressed in all patients in group I and one patient died. The low serum cholinesterase activities increased very slowly and were still very low on day 4 of admission. Serum cholinesterase level in 65 workers were significantly lower than that of the normal subjects. The exposed subjects had still further lower serum cholinesterase activity than those of the non-exposed subjects. There was no significant difference between their red cell cholinesterase activities and those of the normal subjects. Serum and red cell cholinesterase levels in these workers also showed no correlation to the duration of insecticide exposure. These findings indicated that serum cholinesterase activity was a good diagnostic aid in acute exposure because it responded more rapidly than red cell cholinesterase level but it was not sensitive for follow up of the treatment since its recovery rate was too slow. Findings of low serum cholinesterase with normal red cell cholinesterase levels without signs or symptoms of toxicity indicated that these workers had been exposed to some degree of organophosphate insecticides.

Adolescent↗
PubMed1996

Metrifonate and dichlorvos: effects of a single oral administration on cholinesterase activity in rat brain and blood.

Cholinesterase activities in rat forebrain, erythrocytes, and plasma were assessed after a single oral administration of metrifonate or dichlorvos. In 3-month-old rats, the dichlorvos (10 mg/kg p.o.)induced inhibition of cholinesterase reached its peak in brain after l5-45 min and after 10-30 min in erythrocytes and plasma. Cholinesterase activity recovered rapidly after the peak of inhibition, but did not reach control values in brain and erythrocytes within 24 h after drug administration. The recovery of plasma cholinesterase activity, in contrast, was already complete 12 h after dichlorvos treatment. Metrifonate (100 mg/kg p.o.) had qualitatively similar inhibition kinetics as dichlorvos, albeit with a slightly delayed onset. Peak values were attained 45-60 min (brain) and 20-45 min (blood), after drug administration. Apparently complete recovery of cholinesterase activity was noted in both tissues 24 h after treatment. The dose-dependence of drug-induced inhibition of cholinesterase in rat blood and brain was determined at the time of maximal inhibition, i.e., 30 min after dichlorvos treatment and 45 min after metrifonate treatment. The oral ED(50) values obtained for dichlorvos were 8 mg/kg for brain and 6 mg/kg for both erythrocyte and plasma cholinesterase. The corresponding oral ED(50) values for metrifonate were 10 to 15 times higher, i.e., 90 mg/kg in brain and 80 mg/kg in erythrocytes and plasma. In rats deprived of food for 18 h before drug treatment, the corresponding ED(50) values for metrifonate were 60 and 45 mg/kg, respectively, indicating an about two-fold higher sensitivity of fasted rats to metrifonate-induced cholinesterase inhibition compared to non-fasted rats. Compared to 3-month-old rats, 19-month-old rats showed a higher sensitivity towards metrifonate and dichlorvos. At the time of maximal inhibition, there was a strong correlation between the degree of cholinesterase inhibition in brain and blood. These results demonstrate that single oral administration of metrifonate and dichlorvos induces an inhibition of blood and brain cholinesterase in the conscious rat in a dose-dependent and apparently fully reversible manner. While the efficiency of a given dose of inhibitor may vary with the satiety status or age of the animal, the extent of brain ChE inhibition can be estimated from the level of blood ChE activity.

Administration, Oral↗
PubMed1999

Inhibitory effects of donepezil hydrochloride (E2020) on cholinesterase activity in brain and peripheral tissues of young and aged rats.

Donepezil hydrochloride (donepezil: E2020: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride)) is a centrally acting acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. In the present study, its inhibitory effect on the activity of cholinesterase ex vivo was evaluated in the brain, plasma, erythrocytes, heart, small intestine, liver and pectoral muscle of young adult as well as aged rats, in comparison with that of tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride). In aged animals, cholinesterase activity in heart, small intestine and pectoral muscle was lower, whereas that in plasma and liver was higher than in young rats. Both groups showed the highest levels in the brain. Donepezil, at doses of 1.25, 2.5 and 5 mg/kg, p.o., inhibited brain, plasma, erythrocyte, liver and pectoral muscle cholinesterase activity in young rats in a dose-dependent manner but had less effect on cholinesterase activity in heart and small intestine. In aged animals, inhibition of cholinesterase activity in the brain, erythrocytes and pectoral muscle by donepezil was more potent than that in young animals. Tacrine, at doses of 5, 10 and 20 mg/kg, p.o., dose-dependently inhibited cholinesterase activity in all tissues of both young and aged animals, but most potently in heart, small intestine and liver. The inhibition of cholinesterase activity by tacrine in the brain, plasma, erythrocytes, heart and liver was more potent in aged rats than in tissues of young rats. Brain and plasma concentrations of unchanged donepezil and tacrine were measured in the same animals as used for the cholinesterase inhibition study. Brain and plasma concentrations of donepezil and tacrine were higher in aged than in young animals. It is concluded that the inhibitory effects of donepezil and tacrine on cholinesterase activity are greater in aged than in young rats, owing to differences in the tissue concentrations of these compounds between young and aged animals. It is also suggested that the effect of donepezil on cholinesterase activity is more tissue-selective than that of tacrine.

Aging↗
PubMed1970

Cholinesterase activity of motor end plate in human skeletal muscle.

The activity and properties of cholinesterase of the motor end plate in human intercostal muscle were studied in the isolated muscle membrane. This preparation was used because cholinesterase activity of the membrane preparation was localized in the motor end plate without contamination of cholinesterase of other muscle components. Under the experimental conditions, cholinesterase in a human end plate hydrolyzed 1.21 x 10(8) molecules of acetylcholine per msec, which is smaller than hydrolysis of 2.69 x 10(8) by a motor end plate of rat intercostal muscle. Studies with cholinesterase inhibitors and specific substrates indicated that about 90% of cholinesterase of human motor endplates is acetylcholinesterase, and about 10% is pseudocholinesterase. The end plate cholinesterase had an optimal pH of 7.8 and a Michaelis-Menten constant of 4.15 mmoles/liter, and was stable at 4 degrees C for at least 4 wk. Motor end plates were estimated to contain only about 2% of the total cholinesterase activity of human intercostal muscle, compared with about 20% in rat tibialis anterior muscle. The difference is due to the lower cholinesterase activity of the motor end plate and higher cholinesterase activity of non-end plate components in human muscle than in rat muscle. The isolated muscle membrane provides a useful preparation for the study of the properties of motor end plate in human skeletal muscle.

Acetylcholine↗